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Geriatrician advises on use of vitamin D supplementation, lecanemab, and texting for her patients
Vitamin D supplementation and incident fractures
Vitamin D supplementation is a commonly recommended intervention for bone health, but data to support its impact on reducing fracture risk has been variable.
A study in the New England Journal of Medicine by LeBoff and colleagues has garnered much attention since its publication in July 2022.1 In the ancillary study of the Vitamin D and Omega-3-Trial (VITAL), the authors examined the impact of vitamin D supplementation versus placebo on incident fractures. The study found that vitamin D supplementation, as compared with placebo, led to no significant difference in the incidence of total, nonvertebral, and hip fractures in midlife and older adults over the 5-year period of follow-up.
The generalizability of these findings has been raised as a concern as the study does not describe adults at higher risk for fracture. The authors of the study specified in their conclusion that vitamin D supplementation does not reduce fracture risk in “generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass or osteoporosis.”
With a mean participant age of 67 and exclusion of participants with a history of cardiovascular disease, stroke, cirrhosis and other serious illnesses, the study does not reflect the multimorbid older adult population that geriatricians typically care for. Furthermore, efficacy of vitamin D supplementation on fracture risk may be the most impactful in those with osteoporosis and with severe vitamin D deficiency (defined by vitamin D 25[OH]D level less than 12 ng/mL).
In post hoc analyses, there was no significant difference in fracture risk in these subgroups, however the authors acknowledged that the findings may be limited by the small percentage of participants with severe vitamin D deficiency (2.4%) and osteoporosis included in the study (5%).
Lecanemab for mild cognitive impairment and early Alzheimer’s dementia
On Jan. 6, 2023, the Food and Drug Administration approved lecanemab, the second-ever disease-modifying treatment for Alzheimer’s dementia following the approval of aducanumab in 2021. Lecanemab is a monoclonal antibody targeting larger amyloid-beta oligomers, which has been shown in vitro to have higher affinity for amyloid-beta, compared with aducanumab. FDA approval followed shortly after the publication of the CLARITY-AD trial, which investigated the effect of lecanemab versus placebo on cognitive decline and burden of amyloid in adults with mild cognitive impairment and mild Alzheimer’s dementia. Over an 18-month period, the study found that participants who received lecanemab, compared with placebo, had a significantly smaller decline in cognition and function, and reduction in amyloid burden on PET CT.2
The clinical significance of these findings, however, is unclear. As noted by an editorial published in the Lancet in 2022, the difference in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale between the treatment and placebo groups was 0.45. On an 18-point scale, prior research has noted that a minimal clinically significance difference of 0.98 is necessary in those with mild cognitive impairment and 1.63 in mild Alzheimer dementia.3
Additionally, the CLARITY-AD trial reported that lecanemab resulted in infusion reactions in 26.4% of participants and brain edema (an amyloid-related imaging abnormality referred to as ARIA-E) in 12.6% of participants. This finding highlights concerns for safety and the need for close monitoring, as well as ongoing implications of economic feasibility and equitable access for all those who qualify for treatment.2
Social isolation and dementia risk
There is growing awareness of the impact of social isolation on health outcomes, particularly among older adults. Prior research has reported that one in four older adults are considered socially isolated and that social isolation increases risk of premature death, dementia, depression, and cardiovascular disease.4
A study by Huang and colleagues is the first nationally representative cohort study examining the association between social isolation and incident dementia for older adults in community dwelling settings. A cohort of 5,022 older adults participating in the National Health and Aging Trends Study was followed from 2011 to 2020. When adjusting for demographic and health factors, including race, level of education, and number of chronic health conditions, socially isolated adults had a greater risk of developing dementia, compared with adults who were not socially isolated (hazard ratio, 1.27; 95% confidence interval, 1.08-1.49). Potential mechanisms to explain this association include the increased risk of cardiovascular disease and depression in older adults who are socially isolated, thereby increasing dementia risk.
Decreased cognitive activity/engagement and access to resources such as caregiving and health care may also be linked to the increased risk of dementia in socially isolated older adults.5
Another observational cohort study from the National Health and Aging Trends Study investigated whether access and use of technology can lower the risk of social isolation. The study found that older adults who used email or text messaging had a lower risk of social isolation than older adults who did not use technology (incidence rate ratio, 0.64; 95% CI, 0.51-0.80).6 These findings highlight the importance of addressing social isolation as an important modifiable health risk factor, and the need for providing equitable access to technology in vulnerable populations as health intervention.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. LeBoff MS et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022;387(4):299-30.
2. van Dyck CH et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.
3. The Lancet. Lecanemab for Alzheimer’s disease: tempering hype and hope. Lancet. 2022; 400:1899.
4. National Academies of Sciences, Engineering, and Medicine. Social Isolation and Loneliness in Older Adults: Opportunities for the Health Care System. Washington, DC: 2020, The National Academies Press.
5. Huang, AR et al. Social isolation and 9-year dementia risk in community dwelling Medicare beneficiaries in the United States. J Am Geriatr Soc. 2023 Jan 11. doi: 10.1111/jgs18140.
6. Umoh ME etal. Impact of technology on social isolation: Longitudinal analysis from the National Health Aging Trends Study. J Am Geriatr Soc. 2022 Dec 15. doi 10.1111/jgs.18179.
Vitamin D supplementation and incident fractures
Vitamin D supplementation is a commonly recommended intervention for bone health, but data to support its impact on reducing fracture risk has been variable.
A study in the New England Journal of Medicine by LeBoff and colleagues has garnered much attention since its publication in July 2022.1 In the ancillary study of the Vitamin D and Omega-3-Trial (VITAL), the authors examined the impact of vitamin D supplementation versus placebo on incident fractures. The study found that vitamin D supplementation, as compared with placebo, led to no significant difference in the incidence of total, nonvertebral, and hip fractures in midlife and older adults over the 5-year period of follow-up.
The generalizability of these findings has been raised as a concern as the study does not describe adults at higher risk for fracture. The authors of the study specified in their conclusion that vitamin D supplementation does not reduce fracture risk in “generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass or osteoporosis.”
With a mean participant age of 67 and exclusion of participants with a history of cardiovascular disease, stroke, cirrhosis and other serious illnesses, the study does not reflect the multimorbid older adult population that geriatricians typically care for. Furthermore, efficacy of vitamin D supplementation on fracture risk may be the most impactful in those with osteoporosis and with severe vitamin D deficiency (defined by vitamin D 25[OH]D level less than 12 ng/mL).
In post hoc analyses, there was no significant difference in fracture risk in these subgroups, however the authors acknowledged that the findings may be limited by the small percentage of participants with severe vitamin D deficiency (2.4%) and osteoporosis included in the study (5%).
Lecanemab for mild cognitive impairment and early Alzheimer’s dementia
On Jan. 6, 2023, the Food and Drug Administration approved lecanemab, the second-ever disease-modifying treatment for Alzheimer’s dementia following the approval of aducanumab in 2021. Lecanemab is a monoclonal antibody targeting larger amyloid-beta oligomers, which has been shown in vitro to have higher affinity for amyloid-beta, compared with aducanumab. FDA approval followed shortly after the publication of the CLARITY-AD trial, which investigated the effect of lecanemab versus placebo on cognitive decline and burden of amyloid in adults with mild cognitive impairment and mild Alzheimer’s dementia. Over an 18-month period, the study found that participants who received lecanemab, compared with placebo, had a significantly smaller decline in cognition and function, and reduction in amyloid burden on PET CT.2
The clinical significance of these findings, however, is unclear. As noted by an editorial published in the Lancet in 2022, the difference in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale between the treatment and placebo groups was 0.45. On an 18-point scale, prior research has noted that a minimal clinically significance difference of 0.98 is necessary in those with mild cognitive impairment and 1.63 in mild Alzheimer dementia.3
Additionally, the CLARITY-AD trial reported that lecanemab resulted in infusion reactions in 26.4% of participants and brain edema (an amyloid-related imaging abnormality referred to as ARIA-E) in 12.6% of participants. This finding highlights concerns for safety and the need for close monitoring, as well as ongoing implications of economic feasibility and equitable access for all those who qualify for treatment.2
Social isolation and dementia risk
There is growing awareness of the impact of social isolation on health outcomes, particularly among older adults. Prior research has reported that one in four older adults are considered socially isolated and that social isolation increases risk of premature death, dementia, depression, and cardiovascular disease.4
A study by Huang and colleagues is the first nationally representative cohort study examining the association between social isolation and incident dementia for older adults in community dwelling settings. A cohort of 5,022 older adults participating in the National Health and Aging Trends Study was followed from 2011 to 2020. When adjusting for demographic and health factors, including race, level of education, and number of chronic health conditions, socially isolated adults had a greater risk of developing dementia, compared with adults who were not socially isolated (hazard ratio, 1.27; 95% confidence interval, 1.08-1.49). Potential mechanisms to explain this association include the increased risk of cardiovascular disease and depression in older adults who are socially isolated, thereby increasing dementia risk.
Decreased cognitive activity/engagement and access to resources such as caregiving and health care may also be linked to the increased risk of dementia in socially isolated older adults.5
Another observational cohort study from the National Health and Aging Trends Study investigated whether access and use of technology can lower the risk of social isolation. The study found that older adults who used email or text messaging had a lower risk of social isolation than older adults who did not use technology (incidence rate ratio, 0.64; 95% CI, 0.51-0.80).6 These findings highlight the importance of addressing social isolation as an important modifiable health risk factor, and the need for providing equitable access to technology in vulnerable populations as health intervention.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. LeBoff MS et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022;387(4):299-30.
2. van Dyck CH et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.
3. The Lancet. Lecanemab for Alzheimer’s disease: tempering hype and hope. Lancet. 2022; 400:1899.
4. National Academies of Sciences, Engineering, and Medicine. Social Isolation and Loneliness in Older Adults: Opportunities for the Health Care System. Washington, DC: 2020, The National Academies Press.
5. Huang, AR et al. Social isolation and 9-year dementia risk in community dwelling Medicare beneficiaries in the United States. J Am Geriatr Soc. 2023 Jan 11. doi: 10.1111/jgs18140.
6. Umoh ME etal. Impact of technology on social isolation: Longitudinal analysis from the National Health Aging Trends Study. J Am Geriatr Soc. 2022 Dec 15. doi 10.1111/jgs.18179.
Vitamin D supplementation and incident fractures
Vitamin D supplementation is a commonly recommended intervention for bone health, but data to support its impact on reducing fracture risk has been variable.
A study in the New England Journal of Medicine by LeBoff and colleagues has garnered much attention since its publication in July 2022.1 In the ancillary study of the Vitamin D and Omega-3-Trial (VITAL), the authors examined the impact of vitamin D supplementation versus placebo on incident fractures. The study found that vitamin D supplementation, as compared with placebo, led to no significant difference in the incidence of total, nonvertebral, and hip fractures in midlife and older adults over the 5-year period of follow-up.
The generalizability of these findings has been raised as a concern as the study does not describe adults at higher risk for fracture. The authors of the study specified in their conclusion that vitamin D supplementation does not reduce fracture risk in “generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass or osteoporosis.”
With a mean participant age of 67 and exclusion of participants with a history of cardiovascular disease, stroke, cirrhosis and other serious illnesses, the study does not reflect the multimorbid older adult population that geriatricians typically care for. Furthermore, efficacy of vitamin D supplementation on fracture risk may be the most impactful in those with osteoporosis and with severe vitamin D deficiency (defined by vitamin D 25[OH]D level less than 12 ng/mL).
In post hoc analyses, there was no significant difference in fracture risk in these subgroups, however the authors acknowledged that the findings may be limited by the small percentage of participants with severe vitamin D deficiency (2.4%) and osteoporosis included in the study (5%).
Lecanemab for mild cognitive impairment and early Alzheimer’s dementia
On Jan. 6, 2023, the Food and Drug Administration approved lecanemab, the second-ever disease-modifying treatment for Alzheimer’s dementia following the approval of aducanumab in 2021. Lecanemab is a monoclonal antibody targeting larger amyloid-beta oligomers, which has been shown in vitro to have higher affinity for amyloid-beta, compared with aducanumab. FDA approval followed shortly after the publication of the CLARITY-AD trial, which investigated the effect of lecanemab versus placebo on cognitive decline and burden of amyloid in adults with mild cognitive impairment and mild Alzheimer’s dementia. Over an 18-month period, the study found that participants who received lecanemab, compared with placebo, had a significantly smaller decline in cognition and function, and reduction in amyloid burden on PET CT.2
The clinical significance of these findings, however, is unclear. As noted by an editorial published in the Lancet in 2022, the difference in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale between the treatment and placebo groups was 0.45. On an 18-point scale, prior research has noted that a minimal clinically significance difference of 0.98 is necessary in those with mild cognitive impairment and 1.63 in mild Alzheimer dementia.3
Additionally, the CLARITY-AD trial reported that lecanemab resulted in infusion reactions in 26.4% of participants and brain edema (an amyloid-related imaging abnormality referred to as ARIA-E) in 12.6% of participants. This finding highlights concerns for safety and the need for close monitoring, as well as ongoing implications of economic feasibility and equitable access for all those who qualify for treatment.2
Social isolation and dementia risk
There is growing awareness of the impact of social isolation on health outcomes, particularly among older adults. Prior research has reported that one in four older adults are considered socially isolated and that social isolation increases risk of premature death, dementia, depression, and cardiovascular disease.4
A study by Huang and colleagues is the first nationally representative cohort study examining the association between social isolation and incident dementia for older adults in community dwelling settings. A cohort of 5,022 older adults participating in the National Health and Aging Trends Study was followed from 2011 to 2020. When adjusting for demographic and health factors, including race, level of education, and number of chronic health conditions, socially isolated adults had a greater risk of developing dementia, compared with adults who were not socially isolated (hazard ratio, 1.27; 95% confidence interval, 1.08-1.49). Potential mechanisms to explain this association include the increased risk of cardiovascular disease and depression in older adults who are socially isolated, thereby increasing dementia risk.
Decreased cognitive activity/engagement and access to resources such as caregiving and health care may also be linked to the increased risk of dementia in socially isolated older adults.5
Another observational cohort study from the National Health and Aging Trends Study investigated whether access and use of technology can lower the risk of social isolation. The study found that older adults who used email or text messaging had a lower risk of social isolation than older adults who did not use technology (incidence rate ratio, 0.64; 95% CI, 0.51-0.80).6 These findings highlight the importance of addressing social isolation as an important modifiable health risk factor, and the need for providing equitable access to technology in vulnerable populations as health intervention.
Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.
References
1. LeBoff MS et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022;387(4):299-30.
2. van Dyck CH et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.
3. The Lancet. Lecanemab for Alzheimer’s disease: tempering hype and hope. Lancet. 2022; 400:1899.
4. National Academies of Sciences, Engineering, and Medicine. Social Isolation and Loneliness in Older Adults: Opportunities for the Health Care System. Washington, DC: 2020, The National Academies Press.
5. Huang, AR et al. Social isolation and 9-year dementia risk in community dwelling Medicare beneficiaries in the United States. J Am Geriatr Soc. 2023 Jan 11. doi: 10.1111/jgs18140.
6. Umoh ME etal. Impact of technology on social isolation: Longitudinal analysis from the National Health Aging Trends Study. J Am Geriatr Soc. 2022 Dec 15. doi 10.1111/jgs.18179.
Damar Hamlin’s cardiac arrest: Key lessons
This discussion was recorded on Jan. 9, 2023. This transcript has been edited for clarity.
Robert D. Glatter, MD: Welcome. I’m Dr. Robert D. Glatter, medical adviser for Medscape Emergency Medicine. Today, we have Dr. Paul E. Pepe, an emergency medicine physician based in Florida and a highly recognized expert in emergency medical services (EMS), critical care, sports and event medicine, and resuscitation. Also joining us is Dr. Michael S. (“Mick”) Malloy, an emergency medicine physician based in Ireland, also an expert in prehospital care, resuscitation, and sports and event medicine. Welcome, gentlemen.
Dr. Pepe: Thanks for having us here.
Dr. Glatter: the Buffalo Bills safety who went down suffering a cardiac arrest in front of millions of people. Although we don’t know the exact cause of the events that transpired, the goal of our discussion is to guide our audience through a systematic approach to evaluation and management of an athlete suffering blunt force chest and neck trauma, and then suffering a cardiac arrest. We do know, obviously, that Damar was successfully resuscitated, thanks to the medical staff and trainers.
Almost 50 years ago, Chuck Hughes, a Detroit Lions receiver, went down and died with just a minute to go in the game and, unfortunately, didn’t survive.
Paul, can you tell me your impressions after viewing the replay of the events that evening? What were the most likely causes of this syncopal event and the subsequent cardiac arrest?
Dr. Pepe: We don’t know anything specifically. It’s being kept private about what the events were. It’s a little bit complicated in a sense that he basically had an extended resuscitation in the hospital. My experience has been that most people that have ventricular fibrillation, from whatever cause, will most likely be waking up on the field if you get to them. I’ve had personal experience with that.
More importantly than when it starts, when someone goes down on the field, both Dr. Malloy and I take a broader view. We don’t get tunnel vision and think, “Oh, it was a traumatic event,” or “It was cardiac event,” and we just have our minds open. There are many things that could make you stop breathing on the field. It could be a neck or a severe head injury, and then any kind of other internal injury that occurs.
When I saw in the video that Damar Hamlin stood up, that made it a less likely to be a spinal injury. He seemed to be physically functioning, and then he suddenly collapsed. That went along with something that looks like a ventricular fibrillation or ventricular tachycardia type of event and made me think right away that it was commotio cordis. I’m not a Latin scholar, but commotio is like commotion. A literal translation might be an agitation of the heart. I was thinking that he probably got hit somewhere in the middle of the chest at the right moment where the heart is resetting in that repolarization phase, like an R-on-T phenomenon, and then caused this sudden ventricular dysrhythmia.
Most people associate it to that because we have a couple of dozen cases a year of people getting hockey pucks or a baseball hitting their chest, which is very common with adolescents. On the other hand, you can’t get it from a blunt injury like this, and it was too early for it to be, say, a direct cardiac contusion, unless there was a direct injury there. It just happened so quickly.
In Europe, they’ve had a large amount of experience with this same kind of problem before, even just from a direct shoulder hit, for example. Mick Malloy is the dean of the faculty of sports and exercise medicine at the Royal College of Surgeons in Ireland and has vast experience, and now he is the person overseeing the procedures for this. Mick, have you had those kinds of experiences as well?
Dr. Molloy: Yes. It’s something that has occurred over recent decades and has been more recognized. I note that in professional sports, it’s a very different thing because you’ve got such huge teams and teams trained to respond very quickly. And that’s the most important thing in this scenario – having a team that is well functioning as a high-class emergency response team ready to get out on to that field very quickly after the person collapses, getting the automated external defibrillator (AED) on, and then recognizing whether there needs to be a shock given or not. The machine will tell you all that.
In our scenario, we run courses called CARES (Care of the Athlete Resuscitation and Emergencies in Sport) to make sure that our team physicians and team physiotherapists and trainers are all speaking as one when an emergency arises.
I don’t worry so much about the professional sport. It’s more with the amateur sports and the kids sports that I get a bit more concerned because there isn’t the same level of medical care there. Having everybody trained in basic life support would be very important to reduce unnecessary deaths from these types of conditions.
As Paul mentioned, there is a very specific cardiac cause in some of these circumstances, where you get hit just at the wrong time and that hit occurs at a particular electrical point in time. It causes this ventricular fibrillation, and the only real treatment there is the defibrillator as quickly as possible.
Dr. Glatter: What you’re saying ultimately is an important part about rapid defibrillation, and at first, cardiopulmonary resuscitation (CPR). People are concerned about whether they should begin CPR. We’re talking about out-of-hospital cardiac arrest that is outside of a football stadium, for example. Some people are obsessed with taking a person’s pulse, and that’s been a point of contention. If someone is unconscious and not breathing, we should start CPR. Wouldn›t you agree? They will wake up quickly if you begin chest compressions if they’re not necessary.
Dr. Pepe: I tell people, just do it. You’re right, people will wake up and feel it if they don’t need it.
Getting back to Mick’s point of having things ready to go, for example, 8 years ago, we had a professional player on the bench who suddenly collapsed right there in front of the entire audience. We immediately did CPR, and we got the AED on. We shocked him and he was ready, willing, and able to get back on the bench again. It turns out he had underlying coronary artery disease, but we got him back right away.
I did an initial study where we placed an AED in a public place at the Chicago O’Hare Airport to see if the public would use these. Most cardiac arrests occur at home, of course, but in public places, that was a good place to try it. We had almost 10 cases the first year. What was fascinating was that we had almost no survivors over the previous decade, even though there were paramedics at the airport. When we put these out there, we had nine people go down that first year, and six people who had never operated an AED or seen one before knew to get one and use it. Every one of those people survived neurologically intact, and almost every person was waking up before traditional responders got there. That’s how effective this is, but you need to know where the AED is.
Dr. Glatter: How to turn it on, where it is, and how to operate it.
Dr. Pepe: That was the point: These rescuers saved lives in the first year, and it was tremendous. Two points I make about it are that one, you need to know where it is, and two, just go turn it on. It gives you the instructions to follow through; just be in the Nike mode, because it basically won’t hurt a person. It’s rare that there’s ever been any complication of that. The machine algorithms are so good.
Dr. Glatter: Mick, I want to turn to you about the European experience. Specifically in Denmark, we know that there’s a large public health initiative to have AEDs accessible. There have been studies showing that when the public is engaged, especially with studies looking at an app when access is available, survivability doubled in the past 10 years from having access to AEDs. What’s your experience in Ireland in terms of public access to defibrillators?
Dr. Molloy: We’ve got two different streams here. There was a big push to have more AEDs at all sports venues. That was great, but some of the sporting clubs put them inside the locked door. I said that there’s no point to that because nobody can access it. You need to have an external building and you need to leave it open. If somebody needs to use it, they need to know how to get it, open it, and get away, and not get in through a locked door to get access to a defibrillator. We have AEDs now in most stadiums and even in small rural areas, where you might have only 200 people turn up for a game.
From another public access side, if you dial in – in our scenario, it’s 112, not 911 –we have Community First Responder groups. In the rural areas, you have local people who’ve been trained in basic life support and community first response who have AEDs. They’ll have periods of the day where they come home from work as a teacher, a nurse, a policeman, or a fireman, and they turn on an app on their phone and say, “I’m available for the next 5 hours.” If there’s a cardiac arrest rung in within 5 miles of their community, they will drive directly there with the AED that they have. We’ve had numerous saves from that in the country because it could take 40 minutes to get an EMS vehicle there, and obviously, time is crucial in these scenarios. Our dispatchers will talk people through CPR, and then the community responders arrive with the AED. It has been a fantastic initiative.
Dr. Pepe: In many places, people have apps on their phones where they’re locked into the system, and it will go off and tell them there is something nearby and even GPS them into it, and it’s been fantastic.
The two points I want to make to responding to what we just heard Dean Malloy say is one, we always have a designated spot to have these in various places. If I’m at City Hall, we always have them near the red elevators on every floor and down at security. In all the public high schools, we always have one right below the clock where everybody can see it. We set it up in a very standardized form that anybody and everybody will know where it is at the time an event happens.
The other point he made about having the response teams is fantastic. I live in a large high rise and there are two complexes with many people here, and many are older, so there’s going to be a higher risk for having an event. In fact, we’ve just had one recently. The concept we developed here was a community emergency response team, where we sometimes have doctors, nurses, and paramedics who live here be on call and be responsible, or you could try to find an AED. More importantly, we made sure everybody here knew where they were and where to get them. We’ve got most of the people trained, and we’re doing more training in what actions to take during these periods of time when such events happen.
Dr. Glatter: Yes, it’s critical. I wanted to point out that we’ve looked at the use of drones, especially here in the United States. There have been some pilot studies looking at their utility in the setting of out-of-hospital cardiac arrest. I want to get both of your thoughts on this and the feasibility of this.
Dr. Molloy: In a rural area, it’s a fantastic idea. You’re going to get something there as the crow flies very quickly. You probably have to look at exactly in, say, a rural area like Ireland of 32,000 square kilometers, how many you›ll have to put, what kind of distances they can realistically cover, and make sure the batteries are charged. Certainly, that’s a very good initiative because with the AEDs, you can’t do anything wrong. You can’t give a shock unless a shock needs to be given. The machine directs you what to do, so somebody who has had no training can pick one of these out of the box and start to work with it quickly and confidently that they can’t do anything wrong.
It’s a great idea. It would be a little expensive potentially at the moment in getting the drones and having that volume of drones around. In the U.S., you have completely different air traffic than we have, and in cities, you have more helicopters flying around. We certainly wouldn’t have that in our cities because that could cause a challenge if you’ve got drones flying around as well. It’s about making it safe that nothing else can go wrong from a drone in somebody else’s flight path.
Dr. Pepe: In my experience, the earlier the intervention, the better the results. There is a limit here in terms of the drones if they just can’t get there soon enough. Having said that, we are so fortunate in the city of Seattle to have most citizens knowing CPR, and we’d get that person resuscitated because they were doing such a good job with the CPR up front.
That’s why you’re going to see the Buffalo Bills player survive neurologically intact – because he did get immediate treatment right then and there. In the future, we may even have some better devices that will actually even restore normal blood flow right then and there while you’re still in cardiac arrest. There are limitations in every case. But on the other hand, it’s exciting and it paid off in this case recently.
Dr. Molloy: Just a point of interest coming from this small little country over here. The first portable defibrillator was developed in Belfast, Ireland, in the back of a cardiac response car. Despite us being a tiny little country, we do have some advances ahead of the United States.
Dr. Pepe: That was a breakthrough. Dr. Frank Pantridge and John Geddes did this great work and that caught the imagination of everybody here. At first, they were just going out to give people oxygen and sedate them for their chest pain. It turned out that their defibrillators are what made the difference as they went out there. Absolutely, I have to acknowledge the folks in Ireland for giving us this. Many of the EMS systems got started because of the article they published in The Lancet back in 1967.
Dr. Glatter: I wanted to briefly talk about screening of the athletes at the high school/college level, but also at the professional level. Obviously, there are issues, including the risk for false-positives in terms of low incidence, but there are also false negatives, as the case with Christian Eriksen, who had a cardiac arrest in 2021 and who has been through extensive testing. We can debate the validity of such testing, but I wanted to get both of your takes on the utility of screening in such a population.
Dr. Molloy: That’s a very emotive subject. False-positives are difficult because you’re now saying to somebody that they can’t compete in your sport at a decent level. The difficult part is telling somebody that this is the end of their career.
The false-negative is a little bit more difficult. I don’t know Christian Eriksen and I’m not involved in his team in any way, but that is a one-point examination, and you’re dependent on the scale of the process interpreting the ECG, which is again only a couple of seconds and that particular arrhythmia may not have shown up on that.
Also, athletes, by nature of what they’re doing, are operating at 99% of efficiency on a frequent basis. They are at the peak of their physiologic fitness, and it does make them a little bit more prone to picking up viral illnesses from time to time. They may get a small viral myopericarditis, which causes a new arrhythmia that nobody knew about. They had the screening 2 or 3 years ago, and they now developed a new problem because of what they do, which just may not show up.
I was actually surprised that the gentleman came through it very well, which is fantastic. He wasn’t allowed to play football in the country where he was employed, and he has now moved to another country and is playing football with a defibrillator inserted. I don’t know what the rules are in American football where you can play with implantable defibrillators. I’m not so sure it’s a great idea to do that.
Dr. Pepe: One thing that we should bring up is that there are athletes with underlying cardiomyopathies or hypertrophies and things like that, but that was unlikely in this case. It’s possible, but it’s unlikely, because it would have manifested itself before. In terms of screening, I’ve met some very smart medical doctors who have run those tests, and they have been very encouraged even at the high school levels to have screenings done, whether it’s electrocardiography, echocardiography, and so on. I have to reiterate what Dr Malloy just said in that it may have its downsides as well. If you can pick up real obvious cases, I think that may be of value.
Dr. Glatter: I want to conclude and get some pearls and takeaways from each of you regarding the events that transpired and what our audience can really hold onto.
Dr. Molloy: Look at Formula One in the past 50 years. In Formula One, in the beginning it was a 2-minute job to change a tire. Now, they have this down where they’re measuring in fractions of a second and criticizing each other if one guy is 2.6 seconds and the other guy is 2.9 seconds. For me, that’s phenomenal. It takes me 25 minutes to change a tire.
We’ve looked at that from a resuscitation perspective, and we now do pit crew resuscitation before our events. We’ve planned our team and know who’s going to be occupying what role. After the events at the UEFA championships, we had a new rule brought in by UEFA where they handed me a new document saying, “This is what we would like you to do for resuscitation.” It was a three-man triangle, and I said, “No, we’re not going to do that here.” And they said, “Why, you have to; it’s our rule.”
I said, “No, our rule in Ireland is we have a six-person triangle. We’re not downing our standards because of what you have internationally. You’re covering games in some very low-resource environments, I know that. We have a particular standard here that we’re sticking to. We have a six-person group. We know what we’re all doing; we come very quickly to those downed players and get involved and we’ve had good outcomes, so we’re not going to change the standards.”
That’s the thing: You need to practice these things. The players don’t go out on the weekend and do a move for the very first time without practicing it hundreds of times. We need to look at it the same way as the medical team who are looking after that group of players and the crowd because we also look after the crowd.
A particular challenge in some of our stadiums is that the upper decks are so steep, and it’s very hard to get a patient onto a trolley and do CPR as you’re bringing them down to a zone to get them flat. We’ve had to come up with some innovative techniques to try and do that and accommodate that using some of the mechanical CPR devices. That’s the result you’ll only get from having practiced these events and trying to extricate patients. We want to check response times, so you have to practice your response team activity very frequently.
Dr. Pepe: There are two points made by Mick that I want to react to. One, the pit crew approach is critical in so many ways. We do the same thing in what we call the medical first attack, where we knew who the A, B, and C person would be. When we took it out to the NBA trainers, I recommended for them to have a similar approach so that if an event does happen right in the middle of prime time, they are coordinated.
The second point is that we do mass-gathering medicine. It’s not just the sportspeople on the field or the entertainers that we’re looking after; it is the people in the stands. We will see a cardiac arrest once a month. If you think about it, you might see a cardiac arrest occur in any community on a regular basis. Now you’ve got 100,000 people in one stadium, and something is bound to go wrong over those 3 or 4 hours where they are there and may have a critical emergency. Preparation for all of that is really important as well.
The final point is that on a day-to-day basis, most cardiac arrests do occur in the home. Granted, 80% of them are nonshockable cases, but the people who are more apt to survive are going to be the ones who have an electrical event. In fact, when we looked at our data years ago, we found that, of the cases of people with ventricular fibrillation that we resuscitated, half didn’t even have heart damage. Their enzymes were normal. It was a pure electrical event, and they were more resuscitable. They may have an underlying problem, but we can fix that once we get them back.
Everybody needs to know how to do bystander CPR, and second, we must make sure we have AEDs strategically placed, as I alluded to before. We also go out to other parts of the community and give them advice. All those things must be put in place, but more importantly, just get the training and make the training simple. It’s really a “just do it” philosophy, but make it simple.
For example, when I teach a course, I can do it in 15 minutes, and people retain it because I keep reiterating things like, “Okay, there’s one thing you need to know about choking: Pop the cork.” You give them a physiologic image of what’s happening. Everybody says, “I remember you saying to just do it, pop the cork.”
With AEDs, know where it is – that’s why we should have it in standardized places. Go get it, turn it on, and then follow the instructions. Also, the most important thing is making sure you’re doing quality compressions; and there are videos that can help you with that, as well as classes that you can take that will get you through it.
Dr. Glatter: Absolutely. The public still has the misconception that you need to do mouth-to-mouth resuscitation. The message has not permeated through society that you don’t need to do mouth-to-mouth. Hands-only CPR is the gold standard now.
Dr. Pepe: If people have a reversible cause like ventricular fibrillation, often they’re already gasping, which is better than a delivered breath, by the way. Most important, then, are the compressions to make sure you have oxygen going up to the brain, because you’re still theoretically loaded with oxygen in your bloodstream if you had a sudden cardiac arrest from a ventricular fibrillation.
Your points are well taken, and we found that we had better outcomes when we just gave instructions to do compressions only, and that became the standard. Mick, you’ve had some experiences with that as well.
Dr. Molloy: If we’re going to have a long-term benefit from all this, we have to start doing this in elementary school and teaching kids basic life support and some basic health messaging.
I remember trying to get this across to a teacher one day and the teacher saying, “But why would we teach young kids to resuscitate each other?” I said, “I think you forget that the only 60-year-old person in the room is you. You train them, and we train them. They’re the ones who are going to respond and keep you alive. That’s the way you should be looking at this.” That completely changed the mindset of whether we should be doing this for the kids or not.
Dr. Pepe: In fact, what we find is that that’s exactly who gets saved. I had case after case where the kids at the school had learned CPR and saved the teachers or the administrator at the high school or elementary school. It’s a fantastic point that you bring up, Dr. Malloy.
Dr. Glatter: One other brief thing we can interject here is that the team was excellent on field in that they evaluated Damar Hamlin in a primary survey sense of ABCs (i.e., airway, breathing, and circulation) for things like a tension pneumothorax. In the sense in which he was hit, there are reversible causes. Making sure he didn’t have a tension pneumothorax that caused the arrest, in my mind, was critical.
Dr. Pepe: We do the same thing on a day-to-day basis with a car wreck, because it could be that the person had ventricular fibrillation and then had the wreck. It’s not always trauma. That’s a fantastic point that you’re making. That’s exactly what I think happened, and that’s what we do.
Dr. Glatter: Well, thank you, gentlemen. This was an informative and helpful discussion for our audience. I appreciate your time and expertise.
Dr. Glatter, is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes.
Dr. Pepe is a professor of internal medicine, surgery, pediatrics, public health, and emergency medicine at University of Texas Health Science Center in Houston. He’s also a global coordinator of the U.S. Metropolitan Municipalities EMS Medical Directors (“Eagles”) Coalition.
Dr. Molloy works clinically as a consultant in emergency medicine in Wexford General Hospital, part of the Ireland East Hospital Group (IEHG). Internationally, he is a member of the Disaster Medicine Section of the European Society of Emergency Medicine (EUSEM) and has been appointed by the Irish Medical Organization (IMO) as one of two Irish delegates to serve on the European Board and Section of Emergency Medicine of the European Union of Medical Specialists (UEMS), having served for a number of years on its predecessor, the Multidisciplinary Joint Committee on Emergency Medicine.
A version of this article first appeared on Medscape.com.
This discussion was recorded on Jan. 9, 2023. This transcript has been edited for clarity.
Robert D. Glatter, MD: Welcome. I’m Dr. Robert D. Glatter, medical adviser for Medscape Emergency Medicine. Today, we have Dr. Paul E. Pepe, an emergency medicine physician based in Florida and a highly recognized expert in emergency medical services (EMS), critical care, sports and event medicine, and resuscitation. Also joining us is Dr. Michael S. (“Mick”) Malloy, an emergency medicine physician based in Ireland, also an expert in prehospital care, resuscitation, and sports and event medicine. Welcome, gentlemen.
Dr. Pepe: Thanks for having us here.
Dr. Glatter: the Buffalo Bills safety who went down suffering a cardiac arrest in front of millions of people. Although we don’t know the exact cause of the events that transpired, the goal of our discussion is to guide our audience through a systematic approach to evaluation and management of an athlete suffering blunt force chest and neck trauma, and then suffering a cardiac arrest. We do know, obviously, that Damar was successfully resuscitated, thanks to the medical staff and trainers.
Almost 50 years ago, Chuck Hughes, a Detroit Lions receiver, went down and died with just a minute to go in the game and, unfortunately, didn’t survive.
Paul, can you tell me your impressions after viewing the replay of the events that evening? What were the most likely causes of this syncopal event and the subsequent cardiac arrest?
Dr. Pepe: We don’t know anything specifically. It’s being kept private about what the events were. It’s a little bit complicated in a sense that he basically had an extended resuscitation in the hospital. My experience has been that most people that have ventricular fibrillation, from whatever cause, will most likely be waking up on the field if you get to them. I’ve had personal experience with that.
More importantly than when it starts, when someone goes down on the field, both Dr. Malloy and I take a broader view. We don’t get tunnel vision and think, “Oh, it was a traumatic event,” or “It was cardiac event,” and we just have our minds open. There are many things that could make you stop breathing on the field. It could be a neck or a severe head injury, and then any kind of other internal injury that occurs.
When I saw in the video that Damar Hamlin stood up, that made it a less likely to be a spinal injury. He seemed to be physically functioning, and then he suddenly collapsed. That went along with something that looks like a ventricular fibrillation or ventricular tachycardia type of event and made me think right away that it was commotio cordis. I’m not a Latin scholar, but commotio is like commotion. A literal translation might be an agitation of the heart. I was thinking that he probably got hit somewhere in the middle of the chest at the right moment where the heart is resetting in that repolarization phase, like an R-on-T phenomenon, and then caused this sudden ventricular dysrhythmia.
Most people associate it to that because we have a couple of dozen cases a year of people getting hockey pucks or a baseball hitting their chest, which is very common with adolescents. On the other hand, you can’t get it from a blunt injury like this, and it was too early for it to be, say, a direct cardiac contusion, unless there was a direct injury there. It just happened so quickly.
In Europe, they’ve had a large amount of experience with this same kind of problem before, even just from a direct shoulder hit, for example. Mick Malloy is the dean of the faculty of sports and exercise medicine at the Royal College of Surgeons in Ireland and has vast experience, and now he is the person overseeing the procedures for this. Mick, have you had those kinds of experiences as well?
Dr. Molloy: Yes. It’s something that has occurred over recent decades and has been more recognized. I note that in professional sports, it’s a very different thing because you’ve got such huge teams and teams trained to respond very quickly. And that’s the most important thing in this scenario – having a team that is well functioning as a high-class emergency response team ready to get out on to that field very quickly after the person collapses, getting the automated external defibrillator (AED) on, and then recognizing whether there needs to be a shock given or not. The machine will tell you all that.
In our scenario, we run courses called CARES (Care of the Athlete Resuscitation and Emergencies in Sport) to make sure that our team physicians and team physiotherapists and trainers are all speaking as one when an emergency arises.
I don’t worry so much about the professional sport. It’s more with the amateur sports and the kids sports that I get a bit more concerned because there isn’t the same level of medical care there. Having everybody trained in basic life support would be very important to reduce unnecessary deaths from these types of conditions.
As Paul mentioned, there is a very specific cardiac cause in some of these circumstances, where you get hit just at the wrong time and that hit occurs at a particular electrical point in time. It causes this ventricular fibrillation, and the only real treatment there is the defibrillator as quickly as possible.
Dr. Glatter: What you’re saying ultimately is an important part about rapid defibrillation, and at first, cardiopulmonary resuscitation (CPR). People are concerned about whether they should begin CPR. We’re talking about out-of-hospital cardiac arrest that is outside of a football stadium, for example. Some people are obsessed with taking a person’s pulse, and that’s been a point of contention. If someone is unconscious and not breathing, we should start CPR. Wouldn›t you agree? They will wake up quickly if you begin chest compressions if they’re not necessary.
Dr. Pepe: I tell people, just do it. You’re right, people will wake up and feel it if they don’t need it.
Getting back to Mick’s point of having things ready to go, for example, 8 years ago, we had a professional player on the bench who suddenly collapsed right there in front of the entire audience. We immediately did CPR, and we got the AED on. We shocked him and he was ready, willing, and able to get back on the bench again. It turns out he had underlying coronary artery disease, but we got him back right away.
I did an initial study where we placed an AED in a public place at the Chicago O’Hare Airport to see if the public would use these. Most cardiac arrests occur at home, of course, but in public places, that was a good place to try it. We had almost 10 cases the first year. What was fascinating was that we had almost no survivors over the previous decade, even though there were paramedics at the airport. When we put these out there, we had nine people go down that first year, and six people who had never operated an AED or seen one before knew to get one and use it. Every one of those people survived neurologically intact, and almost every person was waking up before traditional responders got there. That’s how effective this is, but you need to know where the AED is.
Dr. Glatter: How to turn it on, where it is, and how to operate it.
Dr. Pepe: That was the point: These rescuers saved lives in the first year, and it was tremendous. Two points I make about it are that one, you need to know where it is, and two, just go turn it on. It gives you the instructions to follow through; just be in the Nike mode, because it basically won’t hurt a person. It’s rare that there’s ever been any complication of that. The machine algorithms are so good.
Dr. Glatter: Mick, I want to turn to you about the European experience. Specifically in Denmark, we know that there’s a large public health initiative to have AEDs accessible. There have been studies showing that when the public is engaged, especially with studies looking at an app when access is available, survivability doubled in the past 10 years from having access to AEDs. What’s your experience in Ireland in terms of public access to defibrillators?
Dr. Molloy: We’ve got two different streams here. There was a big push to have more AEDs at all sports venues. That was great, but some of the sporting clubs put them inside the locked door. I said that there’s no point to that because nobody can access it. You need to have an external building and you need to leave it open. If somebody needs to use it, they need to know how to get it, open it, and get away, and not get in through a locked door to get access to a defibrillator. We have AEDs now in most stadiums and even in small rural areas, where you might have only 200 people turn up for a game.
From another public access side, if you dial in – in our scenario, it’s 112, not 911 –we have Community First Responder groups. In the rural areas, you have local people who’ve been trained in basic life support and community first response who have AEDs. They’ll have periods of the day where they come home from work as a teacher, a nurse, a policeman, or a fireman, and they turn on an app on their phone and say, “I’m available for the next 5 hours.” If there’s a cardiac arrest rung in within 5 miles of their community, they will drive directly there with the AED that they have. We’ve had numerous saves from that in the country because it could take 40 minutes to get an EMS vehicle there, and obviously, time is crucial in these scenarios. Our dispatchers will talk people through CPR, and then the community responders arrive with the AED. It has been a fantastic initiative.
Dr. Pepe: In many places, people have apps on their phones where they’re locked into the system, and it will go off and tell them there is something nearby and even GPS them into it, and it’s been fantastic.
The two points I want to make to responding to what we just heard Dean Malloy say is one, we always have a designated spot to have these in various places. If I’m at City Hall, we always have them near the red elevators on every floor and down at security. In all the public high schools, we always have one right below the clock where everybody can see it. We set it up in a very standardized form that anybody and everybody will know where it is at the time an event happens.
The other point he made about having the response teams is fantastic. I live in a large high rise and there are two complexes with many people here, and many are older, so there’s going to be a higher risk for having an event. In fact, we’ve just had one recently. The concept we developed here was a community emergency response team, where we sometimes have doctors, nurses, and paramedics who live here be on call and be responsible, or you could try to find an AED. More importantly, we made sure everybody here knew where they were and where to get them. We’ve got most of the people trained, and we’re doing more training in what actions to take during these periods of time when such events happen.
Dr. Glatter: Yes, it’s critical. I wanted to point out that we’ve looked at the use of drones, especially here in the United States. There have been some pilot studies looking at their utility in the setting of out-of-hospital cardiac arrest. I want to get both of your thoughts on this and the feasibility of this.
Dr. Molloy: In a rural area, it’s a fantastic idea. You’re going to get something there as the crow flies very quickly. You probably have to look at exactly in, say, a rural area like Ireland of 32,000 square kilometers, how many you›ll have to put, what kind of distances they can realistically cover, and make sure the batteries are charged. Certainly, that’s a very good initiative because with the AEDs, you can’t do anything wrong. You can’t give a shock unless a shock needs to be given. The machine directs you what to do, so somebody who has had no training can pick one of these out of the box and start to work with it quickly and confidently that they can’t do anything wrong.
It’s a great idea. It would be a little expensive potentially at the moment in getting the drones and having that volume of drones around. In the U.S., you have completely different air traffic than we have, and in cities, you have more helicopters flying around. We certainly wouldn’t have that in our cities because that could cause a challenge if you’ve got drones flying around as well. It’s about making it safe that nothing else can go wrong from a drone in somebody else’s flight path.
Dr. Pepe: In my experience, the earlier the intervention, the better the results. There is a limit here in terms of the drones if they just can’t get there soon enough. Having said that, we are so fortunate in the city of Seattle to have most citizens knowing CPR, and we’d get that person resuscitated because they were doing such a good job with the CPR up front.
That’s why you’re going to see the Buffalo Bills player survive neurologically intact – because he did get immediate treatment right then and there. In the future, we may even have some better devices that will actually even restore normal blood flow right then and there while you’re still in cardiac arrest. There are limitations in every case. But on the other hand, it’s exciting and it paid off in this case recently.
Dr. Molloy: Just a point of interest coming from this small little country over here. The first portable defibrillator was developed in Belfast, Ireland, in the back of a cardiac response car. Despite us being a tiny little country, we do have some advances ahead of the United States.
Dr. Pepe: That was a breakthrough. Dr. Frank Pantridge and John Geddes did this great work and that caught the imagination of everybody here. At first, they were just going out to give people oxygen and sedate them for their chest pain. It turned out that their defibrillators are what made the difference as they went out there. Absolutely, I have to acknowledge the folks in Ireland for giving us this. Many of the EMS systems got started because of the article they published in The Lancet back in 1967.
Dr. Glatter: I wanted to briefly talk about screening of the athletes at the high school/college level, but also at the professional level. Obviously, there are issues, including the risk for false-positives in terms of low incidence, but there are also false negatives, as the case with Christian Eriksen, who had a cardiac arrest in 2021 and who has been through extensive testing. We can debate the validity of such testing, but I wanted to get both of your takes on the utility of screening in such a population.
Dr. Molloy: That’s a very emotive subject. False-positives are difficult because you’re now saying to somebody that they can’t compete in your sport at a decent level. The difficult part is telling somebody that this is the end of their career.
The false-negative is a little bit more difficult. I don’t know Christian Eriksen and I’m not involved in his team in any way, but that is a one-point examination, and you’re dependent on the scale of the process interpreting the ECG, which is again only a couple of seconds and that particular arrhythmia may not have shown up on that.
Also, athletes, by nature of what they’re doing, are operating at 99% of efficiency on a frequent basis. They are at the peak of their physiologic fitness, and it does make them a little bit more prone to picking up viral illnesses from time to time. They may get a small viral myopericarditis, which causes a new arrhythmia that nobody knew about. They had the screening 2 or 3 years ago, and they now developed a new problem because of what they do, which just may not show up.
I was actually surprised that the gentleman came through it very well, which is fantastic. He wasn’t allowed to play football in the country where he was employed, and he has now moved to another country and is playing football with a defibrillator inserted. I don’t know what the rules are in American football where you can play with implantable defibrillators. I’m not so sure it’s a great idea to do that.
Dr. Pepe: One thing that we should bring up is that there are athletes with underlying cardiomyopathies or hypertrophies and things like that, but that was unlikely in this case. It’s possible, but it’s unlikely, because it would have manifested itself before. In terms of screening, I’ve met some very smart medical doctors who have run those tests, and they have been very encouraged even at the high school levels to have screenings done, whether it’s electrocardiography, echocardiography, and so on. I have to reiterate what Dr Malloy just said in that it may have its downsides as well. If you can pick up real obvious cases, I think that may be of value.
Dr. Glatter: I want to conclude and get some pearls and takeaways from each of you regarding the events that transpired and what our audience can really hold onto.
Dr. Molloy: Look at Formula One in the past 50 years. In Formula One, in the beginning it was a 2-minute job to change a tire. Now, they have this down where they’re measuring in fractions of a second and criticizing each other if one guy is 2.6 seconds and the other guy is 2.9 seconds. For me, that’s phenomenal. It takes me 25 minutes to change a tire.
We’ve looked at that from a resuscitation perspective, and we now do pit crew resuscitation before our events. We’ve planned our team and know who’s going to be occupying what role. After the events at the UEFA championships, we had a new rule brought in by UEFA where they handed me a new document saying, “This is what we would like you to do for resuscitation.” It was a three-man triangle, and I said, “No, we’re not going to do that here.” And they said, “Why, you have to; it’s our rule.”
I said, “No, our rule in Ireland is we have a six-person triangle. We’re not downing our standards because of what you have internationally. You’re covering games in some very low-resource environments, I know that. We have a particular standard here that we’re sticking to. We have a six-person group. We know what we’re all doing; we come very quickly to those downed players and get involved and we’ve had good outcomes, so we’re not going to change the standards.”
That’s the thing: You need to practice these things. The players don’t go out on the weekend and do a move for the very first time without practicing it hundreds of times. We need to look at it the same way as the medical team who are looking after that group of players and the crowd because we also look after the crowd.
A particular challenge in some of our stadiums is that the upper decks are so steep, and it’s very hard to get a patient onto a trolley and do CPR as you’re bringing them down to a zone to get them flat. We’ve had to come up with some innovative techniques to try and do that and accommodate that using some of the mechanical CPR devices. That’s the result you’ll only get from having practiced these events and trying to extricate patients. We want to check response times, so you have to practice your response team activity very frequently.
Dr. Pepe: There are two points made by Mick that I want to react to. One, the pit crew approach is critical in so many ways. We do the same thing in what we call the medical first attack, where we knew who the A, B, and C person would be. When we took it out to the NBA trainers, I recommended for them to have a similar approach so that if an event does happen right in the middle of prime time, they are coordinated.
The second point is that we do mass-gathering medicine. It’s not just the sportspeople on the field or the entertainers that we’re looking after; it is the people in the stands. We will see a cardiac arrest once a month. If you think about it, you might see a cardiac arrest occur in any community on a regular basis. Now you’ve got 100,000 people in one stadium, and something is bound to go wrong over those 3 or 4 hours where they are there and may have a critical emergency. Preparation for all of that is really important as well.
The final point is that on a day-to-day basis, most cardiac arrests do occur in the home. Granted, 80% of them are nonshockable cases, but the people who are more apt to survive are going to be the ones who have an electrical event. In fact, when we looked at our data years ago, we found that, of the cases of people with ventricular fibrillation that we resuscitated, half didn’t even have heart damage. Their enzymes were normal. It was a pure electrical event, and they were more resuscitable. They may have an underlying problem, but we can fix that once we get them back.
Everybody needs to know how to do bystander CPR, and second, we must make sure we have AEDs strategically placed, as I alluded to before. We also go out to other parts of the community and give them advice. All those things must be put in place, but more importantly, just get the training and make the training simple. It’s really a “just do it” philosophy, but make it simple.
For example, when I teach a course, I can do it in 15 minutes, and people retain it because I keep reiterating things like, “Okay, there’s one thing you need to know about choking: Pop the cork.” You give them a physiologic image of what’s happening. Everybody says, “I remember you saying to just do it, pop the cork.”
With AEDs, know where it is – that’s why we should have it in standardized places. Go get it, turn it on, and then follow the instructions. Also, the most important thing is making sure you’re doing quality compressions; and there are videos that can help you with that, as well as classes that you can take that will get you through it.
Dr. Glatter: Absolutely. The public still has the misconception that you need to do mouth-to-mouth resuscitation. The message has not permeated through society that you don’t need to do mouth-to-mouth. Hands-only CPR is the gold standard now.
Dr. Pepe: If people have a reversible cause like ventricular fibrillation, often they’re already gasping, which is better than a delivered breath, by the way. Most important, then, are the compressions to make sure you have oxygen going up to the brain, because you’re still theoretically loaded with oxygen in your bloodstream if you had a sudden cardiac arrest from a ventricular fibrillation.
Your points are well taken, and we found that we had better outcomes when we just gave instructions to do compressions only, and that became the standard. Mick, you’ve had some experiences with that as well.
Dr. Molloy: If we’re going to have a long-term benefit from all this, we have to start doing this in elementary school and teaching kids basic life support and some basic health messaging.
I remember trying to get this across to a teacher one day and the teacher saying, “But why would we teach young kids to resuscitate each other?” I said, “I think you forget that the only 60-year-old person in the room is you. You train them, and we train them. They’re the ones who are going to respond and keep you alive. That’s the way you should be looking at this.” That completely changed the mindset of whether we should be doing this for the kids or not.
Dr. Pepe: In fact, what we find is that that’s exactly who gets saved. I had case after case where the kids at the school had learned CPR and saved the teachers or the administrator at the high school or elementary school. It’s a fantastic point that you bring up, Dr. Malloy.
Dr. Glatter: One other brief thing we can interject here is that the team was excellent on field in that they evaluated Damar Hamlin in a primary survey sense of ABCs (i.e., airway, breathing, and circulation) for things like a tension pneumothorax. In the sense in which he was hit, there are reversible causes. Making sure he didn’t have a tension pneumothorax that caused the arrest, in my mind, was critical.
Dr. Pepe: We do the same thing on a day-to-day basis with a car wreck, because it could be that the person had ventricular fibrillation and then had the wreck. It’s not always trauma. That’s a fantastic point that you’re making. That’s exactly what I think happened, and that’s what we do.
Dr. Glatter: Well, thank you, gentlemen. This was an informative and helpful discussion for our audience. I appreciate your time and expertise.
Dr. Glatter, is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes.
Dr. Pepe is a professor of internal medicine, surgery, pediatrics, public health, and emergency medicine at University of Texas Health Science Center in Houston. He’s also a global coordinator of the U.S. Metropolitan Municipalities EMS Medical Directors (“Eagles”) Coalition.
Dr. Molloy works clinically as a consultant in emergency medicine in Wexford General Hospital, part of the Ireland East Hospital Group (IEHG). Internationally, he is a member of the Disaster Medicine Section of the European Society of Emergency Medicine (EUSEM) and has been appointed by the Irish Medical Organization (IMO) as one of two Irish delegates to serve on the European Board and Section of Emergency Medicine of the European Union of Medical Specialists (UEMS), having served for a number of years on its predecessor, the Multidisciplinary Joint Committee on Emergency Medicine.
A version of this article first appeared on Medscape.com.
This discussion was recorded on Jan. 9, 2023. This transcript has been edited for clarity.
Robert D. Glatter, MD: Welcome. I’m Dr. Robert D. Glatter, medical adviser for Medscape Emergency Medicine. Today, we have Dr. Paul E. Pepe, an emergency medicine physician based in Florida and a highly recognized expert in emergency medical services (EMS), critical care, sports and event medicine, and resuscitation. Also joining us is Dr. Michael S. (“Mick”) Malloy, an emergency medicine physician based in Ireland, also an expert in prehospital care, resuscitation, and sports and event medicine. Welcome, gentlemen.
Dr. Pepe: Thanks for having us here.
Dr. Glatter: the Buffalo Bills safety who went down suffering a cardiac arrest in front of millions of people. Although we don’t know the exact cause of the events that transpired, the goal of our discussion is to guide our audience through a systematic approach to evaluation and management of an athlete suffering blunt force chest and neck trauma, and then suffering a cardiac arrest. We do know, obviously, that Damar was successfully resuscitated, thanks to the medical staff and trainers.
Almost 50 years ago, Chuck Hughes, a Detroit Lions receiver, went down and died with just a minute to go in the game and, unfortunately, didn’t survive.
Paul, can you tell me your impressions after viewing the replay of the events that evening? What were the most likely causes of this syncopal event and the subsequent cardiac arrest?
Dr. Pepe: We don’t know anything specifically. It’s being kept private about what the events were. It’s a little bit complicated in a sense that he basically had an extended resuscitation in the hospital. My experience has been that most people that have ventricular fibrillation, from whatever cause, will most likely be waking up on the field if you get to them. I’ve had personal experience with that.
More importantly than when it starts, when someone goes down on the field, both Dr. Malloy and I take a broader view. We don’t get tunnel vision and think, “Oh, it was a traumatic event,” or “It was cardiac event,” and we just have our minds open. There are many things that could make you stop breathing on the field. It could be a neck or a severe head injury, and then any kind of other internal injury that occurs.
When I saw in the video that Damar Hamlin stood up, that made it a less likely to be a spinal injury. He seemed to be physically functioning, and then he suddenly collapsed. That went along with something that looks like a ventricular fibrillation or ventricular tachycardia type of event and made me think right away that it was commotio cordis. I’m not a Latin scholar, but commotio is like commotion. A literal translation might be an agitation of the heart. I was thinking that he probably got hit somewhere in the middle of the chest at the right moment where the heart is resetting in that repolarization phase, like an R-on-T phenomenon, and then caused this sudden ventricular dysrhythmia.
Most people associate it to that because we have a couple of dozen cases a year of people getting hockey pucks or a baseball hitting their chest, which is very common with adolescents. On the other hand, you can’t get it from a blunt injury like this, and it was too early for it to be, say, a direct cardiac contusion, unless there was a direct injury there. It just happened so quickly.
In Europe, they’ve had a large amount of experience with this same kind of problem before, even just from a direct shoulder hit, for example. Mick Malloy is the dean of the faculty of sports and exercise medicine at the Royal College of Surgeons in Ireland and has vast experience, and now he is the person overseeing the procedures for this. Mick, have you had those kinds of experiences as well?
Dr. Molloy: Yes. It’s something that has occurred over recent decades and has been more recognized. I note that in professional sports, it’s a very different thing because you’ve got such huge teams and teams trained to respond very quickly. And that’s the most important thing in this scenario – having a team that is well functioning as a high-class emergency response team ready to get out on to that field very quickly after the person collapses, getting the automated external defibrillator (AED) on, and then recognizing whether there needs to be a shock given or not. The machine will tell you all that.
In our scenario, we run courses called CARES (Care of the Athlete Resuscitation and Emergencies in Sport) to make sure that our team physicians and team physiotherapists and trainers are all speaking as one when an emergency arises.
I don’t worry so much about the professional sport. It’s more with the amateur sports and the kids sports that I get a bit more concerned because there isn’t the same level of medical care there. Having everybody trained in basic life support would be very important to reduce unnecessary deaths from these types of conditions.
As Paul mentioned, there is a very specific cardiac cause in some of these circumstances, where you get hit just at the wrong time and that hit occurs at a particular electrical point in time. It causes this ventricular fibrillation, and the only real treatment there is the defibrillator as quickly as possible.
Dr. Glatter: What you’re saying ultimately is an important part about rapid defibrillation, and at first, cardiopulmonary resuscitation (CPR). People are concerned about whether they should begin CPR. We’re talking about out-of-hospital cardiac arrest that is outside of a football stadium, for example. Some people are obsessed with taking a person’s pulse, and that’s been a point of contention. If someone is unconscious and not breathing, we should start CPR. Wouldn›t you agree? They will wake up quickly if you begin chest compressions if they’re not necessary.
Dr. Pepe: I tell people, just do it. You’re right, people will wake up and feel it if they don’t need it.
Getting back to Mick’s point of having things ready to go, for example, 8 years ago, we had a professional player on the bench who suddenly collapsed right there in front of the entire audience. We immediately did CPR, and we got the AED on. We shocked him and he was ready, willing, and able to get back on the bench again. It turns out he had underlying coronary artery disease, but we got him back right away.
I did an initial study where we placed an AED in a public place at the Chicago O’Hare Airport to see if the public would use these. Most cardiac arrests occur at home, of course, but in public places, that was a good place to try it. We had almost 10 cases the first year. What was fascinating was that we had almost no survivors over the previous decade, even though there were paramedics at the airport. When we put these out there, we had nine people go down that first year, and six people who had never operated an AED or seen one before knew to get one and use it. Every one of those people survived neurologically intact, and almost every person was waking up before traditional responders got there. That’s how effective this is, but you need to know where the AED is.
Dr. Glatter: How to turn it on, where it is, and how to operate it.
Dr. Pepe: That was the point: These rescuers saved lives in the first year, and it was tremendous. Two points I make about it are that one, you need to know where it is, and two, just go turn it on. It gives you the instructions to follow through; just be in the Nike mode, because it basically won’t hurt a person. It’s rare that there’s ever been any complication of that. The machine algorithms are so good.
Dr. Glatter: Mick, I want to turn to you about the European experience. Specifically in Denmark, we know that there’s a large public health initiative to have AEDs accessible. There have been studies showing that when the public is engaged, especially with studies looking at an app when access is available, survivability doubled in the past 10 years from having access to AEDs. What’s your experience in Ireland in terms of public access to defibrillators?
Dr. Molloy: We’ve got two different streams here. There was a big push to have more AEDs at all sports venues. That was great, but some of the sporting clubs put them inside the locked door. I said that there’s no point to that because nobody can access it. You need to have an external building and you need to leave it open. If somebody needs to use it, they need to know how to get it, open it, and get away, and not get in through a locked door to get access to a defibrillator. We have AEDs now in most stadiums and even in small rural areas, where you might have only 200 people turn up for a game.
From another public access side, if you dial in – in our scenario, it’s 112, not 911 –we have Community First Responder groups. In the rural areas, you have local people who’ve been trained in basic life support and community first response who have AEDs. They’ll have periods of the day where they come home from work as a teacher, a nurse, a policeman, or a fireman, and they turn on an app on their phone and say, “I’m available for the next 5 hours.” If there’s a cardiac arrest rung in within 5 miles of their community, they will drive directly there with the AED that they have. We’ve had numerous saves from that in the country because it could take 40 minutes to get an EMS vehicle there, and obviously, time is crucial in these scenarios. Our dispatchers will talk people through CPR, and then the community responders arrive with the AED. It has been a fantastic initiative.
Dr. Pepe: In many places, people have apps on their phones where they’re locked into the system, and it will go off and tell them there is something nearby and even GPS them into it, and it’s been fantastic.
The two points I want to make to responding to what we just heard Dean Malloy say is one, we always have a designated spot to have these in various places. If I’m at City Hall, we always have them near the red elevators on every floor and down at security. In all the public high schools, we always have one right below the clock where everybody can see it. We set it up in a very standardized form that anybody and everybody will know where it is at the time an event happens.
The other point he made about having the response teams is fantastic. I live in a large high rise and there are two complexes with many people here, and many are older, so there’s going to be a higher risk for having an event. In fact, we’ve just had one recently. The concept we developed here was a community emergency response team, where we sometimes have doctors, nurses, and paramedics who live here be on call and be responsible, or you could try to find an AED. More importantly, we made sure everybody here knew where they were and where to get them. We’ve got most of the people trained, and we’re doing more training in what actions to take during these periods of time when such events happen.
Dr. Glatter: Yes, it’s critical. I wanted to point out that we’ve looked at the use of drones, especially here in the United States. There have been some pilot studies looking at their utility in the setting of out-of-hospital cardiac arrest. I want to get both of your thoughts on this and the feasibility of this.
Dr. Molloy: In a rural area, it’s a fantastic idea. You’re going to get something there as the crow flies very quickly. You probably have to look at exactly in, say, a rural area like Ireland of 32,000 square kilometers, how many you›ll have to put, what kind of distances they can realistically cover, and make sure the batteries are charged. Certainly, that’s a very good initiative because with the AEDs, you can’t do anything wrong. You can’t give a shock unless a shock needs to be given. The machine directs you what to do, so somebody who has had no training can pick one of these out of the box and start to work with it quickly and confidently that they can’t do anything wrong.
It’s a great idea. It would be a little expensive potentially at the moment in getting the drones and having that volume of drones around. In the U.S., you have completely different air traffic than we have, and in cities, you have more helicopters flying around. We certainly wouldn’t have that in our cities because that could cause a challenge if you’ve got drones flying around as well. It’s about making it safe that nothing else can go wrong from a drone in somebody else’s flight path.
Dr. Pepe: In my experience, the earlier the intervention, the better the results. There is a limit here in terms of the drones if they just can’t get there soon enough. Having said that, we are so fortunate in the city of Seattle to have most citizens knowing CPR, and we’d get that person resuscitated because they were doing such a good job with the CPR up front.
That’s why you’re going to see the Buffalo Bills player survive neurologically intact – because he did get immediate treatment right then and there. In the future, we may even have some better devices that will actually even restore normal blood flow right then and there while you’re still in cardiac arrest. There are limitations in every case. But on the other hand, it’s exciting and it paid off in this case recently.
Dr. Molloy: Just a point of interest coming from this small little country over here. The first portable defibrillator was developed in Belfast, Ireland, in the back of a cardiac response car. Despite us being a tiny little country, we do have some advances ahead of the United States.
Dr. Pepe: That was a breakthrough. Dr. Frank Pantridge and John Geddes did this great work and that caught the imagination of everybody here. At first, they were just going out to give people oxygen and sedate them for their chest pain. It turned out that their defibrillators are what made the difference as they went out there. Absolutely, I have to acknowledge the folks in Ireland for giving us this. Many of the EMS systems got started because of the article they published in The Lancet back in 1967.
Dr. Glatter: I wanted to briefly talk about screening of the athletes at the high school/college level, but also at the professional level. Obviously, there are issues, including the risk for false-positives in terms of low incidence, but there are also false negatives, as the case with Christian Eriksen, who had a cardiac arrest in 2021 and who has been through extensive testing. We can debate the validity of such testing, but I wanted to get both of your takes on the utility of screening in such a population.
Dr. Molloy: That’s a very emotive subject. False-positives are difficult because you’re now saying to somebody that they can’t compete in your sport at a decent level. The difficult part is telling somebody that this is the end of their career.
The false-negative is a little bit more difficult. I don’t know Christian Eriksen and I’m not involved in his team in any way, but that is a one-point examination, and you’re dependent on the scale of the process interpreting the ECG, which is again only a couple of seconds and that particular arrhythmia may not have shown up on that.
Also, athletes, by nature of what they’re doing, are operating at 99% of efficiency on a frequent basis. They are at the peak of their physiologic fitness, and it does make them a little bit more prone to picking up viral illnesses from time to time. They may get a small viral myopericarditis, which causes a new arrhythmia that nobody knew about. They had the screening 2 or 3 years ago, and they now developed a new problem because of what they do, which just may not show up.
I was actually surprised that the gentleman came through it very well, which is fantastic. He wasn’t allowed to play football in the country where he was employed, and he has now moved to another country and is playing football with a defibrillator inserted. I don’t know what the rules are in American football where you can play with implantable defibrillators. I’m not so sure it’s a great idea to do that.
Dr. Pepe: One thing that we should bring up is that there are athletes with underlying cardiomyopathies or hypertrophies and things like that, but that was unlikely in this case. It’s possible, but it’s unlikely, because it would have manifested itself before. In terms of screening, I’ve met some very smart medical doctors who have run those tests, and they have been very encouraged even at the high school levels to have screenings done, whether it’s electrocardiography, echocardiography, and so on. I have to reiterate what Dr Malloy just said in that it may have its downsides as well. If you can pick up real obvious cases, I think that may be of value.
Dr. Glatter: I want to conclude and get some pearls and takeaways from each of you regarding the events that transpired and what our audience can really hold onto.
Dr. Molloy: Look at Formula One in the past 50 years. In Formula One, in the beginning it was a 2-minute job to change a tire. Now, they have this down where they’re measuring in fractions of a second and criticizing each other if one guy is 2.6 seconds and the other guy is 2.9 seconds. For me, that’s phenomenal. It takes me 25 minutes to change a tire.
We’ve looked at that from a resuscitation perspective, and we now do pit crew resuscitation before our events. We’ve planned our team and know who’s going to be occupying what role. After the events at the UEFA championships, we had a new rule brought in by UEFA where they handed me a new document saying, “This is what we would like you to do for resuscitation.” It was a three-man triangle, and I said, “No, we’re not going to do that here.” And they said, “Why, you have to; it’s our rule.”
I said, “No, our rule in Ireland is we have a six-person triangle. We’re not downing our standards because of what you have internationally. You’re covering games in some very low-resource environments, I know that. We have a particular standard here that we’re sticking to. We have a six-person group. We know what we’re all doing; we come very quickly to those downed players and get involved and we’ve had good outcomes, so we’re not going to change the standards.”
That’s the thing: You need to practice these things. The players don’t go out on the weekend and do a move for the very first time without practicing it hundreds of times. We need to look at it the same way as the medical team who are looking after that group of players and the crowd because we also look after the crowd.
A particular challenge in some of our stadiums is that the upper decks are so steep, and it’s very hard to get a patient onto a trolley and do CPR as you’re bringing them down to a zone to get them flat. We’ve had to come up with some innovative techniques to try and do that and accommodate that using some of the mechanical CPR devices. That’s the result you’ll only get from having practiced these events and trying to extricate patients. We want to check response times, so you have to practice your response team activity very frequently.
Dr. Pepe: There are two points made by Mick that I want to react to. One, the pit crew approach is critical in so many ways. We do the same thing in what we call the medical first attack, where we knew who the A, B, and C person would be. When we took it out to the NBA trainers, I recommended for them to have a similar approach so that if an event does happen right in the middle of prime time, they are coordinated.
The second point is that we do mass-gathering medicine. It’s not just the sportspeople on the field or the entertainers that we’re looking after; it is the people in the stands. We will see a cardiac arrest once a month. If you think about it, you might see a cardiac arrest occur in any community on a regular basis. Now you’ve got 100,000 people in one stadium, and something is bound to go wrong over those 3 or 4 hours where they are there and may have a critical emergency. Preparation for all of that is really important as well.
The final point is that on a day-to-day basis, most cardiac arrests do occur in the home. Granted, 80% of them are nonshockable cases, but the people who are more apt to survive are going to be the ones who have an electrical event. In fact, when we looked at our data years ago, we found that, of the cases of people with ventricular fibrillation that we resuscitated, half didn’t even have heart damage. Their enzymes were normal. It was a pure electrical event, and they were more resuscitable. They may have an underlying problem, but we can fix that once we get them back.
Everybody needs to know how to do bystander CPR, and second, we must make sure we have AEDs strategically placed, as I alluded to before. We also go out to other parts of the community and give them advice. All those things must be put in place, but more importantly, just get the training and make the training simple. It’s really a “just do it” philosophy, but make it simple.
For example, when I teach a course, I can do it in 15 minutes, and people retain it because I keep reiterating things like, “Okay, there’s one thing you need to know about choking: Pop the cork.” You give them a physiologic image of what’s happening. Everybody says, “I remember you saying to just do it, pop the cork.”
With AEDs, know where it is – that’s why we should have it in standardized places. Go get it, turn it on, and then follow the instructions. Also, the most important thing is making sure you’re doing quality compressions; and there are videos that can help you with that, as well as classes that you can take that will get you through it.
Dr. Glatter: Absolutely. The public still has the misconception that you need to do mouth-to-mouth resuscitation. The message has not permeated through society that you don’t need to do mouth-to-mouth. Hands-only CPR is the gold standard now.
Dr. Pepe: If people have a reversible cause like ventricular fibrillation, often they’re already gasping, which is better than a delivered breath, by the way. Most important, then, are the compressions to make sure you have oxygen going up to the brain, because you’re still theoretically loaded with oxygen in your bloodstream if you had a sudden cardiac arrest from a ventricular fibrillation.
Your points are well taken, and we found that we had better outcomes when we just gave instructions to do compressions only, and that became the standard. Mick, you’ve had some experiences with that as well.
Dr. Molloy: If we’re going to have a long-term benefit from all this, we have to start doing this in elementary school and teaching kids basic life support and some basic health messaging.
I remember trying to get this across to a teacher one day and the teacher saying, “But why would we teach young kids to resuscitate each other?” I said, “I think you forget that the only 60-year-old person in the room is you. You train them, and we train them. They’re the ones who are going to respond and keep you alive. That’s the way you should be looking at this.” That completely changed the mindset of whether we should be doing this for the kids or not.
Dr. Pepe: In fact, what we find is that that’s exactly who gets saved. I had case after case where the kids at the school had learned CPR and saved the teachers or the administrator at the high school or elementary school. It’s a fantastic point that you bring up, Dr. Malloy.
Dr. Glatter: One other brief thing we can interject here is that the team was excellent on field in that they evaluated Damar Hamlin in a primary survey sense of ABCs (i.e., airway, breathing, and circulation) for things like a tension pneumothorax. In the sense in which he was hit, there are reversible causes. Making sure he didn’t have a tension pneumothorax that caused the arrest, in my mind, was critical.
Dr. Pepe: We do the same thing on a day-to-day basis with a car wreck, because it could be that the person had ventricular fibrillation and then had the wreck. It’s not always trauma. That’s a fantastic point that you’re making. That’s exactly what I think happened, and that’s what we do.
Dr. Glatter: Well, thank you, gentlemen. This was an informative and helpful discussion for our audience. I appreciate your time and expertise.
Dr. Glatter, is an attending physician at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is an editorial adviser and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes.
Dr. Pepe is a professor of internal medicine, surgery, pediatrics, public health, and emergency medicine at University of Texas Health Science Center in Houston. He’s also a global coordinator of the U.S. Metropolitan Municipalities EMS Medical Directors (“Eagles”) Coalition.
Dr. Molloy works clinically as a consultant in emergency medicine in Wexford General Hospital, part of the Ireland East Hospital Group (IEHG). Internationally, he is a member of the Disaster Medicine Section of the European Society of Emergency Medicine (EUSEM) and has been appointed by the Irish Medical Organization (IMO) as one of two Irish delegates to serve on the European Board and Section of Emergency Medicine of the European Union of Medical Specialists (UEMS), having served for a number of years on its predecessor, the Multidisciplinary Joint Committee on Emergency Medicine.
A version of this article first appeared on Medscape.com.
Size of meals, not timing, linked to weight loss
The number of daily meals, but not the timing between first and last daily meals, was significantly associated with weight changes over a 6-year period, in a prospective study of more than 500 adults.
Some studies suggest that timing food intake – through time-restricted eating or intermittent fasting – can promote weight loss, but these strategies have yielded similar weight loss to eating throughout the day in randomized trials, and population-based studies of meal intervals and weight changes are needed, Di Zhao, PhD, of Johns Hopkins University, Baltimore, and colleagues wrote.
“Obesity is an epidemic,” corresponding author Wendy Bennett, MD, also of Johns Hopkins University, said in an interview. “We are interested in identifying ways to prevent weight gain over time and reduce obesity risk, since telling people to ‘just eat less’ doesn’t always work.”
In a study published in the Journal of the American Heart Association, the researchers recruited 1,017 adults who were patients at one of three health systems; of these, complete data were available for 547 individuals.
The participants downloaded an app called Daily24 to record the timing of their meals and sleep for at least 1 day. The researchers used electronic medical records to obtain information on weight and comorbidities of the participants for up to 10 years before study enrollment through 10 months after enrollment.
The mean age of the participants was 51.1 years, 78% were women, and 78% were White; the mean body mass index was 30.8 kg/m2.
The mean interval from first to last meal was 11.5 hours, and this was not associated with change in weight. The mean times from waking up to the first meal and the time from the last meal to sleeping were 1.6 hours and 4.0 hours, respectively, and these were not associated with weight changes over the follow-up period, the researchers wrote. Sleep duration (mean of 7.5 hours) also was not associated with weight change over time.
However, the total daily number of large and medium-sized meals was associated with weight gain over time, while those who reported more smaller meals showed weight loss. A daily increase of one large, medium, or small meal was associated with an average annual weight change of 0.69 kg, 0.97 kg, and –0.30 kg, respectively.
Benefits of time-restricted eating remain unclear
“Animal studies have shown benefits for time restricted feeding, but there are still questions about whether or not it helps prevent weight gain or promotes weight loss in humans,” Dr. Bennett said in an interview.
As for the current study findings, “we were not surprised; humans are more complicated than animals, and we have complicated behaviors, especially with eating,” she said.
“We showed that windows of eating (eating for longer periods of time or less in a day) was not associated with weight change over time among patients from three health systems,” said Dr. Bennett. “The main implication is that restricting your window of eating, such as eating over less time, or having more fasting time, may not reduce weight gain over time, while eating fewer large meals is associated with less weight gain over time.”
The findings were limited by several factors including the exclusion of many younger and less educated individuals, the short follow-up period, and lack of information on weight loss intention at baseline, the researchers noted. Other limitations included the inability to evaluate time-restricted eating or fasting, and the inclusion of individuals currently seeking care, which may limit generalizability.
However, the results were strengthened by the repeated measures of weight, detailed information on obesity risk factors, and real-time assessment of eating behaviors. The results do not support time-restricted eating as a long-term weight-loss strategy, and more studies are needed with a longer follow-up period, the researchers concluded.
However, there may be a role for time restricted eating as a method of total calorie control, Dr. Bennett said.
“Other studies do show that people might be able to use time-restricted eating or intermittent fasting to help them reduce their caloric intake and thus lose weight, so it can still be a helpful weight loss tool for some people who can adhere to it,” she said.
The study was supported by a grant from the American Heart Association to Johns Hopkins University. Dr. Bennett had no financial conflicts to disclose.
The number of daily meals, but not the timing between first and last daily meals, was significantly associated with weight changes over a 6-year period, in a prospective study of more than 500 adults.
Some studies suggest that timing food intake – through time-restricted eating or intermittent fasting – can promote weight loss, but these strategies have yielded similar weight loss to eating throughout the day in randomized trials, and population-based studies of meal intervals and weight changes are needed, Di Zhao, PhD, of Johns Hopkins University, Baltimore, and colleagues wrote.
“Obesity is an epidemic,” corresponding author Wendy Bennett, MD, also of Johns Hopkins University, said in an interview. “We are interested in identifying ways to prevent weight gain over time and reduce obesity risk, since telling people to ‘just eat less’ doesn’t always work.”
In a study published in the Journal of the American Heart Association, the researchers recruited 1,017 adults who were patients at one of three health systems; of these, complete data were available for 547 individuals.
The participants downloaded an app called Daily24 to record the timing of their meals and sleep for at least 1 day. The researchers used electronic medical records to obtain information on weight and comorbidities of the participants for up to 10 years before study enrollment through 10 months after enrollment.
The mean age of the participants was 51.1 years, 78% were women, and 78% were White; the mean body mass index was 30.8 kg/m2.
The mean interval from first to last meal was 11.5 hours, and this was not associated with change in weight. The mean times from waking up to the first meal and the time from the last meal to sleeping were 1.6 hours and 4.0 hours, respectively, and these were not associated with weight changes over the follow-up period, the researchers wrote. Sleep duration (mean of 7.5 hours) also was not associated with weight change over time.
However, the total daily number of large and medium-sized meals was associated with weight gain over time, while those who reported more smaller meals showed weight loss. A daily increase of one large, medium, or small meal was associated with an average annual weight change of 0.69 kg, 0.97 kg, and –0.30 kg, respectively.
Benefits of time-restricted eating remain unclear
“Animal studies have shown benefits for time restricted feeding, but there are still questions about whether or not it helps prevent weight gain or promotes weight loss in humans,” Dr. Bennett said in an interview.
As for the current study findings, “we were not surprised; humans are more complicated than animals, and we have complicated behaviors, especially with eating,” she said.
“We showed that windows of eating (eating for longer periods of time or less in a day) was not associated with weight change over time among patients from three health systems,” said Dr. Bennett. “The main implication is that restricting your window of eating, such as eating over less time, or having more fasting time, may not reduce weight gain over time, while eating fewer large meals is associated with less weight gain over time.”
The findings were limited by several factors including the exclusion of many younger and less educated individuals, the short follow-up period, and lack of information on weight loss intention at baseline, the researchers noted. Other limitations included the inability to evaluate time-restricted eating or fasting, and the inclusion of individuals currently seeking care, which may limit generalizability.
However, the results were strengthened by the repeated measures of weight, detailed information on obesity risk factors, and real-time assessment of eating behaviors. The results do not support time-restricted eating as a long-term weight-loss strategy, and more studies are needed with a longer follow-up period, the researchers concluded.
However, there may be a role for time restricted eating as a method of total calorie control, Dr. Bennett said.
“Other studies do show that people might be able to use time-restricted eating or intermittent fasting to help them reduce their caloric intake and thus lose weight, so it can still be a helpful weight loss tool for some people who can adhere to it,” she said.
The study was supported by a grant from the American Heart Association to Johns Hopkins University. Dr. Bennett had no financial conflicts to disclose.
The number of daily meals, but not the timing between first and last daily meals, was significantly associated with weight changes over a 6-year period, in a prospective study of more than 500 adults.
Some studies suggest that timing food intake – through time-restricted eating or intermittent fasting – can promote weight loss, but these strategies have yielded similar weight loss to eating throughout the day in randomized trials, and population-based studies of meal intervals and weight changes are needed, Di Zhao, PhD, of Johns Hopkins University, Baltimore, and colleagues wrote.
“Obesity is an epidemic,” corresponding author Wendy Bennett, MD, also of Johns Hopkins University, said in an interview. “We are interested in identifying ways to prevent weight gain over time and reduce obesity risk, since telling people to ‘just eat less’ doesn’t always work.”
In a study published in the Journal of the American Heart Association, the researchers recruited 1,017 adults who were patients at one of three health systems; of these, complete data were available for 547 individuals.
The participants downloaded an app called Daily24 to record the timing of their meals and sleep for at least 1 day. The researchers used electronic medical records to obtain information on weight and comorbidities of the participants for up to 10 years before study enrollment through 10 months after enrollment.
The mean age of the participants was 51.1 years, 78% were women, and 78% were White; the mean body mass index was 30.8 kg/m2.
The mean interval from first to last meal was 11.5 hours, and this was not associated with change in weight. The mean times from waking up to the first meal and the time from the last meal to sleeping were 1.6 hours and 4.0 hours, respectively, and these were not associated with weight changes over the follow-up period, the researchers wrote. Sleep duration (mean of 7.5 hours) also was not associated with weight change over time.
However, the total daily number of large and medium-sized meals was associated with weight gain over time, while those who reported more smaller meals showed weight loss. A daily increase of one large, medium, or small meal was associated with an average annual weight change of 0.69 kg, 0.97 kg, and –0.30 kg, respectively.
Benefits of time-restricted eating remain unclear
“Animal studies have shown benefits for time restricted feeding, but there are still questions about whether or not it helps prevent weight gain or promotes weight loss in humans,” Dr. Bennett said in an interview.
As for the current study findings, “we were not surprised; humans are more complicated than animals, and we have complicated behaviors, especially with eating,” she said.
“We showed that windows of eating (eating for longer periods of time or less in a day) was not associated with weight change over time among patients from three health systems,” said Dr. Bennett. “The main implication is that restricting your window of eating, such as eating over less time, or having more fasting time, may not reduce weight gain over time, while eating fewer large meals is associated with less weight gain over time.”
The findings were limited by several factors including the exclusion of many younger and less educated individuals, the short follow-up period, and lack of information on weight loss intention at baseline, the researchers noted. Other limitations included the inability to evaluate time-restricted eating or fasting, and the inclusion of individuals currently seeking care, which may limit generalizability.
However, the results were strengthened by the repeated measures of weight, detailed information on obesity risk factors, and real-time assessment of eating behaviors. The results do not support time-restricted eating as a long-term weight-loss strategy, and more studies are needed with a longer follow-up period, the researchers concluded.
However, there may be a role for time restricted eating as a method of total calorie control, Dr. Bennett said.
“Other studies do show that people might be able to use time-restricted eating or intermittent fasting to help them reduce their caloric intake and thus lose weight, so it can still be a helpful weight loss tool for some people who can adhere to it,” she said.
The study was supported by a grant from the American Heart Association to Johns Hopkins University. Dr. Bennett had no financial conflicts to disclose.
FROM THE JOURNAL OF THE AMERICAN HEART ASSOCIATION
Emotional eating tied to risk of diastolic dysfunction
Eating in response to stress – known as emotional eating – was significantly associated with several markers of long-term cardiovascular damage, based on data from 1,109 individuals.
“We know diet plays a huge role in cardiovascular disease, but we have focused a lot of work on what you eat, not on what makes you eat” – the current study did exactly that, Martha Gulati, MD, who wasn’t involved in the study, said in an interview.
“Emotional eaters consume food to satisfy their brains rather than their stomachs,” study investigator Nicolas Girerd, MD, of the National Institute of Health and Medical Research (INSERM) and a cardiologist at the University Hospital of Nancy (France), wrote in a press release accompanying the study.
Diet plays a role in the development of cardiovascular disease (CVD), but the impact of eating behavior on long-term cardiovascular health remains unclear, wrote Dr. Girerd and colleagues. Previous research has yielded three common psychological dimensions for eating behavior: emotional eating, restrained eating, and external eating.
Both emotional eating and restrained eating have been linked to cardiovascular disease risk, the researchers noted. “Because of previous findings, we hypothesized that [emotional and/or restrained dimensions of eating behavior] are positively associated with cardiovascular damages, as well as with CV risk factors, such as metabolic syndrome,” they wrote.
In a study published in the European Journal of Preventive Cardiology, the researchers reviewed data from 916 adults and 193 adolescents who were participants in the STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux), a longitudinal familial cohort in France. Cardiovascular data were collected at four medical visits as part of a full clinical examination between 1993 and 2016, with one visit every 5-10 years. Roughly one-third (31.0%) of the adults were overweight, 7.9% were obese, and 2.7% were underweight. The median age of the adults at the second visit was 44.7 years; the median age of the adolescent group was 15.2 years.
The primary outcome of cardiovascular damage was measured at the fourth visit. Eating behavior was assessed during the second visit using the Dutch Eating Behaviour Questionnaire (DEBQ), and participants were identified as emotional eaters, restrained eaters, or external eaters.
Among the adults, emotional eating was associated with a 38% increased risk of diastolic dysfunction (odds ratio, 1.38; P = .02), over an average follow-up of 13 years, and this association was mediated by stress in 32% of cases. Emotional eating also was positively linked with a higher carotid-femoral pulse-wave velocity (cfPWV-beta), indicative of increased arterial stiffness. However, none of the three dimensions of eating behavior was associated with cardiovascular damage among the adolescents. In addition, none of the eating-behavior dimensions was tied to metabolic syndrome in the adult group (this association was not measured in the adolescents).
Energy intake had no apparent impact on any associations between eating behavior and CVD measures, Dr. Girerd said in the press release. “We might expect that emotional eaters would consume high-calorie foods, which would in turn lead to cardiovascular problems, but this was not the case. One explanation is that we measured average calorie intake and emotional eaters may binge when stressed and then eat less at other times,” and that the resulting “yo-yo” pattern might negatively affect the heart and blood vessels more than stable food intake, he said.
The study findings were limited by several factors, including the observational design that prevented conclusions of causality, the researchers noted. Other limitations included the use of a nonvalidated scale to measure stress, the lack of data on physical activity, and the use of a mainly healthy population in a limited geographic area, which may limit generalizability, they said.
More research is needed in other contexts and larger cohorts, but the results were strengthened by the large study population and the complete data on eating behaviors and detailed health information, they wrote. The results support previous studies and suggest that patients with emotional eating behavior could benefit from emotion regulation skills training, including cognitive, behavioral, psychological, and interpersonal therapies used in other areas, and from pharmacological treatments, the researchers concluded.
The current study offers a unique and important perspective on the relationship between diet and cardiovascular disease, Dr. Gulati, director of preventive cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center, Los Angeles, told this news organization.
“Examining eating behavior and its relationship with cardiovascular effects in healthy individuals in this prospective way is quite interesting,” said Dr. Gulati, who was not involved in the study.
The researchers examined healthy people at baseline, inquired about their eating habits, and found that emotional eaters “have evidence of cardiovascular changes when compared with the other groups of eaters, after controlling for other risk factors that are associated with cardiovascular disease when following them for 13 years,” said Dr. Gulati, who was recently named Anita Dann Friedman Endowed Chair in Women’s Cardiovascular Medicine and Research at Cedars-Sinai. “This same finding wasn’t seen in adolescents, but this is probably because they are younger, and the effects aren’t seen. That is reassuring, because it means that the more we address eating behaviors, the more likely we are to reduce their effects to the heart,” she noted.
“This study is important because usually, as cardiologists or anyone in medicine, how we assess diet is by assessment of what food people eat; we don’t usually ask about what triggers them to eat,” Dr. Gulati said. “Eating behaviors based on their triggers ultimately affect food choice and food quantity, and help us understand weight changes during a lifetime,” she said.
“I think we don’t have the data to know that an eating behavior would be able to affect cardiac function,” said Dr. Gulati, “but I think we all might hypothesize that emotional eating may be associated with abnormal diastolic function simply through eating high-density food and weight gain.”
The current study did not show a relationship between eating behavior and metabolic syndrome, in contrast with prior studies, Dr. Gulati noted. However, “the authors report that the association between eating behaviors and diastolic dysfunction was mediated through the stress level,” Dr. Gulati said. “It is important to note that this European population was healthy at baseline, and also relatively healthy 13 years later, which makes these findings even more profound.”
Dr. Gulati said that she agrees with the study authors on the need to assess diet and eating behaviors when assessing cardiovascular risk in patient. “Diet assessment as part of prevention is central, but we should ask not only ‘what do you eat,’ but also ‘what makes you eat,’ ” she said.
More research is needed in other populations, Dr. Gulati added. The current study population was healthy at baseline and follow-up. Studies are needed in cohorts in the United States and in the developing world to see how the results might differ; as well as in rural America or in “food deserts” where food choices are limited.
Another research topic is the interplay between eating behaviors and social determinants of health, in terms of their effect on cardiovascular function, Dr. Gulati said, “and it will be valuable to follow this cohort further to see how these eating behaviors and these intermediate measures translate into cardiovascular outcomes.” Future studies should also examine whether the changes in cardiac function are reversible by interventions to modify eating behavior, particularly emotional eating, she said.
Supporters of the study included the Regional University Hospital Center of Nancy, the French Ministry of Solidarity and Health, and a public grant overseen by the French National Research Agency. The researchers had no financial conflicts to disclose.
Dr. Gulati, who serves on the editorial advisory board of MDedge Cardiology, had no financial conflicts to disclose.
Eating in response to stress – known as emotional eating – was significantly associated with several markers of long-term cardiovascular damage, based on data from 1,109 individuals.
“We know diet plays a huge role in cardiovascular disease, but we have focused a lot of work on what you eat, not on what makes you eat” – the current study did exactly that, Martha Gulati, MD, who wasn’t involved in the study, said in an interview.
“Emotional eaters consume food to satisfy their brains rather than their stomachs,” study investigator Nicolas Girerd, MD, of the National Institute of Health and Medical Research (INSERM) and a cardiologist at the University Hospital of Nancy (France), wrote in a press release accompanying the study.
Diet plays a role in the development of cardiovascular disease (CVD), but the impact of eating behavior on long-term cardiovascular health remains unclear, wrote Dr. Girerd and colleagues. Previous research has yielded three common psychological dimensions for eating behavior: emotional eating, restrained eating, and external eating.
Both emotional eating and restrained eating have been linked to cardiovascular disease risk, the researchers noted. “Because of previous findings, we hypothesized that [emotional and/or restrained dimensions of eating behavior] are positively associated with cardiovascular damages, as well as with CV risk factors, such as metabolic syndrome,” they wrote.
In a study published in the European Journal of Preventive Cardiology, the researchers reviewed data from 916 adults and 193 adolescents who were participants in the STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux), a longitudinal familial cohort in France. Cardiovascular data were collected at four medical visits as part of a full clinical examination between 1993 and 2016, with one visit every 5-10 years. Roughly one-third (31.0%) of the adults were overweight, 7.9% were obese, and 2.7% were underweight. The median age of the adults at the second visit was 44.7 years; the median age of the adolescent group was 15.2 years.
The primary outcome of cardiovascular damage was measured at the fourth visit. Eating behavior was assessed during the second visit using the Dutch Eating Behaviour Questionnaire (DEBQ), and participants were identified as emotional eaters, restrained eaters, or external eaters.
Among the adults, emotional eating was associated with a 38% increased risk of diastolic dysfunction (odds ratio, 1.38; P = .02), over an average follow-up of 13 years, and this association was mediated by stress in 32% of cases. Emotional eating also was positively linked with a higher carotid-femoral pulse-wave velocity (cfPWV-beta), indicative of increased arterial stiffness. However, none of the three dimensions of eating behavior was associated with cardiovascular damage among the adolescents. In addition, none of the eating-behavior dimensions was tied to metabolic syndrome in the adult group (this association was not measured in the adolescents).
Energy intake had no apparent impact on any associations between eating behavior and CVD measures, Dr. Girerd said in the press release. “We might expect that emotional eaters would consume high-calorie foods, which would in turn lead to cardiovascular problems, but this was not the case. One explanation is that we measured average calorie intake and emotional eaters may binge when stressed and then eat less at other times,” and that the resulting “yo-yo” pattern might negatively affect the heart and blood vessels more than stable food intake, he said.
The study findings were limited by several factors, including the observational design that prevented conclusions of causality, the researchers noted. Other limitations included the use of a nonvalidated scale to measure stress, the lack of data on physical activity, and the use of a mainly healthy population in a limited geographic area, which may limit generalizability, they said.
More research is needed in other contexts and larger cohorts, but the results were strengthened by the large study population and the complete data on eating behaviors and detailed health information, they wrote. The results support previous studies and suggest that patients with emotional eating behavior could benefit from emotion regulation skills training, including cognitive, behavioral, psychological, and interpersonal therapies used in other areas, and from pharmacological treatments, the researchers concluded.
The current study offers a unique and important perspective on the relationship between diet and cardiovascular disease, Dr. Gulati, director of preventive cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center, Los Angeles, told this news organization.
“Examining eating behavior and its relationship with cardiovascular effects in healthy individuals in this prospective way is quite interesting,” said Dr. Gulati, who was not involved in the study.
The researchers examined healthy people at baseline, inquired about their eating habits, and found that emotional eaters “have evidence of cardiovascular changes when compared with the other groups of eaters, after controlling for other risk factors that are associated with cardiovascular disease when following them for 13 years,” said Dr. Gulati, who was recently named Anita Dann Friedman Endowed Chair in Women’s Cardiovascular Medicine and Research at Cedars-Sinai. “This same finding wasn’t seen in adolescents, but this is probably because they are younger, and the effects aren’t seen. That is reassuring, because it means that the more we address eating behaviors, the more likely we are to reduce their effects to the heart,” she noted.
“This study is important because usually, as cardiologists or anyone in medicine, how we assess diet is by assessment of what food people eat; we don’t usually ask about what triggers them to eat,” Dr. Gulati said. “Eating behaviors based on their triggers ultimately affect food choice and food quantity, and help us understand weight changes during a lifetime,” she said.
“I think we don’t have the data to know that an eating behavior would be able to affect cardiac function,” said Dr. Gulati, “but I think we all might hypothesize that emotional eating may be associated with abnormal diastolic function simply through eating high-density food and weight gain.”
The current study did not show a relationship between eating behavior and metabolic syndrome, in contrast with prior studies, Dr. Gulati noted. However, “the authors report that the association between eating behaviors and diastolic dysfunction was mediated through the stress level,” Dr. Gulati said. “It is important to note that this European population was healthy at baseline, and also relatively healthy 13 years later, which makes these findings even more profound.”
Dr. Gulati said that she agrees with the study authors on the need to assess diet and eating behaviors when assessing cardiovascular risk in patient. “Diet assessment as part of prevention is central, but we should ask not only ‘what do you eat,’ but also ‘what makes you eat,’ ” she said.
More research is needed in other populations, Dr. Gulati added. The current study population was healthy at baseline and follow-up. Studies are needed in cohorts in the United States and in the developing world to see how the results might differ; as well as in rural America or in “food deserts” where food choices are limited.
Another research topic is the interplay between eating behaviors and social determinants of health, in terms of their effect on cardiovascular function, Dr. Gulati said, “and it will be valuable to follow this cohort further to see how these eating behaviors and these intermediate measures translate into cardiovascular outcomes.” Future studies should also examine whether the changes in cardiac function are reversible by interventions to modify eating behavior, particularly emotional eating, she said.
Supporters of the study included the Regional University Hospital Center of Nancy, the French Ministry of Solidarity and Health, and a public grant overseen by the French National Research Agency. The researchers had no financial conflicts to disclose.
Dr. Gulati, who serves on the editorial advisory board of MDedge Cardiology, had no financial conflicts to disclose.
Eating in response to stress – known as emotional eating – was significantly associated with several markers of long-term cardiovascular damage, based on data from 1,109 individuals.
“We know diet plays a huge role in cardiovascular disease, but we have focused a lot of work on what you eat, not on what makes you eat” – the current study did exactly that, Martha Gulati, MD, who wasn’t involved in the study, said in an interview.
“Emotional eaters consume food to satisfy their brains rather than their stomachs,” study investigator Nicolas Girerd, MD, of the National Institute of Health and Medical Research (INSERM) and a cardiologist at the University Hospital of Nancy (France), wrote in a press release accompanying the study.
Diet plays a role in the development of cardiovascular disease (CVD), but the impact of eating behavior on long-term cardiovascular health remains unclear, wrote Dr. Girerd and colleagues. Previous research has yielded three common psychological dimensions for eating behavior: emotional eating, restrained eating, and external eating.
Both emotional eating and restrained eating have been linked to cardiovascular disease risk, the researchers noted. “Because of previous findings, we hypothesized that [emotional and/or restrained dimensions of eating behavior] are positively associated with cardiovascular damages, as well as with CV risk factors, such as metabolic syndrome,” they wrote.
In a study published in the European Journal of Preventive Cardiology, the researchers reviewed data from 916 adults and 193 adolescents who were participants in the STANISLAS (Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux), a longitudinal familial cohort in France. Cardiovascular data were collected at four medical visits as part of a full clinical examination between 1993 and 2016, with one visit every 5-10 years. Roughly one-third (31.0%) of the adults were overweight, 7.9% were obese, and 2.7% were underweight. The median age of the adults at the second visit was 44.7 years; the median age of the adolescent group was 15.2 years.
The primary outcome of cardiovascular damage was measured at the fourth visit. Eating behavior was assessed during the second visit using the Dutch Eating Behaviour Questionnaire (DEBQ), and participants were identified as emotional eaters, restrained eaters, or external eaters.
Among the adults, emotional eating was associated with a 38% increased risk of diastolic dysfunction (odds ratio, 1.38; P = .02), over an average follow-up of 13 years, and this association was mediated by stress in 32% of cases. Emotional eating also was positively linked with a higher carotid-femoral pulse-wave velocity (cfPWV-beta), indicative of increased arterial stiffness. However, none of the three dimensions of eating behavior was associated with cardiovascular damage among the adolescents. In addition, none of the eating-behavior dimensions was tied to metabolic syndrome in the adult group (this association was not measured in the adolescents).
Energy intake had no apparent impact on any associations between eating behavior and CVD measures, Dr. Girerd said in the press release. “We might expect that emotional eaters would consume high-calorie foods, which would in turn lead to cardiovascular problems, but this was not the case. One explanation is that we measured average calorie intake and emotional eaters may binge when stressed and then eat less at other times,” and that the resulting “yo-yo” pattern might negatively affect the heart and blood vessels more than stable food intake, he said.
The study findings were limited by several factors, including the observational design that prevented conclusions of causality, the researchers noted. Other limitations included the use of a nonvalidated scale to measure stress, the lack of data on physical activity, and the use of a mainly healthy population in a limited geographic area, which may limit generalizability, they said.
More research is needed in other contexts and larger cohorts, but the results were strengthened by the large study population and the complete data on eating behaviors and detailed health information, they wrote. The results support previous studies and suggest that patients with emotional eating behavior could benefit from emotion regulation skills training, including cognitive, behavioral, psychological, and interpersonal therapies used in other areas, and from pharmacological treatments, the researchers concluded.
The current study offers a unique and important perspective on the relationship between diet and cardiovascular disease, Dr. Gulati, director of preventive cardiology at the Smidt Heart Institute at Cedars-Sinai Medical Center, Los Angeles, told this news organization.
“Examining eating behavior and its relationship with cardiovascular effects in healthy individuals in this prospective way is quite interesting,” said Dr. Gulati, who was not involved in the study.
The researchers examined healthy people at baseline, inquired about their eating habits, and found that emotional eaters “have evidence of cardiovascular changes when compared with the other groups of eaters, after controlling for other risk factors that are associated with cardiovascular disease when following them for 13 years,” said Dr. Gulati, who was recently named Anita Dann Friedman Endowed Chair in Women’s Cardiovascular Medicine and Research at Cedars-Sinai. “This same finding wasn’t seen in adolescents, but this is probably because they are younger, and the effects aren’t seen. That is reassuring, because it means that the more we address eating behaviors, the more likely we are to reduce their effects to the heart,” she noted.
“This study is important because usually, as cardiologists or anyone in medicine, how we assess diet is by assessment of what food people eat; we don’t usually ask about what triggers them to eat,” Dr. Gulati said. “Eating behaviors based on their triggers ultimately affect food choice and food quantity, and help us understand weight changes during a lifetime,” she said.
“I think we don’t have the data to know that an eating behavior would be able to affect cardiac function,” said Dr. Gulati, “but I think we all might hypothesize that emotional eating may be associated with abnormal diastolic function simply through eating high-density food and weight gain.”
The current study did not show a relationship between eating behavior and metabolic syndrome, in contrast with prior studies, Dr. Gulati noted. However, “the authors report that the association between eating behaviors and diastolic dysfunction was mediated through the stress level,” Dr. Gulati said. “It is important to note that this European population was healthy at baseline, and also relatively healthy 13 years later, which makes these findings even more profound.”
Dr. Gulati said that she agrees with the study authors on the need to assess diet and eating behaviors when assessing cardiovascular risk in patient. “Diet assessment as part of prevention is central, but we should ask not only ‘what do you eat,’ but also ‘what makes you eat,’ ” she said.
More research is needed in other populations, Dr. Gulati added. The current study population was healthy at baseline and follow-up. Studies are needed in cohorts in the United States and in the developing world to see how the results might differ; as well as in rural America or in “food deserts” where food choices are limited.
Another research topic is the interplay between eating behaviors and social determinants of health, in terms of their effect on cardiovascular function, Dr. Gulati said, “and it will be valuable to follow this cohort further to see how these eating behaviors and these intermediate measures translate into cardiovascular outcomes.” Future studies should also examine whether the changes in cardiac function are reversible by interventions to modify eating behavior, particularly emotional eating, she said.
Supporters of the study included the Regional University Hospital Center of Nancy, the French Ministry of Solidarity and Health, and a public grant overseen by the French National Research Agency. The researchers had no financial conflicts to disclose.
Dr. Gulati, who serves on the editorial advisory board of MDedge Cardiology, had no financial conflicts to disclose.
FROM THE EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY
Will your smartphone be the next doctor’s office?
A fingertip pressed against a phone’s camera lens can measure a heart rate. The microphone, kept by the bedside, can screen for sleep apnea. Even the speaker is being tapped, to monitor breathing using sonar technology.
In the best of this new world, the data is conveyed remotely to a medical professional for the convenience and comfort of the patient or, in some cases, to support a clinician without the need for costly hardware.
But using smartphones as diagnostic tools is a work in progress, experts say. Although doctors and their patients have found some real-world success in deploying the phone as a medical device, the overall potential remains unfulfilled and uncertain.
Smartphones come packed with sensors capable of monitoring a patient’s vital signs. They can help assess people for concussions, watch for atrial fibrillation, and conduct mental health wellness checks, to name the uses of a few nascent applications.
Companies and researchers eager to find medical applications for smartphone technology are tapping into modern phones’ built-in cameras and light sensors; microphones; accelerometers, which detect body movements; gyroscopes; and even speakers. The apps then use artificial intelligence software to analyze the collected sights and sounds to create an easy connection between patients and physicians. Earning potential and marketability are evidenced by the more than 350,000 digital health products available in app stores, according to a Grand View Research report.
“It’s very hard to put devices into the patient home or in the hospital, but everybody is just walking around with a cellphone that has a network connection,” said Dr. Andrew Gostine, CEO of the sensor network company Artisight. Most Americans own a smartphone, including more than 60% of people 65 and over, an increase from just 13% a decade ago, according the Pew Research Center. The COVID-19 pandemic has also pushed people to become more comfortable with virtual care.
Some of these products have sought FDA clearance to be marketed as a medical device. That way, if patients must pay to use the software, health insurers are more likely to cover at least part of the cost. Other products are designated as exempt from this regulatory process, placed in the same clinical classification as a Band-Aid. But how the agency handles AI and machine learning–based medical devices is still being adjusted to reflect software’s adaptive nature.
Ensuring accuracy and clinical validation is crucial to securing buy-in from health care providers. And many tools still need fine-tuning, said Eugene Yang, MD, a professor of medicine at the University of Washington, Seattle. Currently, Dr. Yang is testing contactless measurement of blood pressure, heart rate, and oxygen saturation gleaned remotely via Zoom camera footage of a patient’s face.
Judging these new technologies is difficult because they rely on algorithms built by machine learning and artificial intelligence to collect data, rather than the physical tools typically used in hospitals. So researchers cannot “compare apples to apples” with medical industry standards, Dr. Yang said. Failure to build in such assurances undermines the technology’s ultimate goals of easing costs and access because a doctor still must verify results.
“False positives and false negatives lead to more testing and more cost to the health care system,” he said.
Big tech companies like Google have heavily invested in researching this kind of technology, catering to clinicians and in-home caregivers, as well as consumers. Currently, in the Google Fit app, users can check their heart rate by placing their finger on the rear-facing camera lens or track their breathing rate using the front-facing camera.
“If you took the sensor out of the phone and out of a clinical device, they are probably the same thing,” said Shwetak Patel, director of health technologies at Google and a professor of electrical and computer engineering at the University of Washington.
Google’s research uses machine learning and computer vision, a field within AI based on information from visual inputs like videos or images. So instead of using a blood pressure cuff, for example, the algorithm can interpret slight visual changes to the body that serve as proxies and biosignals for a patient’s blood pressure, Mr. Patel said.
Google is also investigating the effectiveness of the built-in microphone for detecting heartbeats and murmurs and using the camera to preserve eyesight by screening for diabetic eye disease, according to information the company published last year.
The tech giant recently purchased Sound Life Sciences, a Seattle startup with an FDA-cleared sonar technology app. It uses a smart device’s speaker to bounce inaudible pulses off a patient’s body to identify movement and monitor breathing.
Binah.ai, based in Israel, is another company using the smartphone camera to calculate vital signs. Its software looks at the region around the eyes, where the skin is a bit thinner, and analyzes the light reflecting off blood vessels back to the lens. The company is wrapping up a U.S. clinical trial and marketing its wellness app directly to insurers and other health companies, said company spokesperson Mona Popilian-Yona.
The applications even reach into disciplines such as optometry and mental health:
- With the microphone, Canary Speech uses the same underlying technology as Amazon’s Alexa to analyze patients’ voices for mental health conditions. The software can integrate with telemedicine appointments and allow clinicians to screen for anxiety and depression using a library of vocal biomarkers and predictive analytics, said Henry O’Connell, the company’s CEO.
- Australia-based ResApp Health last year for its iPhone app that screens for moderate to severe obstructive sleep apnea by listening to breathing and snoring. SleepCheckRx, which will require a prescription, is minimally invasive compared with sleep studies currently used to diagnose sleep apnea. Those can cost thousands of dollars and require an array of tests.
- Brightlamp’s Reflex app is a clinical decision support tool for helping manage concussions and vision rehabilitation, among other things. Using an iPad’s or iPhone’s camera, the mobile app measures how a person’s pupils react to changes in light. Through machine learning analysis, the imagery gives practitioners data points for evaluating patients. Brightlamp sells directly to health care providers and is being used in more than 230 clinics. Clinicians pay a $400 standard annual fee per account, which is currently not covered by insurance. The Department of Defense has an ongoing clinical trial using Reflex.
In some cases, such as with the Reflex app, the data is processed directly on the phone – rather than in the cloud, Brightlamp CEO Kurtis Sluss said. By processing everything on the device, the app avoids running into privacy issues, as streaming data elsewhere requires patient consent.
But algorithms need to be trained and tested by collecting reams of data, and that is an ongoing process.
Researchers, for example, have found that some computer vision applications, like heart rate or blood pressure monitoring, can be less accurate for darker skin. Studies are underway to find better solutions.
Small algorithm glitches can also produce false alarms and frighten patients enough to keep widespread adoption out of reach. For example, Apple’s new car-crash detection feature, available on both the latest iPhone and Apple Watch, was set off when people were riding roller coasters and automatically dialed 911.
“We’re not there yet,” Dr. Yang said. “That’s the bottom line.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
A fingertip pressed against a phone’s camera lens can measure a heart rate. The microphone, kept by the bedside, can screen for sleep apnea. Even the speaker is being tapped, to monitor breathing using sonar technology.
In the best of this new world, the data is conveyed remotely to a medical professional for the convenience and comfort of the patient or, in some cases, to support a clinician without the need for costly hardware.
But using smartphones as diagnostic tools is a work in progress, experts say. Although doctors and their patients have found some real-world success in deploying the phone as a medical device, the overall potential remains unfulfilled and uncertain.
Smartphones come packed with sensors capable of monitoring a patient’s vital signs. They can help assess people for concussions, watch for atrial fibrillation, and conduct mental health wellness checks, to name the uses of a few nascent applications.
Companies and researchers eager to find medical applications for smartphone technology are tapping into modern phones’ built-in cameras and light sensors; microphones; accelerometers, which detect body movements; gyroscopes; and even speakers. The apps then use artificial intelligence software to analyze the collected sights and sounds to create an easy connection between patients and physicians. Earning potential and marketability are evidenced by the more than 350,000 digital health products available in app stores, according to a Grand View Research report.
“It’s very hard to put devices into the patient home or in the hospital, but everybody is just walking around with a cellphone that has a network connection,” said Dr. Andrew Gostine, CEO of the sensor network company Artisight. Most Americans own a smartphone, including more than 60% of people 65 and over, an increase from just 13% a decade ago, according the Pew Research Center. The COVID-19 pandemic has also pushed people to become more comfortable with virtual care.
Some of these products have sought FDA clearance to be marketed as a medical device. That way, if patients must pay to use the software, health insurers are more likely to cover at least part of the cost. Other products are designated as exempt from this regulatory process, placed in the same clinical classification as a Band-Aid. But how the agency handles AI and machine learning–based medical devices is still being adjusted to reflect software’s adaptive nature.
Ensuring accuracy and clinical validation is crucial to securing buy-in from health care providers. And many tools still need fine-tuning, said Eugene Yang, MD, a professor of medicine at the University of Washington, Seattle. Currently, Dr. Yang is testing contactless measurement of blood pressure, heart rate, and oxygen saturation gleaned remotely via Zoom camera footage of a patient’s face.
Judging these new technologies is difficult because they rely on algorithms built by machine learning and artificial intelligence to collect data, rather than the physical tools typically used in hospitals. So researchers cannot “compare apples to apples” with medical industry standards, Dr. Yang said. Failure to build in such assurances undermines the technology’s ultimate goals of easing costs and access because a doctor still must verify results.
“False positives and false negatives lead to more testing and more cost to the health care system,” he said.
Big tech companies like Google have heavily invested in researching this kind of technology, catering to clinicians and in-home caregivers, as well as consumers. Currently, in the Google Fit app, users can check their heart rate by placing their finger on the rear-facing camera lens or track their breathing rate using the front-facing camera.
“If you took the sensor out of the phone and out of a clinical device, they are probably the same thing,” said Shwetak Patel, director of health technologies at Google and a professor of electrical and computer engineering at the University of Washington.
Google’s research uses machine learning and computer vision, a field within AI based on information from visual inputs like videos or images. So instead of using a blood pressure cuff, for example, the algorithm can interpret slight visual changes to the body that serve as proxies and biosignals for a patient’s blood pressure, Mr. Patel said.
Google is also investigating the effectiveness of the built-in microphone for detecting heartbeats and murmurs and using the camera to preserve eyesight by screening for diabetic eye disease, according to information the company published last year.
The tech giant recently purchased Sound Life Sciences, a Seattle startup with an FDA-cleared sonar technology app. It uses a smart device’s speaker to bounce inaudible pulses off a patient’s body to identify movement and monitor breathing.
Binah.ai, based in Israel, is another company using the smartphone camera to calculate vital signs. Its software looks at the region around the eyes, where the skin is a bit thinner, and analyzes the light reflecting off blood vessels back to the lens. The company is wrapping up a U.S. clinical trial and marketing its wellness app directly to insurers and other health companies, said company spokesperson Mona Popilian-Yona.
The applications even reach into disciplines such as optometry and mental health:
- With the microphone, Canary Speech uses the same underlying technology as Amazon’s Alexa to analyze patients’ voices for mental health conditions. The software can integrate with telemedicine appointments and allow clinicians to screen for anxiety and depression using a library of vocal biomarkers and predictive analytics, said Henry O’Connell, the company’s CEO.
- Australia-based ResApp Health last year for its iPhone app that screens for moderate to severe obstructive sleep apnea by listening to breathing and snoring. SleepCheckRx, which will require a prescription, is minimally invasive compared with sleep studies currently used to diagnose sleep apnea. Those can cost thousands of dollars and require an array of tests.
- Brightlamp’s Reflex app is a clinical decision support tool for helping manage concussions and vision rehabilitation, among other things. Using an iPad’s or iPhone’s camera, the mobile app measures how a person’s pupils react to changes in light. Through machine learning analysis, the imagery gives practitioners data points for evaluating patients. Brightlamp sells directly to health care providers and is being used in more than 230 clinics. Clinicians pay a $400 standard annual fee per account, which is currently not covered by insurance. The Department of Defense has an ongoing clinical trial using Reflex.
In some cases, such as with the Reflex app, the data is processed directly on the phone – rather than in the cloud, Brightlamp CEO Kurtis Sluss said. By processing everything on the device, the app avoids running into privacy issues, as streaming data elsewhere requires patient consent.
But algorithms need to be trained and tested by collecting reams of data, and that is an ongoing process.
Researchers, for example, have found that some computer vision applications, like heart rate or blood pressure monitoring, can be less accurate for darker skin. Studies are underway to find better solutions.
Small algorithm glitches can also produce false alarms and frighten patients enough to keep widespread adoption out of reach. For example, Apple’s new car-crash detection feature, available on both the latest iPhone and Apple Watch, was set off when people were riding roller coasters and automatically dialed 911.
“We’re not there yet,” Dr. Yang said. “That’s the bottom line.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
A fingertip pressed against a phone’s camera lens can measure a heart rate. The microphone, kept by the bedside, can screen for sleep apnea. Even the speaker is being tapped, to monitor breathing using sonar technology.
In the best of this new world, the data is conveyed remotely to a medical professional for the convenience and comfort of the patient or, in some cases, to support a clinician without the need for costly hardware.
But using smartphones as diagnostic tools is a work in progress, experts say. Although doctors and their patients have found some real-world success in deploying the phone as a medical device, the overall potential remains unfulfilled and uncertain.
Smartphones come packed with sensors capable of monitoring a patient’s vital signs. They can help assess people for concussions, watch for atrial fibrillation, and conduct mental health wellness checks, to name the uses of a few nascent applications.
Companies and researchers eager to find medical applications for smartphone technology are tapping into modern phones’ built-in cameras and light sensors; microphones; accelerometers, which detect body movements; gyroscopes; and even speakers. The apps then use artificial intelligence software to analyze the collected sights and sounds to create an easy connection between patients and physicians. Earning potential and marketability are evidenced by the more than 350,000 digital health products available in app stores, according to a Grand View Research report.
“It’s very hard to put devices into the patient home or in the hospital, but everybody is just walking around with a cellphone that has a network connection,” said Dr. Andrew Gostine, CEO of the sensor network company Artisight. Most Americans own a smartphone, including more than 60% of people 65 and over, an increase from just 13% a decade ago, according the Pew Research Center. The COVID-19 pandemic has also pushed people to become more comfortable with virtual care.
Some of these products have sought FDA clearance to be marketed as a medical device. That way, if patients must pay to use the software, health insurers are more likely to cover at least part of the cost. Other products are designated as exempt from this regulatory process, placed in the same clinical classification as a Band-Aid. But how the agency handles AI and machine learning–based medical devices is still being adjusted to reflect software’s adaptive nature.
Ensuring accuracy and clinical validation is crucial to securing buy-in from health care providers. And many tools still need fine-tuning, said Eugene Yang, MD, a professor of medicine at the University of Washington, Seattle. Currently, Dr. Yang is testing contactless measurement of blood pressure, heart rate, and oxygen saturation gleaned remotely via Zoom camera footage of a patient’s face.
Judging these new technologies is difficult because they rely on algorithms built by machine learning and artificial intelligence to collect data, rather than the physical tools typically used in hospitals. So researchers cannot “compare apples to apples” with medical industry standards, Dr. Yang said. Failure to build in such assurances undermines the technology’s ultimate goals of easing costs and access because a doctor still must verify results.
“False positives and false negatives lead to more testing and more cost to the health care system,” he said.
Big tech companies like Google have heavily invested in researching this kind of technology, catering to clinicians and in-home caregivers, as well as consumers. Currently, in the Google Fit app, users can check their heart rate by placing their finger on the rear-facing camera lens or track their breathing rate using the front-facing camera.
“If you took the sensor out of the phone and out of a clinical device, they are probably the same thing,” said Shwetak Patel, director of health technologies at Google and a professor of electrical and computer engineering at the University of Washington.
Google’s research uses machine learning and computer vision, a field within AI based on information from visual inputs like videos or images. So instead of using a blood pressure cuff, for example, the algorithm can interpret slight visual changes to the body that serve as proxies and biosignals for a patient’s blood pressure, Mr. Patel said.
Google is also investigating the effectiveness of the built-in microphone for detecting heartbeats and murmurs and using the camera to preserve eyesight by screening for diabetic eye disease, according to information the company published last year.
The tech giant recently purchased Sound Life Sciences, a Seattle startup with an FDA-cleared sonar technology app. It uses a smart device’s speaker to bounce inaudible pulses off a patient’s body to identify movement and monitor breathing.
Binah.ai, based in Israel, is another company using the smartphone camera to calculate vital signs. Its software looks at the region around the eyes, where the skin is a bit thinner, and analyzes the light reflecting off blood vessels back to the lens. The company is wrapping up a U.S. clinical trial and marketing its wellness app directly to insurers and other health companies, said company spokesperson Mona Popilian-Yona.
The applications even reach into disciplines such as optometry and mental health:
- With the microphone, Canary Speech uses the same underlying technology as Amazon’s Alexa to analyze patients’ voices for mental health conditions. The software can integrate with telemedicine appointments and allow clinicians to screen for anxiety and depression using a library of vocal biomarkers and predictive analytics, said Henry O’Connell, the company’s CEO.
- Australia-based ResApp Health last year for its iPhone app that screens for moderate to severe obstructive sleep apnea by listening to breathing and snoring. SleepCheckRx, which will require a prescription, is minimally invasive compared with sleep studies currently used to diagnose sleep apnea. Those can cost thousands of dollars and require an array of tests.
- Brightlamp’s Reflex app is a clinical decision support tool for helping manage concussions and vision rehabilitation, among other things. Using an iPad’s or iPhone’s camera, the mobile app measures how a person’s pupils react to changes in light. Through machine learning analysis, the imagery gives practitioners data points for evaluating patients. Brightlamp sells directly to health care providers and is being used in more than 230 clinics. Clinicians pay a $400 standard annual fee per account, which is currently not covered by insurance. The Department of Defense has an ongoing clinical trial using Reflex.
In some cases, such as with the Reflex app, the data is processed directly on the phone – rather than in the cloud, Brightlamp CEO Kurtis Sluss said. By processing everything on the device, the app avoids running into privacy issues, as streaming data elsewhere requires patient consent.
But algorithms need to be trained and tested by collecting reams of data, and that is an ongoing process.
Researchers, for example, have found that some computer vision applications, like heart rate or blood pressure monitoring, can be less accurate for darker skin. Studies are underway to find better solutions.
Small algorithm glitches can also produce false alarms and frighten patients enough to keep widespread adoption out of reach. For example, Apple’s new car-crash detection feature, available on both the latest iPhone and Apple Watch, was set off when people were riding roller coasters and automatically dialed 911.
“We’re not there yet,” Dr. Yang said. “That’s the bottom line.”
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
Brain differences suggest therapeutic targets in Takotsubo
A new study has identified differences in the brain present in patients with the cardiac disorder Takotsubo syndrome versus control scans, which may lead to new therapeutic targets.
Takotsubo syndrome is an acute heart failure cardiomyopathy mimicking an acute myocardial infarction in its presentation, but on investigation, no obstructive coronary disease is present. The syndrome, which mainly affects women, typically occurs in the aftermath of intense emotional or physical stress and has become known as “broken heart syndrome.”
The mechanism by which emotional processing in the context of stress leads to significant cardiac injury and acute left ventricular dysfunction is not understood. So, the current study examined both structural and functional effects in the brain in patients with Takotsubo syndrome to shed more light on the issue.
“The abnormalities in the thalamus-amygdala-insula and basal ganglia support the concept of involvement of higher-level function centers in Takotsubo syndrome, and interventions aimed at modulating these may be of benefit,” the authors conclude.
The study was published online in JACC: Heart Failure.
Lead author Hilal Khan, MB BCh, BAO, from the University of Aberdeen (Scotland), explained to this news organization that patients with Takotsubo syndrome have a substantial drop in heart function and show an apical ballooning of the heart.
It is a relatively newly defined condition and was first described in 1990 in Japan, and so named because the heart was thought to resemble the Takotsubo pot used by Japanese fishermen to trap octopus.
Although uncommon, the condition is not rare. Dr. Khan estimates that about 1 in 20 women with suspected MI turn out to have Takotsubo syndrome, with cases increasing in times of global stress such as in the recent pandemic.
While patients tend to recover in a few weeks and the pumping function of the heart usually returns to normal, there are some long-term cardiac complications including a reduction in global longitudinal strain, and patients have similar long-term outcomes as those with MI.
“It is believed that these cardiac changes may be triggered by changes in the brain caused by emotional stress, so we wanted to look at this more closely,” Dr. Khan said.
There have been a couple of studies published previously looking at brain changes in Takotsubo syndrome, but they haven’t reported patients in the acute stage of the condition and they haven’t compared the patients to controls, he noted.
For the current study, the researchers looked at brain scans for 25 acute Takotsubo patients and in 25 controls matched for age, gender, comorbidities, and medications. All the patients and controls were examined using the same MRI scanner in the same hospital.
“This is the largest structural and functional brain study of acute Takotsubo syndrome patients compared with matched control subjects,” Dr. Khan said.
The researchers looked at many different factors including brain volume in different regions, cortical thickness, small-vessel disease, and functional and structural connectivity to try and obtain a complete holistic view of the brain.
Key findings were that patients with Takotsubo syndrome had smaller brain volumes, compared with matched controls, driven by a reduction in brain surface area. In contrast, the insula and thalamus regions were larger.
“A reduction in brain volume could be caused by inflammation; this is often seen in depression,” Dr. Khan commented.
The researchers also found that certain areas of the brain had a reduction in functional connectivity, particularly the thalamus – the central autonomic area of the brain, which regulates the autonomic nervous system – and also the insula region, which is also involved in the autonomic regulation of the heart.
They suggest that there may be a loss of parasympathetic inhibition in Takotsubo syndrome, which would fit the theory that Takotsubo brings with it a surge of catecholamines, which could injure the heart.
Reduced functional connectivity was also seen in parts of the basal ganglia, abnormalities of which have been associated with an increased risk of both arrhythmias, and in the amygdala, similar to patients with a tendency to catastrophize events.
The other observation was that there appeared to be an increase in structural connectivity in certain areas of the brain.
“Structural pathways seem to be increased but functional connectivity was reduced, so while physical pathways are enhanced, they don’t seem to be doing anything,” Dr. Khan said. “We don’t know why this occurs, or if this has happened over time and made the brain and heart more vulnerable in some way.”
One possibility is that ,under a significant emotional stress, the brain may divert function from some areas to others to be able to cope, and that this results in reduced functioning in areas of the brain responsible for regulating the heart, Dr. Khan suggested.
“We believe this study confirms that the brain is involved in Takotsubo syndrome, and we have identified markers in the brain that may be contributing to the condition,” he said.
The researchers are planning to further study these markers and whether it might be possible to modulate these changes with various interventions such as exercise or mindfulness.
“We believe there is some interface between the brain changes and the impact on the heart. We don’t think it is just the release of catecholamines that causes damage to the heart. We think there is something else happening as well,” Dr. Khan commented.
It is also possible that the hearts of patients with Takotsubo syndrome are predisposed in some way and more vulnerable to this condition occurring.
“It will be important to obtain a greater understanding of the triggers and identify people who may be vulnerable,” Dr. Khan noted. “Around 10% of individuals who experience Takotsubo syndrome will have a recurrence, so we need to try and develop preventative strategies to reduce this.”
He suggested that possible preventive or therapeutic approaches may involve interventions such as exercise or mindfulness.
This work was supported by National Health Service Grampian Endowment. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new study has identified differences in the brain present in patients with the cardiac disorder Takotsubo syndrome versus control scans, which may lead to new therapeutic targets.
Takotsubo syndrome is an acute heart failure cardiomyopathy mimicking an acute myocardial infarction in its presentation, but on investigation, no obstructive coronary disease is present. The syndrome, which mainly affects women, typically occurs in the aftermath of intense emotional or physical stress and has become known as “broken heart syndrome.”
The mechanism by which emotional processing in the context of stress leads to significant cardiac injury and acute left ventricular dysfunction is not understood. So, the current study examined both structural and functional effects in the brain in patients with Takotsubo syndrome to shed more light on the issue.
“The abnormalities in the thalamus-amygdala-insula and basal ganglia support the concept of involvement of higher-level function centers in Takotsubo syndrome, and interventions aimed at modulating these may be of benefit,” the authors conclude.
The study was published online in JACC: Heart Failure.
Lead author Hilal Khan, MB BCh, BAO, from the University of Aberdeen (Scotland), explained to this news organization that patients with Takotsubo syndrome have a substantial drop in heart function and show an apical ballooning of the heart.
It is a relatively newly defined condition and was first described in 1990 in Japan, and so named because the heart was thought to resemble the Takotsubo pot used by Japanese fishermen to trap octopus.
Although uncommon, the condition is not rare. Dr. Khan estimates that about 1 in 20 women with suspected MI turn out to have Takotsubo syndrome, with cases increasing in times of global stress such as in the recent pandemic.
While patients tend to recover in a few weeks and the pumping function of the heart usually returns to normal, there are some long-term cardiac complications including a reduction in global longitudinal strain, and patients have similar long-term outcomes as those with MI.
“It is believed that these cardiac changes may be triggered by changes in the brain caused by emotional stress, so we wanted to look at this more closely,” Dr. Khan said.
There have been a couple of studies published previously looking at brain changes in Takotsubo syndrome, but they haven’t reported patients in the acute stage of the condition and they haven’t compared the patients to controls, he noted.
For the current study, the researchers looked at brain scans for 25 acute Takotsubo patients and in 25 controls matched for age, gender, comorbidities, and medications. All the patients and controls were examined using the same MRI scanner in the same hospital.
“This is the largest structural and functional brain study of acute Takotsubo syndrome patients compared with matched control subjects,” Dr. Khan said.
The researchers looked at many different factors including brain volume in different regions, cortical thickness, small-vessel disease, and functional and structural connectivity to try and obtain a complete holistic view of the brain.
Key findings were that patients with Takotsubo syndrome had smaller brain volumes, compared with matched controls, driven by a reduction in brain surface area. In contrast, the insula and thalamus regions were larger.
“A reduction in brain volume could be caused by inflammation; this is often seen in depression,” Dr. Khan commented.
The researchers also found that certain areas of the brain had a reduction in functional connectivity, particularly the thalamus – the central autonomic area of the brain, which regulates the autonomic nervous system – and also the insula region, which is also involved in the autonomic regulation of the heart.
They suggest that there may be a loss of parasympathetic inhibition in Takotsubo syndrome, which would fit the theory that Takotsubo brings with it a surge of catecholamines, which could injure the heart.
Reduced functional connectivity was also seen in parts of the basal ganglia, abnormalities of which have been associated with an increased risk of both arrhythmias, and in the amygdala, similar to patients with a tendency to catastrophize events.
The other observation was that there appeared to be an increase in structural connectivity in certain areas of the brain.
“Structural pathways seem to be increased but functional connectivity was reduced, so while physical pathways are enhanced, they don’t seem to be doing anything,” Dr. Khan said. “We don’t know why this occurs, or if this has happened over time and made the brain and heart more vulnerable in some way.”
One possibility is that ,under a significant emotional stress, the brain may divert function from some areas to others to be able to cope, and that this results in reduced functioning in areas of the brain responsible for regulating the heart, Dr. Khan suggested.
“We believe this study confirms that the brain is involved in Takotsubo syndrome, and we have identified markers in the brain that may be contributing to the condition,” he said.
The researchers are planning to further study these markers and whether it might be possible to modulate these changes with various interventions such as exercise or mindfulness.
“We believe there is some interface between the brain changes and the impact on the heart. We don’t think it is just the release of catecholamines that causes damage to the heart. We think there is something else happening as well,” Dr. Khan commented.
It is also possible that the hearts of patients with Takotsubo syndrome are predisposed in some way and more vulnerable to this condition occurring.
“It will be important to obtain a greater understanding of the triggers and identify people who may be vulnerable,” Dr. Khan noted. “Around 10% of individuals who experience Takotsubo syndrome will have a recurrence, so we need to try and develop preventative strategies to reduce this.”
He suggested that possible preventive or therapeutic approaches may involve interventions such as exercise or mindfulness.
This work was supported by National Health Service Grampian Endowment. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new study has identified differences in the brain present in patients with the cardiac disorder Takotsubo syndrome versus control scans, which may lead to new therapeutic targets.
Takotsubo syndrome is an acute heart failure cardiomyopathy mimicking an acute myocardial infarction in its presentation, but on investigation, no obstructive coronary disease is present. The syndrome, which mainly affects women, typically occurs in the aftermath of intense emotional or physical stress and has become known as “broken heart syndrome.”
The mechanism by which emotional processing in the context of stress leads to significant cardiac injury and acute left ventricular dysfunction is not understood. So, the current study examined both structural and functional effects in the brain in patients with Takotsubo syndrome to shed more light on the issue.
“The abnormalities in the thalamus-amygdala-insula and basal ganglia support the concept of involvement of higher-level function centers in Takotsubo syndrome, and interventions aimed at modulating these may be of benefit,” the authors conclude.
The study was published online in JACC: Heart Failure.
Lead author Hilal Khan, MB BCh, BAO, from the University of Aberdeen (Scotland), explained to this news organization that patients with Takotsubo syndrome have a substantial drop in heart function and show an apical ballooning of the heart.
It is a relatively newly defined condition and was first described in 1990 in Japan, and so named because the heart was thought to resemble the Takotsubo pot used by Japanese fishermen to trap octopus.
Although uncommon, the condition is not rare. Dr. Khan estimates that about 1 in 20 women with suspected MI turn out to have Takotsubo syndrome, with cases increasing in times of global stress such as in the recent pandemic.
While patients tend to recover in a few weeks and the pumping function of the heart usually returns to normal, there are some long-term cardiac complications including a reduction in global longitudinal strain, and patients have similar long-term outcomes as those with MI.
“It is believed that these cardiac changes may be triggered by changes in the brain caused by emotional stress, so we wanted to look at this more closely,” Dr. Khan said.
There have been a couple of studies published previously looking at brain changes in Takotsubo syndrome, but they haven’t reported patients in the acute stage of the condition and they haven’t compared the patients to controls, he noted.
For the current study, the researchers looked at brain scans for 25 acute Takotsubo patients and in 25 controls matched for age, gender, comorbidities, and medications. All the patients and controls were examined using the same MRI scanner in the same hospital.
“This is the largest structural and functional brain study of acute Takotsubo syndrome patients compared with matched control subjects,” Dr. Khan said.
The researchers looked at many different factors including brain volume in different regions, cortical thickness, small-vessel disease, and functional and structural connectivity to try and obtain a complete holistic view of the brain.
Key findings were that patients with Takotsubo syndrome had smaller brain volumes, compared with matched controls, driven by a reduction in brain surface area. In contrast, the insula and thalamus regions were larger.
“A reduction in brain volume could be caused by inflammation; this is often seen in depression,” Dr. Khan commented.
The researchers also found that certain areas of the brain had a reduction in functional connectivity, particularly the thalamus – the central autonomic area of the brain, which regulates the autonomic nervous system – and also the insula region, which is also involved in the autonomic regulation of the heart.
They suggest that there may be a loss of parasympathetic inhibition in Takotsubo syndrome, which would fit the theory that Takotsubo brings with it a surge of catecholamines, which could injure the heart.
Reduced functional connectivity was also seen in parts of the basal ganglia, abnormalities of which have been associated with an increased risk of both arrhythmias, and in the amygdala, similar to patients with a tendency to catastrophize events.
The other observation was that there appeared to be an increase in structural connectivity in certain areas of the brain.
“Structural pathways seem to be increased but functional connectivity was reduced, so while physical pathways are enhanced, they don’t seem to be doing anything,” Dr. Khan said. “We don’t know why this occurs, or if this has happened over time and made the brain and heart more vulnerable in some way.”
One possibility is that ,under a significant emotional stress, the brain may divert function from some areas to others to be able to cope, and that this results in reduced functioning in areas of the brain responsible for regulating the heart, Dr. Khan suggested.
“We believe this study confirms that the brain is involved in Takotsubo syndrome, and we have identified markers in the brain that may be contributing to the condition,” he said.
The researchers are planning to further study these markers and whether it might be possible to modulate these changes with various interventions such as exercise or mindfulness.
“We believe there is some interface between the brain changes and the impact on the heart. We don’t think it is just the release of catecholamines that causes damage to the heart. We think there is something else happening as well,” Dr. Khan commented.
It is also possible that the hearts of patients with Takotsubo syndrome are predisposed in some way and more vulnerable to this condition occurring.
“It will be important to obtain a greater understanding of the triggers and identify people who may be vulnerable,” Dr. Khan noted. “Around 10% of individuals who experience Takotsubo syndrome will have a recurrence, so we need to try and develop preventative strategies to reduce this.”
He suggested that possible preventive or therapeutic approaches may involve interventions such as exercise or mindfulness.
This work was supported by National Health Service Grampian Endowment. The authors report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM JACC: HEART FAILURE
Simulation-based training effective for transesophageal echo
Simulation-based teaching of transesophageal echocardiography (TEE) improved cardiology fellows’ knowledge, skills, and comfort with the procedure, compared with traditional training, a new study shows.
“TEE learning may be hampered by the lack of availability of teachers and equipment and by the need for esophageal intubation, which is semi-invasive,” Augustin Coisne, MD, PhD, of the Cardiovascular Research Foundation in New York, said in an interview. “In this setting, simulation emerges as a key educational tool, but we were lacking evidence supporting simulation-based educational programs.”
Fellows in the simulation group achieved higher theoretical test scores and practical test scores after the training than did those in the traditional group.
Furthermore, Dr. Coisne said, “the results of the subgroup analyses were surprising and unexpected. The effect of the simulation-based training was greater among fellows at the beginning of fellowship – i.e., 2 years or less of training – in both theoretical and practical tests and in women [versus men] for the theoretical test.”
Their results, from the randomized SIMULATOR study, were published online in JAMA Cardiology.
More ready, more confident
The researchers randomly assigned 324 cardiology fellows (mean age, 26.4 years; about 30% women) inexperienced in TEE from 42 French university centers to TEE training with or without simulation support. Both groups participated in traditional didactic training using e-learning with an online course that is compulsory for all cardiology fellows in France.
The simulation group also participated in two 2-hour teaching sessions using a TEE simulator.
Each fellow completed a theoretical and a practical test prior to training to assess their baseline TEE level and again 3 months after the end of the training program. A TEE simulator (U/S Mentor Simulator; 3D Systems Simbionix) was used for all tests, and 24 certified echocardiography teachers served as both trainers and raters.
The theoretical tests included 20 online video-based questions to evaluate recognition of standard TEE views, normal anatomy, and some pathological cases. Fellows had 90 seconds to choose the best answer for each question from five multiple-choice options.
For the practical tests, fellows had 3 minutes to familiarize themselves with the handling of the simulator, without specific training and before the probe introduction.
They were asked to show 10 basic views on the simulator and had a maximum of 1 minute for each view.
The coprimary outcomes were the scores in the final theoretical and practical tests. TEE duration and the fellows’ self-assessment of their proficiency were also evaluated.
At baseline, the theoretical and practical test scores were similar between the groups (33.0 for the simulator group vs. 32.5 for the traditional group, and 44.2 vs. 46.1, respectively).
After training, the fellows in the simulation group had higher theoretical and practical test scores than those in the traditional group (47.2% vs. 38.3% and 74.5% vs. 59.0%, respectively).
Score changes were consistently higher when the pretraining scores were lower, an association that was stronger in the simulation group.
Dr. Coisne noted that subgroup analyses showed that the effectiveness of the simulation training was greater when performed at the beginning of the fellowship. On the theoretical test, the point increase was 11.9 for the simulation group versus 4.25 points for the traditional training group; for the practical test, the increases were 24.0 points versus 10.1 points.
After training, it took significantly less time for the simulation group to complete a TEE than it did the traditional group (8.3 vs. 9.4 minutes).
Furthermore, simulation group fellows reported that they felt more ready (mean score, 3.0 vs. 1.7) and more confident (mean score, 3.3 vs. 2.4) about performing a TEE alone after training.
“The simulation approach is definitively scalable to every institution,” Dr. Coisne said. “However, a medico-economic analysis should be interesting because the cost of the simulator and its maintenance might be a limitation to spread simulation-based teaching. The possibility for smaller hospitals to pool their financial input to share a TEE simulator could be considered to increase its cost-effectiveness.”
Real-world outcomes required
Commenting on the study, S. Justin Szawlewicz, MD, chair of cardiovascular medicine at Deborah Heart and Lung Center in Brown Mills, N.J., pointed out that the authors indicated that the number of TEEs performed by the trainees was not collected.
“This would be useful information to determine if those who received simulator training sought out and performed more TEEs, and also to determine if cardiology trainees in France perform a similar number of TEEs as cardiology trainees in the United States.”
In addition, he said, “the 4 hours of simulator training in TEE is extra education and experience that the standard trainees didn’t get. Would 4 extra hours of standard training didactics also improve trainees’ scores?”
Noting that the fellows’ ability to perform TEE in real patients was not assessed, Dr. Szawlewicz said, “a study could be designed that evaluated TEE images from real patients to see if trainees receiving simulator training performed better, more comprehensive and efficient TEEs than standard training.”
Nevertheless, he concluded, “Four hours of simulator training appears to improve TEE knowledge and skills. This is something we would consider at our institution.”
Like Dr. Szawlewicz, Michael Spooner, MD, MBA, of Mercy One North Iowa Heart Center in Mason City, and Kathryn Bertlacher, MD, of the University of Pittsburgh Medical Center, noted in a related editorial, “data are not provided about change in the learner’s behavior or performance on an actual TEE after the course, nor are there data about clinical outcomes such as patient safety or completeness of subsequent TEEs.
“This limitation, which is a limitation of most of the existing TEE simulation literature, is a high bar to cross,” they concluded. “Reaching this bar will require studies such as this to provide foundational understanding.”
Twin-Medical provided the TEE simulators. No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
Simulation-based teaching of transesophageal echocardiography (TEE) improved cardiology fellows’ knowledge, skills, and comfort with the procedure, compared with traditional training, a new study shows.
“TEE learning may be hampered by the lack of availability of teachers and equipment and by the need for esophageal intubation, which is semi-invasive,” Augustin Coisne, MD, PhD, of the Cardiovascular Research Foundation in New York, said in an interview. “In this setting, simulation emerges as a key educational tool, but we were lacking evidence supporting simulation-based educational programs.”
Fellows in the simulation group achieved higher theoretical test scores and practical test scores after the training than did those in the traditional group.
Furthermore, Dr. Coisne said, “the results of the subgroup analyses were surprising and unexpected. The effect of the simulation-based training was greater among fellows at the beginning of fellowship – i.e., 2 years or less of training – in both theoretical and practical tests and in women [versus men] for the theoretical test.”
Their results, from the randomized SIMULATOR study, were published online in JAMA Cardiology.
More ready, more confident
The researchers randomly assigned 324 cardiology fellows (mean age, 26.4 years; about 30% women) inexperienced in TEE from 42 French university centers to TEE training with or without simulation support. Both groups participated in traditional didactic training using e-learning with an online course that is compulsory for all cardiology fellows in France.
The simulation group also participated in two 2-hour teaching sessions using a TEE simulator.
Each fellow completed a theoretical and a practical test prior to training to assess their baseline TEE level and again 3 months after the end of the training program. A TEE simulator (U/S Mentor Simulator; 3D Systems Simbionix) was used for all tests, and 24 certified echocardiography teachers served as both trainers and raters.
The theoretical tests included 20 online video-based questions to evaluate recognition of standard TEE views, normal anatomy, and some pathological cases. Fellows had 90 seconds to choose the best answer for each question from five multiple-choice options.
For the practical tests, fellows had 3 minutes to familiarize themselves with the handling of the simulator, without specific training and before the probe introduction.
They were asked to show 10 basic views on the simulator and had a maximum of 1 minute for each view.
The coprimary outcomes were the scores in the final theoretical and practical tests. TEE duration and the fellows’ self-assessment of their proficiency were also evaluated.
At baseline, the theoretical and practical test scores were similar between the groups (33.0 for the simulator group vs. 32.5 for the traditional group, and 44.2 vs. 46.1, respectively).
After training, the fellows in the simulation group had higher theoretical and practical test scores than those in the traditional group (47.2% vs. 38.3% and 74.5% vs. 59.0%, respectively).
Score changes were consistently higher when the pretraining scores were lower, an association that was stronger in the simulation group.
Dr. Coisne noted that subgroup analyses showed that the effectiveness of the simulation training was greater when performed at the beginning of the fellowship. On the theoretical test, the point increase was 11.9 for the simulation group versus 4.25 points for the traditional training group; for the practical test, the increases were 24.0 points versus 10.1 points.
After training, it took significantly less time for the simulation group to complete a TEE than it did the traditional group (8.3 vs. 9.4 minutes).
Furthermore, simulation group fellows reported that they felt more ready (mean score, 3.0 vs. 1.7) and more confident (mean score, 3.3 vs. 2.4) about performing a TEE alone after training.
“The simulation approach is definitively scalable to every institution,” Dr. Coisne said. “However, a medico-economic analysis should be interesting because the cost of the simulator and its maintenance might be a limitation to spread simulation-based teaching. The possibility for smaller hospitals to pool their financial input to share a TEE simulator could be considered to increase its cost-effectiveness.”
Real-world outcomes required
Commenting on the study, S. Justin Szawlewicz, MD, chair of cardiovascular medicine at Deborah Heart and Lung Center in Brown Mills, N.J., pointed out that the authors indicated that the number of TEEs performed by the trainees was not collected.
“This would be useful information to determine if those who received simulator training sought out and performed more TEEs, and also to determine if cardiology trainees in France perform a similar number of TEEs as cardiology trainees in the United States.”
In addition, he said, “the 4 hours of simulator training in TEE is extra education and experience that the standard trainees didn’t get. Would 4 extra hours of standard training didactics also improve trainees’ scores?”
Noting that the fellows’ ability to perform TEE in real patients was not assessed, Dr. Szawlewicz said, “a study could be designed that evaluated TEE images from real patients to see if trainees receiving simulator training performed better, more comprehensive and efficient TEEs than standard training.”
Nevertheless, he concluded, “Four hours of simulator training appears to improve TEE knowledge and skills. This is something we would consider at our institution.”
Like Dr. Szawlewicz, Michael Spooner, MD, MBA, of Mercy One North Iowa Heart Center in Mason City, and Kathryn Bertlacher, MD, of the University of Pittsburgh Medical Center, noted in a related editorial, “data are not provided about change in the learner’s behavior or performance on an actual TEE after the course, nor are there data about clinical outcomes such as patient safety or completeness of subsequent TEEs.
“This limitation, which is a limitation of most of the existing TEE simulation literature, is a high bar to cross,” they concluded. “Reaching this bar will require studies such as this to provide foundational understanding.”
Twin-Medical provided the TEE simulators. No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
Simulation-based teaching of transesophageal echocardiography (TEE) improved cardiology fellows’ knowledge, skills, and comfort with the procedure, compared with traditional training, a new study shows.
“TEE learning may be hampered by the lack of availability of teachers and equipment and by the need for esophageal intubation, which is semi-invasive,” Augustin Coisne, MD, PhD, of the Cardiovascular Research Foundation in New York, said in an interview. “In this setting, simulation emerges as a key educational tool, but we were lacking evidence supporting simulation-based educational programs.”
Fellows in the simulation group achieved higher theoretical test scores and practical test scores after the training than did those in the traditional group.
Furthermore, Dr. Coisne said, “the results of the subgroup analyses were surprising and unexpected. The effect of the simulation-based training was greater among fellows at the beginning of fellowship – i.e., 2 years or less of training – in both theoretical and practical tests and in women [versus men] for the theoretical test.”
Their results, from the randomized SIMULATOR study, were published online in JAMA Cardiology.
More ready, more confident
The researchers randomly assigned 324 cardiology fellows (mean age, 26.4 years; about 30% women) inexperienced in TEE from 42 French university centers to TEE training with or without simulation support. Both groups participated in traditional didactic training using e-learning with an online course that is compulsory for all cardiology fellows in France.
The simulation group also participated in two 2-hour teaching sessions using a TEE simulator.
Each fellow completed a theoretical and a practical test prior to training to assess their baseline TEE level and again 3 months after the end of the training program. A TEE simulator (U/S Mentor Simulator; 3D Systems Simbionix) was used for all tests, and 24 certified echocardiography teachers served as both trainers and raters.
The theoretical tests included 20 online video-based questions to evaluate recognition of standard TEE views, normal anatomy, and some pathological cases. Fellows had 90 seconds to choose the best answer for each question from five multiple-choice options.
For the practical tests, fellows had 3 minutes to familiarize themselves with the handling of the simulator, without specific training and before the probe introduction.
They were asked to show 10 basic views on the simulator and had a maximum of 1 minute for each view.
The coprimary outcomes were the scores in the final theoretical and practical tests. TEE duration and the fellows’ self-assessment of their proficiency were also evaluated.
At baseline, the theoretical and practical test scores were similar between the groups (33.0 for the simulator group vs. 32.5 for the traditional group, and 44.2 vs. 46.1, respectively).
After training, the fellows in the simulation group had higher theoretical and practical test scores than those in the traditional group (47.2% vs. 38.3% and 74.5% vs. 59.0%, respectively).
Score changes were consistently higher when the pretraining scores were lower, an association that was stronger in the simulation group.
Dr. Coisne noted that subgroup analyses showed that the effectiveness of the simulation training was greater when performed at the beginning of the fellowship. On the theoretical test, the point increase was 11.9 for the simulation group versus 4.25 points for the traditional training group; for the practical test, the increases were 24.0 points versus 10.1 points.
After training, it took significantly less time for the simulation group to complete a TEE than it did the traditional group (8.3 vs. 9.4 minutes).
Furthermore, simulation group fellows reported that they felt more ready (mean score, 3.0 vs. 1.7) and more confident (mean score, 3.3 vs. 2.4) about performing a TEE alone after training.
“The simulation approach is definitively scalable to every institution,” Dr. Coisne said. “However, a medico-economic analysis should be interesting because the cost of the simulator and its maintenance might be a limitation to spread simulation-based teaching. The possibility for smaller hospitals to pool their financial input to share a TEE simulator could be considered to increase its cost-effectiveness.”
Real-world outcomes required
Commenting on the study, S. Justin Szawlewicz, MD, chair of cardiovascular medicine at Deborah Heart and Lung Center in Brown Mills, N.J., pointed out that the authors indicated that the number of TEEs performed by the trainees was not collected.
“This would be useful information to determine if those who received simulator training sought out and performed more TEEs, and also to determine if cardiology trainees in France perform a similar number of TEEs as cardiology trainees in the United States.”
In addition, he said, “the 4 hours of simulator training in TEE is extra education and experience that the standard trainees didn’t get. Would 4 extra hours of standard training didactics also improve trainees’ scores?”
Noting that the fellows’ ability to perform TEE in real patients was not assessed, Dr. Szawlewicz said, “a study could be designed that evaluated TEE images from real patients to see if trainees receiving simulator training performed better, more comprehensive and efficient TEEs than standard training.”
Nevertheless, he concluded, “Four hours of simulator training appears to improve TEE knowledge and skills. This is something we would consider at our institution.”
Like Dr. Szawlewicz, Michael Spooner, MD, MBA, of Mercy One North Iowa Heart Center in Mason City, and Kathryn Bertlacher, MD, of the University of Pittsburgh Medical Center, noted in a related editorial, “data are not provided about change in the learner’s behavior or performance on an actual TEE after the course, nor are there data about clinical outcomes such as patient safety or completeness of subsequent TEEs.
“This limitation, which is a limitation of most of the existing TEE simulation literature, is a high bar to cross,” they concluded. “Reaching this bar will require studies such as this to provide foundational understanding.”
Twin-Medical provided the TEE simulators. No relevant conflicts of interest were disclosed.
A version of this article first appeared on Medscape.com.
FROM JAMA CARDIOLOGY
Evolocumab’s LDL lowering surpassed inclisiran’s in ORION-3
Patients who received an injection of inclisiran (Leqvio), a small interfering RNA (siRNA) agent, every 6 months for as long as 4 years safely maintained about a 45% reduction from baseline in their level of low-density lipoprotein cholesterol (LDL-C) in an open-label extension study with 382 patients.
In addition to providing the longest reported treatment experience with inclisiran, which received Food and Drug Administration marketing approval a little over a year ago, the results also suggest with the most definitive evidence to date that inclisiran is less effective for lowering LDL-C, compared with a class of medications that reduce LDL-C by a related but distinct mechanism: antibodies that directly inhibit activity of the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, a drug class that includes alirocumab (Praluent) and evolocumab (Repatha). Inclisiran cuts PCSK9 activity by blocking this enzyme’s gene transcription in liver cells thereby interfering with PCSK9 production.
Results from this study, the ORION-3 trial, provide “the first prospective long-term evaluation of the durability and safety of an siRNA-based therapy to provide clinically meaningful reductions in LDL cholesterol with a convenient dosing schedule,” wrote Kausik K. Ray, MD, and coauthors in a report in The Lancet Diabetes & Endocrinology.
The findings “provide assurance that siRNA-based therapies are safe and have the potential to provide a convenient approach to managing” LDL-C, wrote Dr. Ray, a cardiologist and professor of public health at Imperial College London, and his associates.
Evolocumab surpasses inclisiran in crossover cohort
The new data from ORION-3 study included findings from 92 patients first treated with evolocumab injections every 2 weeks for a year, an intervention that lowered their LDL-C levels by an average of about 60%, compared with their pretreatment level. ORION-3’s study design then crossed these patients to treatment with injections of inclisiran twice a year during 3 further years of follow-up, during which their average LDL levels reset to a roughly 45% drop from baseline, a potentially clinically meaningful difference, commented Robert S. Rosenson, MD, a lipid management specialist who was not involved in the ORION-3 study.
“This is the first evidence that compared the two classes” within a single study, thereby avoiding a problematic cross-study comparison. “That’s why the data are important. They underscore that the monoclonal antibodies are more effective for lowering LDL-C,” compared with inclisiran, said Dr. Rosenson, professor and director of cardiometabolic disorders at the Icahn School of Medicine at Mount Sinai in New York.
The findings “confirm in a trial that the PCSK9 monoclonal antibodies are indeed more potent,” he said in an interview.
But Dr. Rosenson acknowledged that, while this analysis used data on patients treated with evolocumab and then switched to inclisiran collected prospectively in a single study, it has the limitation of involving a comparison that was not prespecified. The primary goal of the evolocumab-to-inclisiran switch included in ORION-3 was to assess the ease, safety, and efficacy of a switch to inclisiran from treatment with a PCSK9 antibody and was not intended to compare the two drug classes.
The roughly 15% absolute difference in LDL-C lowering between the two tested drug classes can have substantial clinical implications for patients who start treatment with highly elevated levels of LDL-C, more than 190 mg/dL, because they have heterozygous familial hypercholesterolemia, are unable to take a statin because of intolerance, or both. The difference in LDL-C reduction with an antibody or with inclisiran could mean the difference between whether or not a patient like this achieves their LDL-C goal level, Dr. Rosenson explained.
Inclisiran’s upside
On the other hand, inclisiran has a couple of important advantages. First, its mechanism of action means that effective treatment involves one injection every 6 months following a patient’s first two injections at onset and after 90 days, with all injections administered in a clinician’s office. In contrast, both of the monoclonal antibodies require injections every other week, a schedule that depends on patient self-injections using prefilled syringes obtained from a pharmacy.
Twice-a-year dosing by a clinician can be a major attraction because it helps ensure treatment compliance, aids patients with physical or psychological limitations to self-injection, reduces the pill burden for patients who require multiple medications, and facilitates frequent travelers who would otherwise need to carry syringes with them on trips, Dr. Rosenson noted.
The second big advantage of office-based administration of inclisiran for U.S. Medicare patients is that the treatment is billed under a patient’s part B coverage, usually resulting in easier coverage and a significantly lower patient co-pay, compared with Medicare’s coverage for a pharmacy-dispensed agent, which is covered under Medicare part D. “Part B coverage is financially more doable” for most Medicare patients, said Dr. Rosenson.
The administration schedule for inclisiran as well as its superior Medicare coverage makes the agent “transformative” for LDL-C lowering in patients for whom treatment delivery, frequency, and payment are issues, he said.
Inclisiran uptake modest after FDA approval
Despite these pluses, uptake of inclisiran has been modest since it received U.S. marketing approval in December 2021. In its most recent quarterly financial filing, in October 2022, Novartis reported total worldwide income from inclisiran (Leqvio) of $70 million during the first 9 months of 2022, although a Novartis spokesperson noted that the company has seen “positive trends in uptake” over the course of 2022. Inclisiran is labeled as an “adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional lowering” of LDL-C.
During 2022, inclisiran uptake lagged because of the usual problems that slow the introduction of new drugs and new drug classes, especially ones that require dosing by a clinician. Months were spent waiting for billing codes to roll out, for clinical staffs to incorporate inclisiran injections into their routines, and for commercial insurers to get up to speed on their coverage, Dr. Rosenson said.
Also, a key step for widespread uptake of a new medication for improving cardiovascular disease outcomes – results from phase 3 studies that document safety and efficacy for these outcomes – remains several years off. The ORION-4 trial and the VICTORION-2P trial, each assessing the impact of inclisiran on cardiovascular disease events in roughly 15,000 people, will need about another 3-4 years before their results become available.
Professional medical societies that issue cardiovascular-disease management guidelines “prefer agents with proven benefits in phase 3 trials,” Dr. Rosenson noted.
Hence, the most recent update to U.S. LDL-C–management guidelines, released in the second half of 2022 by the American College of Cardiology as an Expert Consensus Decision Pathway, said this about the current role for inclisiran: “At the present time, a PCSK9 monoclonal antibody is preferred as the initial PCSK9 inhibitor of choice in view of its demonstrated safety, efficacy, and benefits for cardiovascular outcomes in the FOURIER [for evolocumab] and ODYSSEY Outcomes [for alirocumab] trials. The ORION-4 and VICTORION-2P cardiovascular outcomes trials with inclisiran are currently underway, and their completion is anticipated in 2026 and 2027, respectively. In view of the twice-yearly dosing regimen, inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 monoclonal antibodies. Patients with adverse effects from both PSCK9 monoclonal antibodies or those who may be unable to self-inject may also be considered for therapy with inclisiran.”
ORION-3 extended the ORION-1 trial
The ORION-1 study was a phase 2 placebo-controlled, dose-ranging safety and efficacy assessment of inclisiran that gave patients two injections of the drug, at day zero and 90 days, and followed them for an additional 120 days (210 days total follow-up duration), and in some cases for as long as 360 days total. Of the 370 patients who received inclisiran in ORION-1, 290 agreed to continue inclisiran in the open-label extension, ORION-3. ORION-1 also included 127 patients randomized to initial placebo treatment, and 92 of these patients agreed to continue in ORION-3 and became the patients initially treated with evolocumab injections every other week for 1 year followed by initiation of an inclisiran regimen.
The primary outcome of ORION-3 was the change in LDL-C from baseline (the ORION-1 baseline) after 210 days of receiving inclisiran in ORION-3 (or a total of roughly 570 days after the start of ORION-1). The primary endpoint showed that, at day 210 of ORION-3 the average reduction in LDL-C from the original baseline level was 47.5%.
But a “more important” outcome, said Dr. Ray when he first reported the ORION-3 results during the American Heart Association scientific sessions in Chicago in November 2022, was that, overall, during 4 years on inclisiran this cohort showed an average cut in LDL-C from baseline of about 45% that consistently remained at this level throughout the 4 years of treatment.
“This provides us with an idea of what happens with chronic inclisiran dosing,” Dr. Ray explained. “There was no loss of biological efficacy, and we achieved these clinically meaningful, time-averaged reductions with a good safety profile. The great thing is that when patients get their injections [every 6 months] you see a consistent LDL-C reduction. A twice-annual injection is an opportunity to redesign” the way patients receive preventive cardiology care and treatment to lower LDL-C, Dr Ray said.
ORION-1 was sponsored by The Medicines Company. ORION-3 was sponsored by Novartis (which acquired The Medicines Company). Dr. Ray has received consulting fees, personal fees, and research grants from Novartis, as well as consulting fees and research grants from Amgen, the company that markets evolocumab (Repatha), and research grants from Regeneron, the company that markets alirocumab (Praluent). He has also received consulting fee, personal fees, and research grants from numerous other companies. Dr. Rosenson has been a consultant to and has received research funding from Amgen, Novartis, and Regeneron, and he has received speaking fees from Amgen and Regeneron, and has ties to several other pharmaceutical companies.
This article was updated on 1/26/2023.
Patients who received an injection of inclisiran (Leqvio), a small interfering RNA (siRNA) agent, every 6 months for as long as 4 years safely maintained about a 45% reduction from baseline in their level of low-density lipoprotein cholesterol (LDL-C) in an open-label extension study with 382 patients.
In addition to providing the longest reported treatment experience with inclisiran, which received Food and Drug Administration marketing approval a little over a year ago, the results also suggest with the most definitive evidence to date that inclisiran is less effective for lowering LDL-C, compared with a class of medications that reduce LDL-C by a related but distinct mechanism: antibodies that directly inhibit activity of the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, a drug class that includes alirocumab (Praluent) and evolocumab (Repatha). Inclisiran cuts PCSK9 activity by blocking this enzyme’s gene transcription in liver cells thereby interfering with PCSK9 production.
Results from this study, the ORION-3 trial, provide “the first prospective long-term evaluation of the durability and safety of an siRNA-based therapy to provide clinically meaningful reductions in LDL cholesterol with a convenient dosing schedule,” wrote Kausik K. Ray, MD, and coauthors in a report in The Lancet Diabetes & Endocrinology.
The findings “provide assurance that siRNA-based therapies are safe and have the potential to provide a convenient approach to managing” LDL-C, wrote Dr. Ray, a cardiologist and professor of public health at Imperial College London, and his associates.
Evolocumab surpasses inclisiran in crossover cohort
The new data from ORION-3 study included findings from 92 patients first treated with evolocumab injections every 2 weeks for a year, an intervention that lowered their LDL-C levels by an average of about 60%, compared with their pretreatment level. ORION-3’s study design then crossed these patients to treatment with injections of inclisiran twice a year during 3 further years of follow-up, during which their average LDL levels reset to a roughly 45% drop from baseline, a potentially clinically meaningful difference, commented Robert S. Rosenson, MD, a lipid management specialist who was not involved in the ORION-3 study.
“This is the first evidence that compared the two classes” within a single study, thereby avoiding a problematic cross-study comparison. “That’s why the data are important. They underscore that the monoclonal antibodies are more effective for lowering LDL-C,” compared with inclisiran, said Dr. Rosenson, professor and director of cardiometabolic disorders at the Icahn School of Medicine at Mount Sinai in New York.
The findings “confirm in a trial that the PCSK9 monoclonal antibodies are indeed more potent,” he said in an interview.
But Dr. Rosenson acknowledged that, while this analysis used data on patients treated with evolocumab and then switched to inclisiran collected prospectively in a single study, it has the limitation of involving a comparison that was not prespecified. The primary goal of the evolocumab-to-inclisiran switch included in ORION-3 was to assess the ease, safety, and efficacy of a switch to inclisiran from treatment with a PCSK9 antibody and was not intended to compare the two drug classes.
The roughly 15% absolute difference in LDL-C lowering between the two tested drug classes can have substantial clinical implications for patients who start treatment with highly elevated levels of LDL-C, more than 190 mg/dL, because they have heterozygous familial hypercholesterolemia, are unable to take a statin because of intolerance, or both. The difference in LDL-C reduction with an antibody or with inclisiran could mean the difference between whether or not a patient like this achieves their LDL-C goal level, Dr. Rosenson explained.
Inclisiran’s upside
On the other hand, inclisiran has a couple of important advantages. First, its mechanism of action means that effective treatment involves one injection every 6 months following a patient’s first two injections at onset and after 90 days, with all injections administered in a clinician’s office. In contrast, both of the monoclonal antibodies require injections every other week, a schedule that depends on patient self-injections using prefilled syringes obtained from a pharmacy.
Twice-a-year dosing by a clinician can be a major attraction because it helps ensure treatment compliance, aids patients with physical or psychological limitations to self-injection, reduces the pill burden for patients who require multiple medications, and facilitates frequent travelers who would otherwise need to carry syringes with them on trips, Dr. Rosenson noted.
The second big advantage of office-based administration of inclisiran for U.S. Medicare patients is that the treatment is billed under a patient’s part B coverage, usually resulting in easier coverage and a significantly lower patient co-pay, compared with Medicare’s coverage for a pharmacy-dispensed agent, which is covered under Medicare part D. “Part B coverage is financially more doable” for most Medicare patients, said Dr. Rosenson.
The administration schedule for inclisiran as well as its superior Medicare coverage makes the agent “transformative” for LDL-C lowering in patients for whom treatment delivery, frequency, and payment are issues, he said.
Inclisiran uptake modest after FDA approval
Despite these pluses, uptake of inclisiran has been modest since it received U.S. marketing approval in December 2021. In its most recent quarterly financial filing, in October 2022, Novartis reported total worldwide income from inclisiran (Leqvio) of $70 million during the first 9 months of 2022, although a Novartis spokesperson noted that the company has seen “positive trends in uptake” over the course of 2022. Inclisiran is labeled as an “adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional lowering” of LDL-C.
During 2022, inclisiran uptake lagged because of the usual problems that slow the introduction of new drugs and new drug classes, especially ones that require dosing by a clinician. Months were spent waiting for billing codes to roll out, for clinical staffs to incorporate inclisiran injections into their routines, and for commercial insurers to get up to speed on their coverage, Dr. Rosenson said.
Also, a key step for widespread uptake of a new medication for improving cardiovascular disease outcomes – results from phase 3 studies that document safety and efficacy for these outcomes – remains several years off. The ORION-4 trial and the VICTORION-2P trial, each assessing the impact of inclisiran on cardiovascular disease events in roughly 15,000 people, will need about another 3-4 years before their results become available.
Professional medical societies that issue cardiovascular-disease management guidelines “prefer agents with proven benefits in phase 3 trials,” Dr. Rosenson noted.
Hence, the most recent update to U.S. LDL-C–management guidelines, released in the second half of 2022 by the American College of Cardiology as an Expert Consensus Decision Pathway, said this about the current role for inclisiran: “At the present time, a PCSK9 monoclonal antibody is preferred as the initial PCSK9 inhibitor of choice in view of its demonstrated safety, efficacy, and benefits for cardiovascular outcomes in the FOURIER [for evolocumab] and ODYSSEY Outcomes [for alirocumab] trials. The ORION-4 and VICTORION-2P cardiovascular outcomes trials with inclisiran are currently underway, and their completion is anticipated in 2026 and 2027, respectively. In view of the twice-yearly dosing regimen, inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 monoclonal antibodies. Patients with adverse effects from both PSCK9 monoclonal antibodies or those who may be unable to self-inject may also be considered for therapy with inclisiran.”
ORION-3 extended the ORION-1 trial
The ORION-1 study was a phase 2 placebo-controlled, dose-ranging safety and efficacy assessment of inclisiran that gave patients two injections of the drug, at day zero and 90 days, and followed them for an additional 120 days (210 days total follow-up duration), and in some cases for as long as 360 days total. Of the 370 patients who received inclisiran in ORION-1, 290 agreed to continue inclisiran in the open-label extension, ORION-3. ORION-1 also included 127 patients randomized to initial placebo treatment, and 92 of these patients agreed to continue in ORION-3 and became the patients initially treated with evolocumab injections every other week for 1 year followed by initiation of an inclisiran regimen.
The primary outcome of ORION-3 was the change in LDL-C from baseline (the ORION-1 baseline) after 210 days of receiving inclisiran in ORION-3 (or a total of roughly 570 days after the start of ORION-1). The primary endpoint showed that, at day 210 of ORION-3 the average reduction in LDL-C from the original baseline level was 47.5%.
But a “more important” outcome, said Dr. Ray when he first reported the ORION-3 results during the American Heart Association scientific sessions in Chicago in November 2022, was that, overall, during 4 years on inclisiran this cohort showed an average cut in LDL-C from baseline of about 45% that consistently remained at this level throughout the 4 years of treatment.
“This provides us with an idea of what happens with chronic inclisiran dosing,” Dr. Ray explained. “There was no loss of biological efficacy, and we achieved these clinically meaningful, time-averaged reductions with a good safety profile. The great thing is that when patients get their injections [every 6 months] you see a consistent LDL-C reduction. A twice-annual injection is an opportunity to redesign” the way patients receive preventive cardiology care and treatment to lower LDL-C, Dr Ray said.
ORION-1 was sponsored by The Medicines Company. ORION-3 was sponsored by Novartis (which acquired The Medicines Company). Dr. Ray has received consulting fees, personal fees, and research grants from Novartis, as well as consulting fees and research grants from Amgen, the company that markets evolocumab (Repatha), and research grants from Regeneron, the company that markets alirocumab (Praluent). He has also received consulting fee, personal fees, and research grants from numerous other companies. Dr. Rosenson has been a consultant to and has received research funding from Amgen, Novartis, and Regeneron, and he has received speaking fees from Amgen and Regeneron, and has ties to several other pharmaceutical companies.
This article was updated on 1/26/2023.
Patients who received an injection of inclisiran (Leqvio), a small interfering RNA (siRNA) agent, every 6 months for as long as 4 years safely maintained about a 45% reduction from baseline in their level of low-density lipoprotein cholesterol (LDL-C) in an open-label extension study with 382 patients.
In addition to providing the longest reported treatment experience with inclisiran, which received Food and Drug Administration marketing approval a little over a year ago, the results also suggest with the most definitive evidence to date that inclisiran is less effective for lowering LDL-C, compared with a class of medications that reduce LDL-C by a related but distinct mechanism: antibodies that directly inhibit activity of the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, a drug class that includes alirocumab (Praluent) and evolocumab (Repatha). Inclisiran cuts PCSK9 activity by blocking this enzyme’s gene transcription in liver cells thereby interfering with PCSK9 production.
Results from this study, the ORION-3 trial, provide “the first prospective long-term evaluation of the durability and safety of an siRNA-based therapy to provide clinically meaningful reductions in LDL cholesterol with a convenient dosing schedule,” wrote Kausik K. Ray, MD, and coauthors in a report in The Lancet Diabetes & Endocrinology.
The findings “provide assurance that siRNA-based therapies are safe and have the potential to provide a convenient approach to managing” LDL-C, wrote Dr. Ray, a cardiologist and professor of public health at Imperial College London, and his associates.
Evolocumab surpasses inclisiran in crossover cohort
The new data from ORION-3 study included findings from 92 patients first treated with evolocumab injections every 2 weeks for a year, an intervention that lowered their LDL-C levels by an average of about 60%, compared with their pretreatment level. ORION-3’s study design then crossed these patients to treatment with injections of inclisiran twice a year during 3 further years of follow-up, during which their average LDL levels reset to a roughly 45% drop from baseline, a potentially clinically meaningful difference, commented Robert S. Rosenson, MD, a lipid management specialist who was not involved in the ORION-3 study.
“This is the first evidence that compared the two classes” within a single study, thereby avoiding a problematic cross-study comparison. “That’s why the data are important. They underscore that the monoclonal antibodies are more effective for lowering LDL-C,” compared with inclisiran, said Dr. Rosenson, professor and director of cardiometabolic disorders at the Icahn School of Medicine at Mount Sinai in New York.
The findings “confirm in a trial that the PCSK9 monoclonal antibodies are indeed more potent,” he said in an interview.
But Dr. Rosenson acknowledged that, while this analysis used data on patients treated with evolocumab and then switched to inclisiran collected prospectively in a single study, it has the limitation of involving a comparison that was not prespecified. The primary goal of the evolocumab-to-inclisiran switch included in ORION-3 was to assess the ease, safety, and efficacy of a switch to inclisiran from treatment with a PCSK9 antibody and was not intended to compare the two drug classes.
The roughly 15% absolute difference in LDL-C lowering between the two tested drug classes can have substantial clinical implications for patients who start treatment with highly elevated levels of LDL-C, more than 190 mg/dL, because they have heterozygous familial hypercholesterolemia, are unable to take a statin because of intolerance, or both. The difference in LDL-C reduction with an antibody or with inclisiran could mean the difference between whether or not a patient like this achieves their LDL-C goal level, Dr. Rosenson explained.
Inclisiran’s upside
On the other hand, inclisiran has a couple of important advantages. First, its mechanism of action means that effective treatment involves one injection every 6 months following a patient’s first two injections at onset and after 90 days, with all injections administered in a clinician’s office. In contrast, both of the monoclonal antibodies require injections every other week, a schedule that depends on patient self-injections using prefilled syringes obtained from a pharmacy.
Twice-a-year dosing by a clinician can be a major attraction because it helps ensure treatment compliance, aids patients with physical or psychological limitations to self-injection, reduces the pill burden for patients who require multiple medications, and facilitates frequent travelers who would otherwise need to carry syringes with them on trips, Dr. Rosenson noted.
The second big advantage of office-based administration of inclisiran for U.S. Medicare patients is that the treatment is billed under a patient’s part B coverage, usually resulting in easier coverage and a significantly lower patient co-pay, compared with Medicare’s coverage for a pharmacy-dispensed agent, which is covered under Medicare part D. “Part B coverage is financially more doable” for most Medicare patients, said Dr. Rosenson.
The administration schedule for inclisiran as well as its superior Medicare coverage makes the agent “transformative” for LDL-C lowering in patients for whom treatment delivery, frequency, and payment are issues, he said.
Inclisiran uptake modest after FDA approval
Despite these pluses, uptake of inclisiran has been modest since it received U.S. marketing approval in December 2021. In its most recent quarterly financial filing, in October 2022, Novartis reported total worldwide income from inclisiran (Leqvio) of $70 million during the first 9 months of 2022, although a Novartis spokesperson noted that the company has seen “positive trends in uptake” over the course of 2022. Inclisiran is labeled as an “adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional lowering” of LDL-C.
During 2022, inclisiran uptake lagged because of the usual problems that slow the introduction of new drugs and new drug classes, especially ones that require dosing by a clinician. Months were spent waiting for billing codes to roll out, for clinical staffs to incorporate inclisiran injections into their routines, and for commercial insurers to get up to speed on their coverage, Dr. Rosenson said.
Also, a key step for widespread uptake of a new medication for improving cardiovascular disease outcomes – results from phase 3 studies that document safety and efficacy for these outcomes – remains several years off. The ORION-4 trial and the VICTORION-2P trial, each assessing the impact of inclisiran on cardiovascular disease events in roughly 15,000 people, will need about another 3-4 years before their results become available.
Professional medical societies that issue cardiovascular-disease management guidelines “prefer agents with proven benefits in phase 3 trials,” Dr. Rosenson noted.
Hence, the most recent update to U.S. LDL-C–management guidelines, released in the second half of 2022 by the American College of Cardiology as an Expert Consensus Decision Pathway, said this about the current role for inclisiran: “At the present time, a PCSK9 monoclonal antibody is preferred as the initial PCSK9 inhibitor of choice in view of its demonstrated safety, efficacy, and benefits for cardiovascular outcomes in the FOURIER [for evolocumab] and ODYSSEY Outcomes [for alirocumab] trials. The ORION-4 and VICTORION-2P cardiovascular outcomes trials with inclisiran are currently underway, and their completion is anticipated in 2026 and 2027, respectively. In view of the twice-yearly dosing regimen, inclisiran may be considered in patients with demonstrated poor adherence to PCSK9 monoclonal antibodies. Patients with adverse effects from both PSCK9 monoclonal antibodies or those who may be unable to self-inject may also be considered for therapy with inclisiran.”
ORION-3 extended the ORION-1 trial
The ORION-1 study was a phase 2 placebo-controlled, dose-ranging safety and efficacy assessment of inclisiran that gave patients two injections of the drug, at day zero and 90 days, and followed them for an additional 120 days (210 days total follow-up duration), and in some cases for as long as 360 days total. Of the 370 patients who received inclisiran in ORION-1, 290 agreed to continue inclisiran in the open-label extension, ORION-3. ORION-1 also included 127 patients randomized to initial placebo treatment, and 92 of these patients agreed to continue in ORION-3 and became the patients initially treated with evolocumab injections every other week for 1 year followed by initiation of an inclisiran regimen.
The primary outcome of ORION-3 was the change in LDL-C from baseline (the ORION-1 baseline) after 210 days of receiving inclisiran in ORION-3 (or a total of roughly 570 days after the start of ORION-1). The primary endpoint showed that, at day 210 of ORION-3 the average reduction in LDL-C from the original baseline level was 47.5%.
But a “more important” outcome, said Dr. Ray when he first reported the ORION-3 results during the American Heart Association scientific sessions in Chicago in November 2022, was that, overall, during 4 years on inclisiran this cohort showed an average cut in LDL-C from baseline of about 45% that consistently remained at this level throughout the 4 years of treatment.
“This provides us with an idea of what happens with chronic inclisiran dosing,” Dr. Ray explained. “There was no loss of biological efficacy, and we achieved these clinically meaningful, time-averaged reductions with a good safety profile. The great thing is that when patients get their injections [every 6 months] you see a consistent LDL-C reduction. A twice-annual injection is an opportunity to redesign” the way patients receive preventive cardiology care and treatment to lower LDL-C, Dr Ray said.
ORION-1 was sponsored by The Medicines Company. ORION-3 was sponsored by Novartis (which acquired The Medicines Company). Dr. Ray has received consulting fees, personal fees, and research grants from Novartis, as well as consulting fees and research grants from Amgen, the company that markets evolocumab (Repatha), and research grants from Regeneron, the company that markets alirocumab (Praluent). He has also received consulting fee, personal fees, and research grants from numerous other companies. Dr. Rosenson has been a consultant to and has received research funding from Amgen, Novartis, and Regeneron, and he has received speaking fees from Amgen and Regeneron, and has ties to several other pharmaceutical companies.
This article was updated on 1/26/2023.
FROM THE LANCET DIABETES & ENDOCRINOLOGY
Possible bivalent vaccine link to strokes in people over 65
who got the shot, the Centers for Disease Control and Prevention and the Food and Drug Administration said in a joint news release.
The release did not recommend people change their vaccine practices, saying the database finding probably did not represent a “true clinical risk.” The CDC said everybody, including people over 65, should stay up to date on their COVID vaccines, including the bivalent booster.
The news release said the Vaccine Safety Datalink (VSD), “a near real-time surveillance system,” raised a safety concern about the Pfizer/BioNTech booster.
“Rapid-response investigation of the signal in the VSD raised a question of whether people 65 and older who have received the Pfizer-BioNTech COVID-19 Vaccine, Bivalent were more likely to have an ischemic stroke in the 21 days following vaccination compared with days 22-44 following vaccination,” the news release said.
Ischemic strokes are blockages of blood to the brain, often caused by blood clots.
“Although the totality of the data currently suggests that it is very unlikely that the signal in VSD (Vaccine Safety Datalink) represents a true clinical risk, we believe it is important to share this information with the public, as we have in the past, when one of our safety monitoring systems detects a signal,” the release said.
No higher likelihood of strokes linked to the Pfizer bivalent vaccine had been found by Pfizer/BioNTech, the Department of Veterans Affairs, the Vaccine Adverse Event Reporting System maintained by the CDC and the FDA, or other agencies that monitor reactions of vaccines, the news release said. No safety issues about strokes have been identified with the Moderna bivalent vaccine.
CNN, citing a CDC official, reported that about 550,000 seniors who got Pfizer bivalent boosters were tracked by the VSD, and 130 of them had strokes within 3 weeks of getting the shot. None of those 130 people died, CNN said. The official spoke on the condition of anonymity because they weren’t authorized to share the data.
The issue will be discussed at the January meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee.
In a joint statement, Pfizer and BioNTech said: “Neither Pfizer and BioNTech nor the CDC or FDA have observed similar findings across numerous other monitoring systems in the U.S. and globally and there is no evidence to conclude that ischemic stroke is associated with the use of the companies’ COVID-19 vaccines.”
Bivalent boosters contain two strains of vaccine – one to protect against the original COVID-19 virus and another targeting Omicron subvariants.
A version of this article first appeared on WebMD.com.
who got the shot, the Centers for Disease Control and Prevention and the Food and Drug Administration said in a joint news release.
The release did not recommend people change their vaccine practices, saying the database finding probably did not represent a “true clinical risk.” The CDC said everybody, including people over 65, should stay up to date on their COVID vaccines, including the bivalent booster.
The news release said the Vaccine Safety Datalink (VSD), “a near real-time surveillance system,” raised a safety concern about the Pfizer/BioNTech booster.
“Rapid-response investigation of the signal in the VSD raised a question of whether people 65 and older who have received the Pfizer-BioNTech COVID-19 Vaccine, Bivalent were more likely to have an ischemic stroke in the 21 days following vaccination compared with days 22-44 following vaccination,” the news release said.
Ischemic strokes are blockages of blood to the brain, often caused by blood clots.
“Although the totality of the data currently suggests that it is very unlikely that the signal in VSD (Vaccine Safety Datalink) represents a true clinical risk, we believe it is important to share this information with the public, as we have in the past, when one of our safety monitoring systems detects a signal,” the release said.
No higher likelihood of strokes linked to the Pfizer bivalent vaccine had been found by Pfizer/BioNTech, the Department of Veterans Affairs, the Vaccine Adverse Event Reporting System maintained by the CDC and the FDA, or other agencies that monitor reactions of vaccines, the news release said. No safety issues about strokes have been identified with the Moderna bivalent vaccine.
CNN, citing a CDC official, reported that about 550,000 seniors who got Pfizer bivalent boosters were tracked by the VSD, and 130 of them had strokes within 3 weeks of getting the shot. None of those 130 people died, CNN said. The official spoke on the condition of anonymity because they weren’t authorized to share the data.
The issue will be discussed at the January meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee.
In a joint statement, Pfizer and BioNTech said: “Neither Pfizer and BioNTech nor the CDC or FDA have observed similar findings across numerous other monitoring systems in the U.S. and globally and there is no evidence to conclude that ischemic stroke is associated with the use of the companies’ COVID-19 vaccines.”
Bivalent boosters contain two strains of vaccine – one to protect against the original COVID-19 virus and another targeting Omicron subvariants.
A version of this article first appeared on WebMD.com.
who got the shot, the Centers for Disease Control and Prevention and the Food and Drug Administration said in a joint news release.
The release did not recommend people change their vaccine practices, saying the database finding probably did not represent a “true clinical risk.” The CDC said everybody, including people over 65, should stay up to date on their COVID vaccines, including the bivalent booster.
The news release said the Vaccine Safety Datalink (VSD), “a near real-time surveillance system,” raised a safety concern about the Pfizer/BioNTech booster.
“Rapid-response investigation of the signal in the VSD raised a question of whether people 65 and older who have received the Pfizer-BioNTech COVID-19 Vaccine, Bivalent were more likely to have an ischemic stroke in the 21 days following vaccination compared with days 22-44 following vaccination,” the news release said.
Ischemic strokes are blockages of blood to the brain, often caused by blood clots.
“Although the totality of the data currently suggests that it is very unlikely that the signal in VSD (Vaccine Safety Datalink) represents a true clinical risk, we believe it is important to share this information with the public, as we have in the past, when one of our safety monitoring systems detects a signal,” the release said.
No higher likelihood of strokes linked to the Pfizer bivalent vaccine had been found by Pfizer/BioNTech, the Department of Veterans Affairs, the Vaccine Adverse Event Reporting System maintained by the CDC and the FDA, or other agencies that monitor reactions of vaccines, the news release said. No safety issues about strokes have been identified with the Moderna bivalent vaccine.
CNN, citing a CDC official, reported that about 550,000 seniors who got Pfizer bivalent boosters were tracked by the VSD, and 130 of them had strokes within 3 weeks of getting the shot. None of those 130 people died, CNN said. The official spoke on the condition of anonymity because they weren’t authorized to share the data.
The issue will be discussed at the January meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee.
In a joint statement, Pfizer and BioNTech said: “Neither Pfizer and BioNTech nor the CDC or FDA have observed similar findings across numerous other monitoring systems in the U.S. and globally and there is no evidence to conclude that ischemic stroke is associated with the use of the companies’ COVID-19 vaccines.”
Bivalent boosters contain two strains of vaccine – one to protect against the original COVID-19 virus and another targeting Omicron subvariants.
A version of this article first appeared on WebMD.com.
Cardiac Adverse Events Following COVID-19 Vaccination in Patients With Prior Vaccine-Associated Myocarditis
Vaccinations have substantially reduced morbidity and mortality from many infectious diseases. Despite the clear value of vaccinations in public health, efforts to better understand adverse events (AEs) following immunization are important to sustain public trust and vaccine confidence. Noninfectious inflammation of the heart may manifest as myocarditis or pericarditis, or occasionally, with shared signs and symptoms of each, as myopericarditis. This is a rare AE following some immunizations. Vaccine-associated myocarditis, pericarditis, or myopericarditis (VAMP) has been most clearly associated with smallpox vaccines and mRNA COVID-19 vaccines.1-6 Although extremely rare, VAMP also has been associated with other vaccines.7,8 Limited information exists to guide shared clinical decision making on COVID-19 vaccination in persons with a history of VAMP. It is unknown whether individuals with a history of VAMP are at higher risk for developing a recurrence or experiencing a more severe outcome following COVID-19 vaccination.
Methods
As part of the collaborative public health mission with the Centers for Disease Control and Prevention (CDC) for enhanced vaccine AE surveillance, the Defense Health Agency Immunization Healthcare Division (IHD) maintains a clinical database of service members and beneficiaries referred for suspected AEs following immunizations. A review of all AEs following immunization cases in this database from January 1, 2003, through February 28, 2022, identified individuals meeting the following criteria: (a) VAMP prior to receipt of COVID-19 vaccine; (b) receipt of COVID-19 vaccine in 2021; and (c) medical documentation in available electronic health records sufficient to describe health status at least 30 days following COVID-19 vaccination.9 If medical entries suggested cardiac symptoms following a COVID-19 vaccine, additional information was sought to verify VAMP based on current published criteria.10,11 Both the initial VAMP cases and the suspected COVID-19 VAMP cases were adjudicated by a team of vaccine experts and specialists in immunology, cardiology, and preventive medicine.
This retrospective review was approved and conducted in accordance with the Walter Reed National Military Medical Center Institutional Review Board protocol #20664. All individuals with recurrent VAMP consented to share their health records and clinical details.
Results
Among 9260 cases in the IHD database, 431 met the case definition for VAMP. 
Among the 179 patients included in this analysis, 171 (96%) were male. Their median age was 39 years at the time of COVID-19 vaccination.
Within 1 month of receipt of any COVID-19 vaccine, 11 individuals had documented symptoms suggesting cardiac involvement, specifically, chest pain, palpitations, or dyspnea. After cardiac evaluation, 4 patients met the criteria for VAMP after COVID-19 vaccination.10,11 Seven patients either did not meet the criteria for VAMP or had alternative causes for their symptoms.
Two men aged 49 and 50 years with a history of vaccine-associated myocarditis following smallpox vaccination (Dryvax and ACAM2000) developed myocarditis 3 days after their second dose of the Moderna vaccine. One of these patients received a Pfizer-BioNTech booster 10 months later with no recurrence of symptoms. A 55-year-old man with a history of vaccine-associated myocarditis following Dryvax vaccination developed myocarditis 2 days after his Pfizer-BioNTech booster. None of the patients who developed post-COVID-19 VAMP reported residual symptoms from their initial VAMP episode, which occurred 12 to 18 years earlier. All were hospitalized briefly for observation and had complete symptom resolution within 6 weeks.
A 25-year-old man developed pericarditis 4 days after his second Pfizer-BioNTech vaccination. His previous ACAM2000 vaccine-associated myocarditis occurred 3 years earlier, with no residual symptoms. Of note, he had a mild COVID-19 infection 78 days before the onset of his pericarditis. After the onset of his COVID-19 vaccine-associated pericarditis, he continued to experience transient bouts of chest pressure and exertional dyspnea that resolved within 7 months of onset.
The median interval between COVID-19 vaccine doses in those who developed post-COVID-19 VAMP was within the recommended mRNA vaccine dosing intervals of 3 to 4 weeks and was consistent with the median mRNA vaccine dosing intervals among the entire cohort.
Due to the small cohort size and other limitations of this study, the suggested rate of cardiac injury in this review (4 cases in 179 persons, or 2.2%) is an imprecise estimate of risk in a small population (95% CI, 0.1%-4.4%). While this rate may seem higher than expected within the general population after COVID-19 vaccination, it is lower than the estimated lifetime risk of recurrent myocarditis from any cause.6,12
Discussion
To our knowledge, this is the first report describing cardiac outcomes after COVID-19 vaccination among a cohort of individuals with prior history of VAMP. Four cases of COVID-19 VAMP were identified among 179 patients with previous VAMP. All cases had experienced VAMP after the smallpox vaccine several years earlier, with complete resolution of symptoms. Three cases presented with recurrent VAMP after their second dose of an mRNA COVID-19 vaccine, and one after an mRNA booster dose. All fully recovered over the course of several months.
Myocarditis is a heterogeneous inflammatory injury with diverse, sometimes idiopathic, etiologies.13 In contrast to infection-related cardiac injury, prior reports of vaccine-associated myocarditis have suggested a hypersensitivity reaction characterized by patchy eosinophilic infiltrates, a benign clinical course, and good prognosis.2,3
There are several common features between VAMP after smallpox and COVID-19 vaccination. Cases occur predominantly in young men. The onset of symptoms after smallpox vaccine (mean, 10 days) and after mRNA COVID-19 vaccine (mean, 3 days) appears to correspond to the timing of peak postvaccination pro-inflammatory cytokine elevation.14 While all VAMP cases are serious events, the majority of patients appear to have a relatively benign clinical course with rapid and full recovery.13
Patients who have experienced an inflammatory cardiac injury may be at higher risk for recurrence, but quantifying risk of this rare phenomenon is challenging. Cases of VAMP after the COVID-19 vaccine have occasionally been reported in patients with previous cardiac injury unrelated to vaccination.15-17 The cases presented here represent the first report of recurrent VAMP following prior non-COVID-19 vaccinations.
Most patients with prior VAMP in this cohort did not experience cardiac-suggestive symptoms following COVID-19 vaccination. Among 11 patients who developed symptoms, 3 had confirmed myocarditis and 1 had confirmed pericarditis. The clinical course for these patients with recurrent VAMP was observed to be no different in severity or duration from those who experience new-onset VAMP.4 All other patients not meeting criteria for VAMP or having alternative explanations for their symptoms also had a benign clinical course. Nonetheless, of the study cohort of 179, recurrent VAMP was diagnosed in 4 of the 11 who developed cardiac-suggestive symptoms following COVID-19 vaccination. The importance of cardiac evaluation should be emphasized for any patient presenting with chest pain, dyspnea, or other cardiac-suggestive symptoms following vaccination.
Strengths and Limitations
The strength of this review of VAMP recurrence associated with COVID-19 vaccination derives from our large and unique longitudinal database of VAMP among current and prior service members. Additionally, the IHD’s ongoing enhanced vaccine AEs surveillance provides the opportunity to contact patients and review their electronic health records over an extended interval of time.
When interpreting this report’s implications, limitations inherent to any retrospective case review should be considered. The cohort of cases of prior VAMP included primarily healthy, fit, young service members; this population is not representative of the general population. The cohort included prior VAMP cases that generally occurred after smallpox vaccination. Experiences after smallpox vaccine may not apply to cardiac injury from other vaccines or etiologies. By the nature of this review, the population studied at the time of COVID-19 vaccination was somewhat older than those most likely to develop an initial bout of VAMP.2 This review was limited by information available in the electronic health records of a small number of patients. Subclinical cases of VAMP and cases without adequate clinical evaluation also could not be included.
Conclusions
Noninfectious inflammation of the heart (myocarditis, pericarditis, or myopericarditis) is a rare AE following certain vaccines, especially live replicating smallpox vaccine and mRNA COVID-19 vaccines. In this observational analysis, the majority of patients with previous VAMP successfully received a COVID-19 vaccine without recurrence. The 4 patients who were identified with recurrent VAMP following COVID-19 vaccination all recovered with supportive care. While the CDC endorses that individuals with a history of infectious myocarditis may receive COVID-19 vaccine after symptoms have resolved, there is currently insufficient safety data regarding COVID-19 vaccination of those with prior non-COVID-19 VAMP or following subsequent COVID-19 vaccination in those with prior VAMP related to COVID-19.10 For these individuals, COVID-19 vaccination is a precaution.10 Although insufficient to determine a precise level of risk, this report does provide data on which to base the CDC-recommended shared decision-making counseling of these patients. More research is needed to better define factors that increase risk for, or protection from, immune-mediated AEs following immunization, including VAMP. While benefits of vaccination have clearly outweighed risks during the COVID-19 pandemic, such research may optimize future vaccine recommendations.18
1. Decker MD, Garman PM, Hughes H, et al. Enhanced safety surveillance study of ACAM2000 smallpox vaccine among US military service members. Vaccine. 2021;39(39):5541-5547. doi:10.1016/j.vaccine.2021.08.041
2. Engler RJ, Nelson MR, Collins LC Jr, et al. A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination. PLoS One. 2015;10(3):e0118283. doi:10.1371/journal.pone.0118283
3. Faix DJ, Gordon DM, Perry LN, et al. Prospective safety surveillance study of ACAM2000 smallpox vaccine in deploying military personnel. Vaccine. 2020;38(46):7323-7330. doi:10.1016/j.vaccine.2020.09.037
4. Montgomery J, Ryan M, Engler R, et al. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military. JAMA Cardiol. 2021;6(10):1202-1206. doi:10.1001/jamacardio.2021.2833
5. Witberg G, Barda N, Hoss S, et al. Myocarditis after Covid-19 vaccination in a large health care organization. N Engl J Med. 2021;385(23):2132-2139. doi:10.1056/NEJMoa2110737
6. Oster ME, Shay DK, Su JR, et al. Myocarditis cases reported after mRNA-based COVID-19 vaccination in the US from December 2020 to August 2021. JAMA. 2022;327(4):331-340. doi:10.1001/jama.2021.24110
7. Su JR, McNeil MM, Welsh KJ, et al. Myopericarditis after vaccination, Vaccine Adverse Event Reporting System (VAERS), 1990-2018. Vaccine. 2021;39(5):839-845. doi:10.1016/j.vaccine.2020.12.046
8. Mei R, Raschi E, Forcesi E, Diemberger I, De Ponti F, Poluzzi E. Myocarditis and pericarditis after immunization: gaining insights through the Vaccine Adverse Event Reporting System. Int J Cardiol. 2018;273:183-186. doi:10.1016/j.ijcard.2018.09.054
9. Centers for Disease Control and Prevention (CDC). Update: cardiac-related events during the civilian smallpox vaccination program—United States, 2003. MMWR Morb Mortal Wkly Rep. 2003;52(21):492-496.
10. Gargano JW, Wallace M, Hadler SC, et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the Advisory Committee on Immunization Practices—United States, June 2021. MMWR Morb Mortal Wkly Rep. 2021;70(27):977-982. doi:10.15585/mmwr.mm7027e2
11. Sexson Tejtel SK, Munoz FM, Al-Ammouri I, et al. Myocarditis and pericarditis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2022;40(10):1499-1511. doi:10.1016/j.vaccine.2021.11.074
12. Sagar S, Liu PP, Cooper LT Jr. Myocarditis. Lancet. 2012;379(9817):738-747. doi:10.1016/S0140-6736(11) 60648-X
13. Heymans S, Cooper LT. Myocarditis after COVID-19 mRNA vaccination: clinical observations and potential mechanisms. Nat Rev Cardiol. 2022;19(2):75-77. doi:10.1038/s41569-021-00662-w
14. Cohen JI, Hohman P, Fulton R, et al. Kinetics of serum cytokines after primary or repeat vaccination with the smallpox vaccine. J Infect Dis. 2010;201(8):1183-1191. doi:10.1086/651453
15. Minocha PK, Better D, Singh RK, Hoque T. Recurrence of acute myocarditis temporally associated with receipt of the mRNA COVID-19 vaccine in an adolescent male. J Pediatr. 2021;238:321-323. doi:10.1016/j.jpeds.2021.06.035
16. Umei TC, Kishino Y, Watanabe K, et al. Recurrence of myopericarditis following mRNA COVID-19 vaccination in a male adolescent. CJC Open. 2022;4(3):350-352. doi:10.1016/j.cjco.2021.12.002
17. Pasha MA, Isaac S, Khan Z. Recurrent myocarditis following COVID-19 infection and the mRNA vaccine. Cureus. 2022;14(7):e26650. doi:10.7759/cureus.26650
18. Block JP, Boehmer TK, Forrest CB, et al. Cardiac complications after SARS-CoV-2 infection and mRNA COVID-19 vaccination—PCORnet, United States, January 2021-January 2022. MMWR Morb Mortal Wkly Rep. 2022;71(14):517-523. Published 2022 Apr 8. doi:10.15585/mmwr.mm7114e1
Vaccinations have substantially reduced morbidity and mortality from many infectious diseases. Despite the clear value of vaccinations in public health, efforts to better understand adverse events (AEs) following immunization are important to sustain public trust and vaccine confidence. Noninfectious inflammation of the heart may manifest as myocarditis or pericarditis, or occasionally, with shared signs and symptoms of each, as myopericarditis. This is a rare AE following some immunizations. Vaccine-associated myocarditis, pericarditis, or myopericarditis (VAMP) has been most clearly associated with smallpox vaccines and mRNA COVID-19 vaccines.1-6 Although extremely rare, VAMP also has been associated with other vaccines.7,8 Limited information exists to guide shared clinical decision making on COVID-19 vaccination in persons with a history of VAMP. It is unknown whether individuals with a history of VAMP are at higher risk for developing a recurrence or experiencing a more severe outcome following COVID-19 vaccination.
Methods
As part of the collaborative public health mission with the Centers for Disease Control and Prevention (CDC) for enhanced vaccine AE surveillance, the Defense Health Agency Immunization Healthcare Division (IHD) maintains a clinical database of service members and beneficiaries referred for suspected AEs following immunizations. A review of all AEs following immunization cases in this database from January 1, 2003, through February 28, 2022, identified individuals meeting the following criteria: (a) VAMP prior to receipt of COVID-19 vaccine; (b) receipt of COVID-19 vaccine in 2021; and (c) medical documentation in available electronic health records sufficient to describe health status at least 30 days following COVID-19 vaccination.9 If medical entries suggested cardiac symptoms following a COVID-19 vaccine, additional information was sought to verify VAMP based on current published criteria.10,11 Both the initial VAMP cases and the suspected COVID-19 VAMP cases were adjudicated by a team of vaccine experts and specialists in immunology, cardiology, and preventive medicine.
This retrospective review was approved and conducted in accordance with the Walter Reed National Military Medical Center Institutional Review Board protocol #20664. All individuals with recurrent VAMP consented to share their health records and clinical details.
Results
Among 9260 cases in the IHD database, 431 met the case definition for VAMP.
Among the 179 patients included in this analysis, 171 (96%) were male. Their median age was 39 years at the time of COVID-19 vaccination.
Within 1 month of receipt of any COVID-19 vaccine, 11 individuals had documented symptoms suggesting cardiac involvement, specifically, chest pain, palpitations, or dyspnea. After cardiac evaluation, 4 patients met the criteria for VAMP after COVID-19 vaccination.10,11 Seven patients either did not meet the criteria for VAMP or had alternative causes for their symptoms.
Two men aged 49 and 50 years with a history of vaccine-associated myocarditis following smallpox vaccination (Dryvax and ACAM2000) developed myocarditis 3 days after their second dose of the Moderna vaccine. One of these patients received a Pfizer-BioNTech booster 10 months later with no recurrence of symptoms. A 55-year-old man with a history of vaccine-associated myocarditis following Dryvax vaccination developed myocarditis 2 days after his Pfizer-BioNTech booster. None of the patients who developed post-COVID-19 VAMP reported residual symptoms from their initial VAMP episode, which occurred 12 to 18 years earlier. All were hospitalized briefly for observation and had complete symptom resolution within 6 weeks.
A 25-year-old man developed pericarditis 4 days after his second Pfizer-BioNTech vaccination. His previous ACAM2000 vaccine-associated myocarditis occurred 3 years earlier, with no residual symptoms. Of note, he had a mild COVID-19 infection 78 days before the onset of his pericarditis. After the onset of his COVID-19 vaccine-associated pericarditis, he continued to experience transient bouts of chest pressure and exertional dyspnea that resolved within 7 months of onset.
The median interval between COVID-19 vaccine doses in those who developed post-COVID-19 VAMP was within the recommended mRNA vaccine dosing intervals of 3 to 4 weeks and was consistent with the median mRNA vaccine dosing intervals among the entire cohort.
Due to the small cohort size and other limitations of this study, the suggested rate of cardiac injury in this review (4 cases in 179 persons, or 2.2%) is an imprecise estimate of risk in a small population (95% CI, 0.1%-4.4%). While this rate may seem higher than expected within the general population after COVID-19 vaccination, it is lower than the estimated lifetime risk of recurrent myocarditis from any cause.6,12
Discussion
To our knowledge, this is the first report describing cardiac outcomes after COVID-19 vaccination among a cohort of individuals with prior history of VAMP. Four cases of COVID-19 VAMP were identified among 179 patients with previous VAMP. All cases had experienced VAMP after the smallpox vaccine several years earlier, with complete resolution of symptoms. Three cases presented with recurrent VAMP after their second dose of an mRNA COVID-19 vaccine, and one after an mRNA booster dose. All fully recovered over the course of several months.
Myocarditis is a heterogeneous inflammatory injury with diverse, sometimes idiopathic, etiologies.13 In contrast to infection-related cardiac injury, prior reports of vaccine-associated myocarditis have suggested a hypersensitivity reaction characterized by patchy eosinophilic infiltrates, a benign clinical course, and good prognosis.2,3
There are several common features between VAMP after smallpox and COVID-19 vaccination. Cases occur predominantly in young men. The onset of symptoms after smallpox vaccine (mean, 10 days) and after mRNA COVID-19 vaccine (mean, 3 days) appears to correspond to the timing of peak postvaccination pro-inflammatory cytokine elevation.14 While all VAMP cases are serious events, the majority of patients appear to have a relatively benign clinical course with rapid and full recovery.13
Patients who have experienced an inflammatory cardiac injury may be at higher risk for recurrence, but quantifying risk of this rare phenomenon is challenging. Cases of VAMP after the COVID-19 vaccine have occasionally been reported in patients with previous cardiac injury unrelated to vaccination.15-17 The cases presented here represent the first report of recurrent VAMP following prior non-COVID-19 vaccinations.
Most patients with prior VAMP in this cohort did not experience cardiac-suggestive symptoms following COVID-19 vaccination. Among 11 patients who developed symptoms, 3 had confirmed myocarditis and 1 had confirmed pericarditis. The clinical course for these patients with recurrent VAMP was observed to be no different in severity or duration from those who experience new-onset VAMP.4 All other patients not meeting criteria for VAMP or having alternative explanations for their symptoms also had a benign clinical course. Nonetheless, of the study cohort of 179, recurrent VAMP was diagnosed in 4 of the 11 who developed cardiac-suggestive symptoms following COVID-19 vaccination. The importance of cardiac evaluation should be emphasized for any patient presenting with chest pain, dyspnea, or other cardiac-suggestive symptoms following vaccination.
Strengths and Limitations
The strength of this review of VAMP recurrence associated with COVID-19 vaccination derives from our large and unique longitudinal database of VAMP among current and prior service members. Additionally, the IHD’s ongoing enhanced vaccine AEs surveillance provides the opportunity to contact patients and review their electronic health records over an extended interval of time.
When interpreting this report’s implications, limitations inherent to any retrospective case review should be considered. The cohort of cases of prior VAMP included primarily healthy, fit, young service members; this population is not representative of the general population. The cohort included prior VAMP cases that generally occurred after smallpox vaccination. Experiences after smallpox vaccine may not apply to cardiac injury from other vaccines or etiologies. By the nature of this review, the population studied at the time of COVID-19 vaccination was somewhat older than those most likely to develop an initial bout of VAMP.2 This review was limited by information available in the electronic health records of a small number of patients. Subclinical cases of VAMP and cases without adequate clinical evaluation also could not be included.
Conclusions
Noninfectious inflammation of the heart (myocarditis, pericarditis, or myopericarditis) is a rare AE following certain vaccines, especially live replicating smallpox vaccine and mRNA COVID-19 vaccines. In this observational analysis, the majority of patients with previous VAMP successfully received a COVID-19 vaccine without recurrence. The 4 patients who were identified with recurrent VAMP following COVID-19 vaccination all recovered with supportive care. While the CDC endorses that individuals with a history of infectious myocarditis may receive COVID-19 vaccine after symptoms have resolved, there is currently insufficient safety data regarding COVID-19 vaccination of those with prior non-COVID-19 VAMP or following subsequent COVID-19 vaccination in those with prior VAMP related to COVID-19.10 For these individuals, COVID-19 vaccination is a precaution.10 Although insufficient to determine a precise level of risk, this report does provide data on which to base the CDC-recommended shared decision-making counseling of these patients. More research is needed to better define factors that increase risk for, or protection from, immune-mediated AEs following immunization, including VAMP. While benefits of vaccination have clearly outweighed risks during the COVID-19 pandemic, such research may optimize future vaccine recommendations.18
Vaccinations have substantially reduced morbidity and mortality from many infectious diseases. Despite the clear value of vaccinations in public health, efforts to better understand adverse events (AEs) following immunization are important to sustain public trust and vaccine confidence. Noninfectious inflammation of the heart may manifest as myocarditis or pericarditis, or occasionally, with shared signs and symptoms of each, as myopericarditis. This is a rare AE following some immunizations. Vaccine-associated myocarditis, pericarditis, or myopericarditis (VAMP) has been most clearly associated with smallpox vaccines and mRNA COVID-19 vaccines.1-6 Although extremely rare, VAMP also has been associated with other vaccines.7,8 Limited information exists to guide shared clinical decision making on COVID-19 vaccination in persons with a history of VAMP. It is unknown whether individuals with a history of VAMP are at higher risk for developing a recurrence or experiencing a more severe outcome following COVID-19 vaccination.
Methods
As part of the collaborative public health mission with the Centers for Disease Control and Prevention (CDC) for enhanced vaccine AE surveillance, the Defense Health Agency Immunization Healthcare Division (IHD) maintains a clinical database of service members and beneficiaries referred for suspected AEs following immunizations. A review of all AEs following immunization cases in this database from January 1, 2003, through February 28, 2022, identified individuals meeting the following criteria: (a) VAMP prior to receipt of COVID-19 vaccine; (b) receipt of COVID-19 vaccine in 2021; and (c) medical documentation in available electronic health records sufficient to describe health status at least 30 days following COVID-19 vaccination.9 If medical entries suggested cardiac symptoms following a COVID-19 vaccine, additional information was sought to verify VAMP based on current published criteria.10,11 Both the initial VAMP cases and the suspected COVID-19 VAMP cases were adjudicated by a team of vaccine experts and specialists in immunology, cardiology, and preventive medicine.
This retrospective review was approved and conducted in accordance with the Walter Reed National Military Medical Center Institutional Review Board protocol #20664. All individuals with recurrent VAMP consented to share their health records and clinical details.
Results
Among 9260 cases in the IHD database, 431 met the case definition for VAMP.
Among the 179 patients included in this analysis, 171 (96%) were male. Their median age was 39 years at the time of COVID-19 vaccination.
Within 1 month of receipt of any COVID-19 vaccine, 11 individuals had documented symptoms suggesting cardiac involvement, specifically, chest pain, palpitations, or dyspnea. After cardiac evaluation, 4 patients met the criteria for VAMP after COVID-19 vaccination.10,11 Seven patients either did not meet the criteria for VAMP or had alternative causes for their symptoms.
Two men aged 49 and 50 years with a history of vaccine-associated myocarditis following smallpox vaccination (Dryvax and ACAM2000) developed myocarditis 3 days after their second dose of the Moderna vaccine. One of these patients received a Pfizer-BioNTech booster 10 months later with no recurrence of symptoms. A 55-year-old man with a history of vaccine-associated myocarditis following Dryvax vaccination developed myocarditis 2 days after his Pfizer-BioNTech booster. None of the patients who developed post-COVID-19 VAMP reported residual symptoms from their initial VAMP episode, which occurred 12 to 18 years earlier. All were hospitalized briefly for observation and had complete symptom resolution within 6 weeks.
A 25-year-old man developed pericarditis 4 days after his second Pfizer-BioNTech vaccination. His previous ACAM2000 vaccine-associated myocarditis occurred 3 years earlier, with no residual symptoms. Of note, he had a mild COVID-19 infection 78 days before the onset of his pericarditis. After the onset of his COVID-19 vaccine-associated pericarditis, he continued to experience transient bouts of chest pressure and exertional dyspnea that resolved within 7 months of onset.
The median interval between COVID-19 vaccine doses in those who developed post-COVID-19 VAMP was within the recommended mRNA vaccine dosing intervals of 3 to 4 weeks and was consistent with the median mRNA vaccine dosing intervals among the entire cohort.
Due to the small cohort size and other limitations of this study, the suggested rate of cardiac injury in this review (4 cases in 179 persons, or 2.2%) is an imprecise estimate of risk in a small population (95% CI, 0.1%-4.4%). While this rate may seem higher than expected within the general population after COVID-19 vaccination, it is lower than the estimated lifetime risk of recurrent myocarditis from any cause.6,12
Discussion
To our knowledge, this is the first report describing cardiac outcomes after COVID-19 vaccination among a cohort of individuals with prior history of VAMP. Four cases of COVID-19 VAMP were identified among 179 patients with previous VAMP. All cases had experienced VAMP after the smallpox vaccine several years earlier, with complete resolution of symptoms. Three cases presented with recurrent VAMP after their second dose of an mRNA COVID-19 vaccine, and one after an mRNA booster dose. All fully recovered over the course of several months.
Myocarditis is a heterogeneous inflammatory injury with diverse, sometimes idiopathic, etiologies.13 In contrast to infection-related cardiac injury, prior reports of vaccine-associated myocarditis have suggested a hypersensitivity reaction characterized by patchy eosinophilic infiltrates, a benign clinical course, and good prognosis.2,3
There are several common features between VAMP after smallpox and COVID-19 vaccination. Cases occur predominantly in young men. The onset of symptoms after smallpox vaccine (mean, 10 days) and after mRNA COVID-19 vaccine (mean, 3 days) appears to correspond to the timing of peak postvaccination pro-inflammatory cytokine elevation.14 While all VAMP cases are serious events, the majority of patients appear to have a relatively benign clinical course with rapid and full recovery.13
Patients who have experienced an inflammatory cardiac injury may be at higher risk for recurrence, but quantifying risk of this rare phenomenon is challenging. Cases of VAMP after the COVID-19 vaccine have occasionally been reported in patients with previous cardiac injury unrelated to vaccination.15-17 The cases presented here represent the first report of recurrent VAMP following prior non-COVID-19 vaccinations.
Most patients with prior VAMP in this cohort did not experience cardiac-suggestive symptoms following COVID-19 vaccination. Among 11 patients who developed symptoms, 3 had confirmed myocarditis and 1 had confirmed pericarditis. The clinical course for these patients with recurrent VAMP was observed to be no different in severity or duration from those who experience new-onset VAMP.4 All other patients not meeting criteria for VAMP or having alternative explanations for their symptoms also had a benign clinical course. Nonetheless, of the study cohort of 179, recurrent VAMP was diagnosed in 4 of the 11 who developed cardiac-suggestive symptoms following COVID-19 vaccination. The importance of cardiac evaluation should be emphasized for any patient presenting with chest pain, dyspnea, or other cardiac-suggestive symptoms following vaccination.
Strengths and Limitations
The strength of this review of VAMP recurrence associated with COVID-19 vaccination derives from our large and unique longitudinal database of VAMP among current and prior service members. Additionally, the IHD’s ongoing enhanced vaccine AEs surveillance provides the opportunity to contact patients and review their electronic health records over an extended interval of time.
When interpreting this report’s implications, limitations inherent to any retrospective case review should be considered. The cohort of cases of prior VAMP included primarily healthy, fit, young service members; this population is not representative of the general population. The cohort included prior VAMP cases that generally occurred after smallpox vaccination. Experiences after smallpox vaccine may not apply to cardiac injury from other vaccines or etiologies. By the nature of this review, the population studied at the time of COVID-19 vaccination was somewhat older than those most likely to develop an initial bout of VAMP.2 This review was limited by information available in the electronic health records of a small number of patients. Subclinical cases of VAMP and cases without adequate clinical evaluation also could not be included.
Conclusions
Noninfectious inflammation of the heart (myocarditis, pericarditis, or myopericarditis) is a rare AE following certain vaccines, especially live replicating smallpox vaccine and mRNA COVID-19 vaccines. In this observational analysis, the majority of patients with previous VAMP successfully received a COVID-19 vaccine without recurrence. The 4 patients who were identified with recurrent VAMP following COVID-19 vaccination all recovered with supportive care. While the CDC endorses that individuals with a history of infectious myocarditis may receive COVID-19 vaccine after symptoms have resolved, there is currently insufficient safety data regarding COVID-19 vaccination of those with prior non-COVID-19 VAMP or following subsequent COVID-19 vaccination in those with prior VAMP related to COVID-19.10 For these individuals, COVID-19 vaccination is a precaution.10 Although insufficient to determine a precise level of risk, this report does provide data on which to base the CDC-recommended shared decision-making counseling of these patients. More research is needed to better define factors that increase risk for, or protection from, immune-mediated AEs following immunization, including VAMP. While benefits of vaccination have clearly outweighed risks during the COVID-19 pandemic, such research may optimize future vaccine recommendations.18
1. Decker MD, Garman PM, Hughes H, et al. Enhanced safety surveillance study of ACAM2000 smallpox vaccine among US military service members. Vaccine. 2021;39(39):5541-5547. doi:10.1016/j.vaccine.2021.08.041
2. Engler RJ, Nelson MR, Collins LC Jr, et al. A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination. PLoS One. 2015;10(3):e0118283. doi:10.1371/journal.pone.0118283
3. Faix DJ, Gordon DM, Perry LN, et al. Prospective safety surveillance study of ACAM2000 smallpox vaccine in deploying military personnel. Vaccine. 2020;38(46):7323-7330. doi:10.1016/j.vaccine.2020.09.037
4. Montgomery J, Ryan M, Engler R, et al. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military. JAMA Cardiol. 2021;6(10):1202-1206. doi:10.1001/jamacardio.2021.2833
5. Witberg G, Barda N, Hoss S, et al. Myocarditis after Covid-19 vaccination in a large health care organization. N Engl J Med. 2021;385(23):2132-2139. doi:10.1056/NEJMoa2110737
6. Oster ME, Shay DK, Su JR, et al. Myocarditis cases reported after mRNA-based COVID-19 vaccination in the US from December 2020 to August 2021. JAMA. 2022;327(4):331-340. doi:10.1001/jama.2021.24110
7. Su JR, McNeil MM, Welsh KJ, et al. Myopericarditis after vaccination, Vaccine Adverse Event Reporting System (VAERS), 1990-2018. Vaccine. 2021;39(5):839-845. doi:10.1016/j.vaccine.2020.12.046
8. Mei R, Raschi E, Forcesi E, Diemberger I, De Ponti F, Poluzzi E. Myocarditis and pericarditis after immunization: gaining insights through the Vaccine Adverse Event Reporting System. Int J Cardiol. 2018;273:183-186. doi:10.1016/j.ijcard.2018.09.054
9. Centers for Disease Control and Prevention (CDC). Update: cardiac-related events during the civilian smallpox vaccination program—United States, 2003. MMWR Morb Mortal Wkly Rep. 2003;52(21):492-496.
10. Gargano JW, Wallace M, Hadler SC, et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the Advisory Committee on Immunization Practices—United States, June 2021. MMWR Morb Mortal Wkly Rep. 2021;70(27):977-982. doi:10.15585/mmwr.mm7027e2
11. Sexson Tejtel SK, Munoz FM, Al-Ammouri I, et al. Myocarditis and pericarditis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2022;40(10):1499-1511. doi:10.1016/j.vaccine.2021.11.074
12. Sagar S, Liu PP, Cooper LT Jr. Myocarditis. Lancet. 2012;379(9817):738-747. doi:10.1016/S0140-6736(11) 60648-X
13. Heymans S, Cooper LT. Myocarditis after COVID-19 mRNA vaccination: clinical observations and potential mechanisms. Nat Rev Cardiol. 2022;19(2):75-77. doi:10.1038/s41569-021-00662-w
14. Cohen JI, Hohman P, Fulton R, et al. Kinetics of serum cytokines after primary or repeat vaccination with the smallpox vaccine. J Infect Dis. 2010;201(8):1183-1191. doi:10.1086/651453
15. Minocha PK, Better D, Singh RK, Hoque T. Recurrence of acute myocarditis temporally associated with receipt of the mRNA COVID-19 vaccine in an adolescent male. J Pediatr. 2021;238:321-323. doi:10.1016/j.jpeds.2021.06.035
16. Umei TC, Kishino Y, Watanabe K, et al. Recurrence of myopericarditis following mRNA COVID-19 vaccination in a male adolescent. CJC Open. 2022;4(3):350-352. doi:10.1016/j.cjco.2021.12.002
17. Pasha MA, Isaac S, Khan Z. Recurrent myocarditis following COVID-19 infection and the mRNA vaccine. Cureus. 2022;14(7):e26650. doi:10.7759/cureus.26650
18. Block JP, Boehmer TK, Forrest CB, et al. Cardiac complications after SARS-CoV-2 infection and mRNA COVID-19 vaccination—PCORnet, United States, January 2021-January 2022. MMWR Morb Mortal Wkly Rep. 2022;71(14):517-523. Published 2022 Apr 8. doi:10.15585/mmwr.mm7114e1
1. Decker MD, Garman PM, Hughes H, et al. Enhanced safety surveillance study of ACAM2000 smallpox vaccine among US military service members. Vaccine. 2021;39(39):5541-5547. doi:10.1016/j.vaccine.2021.08.041
2. Engler RJ, Nelson MR, Collins LC Jr, et al. A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination. PLoS One. 2015;10(3):e0118283. doi:10.1371/journal.pone.0118283
3. Faix DJ, Gordon DM, Perry LN, et al. Prospective safety surveillance study of ACAM2000 smallpox vaccine in deploying military personnel. Vaccine. 2020;38(46):7323-7330. doi:10.1016/j.vaccine.2020.09.037
4. Montgomery J, Ryan M, Engler R, et al. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military. JAMA Cardiol. 2021;6(10):1202-1206. doi:10.1001/jamacardio.2021.2833
5. Witberg G, Barda N, Hoss S, et al. Myocarditis after Covid-19 vaccination in a large health care organization. N Engl J Med. 2021;385(23):2132-2139. doi:10.1056/NEJMoa2110737
6. Oster ME, Shay DK, Su JR, et al. Myocarditis cases reported after mRNA-based COVID-19 vaccination in the US from December 2020 to August 2021. JAMA. 2022;327(4):331-340. doi:10.1001/jama.2021.24110
7. Su JR, McNeil MM, Welsh KJ, et al. Myopericarditis after vaccination, Vaccine Adverse Event Reporting System (VAERS), 1990-2018. Vaccine. 2021;39(5):839-845. doi:10.1016/j.vaccine.2020.12.046
8. Mei R, Raschi E, Forcesi E, Diemberger I, De Ponti F, Poluzzi E. Myocarditis and pericarditis after immunization: gaining insights through the Vaccine Adverse Event Reporting System. Int J Cardiol. 2018;273:183-186. doi:10.1016/j.ijcard.2018.09.054
9. Centers for Disease Control and Prevention (CDC). Update: cardiac-related events during the civilian smallpox vaccination program—United States, 2003. MMWR Morb Mortal Wkly Rep. 2003;52(21):492-496.
10. Gargano JW, Wallace M, Hadler SC, et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the Advisory Committee on Immunization Practices—United States, June 2021. MMWR Morb Mortal Wkly Rep. 2021;70(27):977-982. doi:10.15585/mmwr.mm7027e2
11. Sexson Tejtel SK, Munoz FM, Al-Ammouri I, et al. Myocarditis and pericarditis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2022;40(10):1499-1511. doi:10.1016/j.vaccine.2021.11.074
12. Sagar S, Liu PP, Cooper LT Jr. Myocarditis. Lancet. 2012;379(9817):738-747. doi:10.1016/S0140-6736(11) 60648-X
13. Heymans S, Cooper LT. Myocarditis after COVID-19 mRNA vaccination: clinical observations and potential mechanisms. Nat Rev Cardiol. 2022;19(2):75-77. doi:10.1038/s41569-021-00662-w
14. Cohen JI, Hohman P, Fulton R, et al. Kinetics of serum cytokines after primary or repeat vaccination with the smallpox vaccine. J Infect Dis. 2010;201(8):1183-1191. doi:10.1086/651453
15. Minocha PK, Better D, Singh RK, Hoque T. Recurrence of acute myocarditis temporally associated with receipt of the mRNA COVID-19 vaccine in an adolescent male. J Pediatr. 2021;238:321-323. doi:10.1016/j.jpeds.2021.06.035
16. Umei TC, Kishino Y, Watanabe K, et al. Recurrence of myopericarditis following mRNA COVID-19 vaccination in a male adolescent. CJC Open. 2022;4(3):350-352. doi:10.1016/j.cjco.2021.12.002
17. Pasha MA, Isaac S, Khan Z. Recurrent myocarditis following COVID-19 infection and the mRNA vaccine. Cureus. 2022;14(7):e26650. doi:10.7759/cureus.26650
18. Block JP, Boehmer TK, Forrest CB, et al. Cardiac complications after SARS-CoV-2 infection and mRNA COVID-19 vaccination—PCORnet, United States, January 2021-January 2022. MMWR Morb Mortal Wkly Rep. 2022;71(14):517-523. Published 2022 Apr 8. doi:10.15585/mmwr.mm7114e1