Cardiology

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.

The heart is one of the organs least likely to develop cancer, a long-standing biologic puzzle that may now have an explanation. A study published in Science found that the mechanical load generated by the beating heart suppresses tumor cell proliferation through a molecular pathway that alters gene expression, raising the possibility of new therapeutic targets.

Mechanical Protection

Tumors that originate directly in the myocardium are exceptionally rare, occurring in < 1% of autopsies. Even cardiac metastases, which have been reported in up to 18% of autopsies, are often small, asymptomatic, and incidentally discovered. Although this phenomenon has long been recognized, its biologic basis remains unclear.

The heart is notable for its limited capacity for regeneration. After birth, cardiomyocytes stop dividing and subsequently renew at a rate of about 1% per year. However, when the mechanical load is reduced, such as in patients supported by left ventricular assist devices, cardiomyocytes once again show signs of proliferation.

This observation prompted researchers to investigate whether the same mechanical load that restrains normal cardiac cells might also suppress cancer growth.

More Load, Less Growth

To investigate this question, researchers introduced two genetic alterations commonly found in human cancers, activation of the KRAS oncogene and loss of the TP53, into the liver, skeletal muscle, and hearts of mice. Tumors developed in multiple organs, but not in the heart.

The researchers then used a heterotopic heart transplant model in which a donor mouse’s heart is surgically connected to the neck (cervical) or abdominal vessels of a recipient mouse. The transplanted heart remained perfused but lost its normal mechanical loading (constant beating).

When researchers injected lung adenocarcinoma cells into 2 different hearts of the same animal, they observed entirely different outcomes. The cancer cells did not grow in the native mechanically loaded heart. However, the same cells grew rapidly and extensively in the mechanically unloaded transplanted heart.

Tumor cells had replaced nearly all normal tissue in the unloaded heart, whereas they occupied only approximately 20% of the ventricle in the native heart in 14 days. This difference could not be explained by differences in the initial tumor engraftment or cell death. Instead, the findings pointed to substantial differences in tumor cell proliferation.

Similar results were observed in bioengineered cardiac tissues exposed to varying degrees of mechanical stress. Tumor cells proliferated under conditions of low mechanical load but ceased proliferating as the mechanical load increased. Tumor growth was lowest in regions exposed to the greatest mechanical stimulation of cardiomyocytes in vitro.

However, the possibility of metabolic competition between cardiac and tumor cells for nutrition was ruled out.

From Mechanics to Genes

Next, we examined the influence of mechanical forces on tumor cell behavior.

Gene expression analyses of both human cardiac metastases and mouse tumor cells showed that mechanical stimulation altered chromatin accessibility through the activation of genes involved in chromatin remodeling. These changes promoted the expression of genes that suppress cell division.

The study also identified Nesprin-2, a part of the linker of the nucleoskeleton and cytoskeleton complex, which acts as a physical bridge. It is a multitasking protein that connects the cell’s outer structural network (cytoskeleton) to its inner genetic storage (nucleus) and appears to play a significant role in converting mechanical signals into changes in gene expression.

When Nesprin-2 was inactivated, cancer cells resumed proliferation despite exposure to a mechanical load, both in engineered tissues and animal models.

“Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation,” concluded the authors.

An Actively Protected Organ

Speaking with Univadis Italy, part of the Medscape Professional Network, Giorgio Scita, PhD, director of the Mechanisms of Tumor Cell Migration research unit at AIRC Institute of Molecular Oncology and professor of general pathology at the University of Milan in Milan, Italy, said, “The study addressed a simple but fundamental question: Why is the heart largely resistant to cancer despite being highly vascularized and continuously exposed to circulating tumor cells?

These findings suggest that the heartbeat itself creates a mechanical environment that is hostile to tumor growth. The compressive forces generated by rhythmic myocardial contraction are sensed by cancer cells and translated into biochemical signals that limit their proliferation.

In this view, the heart is not simply an organ that is unfavorable for cancer growth but a tissue actively protected by its own mechanical forces.”

Speaking with Univadis Italy, Serena Zacchigna, PhD, study coauthor and head of the Cardiovascular Biology Laboratory at the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy, said, “Until now, however, attention had focused primarily on signals from the extracellular matrix, such as tissue stiffness. Our study adds a new element: even forces generated directly by the movement of an organ — in this case, cardiac contraction — can influence the growth of cancer cells.”

Beyond the Heart

Scita said the findings have implications that extend well beyond the heart.

“The most significant aspect is that this work identifies tissue mechanics as an active regulator of tumor behavior,” he said. Stiffness, compression, tension, and confinement are not merely consequences of tumor growth, but factors capable of influencing proliferation, invasion, and dormancy.

The concept may apply to many solid tumors. Scita noted that cancer cells growing in confined environments, such as ductal carcinoma in situ of the breast, are exposed to substantial mechanical constraints. Understanding why some tumor cells remain susceptible to these forces whereas others evade them and become invasive remains a major unanswered question in cancer biology.

Research on these mechanisms is expanding internationally and in Italy as well. One example is the AIRC “5 per mille” (5 per thousand) research programs on metastatic disease, which includes projects designed to clarify how the mechanical properties of tumor tissue influence cancer initiation, metastatic spread, and disease progression.

Therapeutic Potential

According to Zacchigna, these findings open 2 principal avenues for future research.

“The first focuses on mechanical stimulation itself. In collaboration with engineers at the University of Siena, including a group led by Domenico Prattichizzo, researchers are developing wearable robotic devices designed to mimic the heartbeat and deliver mechanical stimulation to superficial solid tumors such as certain skin cancers.

The second approach is pharmacology. Researchers are investigating whether epigenetic therapies capable of modifying chromatin remodeling can reproduce the effects of cardiac contraction and suppress tumor cell proliferation.

However, Zacchigna cautioned that this work remains at an early experimental phase.”

However, before therapeutic applications can be pursued, important mechanistic questions remain unanswered.

Zacchigna noted that although the linker of nucleoskeleton and cytoskeleton (LINC) complex and Nesprin-2 are involved in signal transduction leading to chromatin reorganization and activation of cell cycle inhibitory loci, the molecular intermediates involved have yet to be fully defined.

Researchers also need to determine which genes are most critical, whether the mechanism operates across different tumor types, and whether it can be safely manipulated for therapeutic purposes.

In an accompanying commentary published in Science, Wyatt G. Paltzer, PhD, and James F. Martin, MD, from the Department of Integrative Physiology at the Baylor College of Medicine in Houston, noted that the findings suggest enhancing LINC complex activity could potentially suppress tumor growth.

However, because the complex has broad biologic functions, it may prove difficult to target therapeutically. The authors suggested that future studies should focus on identifying proteins that interact with Nesprin-2 or other components of the LINC complex and play a more specific role in inhibiting cancer cell proliferation.

Looking Ahead

Despite these challenges, Scita said that the study’s conceptual significance is already clear.

“Even if therapeutic applications remain years away, the findings suggest that cancer may one day be targeted by altering how tumor cells perceive and interpret physical forces.”

Scita and Zacchigna reported having no relevant conflicts of interest.

This story was translated from Univadis Italy.

A version of this article first appeared on Medscape.com.

The heart is one of the organs least likely to develop cancer, a long-standing biologic puzzle that may now have an explanation. A study published in Science found that the mechanical load generated by the beating heart suppresses tumor cell proliferation through a molecular pathway that alters gene expression, raising the possibility of new therapeutic targets.

Mechanical Protection

Tumors that originate directly in the myocardium are exceptionally rare, occurring in < 1% of autopsies. Even cardiac metastases, which have been reported in up to 18% of autopsies, are often small, asymptomatic, and incidentally discovered. Although this phenomenon has long been recognized, its biologic basis remains unclear.

The heart is notable for its limited capacity for regeneration. After birth, cardiomyocytes stop dividing and subsequently renew at a rate of about 1% per year. However, when the mechanical load is reduced, such as in patients supported by left ventricular assist devices, cardiomyocytes once again show signs of proliferation.

This observation prompted researchers to investigate whether the same mechanical load that restrains normal cardiac cells might also suppress cancer growth.

More Load, Less Growth

To investigate this question, researchers introduced two genetic alterations commonly found in human cancers, activation of the KRAS oncogene and loss of the TP53, into the liver, skeletal muscle, and hearts of mice. Tumors developed in multiple organs, but not in the heart.

The researchers then used a heterotopic heart transplant model in which a donor mouse’s heart is surgically connected to the neck (cervical) or abdominal vessels of a recipient mouse. The transplanted heart remained perfused but lost its normal mechanical loading (constant beating).

When researchers injected lung adenocarcinoma cells into 2 different hearts of the same animal, they observed entirely different outcomes. The cancer cells did not grow in the native mechanically loaded heart. However, the same cells grew rapidly and extensively in the mechanically unloaded transplanted heart.

Tumor cells had replaced nearly all normal tissue in the unloaded heart, whereas they occupied only approximately 20% of the ventricle in the native heart in 14 days. This difference could not be explained by differences in the initial tumor engraftment or cell death. Instead, the findings pointed to substantial differences in tumor cell proliferation.

Similar results were observed in bioengineered cardiac tissues exposed to varying degrees of mechanical stress. Tumor cells proliferated under conditions of low mechanical load but ceased proliferating as the mechanical load increased. Tumor growth was lowest in regions exposed to the greatest mechanical stimulation of cardiomyocytes in vitro.

However, the possibility of metabolic competition between cardiac and tumor cells for nutrition was ruled out.

From Mechanics to Genes

Next, we examined the influence of mechanical forces on tumor cell behavior.

Gene expression analyses of both human cardiac metastases and mouse tumor cells showed that mechanical stimulation altered chromatin accessibility through the activation of genes involved in chromatin remodeling. These changes promoted the expression of genes that suppress cell division.

The study also identified Nesprin-2, a part of the linker of the nucleoskeleton and cytoskeleton complex, which acts as a physical bridge. It is a multitasking protein that connects the cell’s outer structural network (cytoskeleton) to its inner genetic storage (nucleus) and appears to play a significant role in converting mechanical signals into changes in gene expression.

When Nesprin-2 was inactivated, cancer cells resumed proliferation despite exposure to a mechanical load, both in engineered tissues and animal models.

“Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation,” concluded the authors.

An Actively Protected Organ

Speaking with Univadis Italy, part of the Medscape Professional Network, Giorgio Scita, PhD, director of the Mechanisms of Tumor Cell Migration research unit at AIRC Institute of Molecular Oncology and professor of general pathology at the University of Milan in Milan, Italy, said, “The study addressed a simple but fundamental question: Why is the heart largely resistant to cancer despite being highly vascularized and continuously exposed to circulating tumor cells?

These findings suggest that the heartbeat itself creates a mechanical environment that is hostile to tumor growth. The compressive forces generated by rhythmic myocardial contraction are sensed by cancer cells and translated into biochemical signals that limit their proliferation.

In this view, the heart is not simply an organ that is unfavorable for cancer growth but a tissue actively protected by its own mechanical forces.”

Speaking with Univadis Italy, Serena Zacchigna, PhD, study coauthor and head of the Cardiovascular Biology Laboratory at the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy, said, “Until now, however, attention had focused primarily on signals from the extracellular matrix, such as tissue stiffness. Our study adds a new element: even forces generated directly by the movement of an organ — in this case, cardiac contraction — can influence the growth of cancer cells.”

Beyond the Heart

Scita said the findings have implications that extend well beyond the heart.

“The most significant aspect is that this work identifies tissue mechanics as an active regulator of tumor behavior,” he said. Stiffness, compression, tension, and confinement are not merely consequences of tumor growth, but factors capable of influencing proliferation, invasion, and dormancy.

The concept may apply to many solid tumors. Scita noted that cancer cells growing in confined environments, such as ductal carcinoma in situ of the breast, are exposed to substantial mechanical constraints. Understanding why some tumor cells remain susceptible to these forces whereas others evade them and become invasive remains a major unanswered question in cancer biology.

Research on these mechanisms is expanding internationally and in Italy as well. One example is the AIRC “5 per mille” (5 per thousand) research programs on metastatic disease, which includes projects designed to clarify how the mechanical properties of tumor tissue influence cancer initiation, metastatic spread, and disease progression.

Therapeutic Potential

According to Zacchigna, these findings open 2 principal avenues for future research.

“The first focuses on mechanical stimulation itself. In collaboration with engineers at the University of Siena, including a group led by Domenico Prattichizzo, researchers are developing wearable robotic devices designed to mimic the heartbeat and deliver mechanical stimulation to superficial solid tumors such as certain skin cancers.

The second approach is pharmacology. Researchers are investigating whether epigenetic therapies capable of modifying chromatin remodeling can reproduce the effects of cardiac contraction and suppress tumor cell proliferation.

However, Zacchigna cautioned that this work remains at an early experimental phase.”

However, before therapeutic applications can be pursued, important mechanistic questions remain unanswered.

Zacchigna noted that although the linker of nucleoskeleton and cytoskeleton (LINC) complex and Nesprin-2 are involved in signal transduction leading to chromatin reorganization and activation of cell cycle inhibitory loci, the molecular intermediates involved have yet to be fully defined.

Researchers also need to determine which genes are most critical, whether the mechanism operates across different tumor types, and whether it can be safely manipulated for therapeutic purposes.

In an accompanying commentary published in Science, Wyatt G. Paltzer, PhD, and James F. Martin, MD, from the Department of Integrative Physiology at the Baylor College of Medicine in Houston, noted that the findings suggest enhancing LINC complex activity could potentially suppress tumor growth.

However, because the complex has broad biologic functions, it may prove difficult to target therapeutically. The authors suggested that future studies should focus on identifying proteins that interact with Nesprin-2 or other components of the LINC complex and play a more specific role in inhibiting cancer cell proliferation.

Looking Ahead

Despite these challenges, Scita said that the study’s conceptual significance is already clear.

“Even if therapeutic applications remain years away, the findings suggest that cancer may one day be targeted by altering how tumor cells perceive and interpret physical forces.”

Scita and Zacchigna reported having no relevant conflicts of interest.

This story was translated from Univadis Italy.

A version of this article first appeared on Medscape.com.

The heart is one of the organs least likely to develop cancer, a long-standing biologic puzzle that may now have an explanation. A study published in Science found that the mechanical load generated by the beating heart suppresses tumor cell proliferation through a molecular pathway that alters gene expression, raising the possibility of new therapeutic targets.

Mechanical Protection

Tumors that originate directly in the myocardium are exceptionally rare, occurring in < 1% of autopsies. Even cardiac metastases, which have been reported in up to 18% of autopsies, are often small, asymptomatic, and incidentally discovered. Although this phenomenon has long been recognized, its biologic basis remains unclear.

The heart is notable for its limited capacity for regeneration. After birth, cardiomyocytes stop dividing and subsequently renew at a rate of about 1% per year. However, when the mechanical load is reduced, such as in patients supported by left ventricular assist devices, cardiomyocytes once again show signs of proliferation.

This observation prompted researchers to investigate whether the same mechanical load that restrains normal cardiac cells might also suppress cancer growth.

More Load, Less Growth

To investigate this question, researchers introduced two genetic alterations commonly found in human cancers, activation of the KRAS oncogene and loss of the TP53, into the liver, skeletal muscle, and hearts of mice. Tumors developed in multiple organs, but not in the heart.

The researchers then used a heterotopic heart transplant model in which a donor mouse’s heart is surgically connected to the neck (cervical) or abdominal vessels of a recipient mouse. The transplanted heart remained perfused but lost its normal mechanical loading (constant beating).

When researchers injected lung adenocarcinoma cells into 2 different hearts of the same animal, they observed entirely different outcomes. The cancer cells did not grow in the native mechanically loaded heart. However, the same cells grew rapidly and extensively in the mechanically unloaded transplanted heart.

Tumor cells had replaced nearly all normal tissue in the unloaded heart, whereas they occupied only approximately 20% of the ventricle in the native heart in 14 days. This difference could not be explained by differences in the initial tumor engraftment or cell death. Instead, the findings pointed to substantial differences in tumor cell proliferation.

Similar results were observed in bioengineered cardiac tissues exposed to varying degrees of mechanical stress. Tumor cells proliferated under conditions of low mechanical load but ceased proliferating as the mechanical load increased. Tumor growth was lowest in regions exposed to the greatest mechanical stimulation of cardiomyocytes in vitro.

However, the possibility of metabolic competition between cardiac and tumor cells for nutrition was ruled out.

From Mechanics to Genes

Next, we examined the influence of mechanical forces on tumor cell behavior.

Gene expression analyses of both human cardiac metastases and mouse tumor cells showed that mechanical stimulation altered chromatin accessibility through the activation of genes involved in chromatin remodeling. These changes promoted the expression of genes that suppress cell division.

The study also identified Nesprin-2, a part of the linker of the nucleoskeleton and cytoskeleton complex, which acts as a physical bridge. It is a multitasking protein that connects the cell’s outer structural network (cytoskeleton) to its inner genetic storage (nucleus) and appears to play a significant role in converting mechanical signals into changes in gene expression.

When Nesprin-2 was inactivated, cancer cells resumed proliferation despite exposure to a mechanical load, both in engineered tissues and animal models.

“Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation,” concluded the authors.

An Actively Protected Organ

Speaking with Univadis Italy, part of the Medscape Professional Network, Giorgio Scita, PhD, director of the Mechanisms of Tumor Cell Migration research unit at AIRC Institute of Molecular Oncology and professor of general pathology at the University of Milan in Milan, Italy, said, “The study addressed a simple but fundamental question: Why is the heart largely resistant to cancer despite being highly vascularized and continuously exposed to circulating tumor cells?

These findings suggest that the heartbeat itself creates a mechanical environment that is hostile to tumor growth. The compressive forces generated by rhythmic myocardial contraction are sensed by cancer cells and translated into biochemical signals that limit their proliferation.

In this view, the heart is not simply an organ that is unfavorable for cancer growth but a tissue actively protected by its own mechanical forces.”

Speaking with Univadis Italy, Serena Zacchigna, PhD, study coauthor and head of the Cardiovascular Biology Laboratory at the International Centre for Genetic Engineering and Biotechnology, Trieste, Italy, said, “Until now, however, attention had focused primarily on signals from the extracellular matrix, such as tissue stiffness. Our study adds a new element: even forces generated directly by the movement of an organ — in this case, cardiac contraction — can influence the growth of cancer cells.”

Beyond the Heart

Scita said the findings have implications that extend well beyond the heart.

“The most significant aspect is that this work identifies tissue mechanics as an active regulator of tumor behavior,” he said. Stiffness, compression, tension, and confinement are not merely consequences of tumor growth, but factors capable of influencing proliferation, invasion, and dormancy.

The concept may apply to many solid tumors. Scita noted that cancer cells growing in confined environments, such as ductal carcinoma in situ of the breast, are exposed to substantial mechanical constraints. Understanding why some tumor cells remain susceptible to these forces whereas others evade them and become invasive remains a major unanswered question in cancer biology.

Research on these mechanisms is expanding internationally and in Italy as well. One example is the AIRC “5 per mille” (5 per thousand) research programs on metastatic disease, which includes projects designed to clarify how the mechanical properties of tumor tissue influence cancer initiation, metastatic spread, and disease progression.

Therapeutic Potential

According to Zacchigna, these findings open 2 principal avenues for future research.

“The first focuses on mechanical stimulation itself. In collaboration with engineers at the University of Siena, including a group led by Domenico Prattichizzo, researchers are developing wearable robotic devices designed to mimic the heartbeat and deliver mechanical stimulation to superficial solid tumors such as certain skin cancers.

The second approach is pharmacology. Researchers are investigating whether epigenetic therapies capable of modifying chromatin remodeling can reproduce the effects of cardiac contraction and suppress tumor cell proliferation.

However, Zacchigna cautioned that this work remains at an early experimental phase.”

However, before therapeutic applications can be pursued, important mechanistic questions remain unanswered.

Zacchigna noted that although the linker of nucleoskeleton and cytoskeleton (LINC) complex and Nesprin-2 are involved in signal transduction leading to chromatin reorganization and activation of cell cycle inhibitory loci, the molecular intermediates involved have yet to be fully defined.

Researchers also need to determine which genes are most critical, whether the mechanism operates across different tumor types, and whether it can be safely manipulated for therapeutic purposes.

In an accompanying commentary published in Science, Wyatt G. Paltzer, PhD, and James F. Martin, MD, from the Department of Integrative Physiology at the Baylor College of Medicine in Houston, noted that the findings suggest enhancing LINC complex activity could potentially suppress tumor growth.

However, because the complex has broad biologic functions, it may prove difficult to target therapeutically. The authors suggested that future studies should focus on identifying proteins that interact with Nesprin-2 or other components of the LINC complex and play a more specific role in inhibiting cancer cell proliferation.

Looking Ahead

Despite these challenges, Scita said that the study’s conceptual significance is already clear.

“Even if therapeutic applications remain years away, the findings suggest that cancer may one day be targeted by altering how tumor cells perceive and interpret physical forces.”

Scita and Zacchigna reported having no relevant conflicts of interest.

This story was translated from Univadis Italy.

A version of this article first appeared on Medscape.com.

Cardiac rehabilitation (CR) remains dramatically underused among US veterans, as < 11% of eligible patients attend a single session and usage appears to be declining over time, a recently published retrospective cohort study reported. 

CR use is much lower among eligible patients across the US Department of Veterans Affairs (VA) compared with Medicare (10.4% vs. 28%, respectively), reported researchers at Veterans Affairs Connecticut Healthcare System and Yale School of Medicine, in JACC: Advances. 

The overall CR rate in the VA was lower than the 13.2% reported in a 2018 study. And while there was no significant difference in use between men and women, veterans from the poorest neighborhoods were less likely to take advantage of CR compared with veterans from the wealthiest neighborhoods (adjusted odds ratio, 0.82; P < .001).

“As providers, the time to act is now,” Merilyn Varghese, MD, MSc, said in an interview with Federal Practitioner. “We need to urgently get more of our veterans to cardiac rehab.”

As Varghese explained, “CR is a preventive intervention that has been shown to improve quality of life and reduce mortality and hospitalizations for patients with specific cardiac conditions.”

Patients may be eligible if they have experienced myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass surgery (CABG), heart transplant, valve surgery, stable angina, or stable heart failure. 

“CR combines multiple aspects of cardiac care such as exercise training, medication management, and behavioral assessments,” Varghese said. “For example, patients who have had a heart attack may have challenges in getting back to an exercise routine, managing new medications, and adjusting to life after such an event. CR can help bridge the gap between hospital to home.” In-person CR typically includes 3 sessions per week for 12 weeks.  

In 2024, a systematic review and meta-analysis reported that CR reduces all-cause mortality (relative risk, 0.74): “These results support the utilization of CR as a critical element in the management of further secondary prevention of CVDs (cardiovascular diseases).”

Examining VA Data

Researchers conducted the 2026 study “to better understand the current landscape of CR among veterans, particularly among women veterans who comprise a significant part of the veteran population but have previously been underrepresented in research,” Varghese said.

“Women veterans also share a different burden of cardiovascular risk factors, so understanding CR participation among both women and men veterans was of particular interest.”

The study tracked 82,496 VA-enrolled veterans eligible for CR from 2021-2023 (3.6% women). Average age of participants were 64.0 years among women and 71.5 years among men. Among women, 58.3% were White, and 31.8% were Black, and 2.24% were Asian. Among men, 71.9% were White, 18.8% were Black, and 2.3% were Asian. 

The rates of CR participation were low among both men (10.4%) and women (10.2%). Older people and Black patients were less likely to take part in CR than younger people and White patients, according to the study. Those who underwent CABG and PCI were more likely to participate in CR compared with those who had heart attacks only.

As for the gap in use between the wealthiest and poorest neighborhoods, Varghese said: “Area deprivation may compound some of the other barriers to CR access, including transportation difficulties, work responsibilities, and out-of-pocket costs.”

How can CR uptake be improved? “A key first step is understanding who can be referred, and second, to spend time discussing the importance of attending with veterans,” Varghese said. “Studies have shown that provider engagement and championing of CR are important positive facilitators that encourage CR participation.

“The VA has been at the forefront of innovation with the home-based CR program that offers veterans a way to attend CR remotely,” she added. “Expanding such novel methods of CR delivery is likely part of the solution to expand CR access.”

Outside Perspective: Make Referrals the Default

Justin Bachmann, MD, MPH, staff physician and research scientist at VA Tennessee Valley Healthcare System, told Federal Practitioner that CR is an American College of Cardiology/American Heart Association Class I recommended secondary prevention therapy following MI, PCI, and CABG “with strong evidence for reduced cardiovascular mortality and improved function and quality of life.”

Still, CR “has been persistently underused for decades as travel, cost, scheduling, and uneven geographic capacity create real logistical barriers,” said Bachmann, who serves as the medical director of a VA Office of Rural Health home-based CR program. 

Bachmann praised the study methodology and offered this advice to colleagues: “Embed CR referral in the post-MI, post-PCI, and post-CABG order sets so that referral is the default. Scale home-based CR well beyond the roughly 40 sites where it is currently available, and track facility-level referral and enrollment rates as quality measures.”

Preventive cardiology specialist Randal J. Thomas, MD, professor of Medicine at the Mayo Clinic in Rochester, Minn., echoed the importance of physician referral to Federal Practitioner.

“Patients can’t actually participate [directly] in most programs. They must have a physician referral,” he said. “The physician referral and the strength of referral is key. If a physician says, ‘You can go there if you want, but it’s not that important,’ the patients aren’t going to go.”

Outside Perspective: VA Deserves Blame

“The VA lags far behind most medical systems,” according to Quinn R. Pack, MD, associate professor of medicine at the University of Massachusetts Chan Medical School-Baystate. “Some of this is probably the patient population—more mental health problems, more smoking, more disease. But I’d squarely put most of this on the VA health system. They haven’t created the systems of care that make attending cardiac rehabilitation easy, reliable, and consistent.”

He noted that that automatic referral combined with a bedside visit by a liaison such as a representative of a CR program can double or triple enrollment.

“When physicians and nurses really encourage patients to go [to CR], these words are powerful,” Pack said. “When a patient enrolls in cardiac rehabilitation, we help them form new habits of exercise.”

No study fundings are reported. The Varghese discloses a relationship with the Veterans Health Administration. Other study authors had no disclosures. Bachmann disclosed a relationship with the VA. Pack and Thomas have no disclosures. 

Cardiac rehabilitation (CR) remains dramatically underused among US veterans, as < 11% of eligible patients attend a single session and usage appears to be declining over time, a recently published retrospective cohort study reported. 

CR use is much lower among eligible patients across the US Department of Veterans Affairs (VA) compared with Medicare (10.4% vs. 28%, respectively), reported researchers at Veterans Affairs Connecticut Healthcare System and Yale School of Medicine, in JACC: Advances. 

The overall CR rate in the VA was lower than the 13.2% reported in a 2018 study. And while there was no significant difference in use between men and women, veterans from the poorest neighborhoods were less likely to take advantage of CR compared with veterans from the wealthiest neighborhoods (adjusted odds ratio, 0.82; P < .001).

“As providers, the time to act is now,” Merilyn Varghese, MD, MSc, said in an interview with Federal Practitioner. “We need to urgently get more of our veterans to cardiac rehab.”

As Varghese explained, “CR is a preventive intervention that has been shown to improve quality of life and reduce mortality and hospitalizations for patients with specific cardiac conditions.”

Patients may be eligible if they have experienced myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass surgery (CABG), heart transplant, valve surgery, stable angina, or stable heart failure. 

“CR combines multiple aspects of cardiac care such as exercise training, medication management, and behavioral assessments,” Varghese said. “For example, patients who have had a heart attack may have challenges in getting back to an exercise routine, managing new medications, and adjusting to life after such an event. CR can help bridge the gap between hospital to home.” In-person CR typically includes 3 sessions per week for 12 weeks.  

In 2024, a systematic review and meta-analysis reported that CR reduces all-cause mortality (relative risk, 0.74): “These results support the utilization of CR as a critical element in the management of further secondary prevention of CVDs (cardiovascular diseases).”

Examining VA Data

Researchers conducted the 2026 study “to better understand the current landscape of CR among veterans, particularly among women veterans who comprise a significant part of the veteran population but have previously been underrepresented in research,” Varghese said.

“Women veterans also share a different burden of cardiovascular risk factors, so understanding CR participation among both women and men veterans was of particular interest.”

The study tracked 82,496 VA-enrolled veterans eligible for CR from 2021-2023 (3.6% women). Average age of participants were 64.0 years among women and 71.5 years among men. Among women, 58.3% were White, and 31.8% were Black, and 2.24% were Asian. Among men, 71.9% were White, 18.8% were Black, and 2.3% were Asian. 

The rates of CR participation were low among both men (10.4%) and women (10.2%). Older people and Black patients were less likely to take part in CR than younger people and White patients, according to the study. Those who underwent CABG and PCI were more likely to participate in CR compared with those who had heart attacks only.

As for the gap in use between the wealthiest and poorest neighborhoods, Varghese said: “Area deprivation may compound some of the other barriers to CR access, including transportation difficulties, work responsibilities, and out-of-pocket costs.”

How can CR uptake be improved? “A key first step is understanding who can be referred, and second, to spend time discussing the importance of attending with veterans,” Varghese said. “Studies have shown that provider engagement and championing of CR are important positive facilitators that encourage CR participation.

“The VA has been at the forefront of innovation with the home-based CR program that offers veterans a way to attend CR remotely,” she added. “Expanding such novel methods of CR delivery is likely part of the solution to expand CR access.”

Outside Perspective: Make Referrals the Default

Justin Bachmann, MD, MPH, staff physician and research scientist at VA Tennessee Valley Healthcare System, told Federal Practitioner that CR is an American College of Cardiology/American Heart Association Class I recommended secondary prevention therapy following MI, PCI, and CABG “with strong evidence for reduced cardiovascular mortality and improved function and quality of life.”

Still, CR “has been persistently underused for decades as travel, cost, scheduling, and uneven geographic capacity create real logistical barriers,” said Bachmann, who serves as the medical director of a VA Office of Rural Health home-based CR program. 

Bachmann praised the study methodology and offered this advice to colleagues: “Embed CR referral in the post-MI, post-PCI, and post-CABG order sets so that referral is the default. Scale home-based CR well beyond the roughly 40 sites where it is currently available, and track facility-level referral and enrollment rates as quality measures.”

Preventive cardiology specialist Randal J. Thomas, MD, professor of Medicine at the Mayo Clinic in Rochester, Minn., echoed the importance of physician referral to Federal Practitioner.

“Patients can’t actually participate [directly] in most programs. They must have a physician referral,” he said. “The physician referral and the strength of referral is key. If a physician says, ‘You can go there if you want, but it’s not that important,’ the patients aren’t going to go.”

Outside Perspective: VA Deserves Blame

“The VA lags far behind most medical systems,” according to Quinn R. Pack, MD, associate professor of medicine at the University of Massachusetts Chan Medical School-Baystate. “Some of this is probably the patient population—more mental health problems, more smoking, more disease. But I’d squarely put most of this on the VA health system. They haven’t created the systems of care that make attending cardiac rehabilitation easy, reliable, and consistent.”

He noted that that automatic referral combined with a bedside visit by a liaison such as a representative of a CR program can double or triple enrollment.

“When physicians and nurses really encourage patients to go [to CR], these words are powerful,” Pack said. “When a patient enrolls in cardiac rehabilitation, we help them form new habits of exercise.”

No study fundings are reported. The Varghese discloses a relationship with the Veterans Health Administration. Other study authors had no disclosures. Bachmann disclosed a relationship with the VA. Pack and Thomas have no disclosures. 

Cardiac rehabilitation (CR) remains dramatically underused among US veterans, as < 11% of eligible patients attend a single session and usage appears to be declining over time, a recently published retrospective cohort study reported. 

CR use is much lower among eligible patients across the US Department of Veterans Affairs (VA) compared with Medicare (10.4% vs. 28%, respectively), reported researchers at Veterans Affairs Connecticut Healthcare System and Yale School of Medicine, in JACC: Advances. 

The overall CR rate in the VA was lower than the 13.2% reported in a 2018 study. And while there was no significant difference in use between men and women, veterans from the poorest neighborhoods were less likely to take advantage of CR compared with veterans from the wealthiest neighborhoods (adjusted odds ratio, 0.82; P < .001).

“As providers, the time to act is now,” Merilyn Varghese, MD, MSc, said in an interview with Federal Practitioner. “We need to urgently get more of our veterans to cardiac rehab.”

As Varghese explained, “CR is a preventive intervention that has been shown to improve quality of life and reduce mortality and hospitalizations for patients with specific cardiac conditions.”

Patients may be eligible if they have experienced myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass surgery (CABG), heart transplant, valve surgery, stable angina, or stable heart failure. 

“CR combines multiple aspects of cardiac care such as exercise training, medication management, and behavioral assessments,” Varghese said. “For example, patients who have had a heart attack may have challenges in getting back to an exercise routine, managing new medications, and adjusting to life after such an event. CR can help bridge the gap between hospital to home.” In-person CR typically includes 3 sessions per week for 12 weeks.  

In 2024, a systematic review and meta-analysis reported that CR reduces all-cause mortality (relative risk, 0.74): “These results support the utilization of CR as a critical element in the management of further secondary prevention of CVDs (cardiovascular diseases).”

Examining VA Data

Researchers conducted the 2026 study “to better understand the current landscape of CR among veterans, particularly among women veterans who comprise a significant part of the veteran population but have previously been underrepresented in research,” Varghese said.

“Women veterans also share a different burden of cardiovascular risk factors, so understanding CR participation among both women and men veterans was of particular interest.”

The study tracked 82,496 VA-enrolled veterans eligible for CR from 2021-2023 (3.6% women). Average age of participants were 64.0 years among women and 71.5 years among men. Among women, 58.3% were White, and 31.8% were Black, and 2.24% were Asian. Among men, 71.9% were White, 18.8% were Black, and 2.3% were Asian. 

The rates of CR participation were low among both men (10.4%) and women (10.2%). Older people and Black patients were less likely to take part in CR than younger people and White patients, according to the study. Those who underwent CABG and PCI were more likely to participate in CR compared with those who had heart attacks only.

As for the gap in use between the wealthiest and poorest neighborhoods, Varghese said: “Area deprivation may compound some of the other barriers to CR access, including transportation difficulties, work responsibilities, and out-of-pocket costs.”

How can CR uptake be improved? “A key first step is understanding who can be referred, and second, to spend time discussing the importance of attending with veterans,” Varghese said. “Studies have shown that provider engagement and championing of CR are important positive facilitators that encourage CR participation.

“The VA has been at the forefront of innovation with the home-based CR program that offers veterans a way to attend CR remotely,” she added. “Expanding such novel methods of CR delivery is likely part of the solution to expand CR access.”

Outside Perspective: Make Referrals the Default

Justin Bachmann, MD, MPH, staff physician and research scientist at VA Tennessee Valley Healthcare System, told Federal Practitioner that CR is an American College of Cardiology/American Heart Association Class I recommended secondary prevention therapy following MI, PCI, and CABG “with strong evidence for reduced cardiovascular mortality and improved function and quality of life.”

Still, CR “has been persistently underused for decades as travel, cost, scheduling, and uneven geographic capacity create real logistical barriers,” said Bachmann, who serves as the medical director of a VA Office of Rural Health home-based CR program. 

Bachmann praised the study methodology and offered this advice to colleagues: “Embed CR referral in the post-MI, post-PCI, and post-CABG order sets so that referral is the default. Scale home-based CR well beyond the roughly 40 sites where it is currently available, and track facility-level referral and enrollment rates as quality measures.”

Preventive cardiology specialist Randal J. Thomas, MD, professor of Medicine at the Mayo Clinic in Rochester, Minn., echoed the importance of physician referral to Federal Practitioner.

“Patients can’t actually participate [directly] in most programs. They must have a physician referral,” he said. “The physician referral and the strength of referral is key. If a physician says, ‘You can go there if you want, but it’s not that important,’ the patients aren’t going to go.”

Outside Perspective: VA Deserves Blame

“The VA lags far behind most medical systems,” according to Quinn R. Pack, MD, associate professor of medicine at the University of Massachusetts Chan Medical School-Baystate. “Some of this is probably the patient population—more mental health problems, more smoking, more disease. But I’d squarely put most of this on the VA health system. They haven’t created the systems of care that make attending cardiac rehabilitation easy, reliable, and consistent.”

He noted that that automatic referral combined with a bedside visit by a liaison such as a representative of a CR program can double or triple enrollment.

“When physicians and nurses really encourage patients to go [to CR], these words are powerful,” Pack said. “When a patient enrolls in cardiac rehabilitation, we help them form new habits of exercise.”

No study fundings are reported. The Varghese discloses a relationship with the Veterans Health Administration. Other study authors had no disclosures. Bachmann disclosed a relationship with the VA. Pack and Thomas have no disclosures. 

TOPLINE:

Among US veterans with type 2 diabetes (T2D), adherence to 6 to 8 healthy lifestyle factors combined with GLP‑1 receptor agonist (RA) use was associated with a notably lower risk for major adverse cardiovascular events (MACE) than adherence to three or fewer lifestyle factors without GLP‑1 therapy.

METHODOLOGY:

• GLP-1 RAs help manage cardiovascular risk in patients with T2D; however, lifestyle change remains the foundation of diabetes care. The long-term combined effect of these drugs together with a healthy lifestyle on MACE is not fully understood.
• Researchers conducted a prospective cohort study of 98,261 US veterans with T2D between January 2011 and September 2023, with a follow-up duration of 632,543 person-years, to examine the combined impact of GLP-1 RA use and adherence to eight lifestyle habits on cardiovascular outcomes.
• The 8 low-risk lifestyle habits assessed were healthy eating, regular physical activity (≥ 7.5 metabolic equivalent hours/week), nonsmoking, restful sleep (7-9 hours/day), no or moderate alcohol intake (absence of frequent heavy drinking), good stress management, strong social connection and support, and no opioid use disorder.
• GLP‑1 RA use was ascertained from Veterans Health Administration pharmacy records. The primary outcome was MACE, defined as nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death.

TAKEAWAY:

• Participants adhering to all 8 low-risk lifestyle habits had a 60% lower risk for MACE than those adhering to ≤ 1 (multivariable-adjusted hazard ratio [HR], 0.40; P < .0001).
• All 8 low-risk lifestyle factors were independently associated with a lower risk for MACE, with no opioid use disorder showing the strongest association (HR, 0.77; 95% CI, 0.66-0.89).
• Participants using GLP-1 RAs had a 16% lower risk for MACE than those not receiving GLP-1 therapy and receiving usual care (multivariable-adjusted HR, 0.84; 95% CI, 0.76-0.92).
• Participants using GLP-1 RAs who also adhered to 6 to 8 low-risk lifestyle factors had a 43% lower risk for MACE than those not receiving GLP-1 therapy who adhered to three or fewer lifestyle factors (HR, 0.57; 95% CI, 0.46-0.71).

IN PRACTICE:

"In a healthcare landscape, in which GLP-1 [RAs] remain costly and access is uneven, the additive benefit of lifestyle adherence highlighted by this study has important implications for health equity, resource allocation, and the long-term sustainability of diabetes care," experts noted in an accompanying editorial.

SOURCE:

The study was led by Xuan-Mai T. Nguyen, MD, Department of Medicine, UCLA David Geffen School of Medicine in Los Angeles. It was published online in The Lancet Diabetes & Endocrinology.

LIMITATIONS:

The analyses were based on Veterans Health Administration electronic health record data, and healthcare use outside this system was only incompletely captured. The estimation was based on observational data in which lifestyle factors were assessed at baseline. The cohort consisted of predominantly male veterans, which might limit generalizability to other populations.

DISCLOSURES:

The study used data from the Million Veteran Program (MVP) and was supported by Veterans Affairs MVP awards, along with additional support from other sources. One author reported receiving consulting fees, speaker honoraria, meeting/travel support; participation on advisory boards; and ownership of stock or stock options from certain companies in the healthcare and life sciences sectors. Another author reported receiving a research grant from a consulting/analysis firm.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

Among US veterans with type 2 diabetes (T2D), adherence to 6 to 8 healthy lifestyle factors combined with GLP‑1 receptor agonist (RA) use was associated with a notably lower risk for major adverse cardiovascular events (MACE) than adherence to three or fewer lifestyle factors without GLP‑1 therapy.

METHODOLOGY:

• GLP-1 RAs help manage cardiovascular risk in patients with T2D; however, lifestyle change remains the foundation of diabetes care. The long-term combined effect of these drugs together with a healthy lifestyle on MACE is not fully understood.
• Researchers conducted a prospective cohort study of 98,261 US veterans with T2D between January 2011 and September 2023, with a follow-up duration of 632,543 person-years, to examine the combined impact of GLP-1 RA use and adherence to eight lifestyle habits on cardiovascular outcomes.
• The 8 low-risk lifestyle habits assessed were healthy eating, regular physical activity (≥ 7.5 metabolic equivalent hours/week), nonsmoking, restful sleep (7-9 hours/day), no or moderate alcohol intake (absence of frequent heavy drinking), good stress management, strong social connection and support, and no opioid use disorder.
• GLP‑1 RA use was ascertained from Veterans Health Administration pharmacy records. The primary outcome was MACE, defined as nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death.

TAKEAWAY:

• Participants adhering to all 8 low-risk lifestyle habits had a 60% lower risk for MACE than those adhering to ≤ 1 (multivariable-adjusted hazard ratio [HR], 0.40; P < .0001).
• All 8 low-risk lifestyle factors were independently associated with a lower risk for MACE, with no opioid use disorder showing the strongest association (HR, 0.77; 95% CI, 0.66-0.89).
• Participants using GLP-1 RAs had a 16% lower risk for MACE than those not receiving GLP-1 therapy and receiving usual care (multivariable-adjusted HR, 0.84; 95% CI, 0.76-0.92).
• Participants using GLP-1 RAs who also adhered to 6 to 8 low-risk lifestyle factors had a 43% lower risk for MACE than those not receiving GLP-1 therapy who adhered to three or fewer lifestyle factors (HR, 0.57; 95% CI, 0.46-0.71).

IN PRACTICE:

"In a healthcare landscape, in which GLP-1 [RAs] remain costly and access is uneven, the additive benefit of lifestyle adherence highlighted by this study has important implications for health equity, resource allocation, and the long-term sustainability of diabetes care," experts noted in an accompanying editorial.

SOURCE:

The study was led by Xuan-Mai T. Nguyen, MD, Department of Medicine, UCLA David Geffen School of Medicine in Los Angeles. It was published online in The Lancet Diabetes & Endocrinology.

LIMITATIONS:

The analyses were based on Veterans Health Administration electronic health record data, and healthcare use outside this system was only incompletely captured. The estimation was based on observational data in which lifestyle factors were assessed at baseline. The cohort consisted of predominantly male veterans, which might limit generalizability to other populations.

DISCLOSURES:

The study used data from the Million Veteran Program (MVP) and was supported by Veterans Affairs MVP awards, along with additional support from other sources. One author reported receiving consulting fees, speaker honoraria, meeting/travel support; participation on advisory boards; and ownership of stock or stock options from certain companies in the healthcare and life sciences sectors. Another author reported receiving a research grant from a consulting/analysis firm.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

Among US veterans with type 2 diabetes (T2D), adherence to 6 to 8 healthy lifestyle factors combined with GLP‑1 receptor agonist (RA) use was associated with a notably lower risk for major adverse cardiovascular events (MACE) than adherence to three or fewer lifestyle factors without GLP‑1 therapy.

METHODOLOGY:

• GLP-1 RAs help manage cardiovascular risk in patients with T2D; however, lifestyle change remains the foundation of diabetes care. The long-term combined effect of these drugs together with a healthy lifestyle on MACE is not fully understood.
• Researchers conducted a prospective cohort study of 98,261 US veterans with T2D between January 2011 and September 2023, with a follow-up duration of 632,543 person-years, to examine the combined impact of GLP-1 RA use and adherence to eight lifestyle habits on cardiovascular outcomes.
• The 8 low-risk lifestyle habits assessed were healthy eating, regular physical activity (≥ 7.5 metabolic equivalent hours/week), nonsmoking, restful sleep (7-9 hours/day), no or moderate alcohol intake (absence of frequent heavy drinking), good stress management, strong social connection and support, and no opioid use disorder.
• GLP‑1 RA use was ascertained from Veterans Health Administration pharmacy records. The primary outcome was MACE, defined as nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death.

TAKEAWAY:

• Participants adhering to all 8 low-risk lifestyle habits had a 60% lower risk for MACE than those adhering to ≤ 1 (multivariable-adjusted hazard ratio [HR], 0.40; P < .0001).
• All 8 low-risk lifestyle factors were independently associated with a lower risk for MACE, with no opioid use disorder showing the strongest association (HR, 0.77; 95% CI, 0.66-0.89).
• Participants using GLP-1 RAs had a 16% lower risk for MACE than those not receiving GLP-1 therapy and receiving usual care (multivariable-adjusted HR, 0.84; 95% CI, 0.76-0.92).
• Participants using GLP-1 RAs who also adhered to 6 to 8 low-risk lifestyle factors had a 43% lower risk for MACE than those not receiving GLP-1 therapy who adhered to three or fewer lifestyle factors (HR, 0.57; 95% CI, 0.46-0.71).

IN PRACTICE:

"In a healthcare landscape, in which GLP-1 [RAs] remain costly and access is uneven, the additive benefit of lifestyle adherence highlighted by this study has important implications for health equity, resource allocation, and the long-term sustainability of diabetes care," experts noted in an accompanying editorial.

SOURCE:

The study was led by Xuan-Mai T. Nguyen, MD, Department of Medicine, UCLA David Geffen School of Medicine in Los Angeles. It was published online in The Lancet Diabetes & Endocrinology.

LIMITATIONS:

The analyses were based on Veterans Health Administration electronic health record data, and healthcare use outside this system was only incompletely captured. The estimation was based on observational data in which lifestyle factors were assessed at baseline. The cohort consisted of predominantly male veterans, which might limit generalizability to other populations.

DISCLOSURES:

The study used data from the Million Veteran Program (MVP) and was supported by Veterans Affairs MVP awards, along with additional support from other sources. One author reported receiving consulting fees, speaker honoraria, meeting/travel support; participation on advisory boards; and ownership of stock or stock options from certain companies in the healthcare and life sciences sectors. Another author reported receiving a research grant from a consulting/analysis firm.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

Two studies published in March by researchers at the Veterans Affairs Saint Louis Healthcare System highlight the clinical significance of glucagon-like peptide 1 receptor agonists (GLP-1s) and their impact on reducing substance use disorder (SUD) risks. The studies also explore the impact of GLP-1 discontinuation or interruption on their effectiveness in protection against the cardiovascular events.

In one study, Al-Aly et al assigned 606,434 veterans with type 2 diabetes to 1 of 2 protocols, comparing GLP-1s with sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and followed the patients for up to 3 years. Al-Aly et al found that GLP-1s were “consistently associated” with a lower risk of developing SUDs, including those involving alcohol, cannabis, cocaine, nicotine, and opioids. The findings suggested “potential preventive effects across a broad range of addictive substances.”

In participants with pre-existing SUDs, GLP-1s were also associated with reduced risks of SUD-related emergency department visits, hospital admissions, and mortality, in addition to drug overdoses and suicidal behaviors. A study published in 2025 from the same research group reported that GLP-1s could have a variety of health benefits, including reducing the risk of incident alcohol and cannabis disorders, neurocognitive disorders (such as Alzheimer's disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions, but less was known about the potential for preventing development of opioid use disorder and other SUDs. 

GLP-1s target the brain’s reward pathways and have recently made attention-grabbing headlines regarding celebrity weight loss, with social media boosting public interest. One study, for example, found 100 videos on TikTok with the #Ozempic viewed nearly 70 million times.

Al-Aly et al used SGLT-2 inhibitors as active comparators because “they have no established direct actions on mesolimbic reward circuits in the brain, whereas GLP-1 receptors are present in areas of the brain involved in impulse control and reward signaling.”

The second study found that quitting or pausing GLP-1 treatment for 6 months could have a rebound effect and possibly reverse any progress. Discontinuing GLP-1 treatment is common, with rates ranging from 36% to 81% in the first year. Stopping or interrupting the treatment is often followed by weight regain and a rebound in inflammation, both major drivers in cardiovascular disease risk. 

The study followed 132,551 VA patients using GLP-1s and 201,136 using sulfonylureas from 2017 through 2023. About two-thirds of participants took semaglutide, prescribed as Ozempic to treat diabetes and Wegovy to reduce obesity. A total of 26% of the participants stopped GLP-1 treatment during the follow-up period, with 64% occurring during the first year. Most (67%) treatment interruptions also came in the first year.

Compared with incident use of sulfonylureas, incident use of GLP-1s was associated with a reduced risk of heart attack, stroke, or death. Patients who took the GLP-1s without interruption > 3 years experienced an 18% lower risk for heart attack or stroke.  

Cardiovascular benefits accumulated with continuous use over 3 years, but even brief periods of discontinuations or interruptions could progressively erode and ultimately reverse this protection, the researchers found. Discontinuing treatment for half a year was associated with an increased risk of major adverse cardiovascular events (incidence risk ratio [IRR], 1.04), while longer gaps were progressively associated with a higher risk of disease (IRR, 1.12 for 1 year; IRR, 1.16 for 2 years of interrupted use, respectively).

Dr. Ziyad Al-Aly, a study author and Chief of the Research and Education Service at the Veterans Affairs Saint Louis Healthcare System, called it “metabolic whiplash.” In an interview, he said it was important to caution patients that these medications “need to be taken for the long haul. This is not something (patients) can take for a month or 2 or 3 and get off of it. It's not going to work like that.”

Two studies published in March by researchers at the Veterans Affairs Saint Louis Healthcare System highlight the clinical significance of glucagon-like peptide 1 receptor agonists (GLP-1s) and their impact on reducing substance use disorder (SUD) risks. The studies also explore the impact of GLP-1 discontinuation or interruption on their effectiveness in protection against the cardiovascular events.

In one study, Al-Aly et al assigned 606,434 veterans with type 2 diabetes to 1 of 2 protocols, comparing GLP-1s with sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and followed the patients for up to 3 years. Al-Aly et al found that GLP-1s were “consistently associated” with a lower risk of developing SUDs, including those involving alcohol, cannabis, cocaine, nicotine, and opioids. The findings suggested “potential preventive effects across a broad range of addictive substances.”

In participants with pre-existing SUDs, GLP-1s were also associated with reduced risks of SUD-related emergency department visits, hospital admissions, and mortality, in addition to drug overdoses and suicidal behaviors. A study published in 2025 from the same research group reported that GLP-1s could have a variety of health benefits, including reducing the risk of incident alcohol and cannabis disorders, neurocognitive disorders (such as Alzheimer's disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions, but less was known about the potential for preventing development of opioid use disorder and other SUDs. 

GLP-1s target the brain’s reward pathways and have recently made attention-grabbing headlines regarding celebrity weight loss, with social media boosting public interest. One study, for example, found 100 videos on TikTok with the #Ozempic viewed nearly 70 million times.

Al-Aly et al used SGLT-2 inhibitors as active comparators because “they have no established direct actions on mesolimbic reward circuits in the brain, whereas GLP-1 receptors are present in areas of the brain involved in impulse control and reward signaling.”

The second study found that quitting or pausing GLP-1 treatment for 6 months could have a rebound effect and possibly reverse any progress. Discontinuing GLP-1 treatment is common, with rates ranging from 36% to 81% in the first year. Stopping or interrupting the treatment is often followed by weight regain and a rebound in inflammation, both major drivers in cardiovascular disease risk. 

The study followed 132,551 VA patients using GLP-1s and 201,136 using sulfonylureas from 2017 through 2023. About two-thirds of participants took semaglutide, prescribed as Ozempic to treat diabetes and Wegovy to reduce obesity. A total of 26% of the participants stopped GLP-1 treatment during the follow-up period, with 64% occurring during the first year. Most (67%) treatment interruptions also came in the first year.

Compared with incident use of sulfonylureas, incident use of GLP-1s was associated with a reduced risk of heart attack, stroke, or death. Patients who took the GLP-1s without interruption > 3 years experienced an 18% lower risk for heart attack or stroke.  

Cardiovascular benefits accumulated with continuous use over 3 years, but even brief periods of discontinuations or interruptions could progressively erode and ultimately reverse this protection, the researchers found. Discontinuing treatment for half a year was associated with an increased risk of major adverse cardiovascular events (incidence risk ratio [IRR], 1.04), while longer gaps were progressively associated with a higher risk of disease (IRR, 1.12 for 1 year; IRR, 1.16 for 2 years of interrupted use, respectively).

Dr. Ziyad Al-Aly, a study author and Chief of the Research and Education Service at the Veterans Affairs Saint Louis Healthcare System, called it “metabolic whiplash.” In an interview, he said it was important to caution patients that these medications “need to be taken for the long haul. This is not something (patients) can take for a month or 2 or 3 and get off of it. It's not going to work like that.”

Two studies published in March by researchers at the Veterans Affairs Saint Louis Healthcare System highlight the clinical significance of glucagon-like peptide 1 receptor agonists (GLP-1s) and their impact on reducing substance use disorder (SUD) risks. The studies also explore the impact of GLP-1 discontinuation or interruption on their effectiveness in protection against the cardiovascular events.

In one study, Al-Aly et al assigned 606,434 veterans with type 2 diabetes to 1 of 2 protocols, comparing GLP-1s with sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and followed the patients for up to 3 years. Al-Aly et al found that GLP-1s were “consistently associated” with a lower risk of developing SUDs, including those involving alcohol, cannabis, cocaine, nicotine, and opioids. The findings suggested “potential preventive effects across a broad range of addictive substances.”

In participants with pre-existing SUDs, GLP-1s were also associated with reduced risks of SUD-related emergency department visits, hospital admissions, and mortality, in addition to drug overdoses and suicidal behaviors. A study published in 2025 from the same research group reported that GLP-1s could have a variety of health benefits, including reducing the risk of incident alcohol and cannabis disorders, neurocognitive disorders (such as Alzheimer's disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions, but less was known about the potential for preventing development of opioid use disorder and other SUDs. 

GLP-1s target the brain’s reward pathways and have recently made attention-grabbing headlines regarding celebrity weight loss, with social media boosting public interest. One study, for example, found 100 videos on TikTok with the #Ozempic viewed nearly 70 million times.

Al-Aly et al used SGLT-2 inhibitors as active comparators because “they have no established direct actions on mesolimbic reward circuits in the brain, whereas GLP-1 receptors are present in areas of the brain involved in impulse control and reward signaling.”

The second study found that quitting or pausing GLP-1 treatment for 6 months could have a rebound effect and possibly reverse any progress. Discontinuing GLP-1 treatment is common, with rates ranging from 36% to 81% in the first year. Stopping or interrupting the treatment is often followed by weight regain and a rebound in inflammation, both major drivers in cardiovascular disease risk. 

The study followed 132,551 VA patients using GLP-1s and 201,136 using sulfonylureas from 2017 through 2023. About two-thirds of participants took semaglutide, prescribed as Ozempic to treat diabetes and Wegovy to reduce obesity. A total of 26% of the participants stopped GLP-1 treatment during the follow-up period, with 64% occurring during the first year. Most (67%) treatment interruptions also came in the first year.

Compared with incident use of sulfonylureas, incident use of GLP-1s was associated with a reduced risk of heart attack, stroke, or death. Patients who took the GLP-1s without interruption > 3 years experienced an 18% lower risk for heart attack or stroke.  

Cardiovascular benefits accumulated with continuous use over 3 years, but even brief periods of discontinuations or interruptions could progressively erode and ultimately reverse this protection, the researchers found. Discontinuing treatment for half a year was associated with an increased risk of major adverse cardiovascular events (incidence risk ratio [IRR], 1.04), while longer gaps were progressively associated with a higher risk of disease (IRR, 1.12 for 1 year; IRR, 1.16 for 2 years of interrupted use, respectively).

Dr. Ziyad Al-Aly, a study author and Chief of the Research and Education Service at the Veterans Affairs Saint Louis Healthcare System, called it “metabolic whiplash.” In an interview, he said it was important to caution patients that these medications “need to be taken for the long haul. This is not something (patients) can take for a month or 2 or 3 and get off of it. It's not going to work like that.”

TOPLINE:

Veterans received a diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) a median of 490 days after heart failure (HF) diagnosis. Those who had atrial fibrillation, coronary artery disease, or chronic kidney disease experienced longer diagnostic delays, whereas older or Black patients experienced shorter delays.

METHODOLOGY:

• Researchers conducted a retrospective cohort study using data from the US Veterans Health Administration to quantify the time from HF diagnosis to ATTR-CM diagnosis and identify predictors of delays in diagnosis.
• They included veterans with HF and incident ATTR-CM diagnosed between 2016 and 2022; these veterans were identified using an algorithm based on diagnoses and medications.
• The final analysis included 2557 veterans, with a median age of 80.5 years; 99.5% were men, and 56.3% were White individuals.
• Assessments captured the time from the first HF diagnosis, the first outpatient prescription for a loop diuretic, and the first hospitalization for HF to the first ATTR-CM diagnosis, along with demographics and comorbidities.
• The primary outcome was the number of days from incident HF diagnosis to incident ATTR-CM diagnosis; a delay of > 6 months was considered meaningful.

TAKEAWAY:

• The median time from HF diagnosis to ATTR-CM diagnosis was 490 days. Overall, 65% of veterans experienced diagnostic delays > 6 months, and > 25% had delays longer than 3 years.
• Factors associated with a shorter time to ATTR-CM diagnosis included Black race (adjusted odds ratio [aOR], 0.71; 95% CI, 0.57-0.88) and older age (aOR per 10 years, 0.66; 95% CI, 0.59-0.73).
• The likelihood of longer diagnostic delays was higher in patients with coronary artery disease (aOR, 1.38; 95% CI, 1.15-1.64) and chronic kidney disease (aOR, 1.79; 95% CI, 1.50-2.15). Those with atrial fibrillation were more likely to have longer delays, although the lower bound of 95% CI was borderline (aOR, 1.21; 95% CI, 1.00-1.45).
• Among veterans with prior prescriptions of loop diuretics, the median time from the first prescription to ATTR-CM diagnosis was 835 days. Among those with a prior hospitalization for HF, the median time from hospitalization to ATTR-CM diagnosis was 300 days.

IN PRACTICE:

“This study supports the need for increased testing for ATTR-CM, thorough evaluation of cardiomyopathy etiologies at the time of HF diagnosis, and the need for new interventions that shorten the diagnostic delay in ATTR-CM,” the researchers reported.

SOURCE:

This study was led by Gabriela Spencer-Bonilla, MD, MSc, of Stanford University School of Medicine in Stanford, California. It was published online on JACC .

LIMITATIONS:

The analysis was limited to veterans engaged long enough for diagnoses of both HF and ATTR-CM. The findings may not be generalized to women given the predominantly male cohort. Echocardiography and ATTR subtype or genetic data were unavailable.

DISCLOSURES:

This study received funding from AstraZeneca. Four authors reported being the employees and stockholders of AstraZeneca. Several authors reported receiving research funding, consulting fees, and/or having equity in multiple pharmaceutical and healthcare companies, including Novo Nordisk, Bridge Bio, and Pfizer. Two authors reported receiving support from the American Heart Association, with one of them also receiving support from the National Institutes of Health.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

Veterans received a diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) a median of 490 days after heart failure (HF) diagnosis. Those who had atrial fibrillation, coronary artery disease, or chronic kidney disease experienced longer diagnostic delays, whereas older or Black patients experienced shorter delays.

METHODOLOGY:

• Researchers conducted a retrospective cohort study using data from the US Veterans Health Administration to quantify the time from HF diagnosis to ATTR-CM diagnosis and identify predictors of delays in diagnosis.
• They included veterans with HF and incident ATTR-CM diagnosed between 2016 and 2022; these veterans were identified using an algorithm based on diagnoses and medications.
• The final analysis included 2557 veterans, with a median age of 80.5 years; 99.5% were men, and 56.3% were White individuals.
• Assessments captured the time from the first HF diagnosis, the first outpatient prescription for a loop diuretic, and the first hospitalization for HF to the first ATTR-CM diagnosis, along with demographics and comorbidities.
• The primary outcome was the number of days from incident HF diagnosis to incident ATTR-CM diagnosis; a delay of > 6 months was considered meaningful.

TAKEAWAY:

• The median time from HF diagnosis to ATTR-CM diagnosis was 490 days. Overall, 65% of veterans experienced diagnostic delays > 6 months, and > 25% had delays longer than 3 years.
• Factors associated with a shorter time to ATTR-CM diagnosis included Black race (adjusted odds ratio [aOR], 0.71; 95% CI, 0.57-0.88) and older age (aOR per 10 years, 0.66; 95% CI, 0.59-0.73).
• The likelihood of longer diagnostic delays was higher in patients with coronary artery disease (aOR, 1.38; 95% CI, 1.15-1.64) and chronic kidney disease (aOR, 1.79; 95% CI, 1.50-2.15). Those with atrial fibrillation were more likely to have longer delays, although the lower bound of 95% CI was borderline (aOR, 1.21; 95% CI, 1.00-1.45).
• Among veterans with prior prescriptions of loop diuretics, the median time from the first prescription to ATTR-CM diagnosis was 835 days. Among those with a prior hospitalization for HF, the median time from hospitalization to ATTR-CM diagnosis was 300 days.

IN PRACTICE:

“This study supports the need for increased testing for ATTR-CM, thorough evaluation of cardiomyopathy etiologies at the time of HF diagnosis, and the need for new interventions that shorten the diagnostic delay in ATTR-CM,” the researchers reported.

SOURCE:

This study was led by Gabriela Spencer-Bonilla, MD, MSc, of Stanford University School of Medicine in Stanford, California. It was published online on JACC .

LIMITATIONS:

The analysis was limited to veterans engaged long enough for diagnoses of both HF and ATTR-CM. The findings may not be generalized to women given the predominantly male cohort. Echocardiography and ATTR subtype or genetic data were unavailable.

DISCLOSURES:

This study received funding from AstraZeneca. Four authors reported being the employees and stockholders of AstraZeneca. Several authors reported receiving research funding, consulting fees, and/or having equity in multiple pharmaceutical and healthcare companies, including Novo Nordisk, Bridge Bio, and Pfizer. Two authors reported receiving support from the American Heart Association, with one of them also receiving support from the National Institutes of Health.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.

TOPLINE:

Veterans received a diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) a median of 490 days after heart failure (HF) diagnosis. Those who had atrial fibrillation, coronary artery disease, or chronic kidney disease experienced longer diagnostic delays, whereas older or Black patients experienced shorter delays.

METHODOLOGY:

• Researchers conducted a retrospective cohort study using data from the US Veterans Health Administration to quantify the time from HF diagnosis to ATTR-CM diagnosis and identify predictors of delays in diagnosis.
• They included veterans with HF and incident ATTR-CM diagnosed between 2016 and 2022; these veterans were identified using an algorithm based on diagnoses and medications.
• The final analysis included 2557 veterans, with a median age of 80.5 years; 99.5% were men, and 56.3% were White individuals.
• Assessments captured the time from the first HF diagnosis, the first outpatient prescription for a loop diuretic, and the first hospitalization for HF to the first ATTR-CM diagnosis, along with demographics and comorbidities.
• The primary outcome was the number of days from incident HF diagnosis to incident ATTR-CM diagnosis; a delay of > 6 months was considered meaningful.

TAKEAWAY:

• The median time from HF diagnosis to ATTR-CM diagnosis was 490 days. Overall, 65% of veterans experienced diagnostic delays > 6 months, and > 25% had delays longer than 3 years.
• Factors associated with a shorter time to ATTR-CM diagnosis included Black race (adjusted odds ratio [aOR], 0.71; 95% CI, 0.57-0.88) and older age (aOR per 10 years, 0.66; 95% CI, 0.59-0.73).
• The likelihood of longer diagnostic delays was higher in patients with coronary artery disease (aOR, 1.38; 95% CI, 1.15-1.64) and chronic kidney disease (aOR, 1.79; 95% CI, 1.50-2.15). Those with atrial fibrillation were more likely to have longer delays, although the lower bound of 95% CI was borderline (aOR, 1.21; 95% CI, 1.00-1.45).
• Among veterans with prior prescriptions of loop diuretics, the median time from the first prescription to ATTR-CM diagnosis was 835 days. Among those with a prior hospitalization for HF, the median time from hospitalization to ATTR-CM diagnosis was 300 days.

IN PRACTICE:

“This study supports the need for increased testing for ATTR-CM, thorough evaluation of cardiomyopathy etiologies at the time of HF diagnosis, and the need for new interventions that shorten the diagnostic delay in ATTR-CM,” the researchers reported.

SOURCE:

This study was led by Gabriela Spencer-Bonilla, MD, MSc, of Stanford University School of Medicine in Stanford, California. It was published online on JACC .

LIMITATIONS:

The analysis was limited to veterans engaged long enough for diagnoses of both HF and ATTR-CM. The findings may not be generalized to women given the predominantly male cohort. Echocardiography and ATTR subtype or genetic data were unavailable.

DISCLOSURES:

This study received funding from AstraZeneca. Four authors reported being the employees and stockholders of AstraZeneca. Several authors reported receiving research funding, consulting fees, and/or having equity in multiple pharmaceutical and healthcare companies, including Novo Nordisk, Bridge Bio, and Pfizer. Two authors reported receiving support from the American Heart Association, with one of them also receiving support from the National Institutes of Health.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article first appeared on Medscape.com.