The vaccines against human papillomavirus (HPV) are the only ones designed to prevent cancer caused by a virus^1,2—surely a good goal. But because HPV is sexually transmitted, HPV vaccination has met with public controversy.³ To counter the objections and better protect their patients’ health, primary care providers and other clinicians need a clear understanding of the benefits and the low risk of HPV vaccination—and the reasons so many people object to it.³

In this article, we will review:

• The impact of HPV-related diseases
• The basic biologic features of HPV vaccines
• The host immune response to natural HPV infection vs the response to HPV vaccines
• The clinical efficacy and safety of HPV vaccines
• The latest guidelines for HPV vaccination
• The challenges to vaccination implementation
• Frequently asked practical questions about HPV vaccination.

HPV-RELATED DISEASES: FROM BOTHERSOME TO DEADLY

Clinical sequelae of HPV infection include genital warts; cancers of the cervix, vulva, vagina, anus, penis, and oropharynx; and recurrent respiratory papillomatosis.^4–6

Genital warts

HPV types 6 and 11 are responsible for more than 90% of the 1 million new cases of genital warts diagnosed annually in the United States.^7–10

Bothersome and embarrassing, HPV-related genital warts can cause itching, burning, erythema, and pain, as well as epithelial erosions, ulcerations, depigmentation, and urethral and vaginal bleeding and discharge.^11,12 Although they are benign in the oncologic sense, they can cause a good deal of emotional and financial stress. Patients may feel anxiety, embarrassment,¹³ and vulnerability. Adolescents and adults who have or have had genital warts need to inform their current and future partners or else risk infecting them—and facing the consequences.

Direct health care costs of genital warts in the United States have been estimated to be at least $200 million per year.¹⁴

Cervical cancer

Cervical cancer cannot develop unless the cervical epithelium is infected with one of the oncogenic HPV types. Indeed, oncogenic HPV is present in as many as 99.8% of cervical cancer specimens.¹⁵ HPV 16 and 18 are the most oncogenic HPV genotypes and account for 75% of all cases of cervical cancer. Ten other HPV genotypes account for the remaining 25%.¹⁶

In 2012, there were an estimated 12,170 new cases of invasive cervical cancer in the United States and 4,220 related deaths.¹⁷ The cost associated with cervical cancer screening, managing abnormal findings, and treating invasive cervical cancer in the United States is estimated to be $3.3 billion per year.¹⁸

Although the incidence and the mortality rates of cervical cancer have decreased more than 50% in the United States over the past 3 decades thanks to screening,¹⁹ cervical cancer remains the second leading cause of death from cancer in women worldwide. Each year, an estimated 500,000 women contract the disease and 240,000 die of it.²⁰

Anal cancer

A recent study indicated that oncogenic HPV can also cause anal cancer, and the proportion of such cancers associated with HPV 16 or HPV 18 infection is as high as or higher than for cervical cancers, and estimated at 80%.²¹

The incidence of anal cancer is increasing by approximately 2% per year in both men and women in the general population,²² and rates are even higher in men who have sex with men and people infected with the human immunodeficiency virus.²³

Hu and Goldie²⁴ estimated that the lifetime costs of caring for all the people in the United States who in just 1 year (2003) acquired anal cancer attributable to HPV would total $92 million.

Oropharyngeal cancer

HPV types 16, 18, 31, 33, and 35 also cause oropharyngeal cancer. HPV 16 accounts for more than 90% of cases of HPV-related oropharyngeal cancer.²⁵

Chaturvedi et al⁶ tested tissue samples from three national cancer registries and found that the number of oropharyngeal cancers that were HPV-positive increased from 16.3% in 1984–1989 to 71.7% in 2000–2004, while the number of HPV-negative oropharyngeal cancers fell by 50%, paralleling the drop in cigarette smoking in the United States.

Hu and Goldie²⁴ estimated that the total lifetime cost for all new HPV-related oropharyngeal cancers that arose in 2003 would come to $38.1 million.²⁴

Vulvar and vaginal cancers

HPV 16 and 18 are also responsible for approximately 50% of vulvar cancers and 50% to 75% of vaginal cancers.^4,5

Recurrent respiratory papillomatosis

HPV 6 and 11 cause almost all cases of juvenile- and adult-onset recurrent respiratory papillomatosis.²⁶ The annual cost for surgical procedures for this condition in the United States has been estimated at $151 million.²⁷

HPV VACCINES ARE NONINFECTIOUS AND NONCARCINOGENIC

Currently, two HPV vaccines are available: a quadrivalent vaccine against types 6, 11, 16, and 18 (Gardasil; Merck) and a bivalent vaccine against types 16 and 18 (Cervarix; Glaxo-SmithKline). The quadrivalent vaccine was approved by the US Food and Drug Administration (FDA) in 2006, and the bivalent vaccine was approved in 2009.^28,29

Both vaccines contain virus-like particles, ie, viral capsids that contain no DNA. HPV has a circular DNA genome of 8,000 nucleotides divided into two regions: the early region, for viral replication, and the late region, for viral capsid production. The host produces neutralizing antibodies in response to the L1 capsid protein, which is different in different HPV types.

In manufacturing the vaccines, the viral L1 gene is incorporated into a yeast genome or an insect virus genome using recombinant DNA technology (Figure 1). Grown in culture, the yeast or the insect cells produce the HPV L1 major capsid protein, which has the intrinsic capacity to self-assemble into virus-like particles.^30–33 These particles are subsequently purified for use in the vaccines.³⁴

Recombinant virus-like particles are morphologically indistinguishable from authentic HPV virions and contain the same typespecific antigens present in authentic virions. Therefore, they are highly effective in inducing a host humoral immune response. And because they do not contain HPV DNA, the recombinant HPV vaccines are noninfectious and noncarcinogenic.³⁵

VACCINATION INDUCES A STRONGER IMMUNE RESPONSE THAN INFECTION

HPV infections trigger both a humoral and a cellular response in the host immune system.

The humoral immune response to HPV infection involves producing neutralizing antibody against the specific HPV type, specifically the specific L1 major capsid protein. This process is typically somewhat slow and weak, and only about 60% of women with a new HPV infection develop antibodies to it.^36,37

HPV has several ways to evade the host immune system. It does not infect or replicate within the antigen-presenting cells in the epithelium. In addition, HPV-infected keratinocytes are less susceptible to cytotoxic lymphocytic-mediated lysis. Moreover, HPV infection cause very little tissue destruction. And finally, natural cervical HPV infection does not result in viremia. As a result, antigen-presenting cells have no chance to engulf the virions and present virion-derived antigen to the host immune system. The immune system outside the epithelium has limited opportunity to detect the virus because HPV infection does not have a blood-borne phase.^38,39

The cell-mediated immune response to early HPV oncoproteins may help eliminate established HPV infection.⁴⁰ In contrast to antibodies, the T-cell response to HPV has not been shown to be specific to HPV type.⁴¹ Clinically, cervical HPV infection is common, but most lesions go into remission or resolve as a result of the cell-mediated immune response.^40,41

In contrast to the weak, somewhat ineffective immune response to natural HPV infection, the antibody response to HPV vaccines is rather robust. In randomized controlled trials, almost all vaccinated people have seroconverted. The peak antibody concentrations are 50 to 10,000 times greater than in natural infection. Furthermore, the neutralizing antibodies induced by HPV vaccines persist for as long as 7 to 9 years after immunization.⁴² However, the protection provided by HPV vaccines against HPV-related cervical intraepithelial neoplasia does not necessarily correlate with the antibody concentration.^43–47

Why does the vaccine work so well?

Why are vaccine-induced antibody responses so much stronger than those induced by natural HPV infection?

The first reason is that the vaccine, delivered intramuscularly, rapidly enters into blood vessels and the lymphatic system. In contrast, in natural intraepithelial infection, the virus is shed from mucosal surfaces and does not result in viremia.⁴⁸

In addition, the strong immunogenic nature of the virus-like particles induces a robust host antibody response even in the absence of adjuvant because of concentrated neutralizing epitopes and excellent induction of the T-helper cell response.^35,49,50

The neutralizing antibody to L1 prevents HPV infection by blocking HPV from binding to the basement membrane as well as to the epithelial cell receptor during epithelial microabrasion and viral entry. The subsequent micro-wound healing leads to serous exudation and rapid access of serum immunoglobulin G (IgG) to HPV virus particles and encounters with circulatory B memory cells.

Furthermore, emerging evidence suggests that even very low antibody concentrations are sufficient to prevent viral entry into cervical epithelial cells.^{46–48,51–53}

THE HPV VACCINES ARE HIGHLY EFFECTIVE AND SAFE

The efficacy and safety of the quadrivalent and the bivalent HPV vaccines have been evaluated in large randomized clinical trials.^{23,28,29,54,55} Table 1 summarizes the key findings.

The Females United to Unilaterally Reduce Endo/ectocervical Disease (FUTURE I)⁵⁴ and FUTURE II²⁸ trials showed conclusively that the quadrivalent HPV vaccine is 98% to 100% efficacious in preventing HPV 16- and 18-related cervical intraepithelial neoplasia, carcinoma in situ, and invasive cervical cancer in women who had not been infected with HPV before. Similarly, the Papilloma Trial against Cancer in Young Adults (PATRICIA) concluded that the bivalent HPV vaccine is 93% efficacious.²⁹

Giuliano et al⁵⁵ and Palefsky et al²³ conducted randomized clinical trials of the quadrivalent HPV vaccine for preventing genital disease and anal intraepithelial neoplasia in boys and men; the efficacy rates were 90.4%⁵⁵ and 77.5%.²³

A recent Finnish trial in boys age 10 to 18 found 100% seroconversion rates for HPV 16 and HPV 18 antibodies after they received bivalent HPV vaccine.⁵⁶ Similar efficacy has been demonstrated for the quadrivalent HPV vaccine in boys.⁵⁷

Adverse events after vaccination

After the FDA approved the quadrivalent HPV vaccine for girls in 2006, the US Centers for Disease Control and Prevention (CDC) conducted a thorough survey of adverse events after immunization from June 1, 2006 through December 31, 2008.⁵⁸ There were about 54 reports of adverse events per 100,000 distributed vaccine doses, similar to rates for other vaccines. However, the incidence rates of syncope and venous thrombosis were disproportionately higher, according to data from the US Vaccine Adverse Event Reporting System. The rate of syncope was 8.2 per 100,000 vaccine doses, and the rate of venous thrombotic events was 0.2 per 100,000 doses.⁵⁸

There were 32 reports of deaths after HPV vaccination, but these were without clear causation. Hence, this information must be interpreted with caution and should not be used to infer causal associations between HPV vaccines and adverse outcomes. The causes of death included diabetic ketoacidosis, pulmonary embolism, prescription drug abuse, amyotrophic lateral sclerosis, meningoencephalitis, influenza B viral sepsis, arrhythmia, myocarditis, and idiopathic seizure disorder.⁵⁸

Furthermore, it is important to note that vasovagal syncope and venous thromboembolic events are more common in young females in general.⁵⁹ For example, the background rates of venous thromboembolism in females age 14 to 29 using oral contraceptives is 21 to 31 per 100,000 woman-years.⁶⁰

Overall, the quadrivalent HPV vaccine is well tolerated and clinically safe. Postlicensure evaluation found that the quadrivalent and bivalent HPV vaccines had similar safety profiles.⁶¹

Vaccination is contraindicated in people with known hypersensitivity or prior severe allergic reactions to vaccine or yeast or who have bleeding disorders.

HPV VACCINATION DOES MORE THAN PREVENT CERVICAL CANCER IN FEMALES

The quadrivalent HPV vaccine was licensed by the FDA in 2006 for use in females age 9 to 26 to prevent cervical cancer, cervical cancer precursors, vaginal and vulval cancer precursors, and anogenital warts caused by HPV types 6, 11, 16, and 18. The CDC’s Advisory Committee on Immunization Practices (ACIP) issued its recommendation for initiating HPV vaccination for females age 11 to 12 in March 2007. The ACIP stated that the vaccine could be given to girls as early as age 9 and recommended catch-up vaccinations for those age 13 to 26.^62,63

The quadrivalent HPV vaccine was licensed by the FDA in 2009 for use in boys and men for the prevention of genital warts. In December 2010, the quadrivalent HPV vaccine received extended licensure from the FDA for use in males and females for the prevention of anal cancer. In October 2011, the ACIP voted to recommend routine use of the quadrivalent HPV vaccine for boys age 11 to 12; catch-up vaccination should occur for those age 13 to 22, with an option to vaccinate men age 23 to 26.

These recommendations replace the “permissive use” recommendations from the ACIP in October 2009 that said the quadrivalent HPV vaccine may be given to males age 9 to 26.⁶⁴ This shift from a permissive to an active recommendation connotes a positive change reflecting recognition of rising oropharyngeal cancer rates attributable to oncogenic, preventable HPV, rising HPV-related anal cancer incidence, and the burden of the disease in female partners of infected men, with associated rising health care costs.

The bivalent HPV vaccine received FDA licensure in October 2009 for use in females age 10 to 25 to prevent cervical cancer and precursor lesions. The ACIP included the bivalent HPV vaccine in its updated recommendations in May 2010 for use in girls age 11 to 12. Numerous national and international organizations have endorsed HPV vaccination.^65–71

Table 2 outlines the recommendations from these organizations.

HPV VACCINATION RATES ARE STILL LOW

HPV vaccine offers us the hope of eventually eradicating cervical cancer. However, the immunization program still faces many challenges, since HPV vaccination touches on issues related to adolescent sexuality, parental autonomy, and cost. As a result, HPV immunization rates remain relatively low in the United States according to several national surveys. Only 40% to 49% of girls eligible for the vaccine received even one dose, and of those who received even one dose, only 32% to 53.3% came back for all three doses.^72–75 Furthermore, indigent and minority teens were less likely to finish the three-dose HPV vaccine series.

Why are the vaccination rates so low?

Parental barriers. In one survey,⁷³ reasons that parents gave for not having their daughters vaccinated included:

• Lack of knowledge of the vaccine (19.4%)
• Lack of perceived need for the vaccine (18.8%)
• Belief that their daughter was not sexually active (18.3%)
• Clinician not recommending vaccination (13.1%).

In an effort to improve HPV vaccination rates,⁴¹ several states proposed legislation for mandatory HPV vaccination of schoolgirls shortly after licensure of the quadrivalent HPV vaccine.³ Since then, we have seen a wave of public opposition rooted in concerns and misinformation about safety, teenage sexuality, governmental coercion, and cost. Widespread media coverage has also highlighted unsubstantiated claims about side effects attributable to the vaccine that can raise parents’ mistrust of vaccines.⁷⁶ Concerns have also been raised about a threat to parental autonomy in how and when to educate their children about sex.⁷⁷

Moreover, the vaccine has raised ethical concerns in some parents and politicians that mandatory vaccination could undermine abstinence messages in sexual education and may alter sexual activity by condoning risky behavior.⁷⁸ However, a recent study indicated that there is no significant change in sexual behavior related to HPV vaccination in young girls.⁷⁹

In 2012, Mullins et al⁸⁰ also found that an urban population of adolescent girls (76.4% black, 57.5% sexually experienced) did not feel they could forgo safer sexual practices after first HPV vaccination, although the girls did perceive less risk from HPV than from other sexually transmitted infections after HPV vaccination (P < .001).⁸⁰ Inadequate knowledge about HPV-related disease and HPV vaccine correlated with less perceived risk from HPV after vaccination among the girls, and a lack of knowledge about HPV and less communication with their daughters about HPV correlated with less perceived risk from HPV in the mothers of the study population.⁸¹

Health-care-provider barriers. Physician endorsement of vaccines represents a key predictor of vaccine acceptance by patients, families, and other clinicians.^82–84 In 2008, a cross-sectional, Internet-based survey of 1,122 Texas pediatricians, family practice physicians, obstetricians, gynecologists, and internal medicine physicians providing direct patient care found that only 48.5% always recommended HPV vaccination to girls.⁷⁴ Of all respondents, 68.4% were likely to recommend the vaccine to boys, and 41.7% agreed with mandated vaccination. Thus, more than half of the physicians were not following the current recommendations for universal HPV vaccination for 11- to -12-year-olds.

In a survey of 1,013 physicians during the spring and summer of 2009, only 34.6% said they always recommend HPV vaccination to early adolescents, 52.7% to middle adolescents, and 50.2% to late adolescents and young adults.⁸⁵ Pediatricians were more likely than family physicians and obstetrician-gynecologists to always recommend HPV vaccine across all age groups (P < .001). Educational interventions targeting various specialties may help overcome physician-related barriers to immunization.⁸⁵

Financial barriers. HPV vaccine, which must be given in three doses, is more expensive than other vaccines, and this expense is yet another barrier, especially for the uninsured.⁸⁶ Australia launched a government-funded program of HPV vaccination (with the quadrivalent vaccine) in schools in 2007, and it has been very successful. Garland et al⁸⁷ reported that new cases of genital warts have decreased by 73% since the program began, and the rate of high-grade abnormalities on Papanicolaou testing has declined by a small but significant amount.

For HPV vaccination to have an impact on public health, vaccination rates in the general population need to be high. In order to achieve these rates, we need to educate our patients on vaccine safety and efficacy and counsel vaccine recipients about the prevention of sexually transmitted infections and the importance of regular cervical cancer screening after age 21. Clinicians can actively “myth-bust” with patients, who may not realize that the vaccine should be given despite a history of HPV infection or abnormal Pap smear.

FREQUENTLY ASKED QUESTIONS

What if the patient is late for a shot?

The current recommended vaccination schedule for the bivalent and quadrivalent HPV vaccines is a three-dose series administered at 0, 2, and 6 months, given as an intramuscular injection, preferably in the deltoid muscle. The minimal dosing interval is 4 weeks between the first and second doses and 12 weeks between the second and third doses.

The vaccines use different adjuncts with different specific mechanisms for immunogenicity; therefore, it is recommended that the same vaccine be used for the entire three-dose series. However, if circumstances preclude the completion of a series with the same vaccine, the other HPV vaccine may be used.⁶³ Starting the series over is not recommended.

Long-term studies demonstrated clinical efficacy 8.5 years after vaccination.⁴⁷ Amnestic response by virtue of activation of pools of memory B cells has been demonstrated, suggesting the vaccine may afford lifelong immunity.⁸⁸

Is a pregnancy test needed before HPV vaccination?

The ACIP states that pregnancy testing is not required before receiving either of the available HPV vaccines.

A recent retrospective review of phase III efficacy trials and pregnancy registry surveillance data for both vaccines revealed no increase in spontaneous abortions, fetal malformations, or adverse pregnancy outcomes.⁸⁹ Data are limited on bivalent and quadrivalent HPV vaccine given within 30 days of pregnancy and subsequent pregnancy and fetal outcomes. Both vaccines have been assigned a pregnancy rating of category B; however, the ACIP recommends that neither vaccine be given if the recipient is known to be pregnant. If pregnancy occurs, it is recommended that the remainder of the series be deferred until after delivery.⁶²

It is not known whether the vaccine is excreted in breast milk. The manufacturers of both the bivalent and quadrivalent HPV vaccines recommend caution when vaccinating lactating women.^30,31

Can HPV vaccine be given with other vaccines?

In randomized trials, giving the bivalent HPV vaccine with the combined hepatitis A, hepatitis B, meningococcal conjugate and the combined tetanus, diphtheria, and acellular pertussis vaccines did not interfere with the immunogenic response, was safe, and was well tolerated.^90,91 Coadministration of the quadrivalent HPV vaccine has been studied only with hepatitis B vaccine, with similar safety and efficacy noted.

The ACIP recommends giving HPV vaccine at the same visit with other age-appropriate immunizations to increase the likelihood of adherence to recommended vaccination schedules.⁶²

Is HPV vaccination cost-effective?

Kim and Goldie⁸⁶ performed a cost-effectiveness analysis of HPV vaccination of girls at age 12 and catch-up vaccination up to the ages of 18, 21, and 26. For their analysis, they considered prevention of cancers associated with HPV types 16 and 18, of genital warts associated with types 6 and 11, and of recurrent respiratory papillomatosis. They also assumed that immunity would be lifelong, and current screening practices would continue.

They calculated that routine vaccination of 12-year-old girls resulted in an incremental cost-effective ratio of $34,900 per quality-adjusted life-year (QALY) gained. A threshold of less than $50,000 per QALY gained is considered reasonably cost-effective, with an upper limit of $100,000 considered acceptable.⁹²

In the same analysis by Kim and Goldie,⁸⁶ catch-up vaccination of girls through age 18 resulted in a cost of $50,000 to $100,000 per QALY gained, and catch-up vaccination of females through age 26 was significantly less cost-effective at more then $130,000 per QALY gained. The vaccine was also significantly less cost-effective if 5% of the population was neither screened nor vaccinated, if a 10-year booster was required, and if frequent cervical cancer screening intervals were adopted.

This analysis did not include costs related to the evaluation and treatment of abnormal Pap smears and cross-protection against other HPV-related cancers.

The cost-effectiveness of HPV vaccination depends on reaching more girls at younger ages (ideally before sexual debut) and completing the three-dose schedule to optimize duration of immunity.⁹² Appropriate modification of the current recommendations for the intervals of cervical cancer screening for vaccinated individuals will further improve the cost-effectiveness of vaccination. The inclusion of male vaccination generally has more favorable cost per QALY in scenarios in which female coverage rates are less than 50%⁹³ and among men who have sex with men.⁹⁴

TO ERADICATE CERVICAL CANCER

Given the remarkable efficacy and expected long-term immunogenicity of HPV vaccines, we anticipate a decline in HPV-related cervical cancer and other related diseases in the years to come. However, modeling studies predicting the impact of HPV vaccination suggest that although substantial reductions in diseases can be expected, the benefit, assuming high vaccination rates, will not be apparent for at least another decade.⁹⁵ Furthermore, the current HPV vaccines contain only HPV 16 and 18 L1 protein for cancer protection and, therefore, do not provide optimal protection against all oncogenic HPV-related cancers.

The real hope of eradicating cervical cancer and all HPV-related disease relies on a successful global implementation of multivalent HPV vaccination, effective screening strategies, and successful treatment.

The vaccines against human papillomavirus (HPV) are the only ones designed to prevent cancer caused by a virus^1,2—surely a good goal. But because HPV is sexually transmitted, HPV vaccination has met with public controversy.³ To counter the objections and better protect their patients’ health, primary care providers and other clinicians need a clear understanding of the benefits and the low risk of HPV vaccination—and the reasons so many people object to it.³

In this article, we will review:

• The impact of HPV-related diseases
• The basic biologic features of HPV vaccines
• The host immune response to natural HPV infection vs the response to HPV vaccines
• The clinical efficacy and safety of HPV vaccines
• The latest guidelines for HPV vaccination
• The challenges to vaccination implementation
• Frequently asked practical questions about HPV vaccination.

HPV-RELATED DISEASES: FROM BOTHERSOME TO DEADLY

Clinical sequelae of HPV infection include genital warts; cancers of the cervix, vulva, vagina, anus, penis, and oropharynx; and recurrent respiratory papillomatosis.^4–6

Genital warts

HPV types 6 and 11 are responsible for more than 90% of the 1 million new cases of genital warts diagnosed annually in the United States.^7–10

Bothersome and embarrassing, HPV-related genital warts can cause itching, burning, erythema, and pain, as well as epithelial erosions, ulcerations, depigmentation, and urethral and vaginal bleeding and discharge.^11,12 Although they are benign in the oncologic sense, they can cause a good deal of emotional and financial stress. Patients may feel anxiety, embarrassment,¹³ and vulnerability. Adolescents and adults who have or have had genital warts need to inform their current and future partners or else risk infecting them—and facing the consequences.

Direct health care costs of genital warts in the United States have been estimated to be at least $200 million per year.¹⁴

Cervical cancer

Cervical cancer cannot develop unless the cervical epithelium is infected with one of the oncogenic HPV types. Indeed, oncogenic HPV is present in as many as 99.8% of cervical cancer specimens.¹⁵ HPV 16 and 18 are the most oncogenic HPV genotypes and account for 75% of all cases of cervical cancer. Ten other HPV genotypes account for the remaining 25%.¹⁶

In 2012, there were an estimated 12,170 new cases of invasive cervical cancer in the United States and 4,220 related deaths.¹⁷ The cost associated with cervical cancer screening, managing abnormal findings, and treating invasive cervical cancer in the United States is estimated to be $3.3 billion per year.¹⁸

Although the incidence and the mortality rates of cervical cancer have decreased more than 50% in the United States over the past 3 decades thanks to screening,¹⁹ cervical cancer remains the second leading cause of death from cancer in women worldwide. Each year, an estimated 500,000 women contract the disease and 240,000 die of it.²⁰

Anal cancer

A recent study indicated that oncogenic HPV can also cause anal cancer, and the proportion of such cancers associated with HPV 16 or HPV 18 infection is as high as or higher than for cervical cancers, and estimated at 80%.²¹

The incidence of anal cancer is increasing by approximately 2% per year in both men and women in the general population,²² and rates are even higher in men who have sex with men and people infected with the human immunodeficiency virus.²³

Hu and Goldie²⁴ estimated that the lifetime costs of caring for all the people in the United States who in just 1 year (2003) acquired anal cancer attributable to HPV would total $92 million.

Oropharyngeal cancer

HPV types 16, 18, 31, 33, and 35 also cause oropharyngeal cancer. HPV 16 accounts for more than 90% of cases of HPV-related oropharyngeal cancer.²⁵

Chaturvedi et al⁶ tested tissue samples from three national cancer registries and found that the number of oropharyngeal cancers that were HPV-positive increased from 16.3% in 1984–1989 to 71.7% in 2000–2004, while the number of HPV-negative oropharyngeal cancers fell by 50%, paralleling the drop in cigarette smoking in the United States.

Hu and Goldie²⁴ estimated that the total lifetime cost for all new HPV-related oropharyngeal cancers that arose in 2003 would come to $38.1 million.²⁴

Vulvar and vaginal cancers

HPV 16 and 18 are also responsible for approximately 50% of vulvar cancers and 50% to 75% of vaginal cancers.^4,5

Recurrent respiratory papillomatosis

HPV 6 and 11 cause almost all cases of juvenile- and adult-onset recurrent respiratory papillomatosis.²⁶ The annual cost for surgical procedures for this condition in the United States has been estimated at $151 million.²⁷

HPV VACCINES ARE NONINFECTIOUS AND NONCARCINOGENIC

Currently, two HPV vaccines are available: a quadrivalent vaccine against types 6, 11, 16, and 18 (Gardasil; Merck) and a bivalent vaccine against types 16 and 18 (Cervarix; Glaxo-SmithKline). The quadrivalent vaccine was approved by the US Food and Drug Administration (FDA) in 2006, and the bivalent vaccine was approved in 2009.^28,29

Both vaccines contain virus-like particles, ie, viral capsids that contain no DNA. HPV has a circular DNA genome of 8,000 nucleotides divided into two regions: the early region, for viral replication, and the late region, for viral capsid production. The host produces neutralizing antibodies in response to the L1 capsid protein, which is different in different HPV types.

In manufacturing the vaccines, the viral L1 gene is incorporated into a yeast genome or an insect virus genome using recombinant DNA technology (Figure 1). Grown in culture, the yeast or the insect cells produce the HPV L1 major capsid protein, which has the intrinsic capacity to self-assemble into virus-like particles.^30–33 These particles are subsequently purified for use in the vaccines.³⁴

Recombinant virus-like particles are morphologically indistinguishable from authentic HPV virions and contain the same typespecific antigens present in authentic virions. Therefore, they are highly effective in inducing a host humoral immune response. And because they do not contain HPV DNA, the recombinant HPV vaccines are noninfectious and noncarcinogenic.³⁵

VACCINATION INDUCES A STRONGER IMMUNE RESPONSE THAN INFECTION

HPV infections trigger both a humoral and a cellular response in the host immune system.

The humoral immune response to HPV infection involves producing neutralizing antibody against the specific HPV type, specifically the specific L1 major capsid protein. This process is typically somewhat slow and weak, and only about 60% of women with a new HPV infection develop antibodies to it.^36,37

HPV has several ways to evade the host immune system. It does not infect or replicate within the antigen-presenting cells in the epithelium. In addition, HPV-infected keratinocytes are less susceptible to cytotoxic lymphocytic-mediated lysis. Moreover, HPV infection cause very little tissue destruction. And finally, natural cervical HPV infection does not result in viremia. As a result, antigen-presenting cells have no chance to engulf the virions and present virion-derived antigen to the host immune system. The immune system outside the epithelium has limited opportunity to detect the virus because HPV infection does not have a blood-borne phase.^38,39

The cell-mediated immune response to early HPV oncoproteins may help eliminate established HPV infection.⁴⁰ In contrast to antibodies, the T-cell response to HPV has not been shown to be specific to HPV type.⁴¹ Clinically, cervical HPV infection is common, but most lesions go into remission or resolve as a result of the cell-mediated immune response.^40,41

In contrast to the weak, somewhat ineffective immune response to natural HPV infection, the antibody response to HPV vaccines is rather robust. In randomized controlled trials, almost all vaccinated people have seroconverted. The peak antibody concentrations are 50 to 10,000 times greater than in natural infection. Furthermore, the neutralizing antibodies induced by HPV vaccines persist for as long as 7 to 9 years after immunization.⁴² However, the protection provided by HPV vaccines against HPV-related cervical intraepithelial neoplasia does not necessarily correlate with the antibody concentration.^43–47

Why does the vaccine work so well?

Why are vaccine-induced antibody responses so much stronger than those induced by natural HPV infection?

The first reason is that the vaccine, delivered intramuscularly, rapidly enters into blood vessels and the lymphatic system. In contrast, in natural intraepithelial infection, the virus is shed from mucosal surfaces and does not result in viremia.⁴⁸

In addition, the strong immunogenic nature of the virus-like particles induces a robust host antibody response even in the absence of adjuvant because of concentrated neutralizing epitopes and excellent induction of the T-helper cell response.^35,49,50

The neutralizing antibody to L1 prevents HPV infection by blocking HPV from binding to the basement membrane as well as to the epithelial cell receptor during epithelial microabrasion and viral entry. The subsequent micro-wound healing leads to serous exudation and rapid access of serum immunoglobulin G (IgG) to HPV virus particles and encounters with circulatory B memory cells.

Furthermore, emerging evidence suggests that even very low antibody concentrations are sufficient to prevent viral entry into cervical epithelial cells.^{46–48,51–53}

THE HPV VACCINES ARE HIGHLY EFFECTIVE AND SAFE

The efficacy and safety of the quadrivalent and the bivalent HPV vaccines have been evaluated in large randomized clinical trials.^{23,28,29,54,55} Table 1 summarizes the key findings.

The Females United to Unilaterally Reduce Endo/ectocervical Disease (FUTURE I)⁵⁴ and FUTURE II²⁸ trials showed conclusively that the quadrivalent HPV vaccine is 98% to 100% efficacious in preventing HPV 16- and 18-related cervical intraepithelial neoplasia, carcinoma in situ, and invasive cervical cancer in women who had not been infected with HPV before. Similarly, the Papilloma Trial against Cancer in Young Adults (PATRICIA) concluded that the bivalent HPV vaccine is 93% efficacious.²⁹

Giuliano et al⁵⁵ and Palefsky et al²³ conducted randomized clinical trials of the quadrivalent HPV vaccine for preventing genital disease and anal intraepithelial neoplasia in boys and men; the efficacy rates were 90.4%⁵⁵ and 77.5%.²³

A recent Finnish trial in boys age 10 to 18 found 100% seroconversion rates for HPV 16 and HPV 18 antibodies after they received bivalent HPV vaccine.⁵⁶ Similar efficacy has been demonstrated for the quadrivalent HPV vaccine in boys.⁵⁷

Adverse events after vaccination

After the FDA approved the quadrivalent HPV vaccine for girls in 2006, the US Centers for Disease Control and Prevention (CDC) conducted a thorough survey of adverse events after immunization from June 1, 2006 through December 31, 2008.⁵⁸ There were about 54 reports of adverse events per 100,000 distributed vaccine doses, similar to rates for other vaccines. However, the incidence rates of syncope and venous thrombosis were disproportionately higher, according to data from the US Vaccine Adverse Event Reporting System. The rate of syncope was 8.2 per 100,000 vaccine doses, and the rate of venous thrombotic events was 0.2 per 100,000 doses.⁵⁸

There were 32 reports of deaths after HPV vaccination, but these were without clear causation. Hence, this information must be interpreted with caution and should not be used to infer causal associations between HPV vaccines and adverse outcomes. The causes of death included diabetic ketoacidosis, pulmonary embolism, prescription drug abuse, amyotrophic lateral sclerosis, meningoencephalitis, influenza B viral sepsis, arrhythmia, myocarditis, and idiopathic seizure disorder.⁵⁸

Furthermore, it is important to note that vasovagal syncope and venous thromboembolic events are more common in young females in general.⁵⁹ For example, the background rates of venous thromboembolism in females age 14 to 29 using oral contraceptives is 21 to 31 per 100,000 woman-years.⁶⁰

Overall, the quadrivalent HPV vaccine is well tolerated and clinically safe. Postlicensure evaluation found that the quadrivalent and bivalent HPV vaccines had similar safety profiles.⁶¹

Vaccination is contraindicated in people with known hypersensitivity or prior severe allergic reactions to vaccine or yeast or who have bleeding disorders.

HPV VACCINATION DOES MORE THAN PREVENT CERVICAL CANCER IN FEMALES

The quadrivalent HPV vaccine was licensed by the FDA in 2006 for use in females age 9 to 26 to prevent cervical cancer, cervical cancer precursors, vaginal and vulval cancer precursors, and anogenital warts caused by HPV types 6, 11, 16, and 18. The CDC’s Advisory Committee on Immunization Practices (ACIP) issued its recommendation for initiating HPV vaccination for females age 11 to 12 in March 2007. The ACIP stated that the vaccine could be given to girls as early as age 9 and recommended catch-up vaccinations for those age 13 to 26.^62,63

The quadrivalent HPV vaccine was licensed by the FDA in 2009 for use in boys and men for the prevention of genital warts. In December 2010, the quadrivalent HPV vaccine received extended licensure from the FDA for use in males and females for the prevention of anal cancer. In October 2011, the ACIP voted to recommend routine use of the quadrivalent HPV vaccine for boys age 11 to 12; catch-up vaccination should occur for those age 13 to 22, with an option to vaccinate men age 23 to 26.

These recommendations replace the “permissive use” recommendations from the ACIP in October 2009 that said the quadrivalent HPV vaccine may be given to males age 9 to 26.⁶⁴ This shift from a permissive to an active recommendation connotes a positive change reflecting recognition of rising oropharyngeal cancer rates attributable to oncogenic, preventable HPV, rising HPV-related anal cancer incidence, and the burden of the disease in female partners of infected men, with associated rising health care costs.

The bivalent HPV vaccine received FDA licensure in October 2009 for use in females age 10 to 25 to prevent cervical cancer and precursor lesions. The ACIP included the bivalent HPV vaccine in its updated recommendations in May 2010 for use in girls age 11 to 12. Numerous national and international organizations have endorsed HPV vaccination.^65–71

Table 2 outlines the recommendations from these organizations.

HPV VACCINATION RATES ARE STILL LOW

HPV vaccine offers us the hope of eventually eradicating cervical cancer. However, the immunization program still faces many challenges, since HPV vaccination touches on issues related to adolescent sexuality, parental autonomy, and cost. As a result, HPV immunization rates remain relatively low in the United States according to several national surveys. Only 40% to 49% of girls eligible for the vaccine received even one dose, and of those who received even one dose, only 32% to 53.3% came back for all three doses.^72–75 Furthermore, indigent and minority teens were less likely to finish the three-dose HPV vaccine series.

Why are the vaccination rates so low?

Parental barriers. In one survey,⁷³ reasons that parents gave for not having their daughters vaccinated included:

• Lack of knowledge of the vaccine (19.4%)
• Lack of perceived need for the vaccine (18.8%)
• Belief that their daughter was not sexually active (18.3%)
• Clinician not recommending vaccination (13.1%).

In an effort to improve HPV vaccination rates,⁴¹ several states proposed legislation for mandatory HPV vaccination of schoolgirls shortly after licensure of the quadrivalent HPV vaccine.³ Since then, we have seen a wave of public opposition rooted in concerns and misinformation about safety, teenage sexuality, governmental coercion, and cost. Widespread media coverage has also highlighted unsubstantiated claims about side effects attributable to the vaccine that can raise parents’ mistrust of vaccines.⁷⁶ Concerns have also been raised about a threat to parental autonomy in how and when to educate their children about sex.⁷⁷

Moreover, the vaccine has raised ethical concerns in some parents and politicians that mandatory vaccination could undermine abstinence messages in sexual education and may alter sexual activity by condoning risky behavior.⁷⁸ However, a recent study indicated that there is no significant change in sexual behavior related to HPV vaccination in young girls.⁷⁹

In 2012, Mullins et al⁸⁰ also found that an urban population of adolescent girls (76.4% black, 57.5% sexually experienced) did not feel they could forgo safer sexual practices after first HPV vaccination, although the girls did perceive less risk from HPV than from other sexually transmitted infections after HPV vaccination (P < .001).⁸⁰ Inadequate knowledge about HPV-related disease and HPV vaccine correlated with less perceived risk from HPV after vaccination among the girls, and a lack of knowledge about HPV and less communication with their daughters about HPV correlated with less perceived risk from HPV in the mothers of the study population.⁸¹

Health-care-provider barriers. Physician endorsement of vaccines represents a key predictor of vaccine acceptance by patients, families, and other clinicians.^82–84 In 2008, a cross-sectional, Internet-based survey of 1,122 Texas pediatricians, family practice physicians, obstetricians, gynecologists, and internal medicine physicians providing direct patient care found that only 48.5% always recommended HPV vaccination to girls.⁷⁴ Of all respondents, 68.4% were likely to recommend the vaccine to boys, and 41.7% agreed with mandated vaccination. Thus, more than half of the physicians were not following the current recommendations for universal HPV vaccination for 11- to -12-year-olds.

In a survey of 1,013 physicians during the spring and summer of 2009, only 34.6% said they always recommend HPV vaccination to early adolescents, 52.7% to middle adolescents, and 50.2% to late adolescents and young adults.⁸⁵ Pediatricians were more likely than family physicians and obstetrician-gynecologists to always recommend HPV vaccine across all age groups (P < .001). Educational interventions targeting various specialties may help overcome physician-related barriers to immunization.⁸⁵

Financial barriers. HPV vaccine, which must be given in three doses, is more expensive than other vaccines, and this expense is yet another barrier, especially for the uninsured.⁸⁶ Australia launched a government-funded program of HPV vaccination (with the quadrivalent vaccine) in schools in 2007, and it has been very successful. Garland et al⁸⁷ reported that new cases of genital warts have decreased by 73% since the program began, and the rate of high-grade abnormalities on Papanicolaou testing has declined by a small but significant amount.

For HPV vaccination to have an impact on public health, vaccination rates in the general population need to be high. In order to achieve these rates, we need to educate our patients on vaccine safety and efficacy and counsel vaccine recipients about the prevention of sexually transmitted infections and the importance of regular cervical cancer screening after age 21. Clinicians can actively “myth-bust” with patients, who may not realize that the vaccine should be given despite a history of HPV infection or abnormal Pap smear.

FREQUENTLY ASKED QUESTIONS

What if the patient is late for a shot?

The current recommended vaccination schedule for the bivalent and quadrivalent HPV vaccines is a three-dose series administered at 0, 2, and 6 months, given as an intramuscular injection, preferably in the deltoid muscle. The minimal dosing interval is 4 weeks between the first and second doses and 12 weeks between the second and third doses.

The vaccines use different adjuncts with different specific mechanisms for immunogenicity; therefore, it is recommended that the same vaccine be used for the entire three-dose series. However, if circumstances preclude the completion of a series with the same vaccine, the other HPV vaccine may be used.⁶³ Starting the series over is not recommended.

Long-term studies demonstrated clinical efficacy 8.5 years after vaccination.⁴⁷ Amnestic response by virtue of activation of pools of memory B cells has been demonstrated, suggesting the vaccine may afford lifelong immunity.⁸⁸

Is a pregnancy test needed before HPV vaccination?

The ACIP states that pregnancy testing is not required before receiving either of the available HPV vaccines.

A recent retrospective review of phase III efficacy trials and pregnancy registry surveillance data for both vaccines revealed no increase in spontaneous abortions, fetal malformations, or adverse pregnancy outcomes.⁸⁹ Data are limited on bivalent and quadrivalent HPV vaccine given within 30 days of pregnancy and subsequent pregnancy and fetal outcomes. Both vaccines have been assigned a pregnancy rating of category B; however, the ACIP recommends that neither vaccine be given if the recipient is known to be pregnant. If pregnancy occurs, it is recommended that the remainder of the series be deferred until after delivery.⁶²

It is not known whether the vaccine is excreted in breast milk. The manufacturers of both the bivalent and quadrivalent HPV vaccines recommend caution when vaccinating lactating women.^30,31

Can HPV vaccine be given with other vaccines?

In randomized trials, giving the bivalent HPV vaccine with the combined hepatitis A, hepatitis B, meningococcal conjugate and the combined tetanus, diphtheria, and acellular pertussis vaccines did not interfere with the immunogenic response, was safe, and was well tolerated.^90,91 Coadministration of the quadrivalent HPV vaccine has been studied only with hepatitis B vaccine, with similar safety and efficacy noted.

The ACIP recommends giving HPV vaccine at the same visit with other age-appropriate immunizations to increase the likelihood of adherence to recommended vaccination schedules.⁶²

Is HPV vaccination cost-effective?

Kim and Goldie⁸⁶ performed a cost-effectiveness analysis of HPV vaccination of girls at age 12 and catch-up vaccination up to the ages of 18, 21, and 26. For their analysis, they considered prevention of cancers associated with HPV types 16 and 18, of genital warts associated with types 6 and 11, and of recurrent respiratory papillomatosis. They also assumed that immunity would be lifelong, and current screening practices would continue.

They calculated that routine vaccination of 12-year-old girls resulted in an incremental cost-effective ratio of $34,900 per quality-adjusted life-year (QALY) gained. A threshold of less than $50,000 per QALY gained is considered reasonably cost-effective, with an upper limit of $100,000 considered acceptable.⁹²

In the same analysis by Kim and Goldie,⁸⁶ catch-up vaccination of girls through age 18 resulted in a cost of $50,000 to $100,000 per QALY gained, and catch-up vaccination of females through age 26 was significantly less cost-effective at more then $130,000 per QALY gained. The vaccine was also significantly less cost-effective if 5% of the population was neither screened nor vaccinated, if a 10-year booster was required, and if frequent cervical cancer screening intervals were adopted.

This analysis did not include costs related to the evaluation and treatment of abnormal Pap smears and cross-protection against other HPV-related cancers.

The cost-effectiveness of HPV vaccination depends on reaching more girls at younger ages (ideally before sexual debut) and completing the three-dose schedule to optimize duration of immunity.⁹² Appropriate modification of the current recommendations for the intervals of cervical cancer screening for vaccinated individuals will further improve the cost-effectiveness of vaccination. The inclusion of male vaccination generally has more favorable cost per QALY in scenarios in which female coverage rates are less than 50%⁹³ and among men who have sex with men.⁹⁴

TO ERADICATE CERVICAL CANCER

Given the remarkable efficacy and expected long-term immunogenicity of HPV vaccines, we anticipate a decline in HPV-related cervical cancer and other related diseases in the years to come. However, modeling studies predicting the impact of HPV vaccination suggest that although substantial reductions in diseases can be expected, the benefit, assuming high vaccination rates, will not be apparent for at least another decade.⁹⁵ Furthermore, the current HPV vaccines contain only HPV 16 and 18 L1 protein for cancer protection and, therefore, do not provide optimal protection against all oncogenic HPV-related cancers.

The real hope of eradicating cervical cancer and all HPV-related disease relies on a successful global implementation of multivalent HPV vaccination, effective screening strategies, and successful treatment.

The vaccines against human papillomavirus (HPV) are the only ones designed to prevent cancer caused by a virus^1,2—surely a good goal. But because HPV is sexually transmitted, HPV vaccination has met with public controversy.³ To counter the objections and better protect their patients’ health, primary care providers and other clinicians need a clear understanding of the benefits and the low risk of HPV vaccination—and the reasons so many people object to it.³

In this article, we will review:

• The impact of HPV-related diseases
• The basic biologic features of HPV vaccines
• The host immune response to natural HPV infection vs the response to HPV vaccines
• The clinical efficacy and safety of HPV vaccines
• The latest guidelines for HPV vaccination
• The challenges to vaccination implementation
• Frequently asked practical questions about HPV vaccination.

HPV-RELATED DISEASES: FROM BOTHERSOME TO DEADLY

Clinical sequelae of HPV infection include genital warts; cancers of the cervix, vulva, vagina, anus, penis, and oropharynx; and recurrent respiratory papillomatosis.^4–6

Genital warts

HPV types 6 and 11 are responsible for more than 90% of the 1 million new cases of genital warts diagnosed annually in the United States.^7–10

Bothersome and embarrassing, HPV-related genital warts can cause itching, burning, erythema, and pain, as well as epithelial erosions, ulcerations, depigmentation, and urethral and vaginal bleeding and discharge.^11,12 Although they are benign in the oncologic sense, they can cause a good deal of emotional and financial stress. Patients may feel anxiety, embarrassment,¹³ and vulnerability. Adolescents and adults who have or have had genital warts need to inform their current and future partners or else risk infecting them—and facing the consequences.

Direct health care costs of genital warts in the United States have been estimated to be at least $200 million per year.¹⁴

Cervical cancer

Cervical cancer cannot develop unless the cervical epithelium is infected with one of the oncogenic HPV types. Indeed, oncogenic HPV is present in as many as 99.8% of cervical cancer specimens.¹⁵ HPV 16 and 18 are the most oncogenic HPV genotypes and account for 75% of all cases of cervical cancer. Ten other HPV genotypes account for the remaining 25%.¹⁶

In 2012, there were an estimated 12,170 new cases of invasive cervical cancer in the United States and 4,220 related deaths.¹⁷ The cost associated with cervical cancer screening, managing abnormal findings, and treating invasive cervical cancer in the United States is estimated to be $3.3 billion per year.¹⁸

Although the incidence and the mortality rates of cervical cancer have decreased more than 50% in the United States over the past 3 decades thanks to screening,¹⁹ cervical cancer remains the second leading cause of death from cancer in women worldwide. Each year, an estimated 500,000 women contract the disease and 240,000 die of it.²⁰

Anal cancer

A recent study indicated that oncogenic HPV can also cause anal cancer, and the proportion of such cancers associated with HPV 16 or HPV 18 infection is as high as or higher than for cervical cancers, and estimated at 80%.²¹

The incidence of anal cancer is increasing by approximately 2% per year in both men and women in the general population,²² and rates are even higher in men who have sex with men and people infected with the human immunodeficiency virus.²³

Hu and Goldie²⁴ estimated that the lifetime costs of caring for all the people in the United States who in just 1 year (2003) acquired anal cancer attributable to HPV would total $92 million.

Oropharyngeal cancer

HPV types 16, 18, 31, 33, and 35 also cause oropharyngeal cancer. HPV 16 accounts for more than 90% of cases of HPV-related oropharyngeal cancer.²⁵

Chaturvedi et al⁶ tested tissue samples from three national cancer registries and found that the number of oropharyngeal cancers that were HPV-positive increased from 16.3% in 1984–1989 to 71.7% in 2000–2004, while the number of HPV-negative oropharyngeal cancers fell by 50%, paralleling the drop in cigarette smoking in the United States.

Hu and Goldie²⁴ estimated that the total lifetime cost for all new HPV-related oropharyngeal cancers that arose in 2003 would come to $38.1 million.²⁴

Vulvar and vaginal cancers

HPV 16 and 18 are also responsible for approximately 50% of vulvar cancers and 50% to 75% of vaginal cancers.^4,5

Recurrent respiratory papillomatosis

HPV 6 and 11 cause almost all cases of juvenile- and adult-onset recurrent respiratory papillomatosis.²⁶ The annual cost for surgical procedures for this condition in the United States has been estimated at $151 million.²⁷

HPV VACCINES ARE NONINFECTIOUS AND NONCARCINOGENIC

Currently, two HPV vaccines are available: a quadrivalent vaccine against types 6, 11, 16, and 18 (Gardasil; Merck) and a bivalent vaccine against types 16 and 18 (Cervarix; Glaxo-SmithKline). The quadrivalent vaccine was approved by the US Food and Drug Administration (FDA) in 2006, and the bivalent vaccine was approved in 2009.^28,29

Both vaccines contain virus-like particles, ie, viral capsids that contain no DNA. HPV has a circular DNA genome of 8,000 nucleotides divided into two regions: the early region, for viral replication, and the late region, for viral capsid production. The host produces neutralizing antibodies in response to the L1 capsid protein, which is different in different HPV types.

In manufacturing the vaccines, the viral L1 gene is incorporated into a yeast genome or an insect virus genome using recombinant DNA technology (Figure 1). Grown in culture, the yeast or the insect cells produce the HPV L1 major capsid protein, which has the intrinsic capacity to self-assemble into virus-like particles.^30–33 These particles are subsequently purified for use in the vaccines.³⁴

Recombinant virus-like particles are morphologically indistinguishable from authentic HPV virions and contain the same typespecific antigens present in authentic virions. Therefore, they are highly effective in inducing a host humoral immune response. And because they do not contain HPV DNA, the recombinant HPV vaccines are noninfectious and noncarcinogenic.³⁵

VACCINATION INDUCES A STRONGER IMMUNE RESPONSE THAN INFECTION

HPV infections trigger both a humoral and a cellular response in the host immune system.

The humoral immune response to HPV infection involves producing neutralizing antibody against the specific HPV type, specifically the specific L1 major capsid protein. This process is typically somewhat slow and weak, and only about 60% of women with a new HPV infection develop antibodies to it.^36,37

HPV has several ways to evade the host immune system. It does not infect or replicate within the antigen-presenting cells in the epithelium. In addition, HPV-infected keratinocytes are less susceptible to cytotoxic lymphocytic-mediated lysis. Moreover, HPV infection cause very little tissue destruction. And finally, natural cervical HPV infection does not result in viremia. As a result, antigen-presenting cells have no chance to engulf the virions and present virion-derived antigen to the host immune system. The immune system outside the epithelium has limited opportunity to detect the virus because HPV infection does not have a blood-borne phase.^38,39

The cell-mediated immune response to early HPV oncoproteins may help eliminate established HPV infection.⁴⁰ In contrast to antibodies, the T-cell response to HPV has not been shown to be specific to HPV type.⁴¹ Clinically, cervical HPV infection is common, but most lesions go into remission or resolve as a result of the cell-mediated immune response.^40,41

In contrast to the weak, somewhat ineffective immune response to natural HPV infection, the antibody response to HPV vaccines is rather robust. In randomized controlled trials, almost all vaccinated people have seroconverted. The peak antibody concentrations are 50 to 10,000 times greater than in natural infection. Furthermore, the neutralizing antibodies induced by HPV vaccines persist for as long as 7 to 9 years after immunization.⁴² However, the protection provided by HPV vaccines against HPV-related cervical intraepithelial neoplasia does not necessarily correlate with the antibody concentration.^43–47

Why does the vaccine work so well?

Why are vaccine-induced antibody responses so much stronger than those induced by natural HPV infection?

The first reason is that the vaccine, delivered intramuscularly, rapidly enters into blood vessels and the lymphatic system. In contrast, in natural intraepithelial infection, the virus is shed from mucosal surfaces and does not result in viremia.⁴⁸

In addition, the strong immunogenic nature of the virus-like particles induces a robust host antibody response even in the absence of adjuvant because of concentrated neutralizing epitopes and excellent induction of the T-helper cell response.^35,49,50

The neutralizing antibody to L1 prevents HPV infection by blocking HPV from binding to the basement membrane as well as to the epithelial cell receptor during epithelial microabrasion and viral entry. The subsequent micro-wound healing leads to serous exudation and rapid access of serum immunoglobulin G (IgG) to HPV virus particles and encounters with circulatory B memory cells.

Furthermore, emerging evidence suggests that even very low antibody concentrations are sufficient to prevent viral entry into cervical epithelial cells.^{46–48,51–53}

THE HPV VACCINES ARE HIGHLY EFFECTIVE AND SAFE

The efficacy and safety of the quadrivalent and the bivalent HPV vaccines have been evaluated in large randomized clinical trials.^{23,28,29,54,55} Table 1 summarizes the key findings.

The Females United to Unilaterally Reduce Endo/ectocervical Disease (FUTURE I)⁵⁴ and FUTURE II²⁸ trials showed conclusively that the quadrivalent HPV vaccine is 98% to 100% efficacious in preventing HPV 16- and 18-related cervical intraepithelial neoplasia, carcinoma in situ, and invasive cervical cancer in women who had not been infected with HPV before. Similarly, the Papilloma Trial against Cancer in Young Adults (PATRICIA) concluded that the bivalent HPV vaccine is 93% efficacious.²⁹

Giuliano et al⁵⁵ and Palefsky et al²³ conducted randomized clinical trials of the quadrivalent HPV vaccine for preventing genital disease and anal intraepithelial neoplasia in boys and men; the efficacy rates were 90.4%⁵⁵ and 77.5%.²³

A recent Finnish trial in boys age 10 to 18 found 100% seroconversion rates for HPV 16 and HPV 18 antibodies after they received bivalent HPV vaccine.⁵⁶ Similar efficacy has been demonstrated for the quadrivalent HPV vaccine in boys.⁵⁷

Adverse events after vaccination

After the FDA approved the quadrivalent HPV vaccine for girls in 2006, the US Centers for Disease Control and Prevention (CDC) conducted a thorough survey of adverse events after immunization from June 1, 2006 through December 31, 2008.⁵⁸ There were about 54 reports of adverse events per 100,000 distributed vaccine doses, similar to rates for other vaccines. However, the incidence rates of syncope and venous thrombosis were disproportionately higher, according to data from the US Vaccine Adverse Event Reporting System. The rate of syncope was 8.2 per 100,000 vaccine doses, and the rate of venous thrombotic events was 0.2 per 100,000 doses.⁵⁸

There were 32 reports of deaths after HPV vaccination, but these were without clear causation. Hence, this information must be interpreted with caution and should not be used to infer causal associations between HPV vaccines and adverse outcomes. The causes of death included diabetic ketoacidosis, pulmonary embolism, prescription drug abuse, amyotrophic lateral sclerosis, meningoencephalitis, influenza B viral sepsis, arrhythmia, myocarditis, and idiopathic seizure disorder.⁵⁸

Furthermore, it is important to note that vasovagal syncope and venous thromboembolic events are more common in young females in general.⁵⁹ For example, the background rates of venous thromboembolism in females age 14 to 29 using oral contraceptives is 21 to 31 per 100,000 woman-years.⁶⁰

Overall, the quadrivalent HPV vaccine is well tolerated and clinically safe. Postlicensure evaluation found that the quadrivalent and bivalent HPV vaccines had similar safety profiles.⁶¹

Vaccination is contraindicated in people with known hypersensitivity or prior severe allergic reactions to vaccine or yeast or who have bleeding disorders.

HPV VACCINATION DOES MORE THAN PREVENT CERVICAL CANCER IN FEMALES

The quadrivalent HPV vaccine was licensed by the FDA in 2006 for use in females age 9 to 26 to prevent cervical cancer, cervical cancer precursors, vaginal and vulval cancer precursors, and anogenital warts caused by HPV types 6, 11, 16, and 18. The CDC’s Advisory Committee on Immunization Practices (ACIP) issued its recommendation for initiating HPV vaccination for females age 11 to 12 in March 2007. The ACIP stated that the vaccine could be given to girls as early as age 9 and recommended catch-up vaccinations for those age 13 to 26.^62,63

The quadrivalent HPV vaccine was licensed by the FDA in 2009 for use in boys and men for the prevention of genital warts. In December 2010, the quadrivalent HPV vaccine received extended licensure from the FDA for use in males and females for the prevention of anal cancer. In October 2011, the ACIP voted to recommend routine use of the quadrivalent HPV vaccine for boys age 11 to 12; catch-up vaccination should occur for those age 13 to 22, with an option to vaccinate men age 23 to 26.

These recommendations replace the “permissive use” recommendations from the ACIP in October 2009 that said the quadrivalent HPV vaccine may be given to males age 9 to 26.⁶⁴ This shift from a permissive to an active recommendation connotes a positive change reflecting recognition of rising oropharyngeal cancer rates attributable to oncogenic, preventable HPV, rising HPV-related anal cancer incidence, and the burden of the disease in female partners of infected men, with associated rising health care costs.

The bivalent HPV vaccine received FDA licensure in October 2009 for use in females age 10 to 25 to prevent cervical cancer and precursor lesions. The ACIP included the bivalent HPV vaccine in its updated recommendations in May 2010 for use in girls age 11 to 12. Numerous national and international organizations have endorsed HPV vaccination.^65–71

Table 2 outlines the recommendations from these organizations.

HPV VACCINATION RATES ARE STILL LOW

HPV vaccine offers us the hope of eventually eradicating cervical cancer. However, the immunization program still faces many challenges, since HPV vaccination touches on issues related to adolescent sexuality, parental autonomy, and cost. As a result, HPV immunization rates remain relatively low in the United States according to several national surveys. Only 40% to 49% of girls eligible for the vaccine received even one dose, and of those who received even one dose, only 32% to 53.3% came back for all three doses.^72–75 Furthermore, indigent and minority teens were less likely to finish the three-dose HPV vaccine series.

Why are the vaccination rates so low?

Parental barriers. In one survey,⁷³ reasons that parents gave for not having their daughters vaccinated included:

• Lack of knowledge of the vaccine (19.4%)
• Lack of perceived need for the vaccine (18.8%)
• Belief that their daughter was not sexually active (18.3%)
• Clinician not recommending vaccination (13.1%).

In an effort to improve HPV vaccination rates,⁴¹ several states proposed legislation for mandatory HPV vaccination of schoolgirls shortly after licensure of the quadrivalent HPV vaccine.³ Since then, we have seen a wave of public opposition rooted in concerns and misinformation about safety, teenage sexuality, governmental coercion, and cost. Widespread media coverage has also highlighted unsubstantiated claims about side effects attributable to the vaccine that can raise parents’ mistrust of vaccines.⁷⁶ Concerns have also been raised about a threat to parental autonomy in how and when to educate their children about sex.⁷⁷

Moreover, the vaccine has raised ethical concerns in some parents and politicians that mandatory vaccination could undermine abstinence messages in sexual education and may alter sexual activity by condoning risky behavior.⁷⁸ However, a recent study indicated that there is no significant change in sexual behavior related to HPV vaccination in young girls.⁷⁹

In 2012, Mullins et al⁸⁰ also found that an urban population of adolescent girls (76.4% black, 57.5% sexually experienced) did not feel they could forgo safer sexual practices after first HPV vaccination, although the girls did perceive less risk from HPV than from other sexually transmitted infections after HPV vaccination (P < .001).⁸⁰ Inadequate knowledge about HPV-related disease and HPV vaccine correlated with less perceived risk from HPV after vaccination among the girls, and a lack of knowledge about HPV and less communication with their daughters about HPV correlated with less perceived risk from HPV in the mothers of the study population.⁸¹

Health-care-provider barriers. Physician endorsement of vaccines represents a key predictor of vaccine acceptance by patients, families, and other clinicians.^82–84 In 2008, a cross-sectional, Internet-based survey of 1,122 Texas pediatricians, family practice physicians, obstetricians, gynecologists, and internal medicine physicians providing direct patient care found that only 48.5% always recommended HPV vaccination to girls.⁷⁴ Of all respondents, 68.4% were likely to recommend the vaccine to boys, and 41.7% agreed with mandated vaccination. Thus, more than half of the physicians were not following the current recommendations for universal HPV vaccination for 11- to -12-year-olds.

In a survey of 1,013 physicians during the spring and summer of 2009, only 34.6% said they always recommend HPV vaccination to early adolescents, 52.7% to middle adolescents, and 50.2% to late adolescents and young adults.⁸⁵ Pediatricians were more likely than family physicians and obstetrician-gynecologists to always recommend HPV vaccine across all age groups (P < .001). Educational interventions targeting various specialties may help overcome physician-related barriers to immunization.⁸⁵

Financial barriers. HPV vaccine, which must be given in three doses, is more expensive than other vaccines, and this expense is yet another barrier, especially for the uninsured.⁸⁶ Australia launched a government-funded program of HPV vaccination (with the quadrivalent vaccine) in schools in 2007, and it has been very successful. Garland et al⁸⁷ reported that new cases of genital warts have decreased by 73% since the program began, and the rate of high-grade abnormalities on Papanicolaou testing has declined by a small but significant amount.

For HPV vaccination to have an impact on public health, vaccination rates in the general population need to be high. In order to achieve these rates, we need to educate our patients on vaccine safety and efficacy and counsel vaccine recipients about the prevention of sexually transmitted infections and the importance of regular cervical cancer screening after age 21. Clinicians can actively “myth-bust” with patients, who may not realize that the vaccine should be given despite a history of HPV infection or abnormal Pap smear.

FREQUENTLY ASKED QUESTIONS

What if the patient is late for a shot?

The current recommended vaccination schedule for the bivalent and quadrivalent HPV vaccines is a three-dose series administered at 0, 2, and 6 months, given as an intramuscular injection, preferably in the deltoid muscle. The minimal dosing interval is 4 weeks between the first and second doses and 12 weeks between the second and third doses.

The vaccines use different adjuncts with different specific mechanisms for immunogenicity; therefore, it is recommended that the same vaccine be used for the entire three-dose series. However, if circumstances preclude the completion of a series with the same vaccine, the other HPV vaccine may be used.⁶³ Starting the series over is not recommended.

Long-term studies demonstrated clinical efficacy 8.5 years after vaccination.⁴⁷ Amnestic response by virtue of activation of pools of memory B cells has been demonstrated, suggesting the vaccine may afford lifelong immunity.⁸⁸

Is a pregnancy test needed before HPV vaccination?

The ACIP states that pregnancy testing is not required before receiving either of the available HPV vaccines.

A recent retrospective review of phase III efficacy trials and pregnancy registry surveillance data for both vaccines revealed no increase in spontaneous abortions, fetal malformations, or adverse pregnancy outcomes.⁸⁹ Data are limited on bivalent and quadrivalent HPV vaccine given within 30 days of pregnancy and subsequent pregnancy and fetal outcomes. Both vaccines have been assigned a pregnancy rating of category B; however, the ACIP recommends that neither vaccine be given if the recipient is known to be pregnant. If pregnancy occurs, it is recommended that the remainder of the series be deferred until after delivery.⁶²

It is not known whether the vaccine is excreted in breast milk. The manufacturers of both the bivalent and quadrivalent HPV vaccines recommend caution when vaccinating lactating women.^30,31

Can HPV vaccine be given with other vaccines?

In randomized trials, giving the bivalent HPV vaccine with the combined hepatitis A, hepatitis B, meningococcal conjugate and the combined tetanus, diphtheria, and acellular pertussis vaccines did not interfere with the immunogenic response, was safe, and was well tolerated.^90,91 Coadministration of the quadrivalent HPV vaccine has been studied only with hepatitis B vaccine, with similar safety and efficacy noted.

The ACIP recommends giving HPV vaccine at the same visit with other age-appropriate immunizations to increase the likelihood of adherence to recommended vaccination schedules.⁶²

Is HPV vaccination cost-effective?

Kim and Goldie⁸⁶ performed a cost-effectiveness analysis of HPV vaccination of girls at age 12 and catch-up vaccination up to the ages of 18, 21, and 26. For their analysis, they considered prevention of cancers associated with HPV types 16 and 18, of genital warts associated with types 6 and 11, and of recurrent respiratory papillomatosis. They also assumed that immunity would be lifelong, and current screening practices would continue.

They calculated that routine vaccination of 12-year-old girls resulted in an incremental cost-effective ratio of $34,900 per quality-adjusted life-year (QALY) gained. A threshold of less than $50,000 per QALY gained is considered reasonably cost-effective, with an upper limit of $100,000 considered acceptable.⁹²

In the same analysis by Kim and Goldie,⁸⁶ catch-up vaccination of girls through age 18 resulted in a cost of $50,000 to $100,000 per QALY gained, and catch-up vaccination of females through age 26 was significantly less cost-effective at more then $130,000 per QALY gained. The vaccine was also significantly less cost-effective if 5% of the population was neither screened nor vaccinated, if a 10-year booster was required, and if frequent cervical cancer screening intervals were adopted.

This analysis did not include costs related to the evaluation and treatment of abnormal Pap smears and cross-protection against other HPV-related cancers.

The cost-effectiveness of HPV vaccination depends on reaching more girls at younger ages (ideally before sexual debut) and completing the three-dose schedule to optimize duration of immunity.⁹² Appropriate modification of the current recommendations for the intervals of cervical cancer screening for vaccinated individuals will further improve the cost-effectiveness of vaccination. The inclusion of male vaccination generally has more favorable cost per QALY in scenarios in which female coverage rates are less than 50%⁹³ and among men who have sex with men.⁹⁴

TO ERADICATE CERVICAL CANCER

Given the remarkable efficacy and expected long-term immunogenicity of HPV vaccines, we anticipate a decline in HPV-related cervical cancer and other related diseases in the years to come. However, modeling studies predicting the impact of HPV vaccination suggest that although substantial reductions in diseases can be expected, the benefit, assuming high vaccination rates, will not be apparent for at least another decade.⁹⁵ Furthermore, the current HPV vaccines contain only HPV 16 and 18 L1 protein for cancer protection and, therefore, do not provide optimal protection against all oncogenic HPV-related cancers.

The real hope of eradicating cervical cancer and all HPV-related disease relies on a successful global implementation of multivalent HPV vaccination, effective screening strategies, and successful treatment.

Sudden cardiac death in a young person is a devastating event that has puzzled physicians for decades. In recent years, many of the underlying cardiac pathologies have been identified. These include structural abnormalities such as hypertrophic cardiomyopathy and nonstructural disorders associated with unstable rhythms that lead to sudden cardiac death.

The best known of these “channelopathies” are the long QT syndromes, which result from abnormal potassium and sodium channels in myocytes. Recently, interest has been growing in a disorder that may carry a similarly grim prognosis but that has an opposite finding on electrocardiography (ECG).

Short QT syndrome is a recently described heterogeneous genetic channelopathy that causes both atrial and ventricular arrhythmias and that has been documented to cause sudden cardiac death.

In 1996, a 37-year-old woman from Spain died suddenly; ECG several days earlier had shown a short QT interval of 266 ms.¹ Two years later, an unrelated 17-year-old American woman undergoing laparoscopic cholecystectomy suddenly developed atrial fibrillation with a rapid ventricular response.¹ Her QT interval was 225 ms. Her brother had a QT interval of 240 ms, and her mother’s was 230 ms. The patient’s maternal grandfather had a history of atrial fibrillation, and his QT interval was 245 ms. These cases led to the description of this new clinical syndrome (see below).²

CLINICAL FEATURES

Short QT syndrome has been associated with both atrial and ventricular arrhythmias. Atrial fibrillation, polymorphic ventricular tachycardia, and ventricular fibrillation have all been well described. Patients who have symptoms usually present with palpitations, presyncope, syncope, or sudden or aborted cardiac death.^3,4

ELECTROCARDIOGRAPHIC FEATURES

The primary finding on ECG is a short QT interval. However, others have been noted (Figure 1):

Short or absent ST segment

This finding is not merely a consequence of the short QT interval. In 10 patients with short QT syndrome, the distance from the J point to the peak T wave ranged from 80 to 120 ms. In 12 healthy people whose QT interval was less than 320 ms, this distance ranged from 150 ms to 240 ms.⁵

Tall and peaked T wave

A tall and peaked T wave is a common feature in short QT syndrome. However, it was also evident in people with short QT intervals who had no other features of the syndrome.⁵

QT response to heart rate

Normally, the QT interval is inversely related to the heart rate, but this is not true in short QT syndrome: the QT interval remains relatively fixed with changes in heart rate.^6,7 This feature is less helpful in the office setting but may be found with Holter monitoring by measuring the QT interval at different heart rates.

BUT WHAT IS CONSIDERED A SHORT QT INTERVAL?

In clinical practice, the QT interval is corrected for the heart rate by the Bazett formula:

Corrected QT (QTc) = [QT interval/square root of the RR interval]

Review of ECGs from large populations in Finland (n = 10,822), Japan (n = 12,149), the United States (n = 79,743), and Switzerland (n = 41,676) revealed that a QTc value of 350 ms in males and 365 ms in females was 2.0 standard deviations (SD) below the mean.^8–11 However, a QTc less than the 2.0 SD cutoff did not necessarily equal arrhythmogenic potential. This was illustrated in a 29-year follow-up study of Finnish patients with QTc values as short as 320 ms, in whom no arrhythmias were documented.⁸ Conversely, some patients with purported short QT syndrome had QTc intervals as long as 381 ms.¹²

Similar problems with uncertainty of values have plagued the diagnosis of long QT syndrome.¹³ The lack of reference ranges and the overlap between healthy and affected people called for the development of a scoring system that involves criteria based on ECG and on the clinical evaluation.^14,15

ESTABLISHING THE DIAGNOSIS OF SHORT QT SYNDROME

Clearly, the diagnosis of short QT syndrome can be challenging to establish. The first step is to rule out other causes of a short QT interval.

Differential diagnosis of short QT interval

In addition to genetic channelopathies, other causes of short QT interval must be ruled out before entertaining the diagnosis of short QT syndrome.

• Hypercalcemia is the most important of these: there is usually an accompanying prolonged PR interval and a wide QRS complex¹⁶
• Hyperkalemia¹⁷
• Acidosis¹⁷
• Increased vagal tone¹⁷
• After ventricular fibrillation (thought to be related to increased intracellular calcium)¹⁸
• Digitalis use¹⁹
• Androgen use.²⁰

Interestingly, a shorter-than-expected QT interval was noted in patients with chronic fatigue syndrome.²¹

Which interval to use: QT or QTc?

Unfortunately, most population-based studies that searched for a short QT interval on ECG have used QTc as the main search parameter.^8–11 As already mentioned, in patients with short QT syndrome, the QT interval is, uniquely, not shortened if the heart beats faster. In contrast, the QTc often overestimates the QT interval in patients with short QT syndrome, especially when the heart rate is in the 80s to 90s.¹⁶

In a review of cases of short QT syndrome worldwide, Bjerregaard et al²² found that the QT interval ranged from 210 ms to 340 ms with a mean ± 2 SD of 282 ± 62 ms. On the other hand, the QTc ranged from 248 ms to 345 ms with a mean ± 2 SD of 305 ± 42 ms.

Therefore, correction formulas (such as the Bazett formula) do not perform well in ruling in the diagnosis of short QT syndrome—and they do even worse in ruling it out.^16,22

To establish a diagnosis of short QT syndrome in someone with prior evidence of atrial or ventricular fibrillation, a QT interval less than 340 ms or a QTc less than 345 ms is usually sufficient.²² In borderline cases in which the QT interval is slightly longer, some experts recommend other tests, although strong evidence validating their predictive value does not exist. These tests include genotyping, analysis of T wave morphology, and electrophysiologic studies.¹⁶

Recently, Gollob et al²³ proposed a scoring system for short QT syndrome (Table 1). After reviewing the literature and comparing the diagnostic markers, the investigators determined diagnostic criteria that, when applied to the previously reported cases, were able to identify 58 (95.08%) of 61 patients with short QT syndrome (ie, a sensitivity of 95%).

For patients with intermediate probability, the authors recommended continued medical and ECG surveillance as well as ECGs for first-degree relatives, to further clarify the diagnosis.

Again, a principal caveat about this system is that it relies on the QTc interval rather than the QT interval to diagnose short QT syndrome.

THE SCOPE OF THE DISEASE

In a recent review of the literature, Gollob et al²³ found a total of 61 cases of short QT syndrome reported in English. The cohort was predominantly male (75.4%), and most of the symptomatic patients presented during late adolescence and early adulthood. However, there have been reports of infants (4 and 8 months old), and of a man who presented for the first time at the age of 70. Of note, the authors only considered short QT syndrome types 1, 2, and 3 (see below) in their search for cases.

Whether the syndrome is truly this rare or, rather, whether many physicians are not aware of it is still to be determined. In addition, it is possible that incorrectly measuring the QT interval contributes to the lack of identification of this entity. Both of these factors were implicated in the rarity of reported long QT syndrome early after its discovery.^14,15

MUTATIONS IN CARDIAC ION CHANNELS

Five distinct genetic defects have been associated with short QT syndrome. As in long QT syndrome, these give rise to subtypes of short QT syndrome, which are numbered 1 to 5 (see below).

The cardiac action potential

To understand how the mutations shorten the QT interval, we will briefly review of the cardiac myocyte action potential.²⁴ In nonpacemaker cells of the heart, the activation of the cell membrane initiates a series of changes in ion channels that allow the movement of ions along an electrical gradient. This movement occurs in five phases and is repeated with every cardiac cycle (Figure 2).

In phase 0, the cardiac cell rapidly depolarizes.

Repolarization occurs in phases 1, 2, and 3 and is largely a function of potassium ions leaving the cell. During phase 2, calcium and sodium ions enter the cell and balance the outward potassium flow, creating the “flat” portion of the repolarization curve. Phase 3 is the main phase of repolarization in which the membrane potential rapidly falls back to its resting state (–90 mV). During phases 1 and 2, the cell membrane is completely refractory to stimulation, whereas phase 3 is divided into three parts:

• The effective refractory period: the cell is able to generate a potential that is too weak to be propagated
• The relative refractory period: the cell can respond to a stimulus that is stronger than normal
• The supernormal phase: the last small portion of phase 3, in which a less-than-normal stimulus can yield a response in the cell.

In phase 4, the cell is completely repolarized, and the cycle can start again.

Short QT syndrome 1. In 2004, Brugada et al²⁵ identified the first mutation that causes abnormal shortening of the action potential duration. In contrast to the mutations that underlie long QT syndrome, this mutation actually causes a gain of function in the gene coding the rapidly acting delayed potassium current (IKr) channel proteins KCNH2 or HERG. Potassium leaving at a more rapid rate causes the cell to repolarize more quickly and shortens the QT interval. The clinical syndrome associated with KCNH2 gene gain-of-function mutation is called short QT syndrome 1.

Short QT syndromes 2 and 3. Other IK (potassium channel) proteins have been implicated as well. Gain-of-function mutations in the KCNQ1 and KCNJ2 genes are believed to account for short QT syndromes 2 and 3, respectively. KCNQ1 codes for the IKs protein, and KCNJ2 codes for the IK1 protein.^26,27

Short QT syndromes 4 and 5 were identified by Antzelevitch et al,²⁸ who described several patients who had a combination of channel abnormalities and ECG findings. Their ECGs showed “Brugada-syndrome-like” ST elevation in the right precordial leads, but with a short QT interval. These new syndromes were found to be associated with genetic abnormalities distinct from those of Brugada syndrome and other short QT syndromes. These abnormalities involved loss-of-function mutations in the CACNA1C gene (which codes for the alpha-1 subunit of the L-type cardiac calcium channel) and in the CACNB2 gene (which codes for the beta-2b subunit of the same channel). The two defects correspond to the clinical syndromes short QT syndrome 4 and short QT syndrome 5, respectively.²⁸

MECHANISM OF ARRHYTHMOGENESIS IN SHORT QT SYNDROME

The myocardium is made of different layers: the epicardium, the endocardium, and the middle layer of myocytes composed mainly of M cells. Cells in the different layers differ in the concentration of their channels and can be affected differently in various syndromes. When cells in one or two of the layers repolarize at a rate different from cells in another layer, they create different degrees of refractoriness, which establishes the potential for reentry circuits to form.

It is believed that in short QT syndrome the endocardial cells and M cells repolarize faster than the epicardial cells, predisposing to reentry and arrhythmias. This accentuation of “transmural dispersion of repolarization” accounts for arrhythmogenesis in short QT syndrome as well as in long QT syndrome and the Brugada syndromes. The difference between these syndromes appears to be the layer or area of the myocardium that is affected more by the channelopathy (the M cells in long QT syndrome and the epicardium of the right ventricle in the Brugada syndrome).²⁹

WHEN TO THINK OF SHORT QT SYNDROME

In any survivor of sudden cardiac death, the QT interval should be thoroughly scrutinized, and family members should undergo ECG. Patients in whom a short QT interval is incidentally discovered and for which other reasons are ruled out (see differential diagnosis) should be encouraged to have family members undergo ECG. Other potential patients are young people who develop atrial fibrillation and patients who have idiopathic ventricular fibrillation.⁴

TREATMENT AND PROGNOSIS

Evidence-based recommendations for the management of short QT syndrome do not yet exist, mainly because the number of patients identified to date is small.

Implantable cardioverter-defibrillators

Although placing an implantable cardioverter-defibrillator (ICD) seems to be warranted in patients who experience ventricular fibrillation, ventricular tachycardia, or aborted cardiac death, or in patients who have a family history of the same symptoms, the best management option is less clear for patients who have no symptoms and no family history.³⁰ In addition, some patients may not want an ICD or may even not qualify for this therapy.

A unique problem with ICDs in short QT syndrome stems from one of the syndrome’s main features on ECG: the tall and peaked T wave that closely follows the R wave can sometimes be interpreted as a short R-R interval, provoking an inappropriate shock from the ICD.³¹

For the above reasons, we strongly encourage consulting a center with expertise in QT-interval-related disorders before placing an ICD in a patient suspected of having short QT syndrome.

Antiarrhythmic drugs

Prolongation of the QT interval (and the effective refractory period) with drugs has been an interesting area of research. Gaita et al³² studied the effect of four antiarrhythmics—flecainide (Tambocor), sotalol (Betapace), ibutilide (Corvert), and quinidine—in six patients with short QT syndrome. Only quinidine was associated with significant QT prolongation, from 263 ± 12 ms to 362 ms ± 25 ms. This resulted in a longer ventricular effective refractory period (> 200 ms), and ventricular fibrillation was no longer inducible during provocative testing.

In a recent study of long-term outcomes of 53 patients with short QT syndrome, Giustetto et al³³ noticed that none of the patients taking quinidine, including those with a history of cardiac arrest, had any further arrhythmsic events. On the other hand, the incidence of arrhythmic events during the follow-up was 4.9% per year in patients not taking this drug. Quinidine had a stronger effect on the QT interval in patients with the HERG mutation than in those without.

RESEARCH MAY LEAD TO A BETTER UNDERSTANDING OF OTHER DISEASES

The short QT syndrome is one of the most recently recognized cardiac channelopathies associated with malignant arrhythmias. As with long QT syndrome, research in short QT syndrome may lead to a better understanding of the pathogenesis of more common but still poorly understood arrhythmias such as lone atrial fibrillation and idiopathic ventricular fibrillation.

Sudden cardiac death in a young person is a devastating event that has puzzled physicians for decades. In recent years, many of the underlying cardiac pathologies have been identified. These include structural abnormalities such as hypertrophic cardiomyopathy and nonstructural disorders associated with unstable rhythms that lead to sudden cardiac death.

The best known of these “channelopathies” are the long QT syndromes, which result from abnormal potassium and sodium channels in myocytes. Recently, interest has been growing in a disorder that may carry a similarly grim prognosis but that has an opposite finding on electrocardiography (ECG).

Short QT syndrome is a recently described heterogeneous genetic channelopathy that causes both atrial and ventricular arrhythmias and that has been documented to cause sudden cardiac death.

In 1996, a 37-year-old woman from Spain died suddenly; ECG several days earlier had shown a short QT interval of 266 ms.¹ Two years later, an unrelated 17-year-old American woman undergoing laparoscopic cholecystectomy suddenly developed atrial fibrillation with a rapid ventricular response.¹ Her QT interval was 225 ms. Her brother had a QT interval of 240 ms, and her mother’s was 230 ms. The patient’s maternal grandfather had a history of atrial fibrillation, and his QT interval was 245 ms. These cases led to the description of this new clinical syndrome (see below).²

CLINICAL FEATURES

Short QT syndrome has been associated with both atrial and ventricular arrhythmias. Atrial fibrillation, polymorphic ventricular tachycardia, and ventricular fibrillation have all been well described. Patients who have symptoms usually present with palpitations, presyncope, syncope, or sudden or aborted cardiac death.^3,4

ELECTROCARDIOGRAPHIC FEATURES

The primary finding on ECG is a short QT interval. However, others have been noted (Figure 1):

Short or absent ST segment

This finding is not merely a consequence of the short QT interval. In 10 patients with short QT syndrome, the distance from the J point to the peak T wave ranged from 80 to 120 ms. In 12 healthy people whose QT interval was less than 320 ms, this distance ranged from 150 ms to 240 ms.⁵

Tall and peaked T wave

A tall and peaked T wave is a common feature in short QT syndrome. However, it was also evident in people with short QT intervals who had no other features of the syndrome.⁵

QT response to heart rate

Normally, the QT interval is inversely related to the heart rate, but this is not true in short QT syndrome: the QT interval remains relatively fixed with changes in heart rate.^6,7 This feature is less helpful in the office setting but may be found with Holter monitoring by measuring the QT interval at different heart rates.

BUT WHAT IS CONSIDERED A SHORT QT INTERVAL?

In clinical practice, the QT interval is corrected for the heart rate by the Bazett formula:

Corrected QT (QTc) = [QT interval/square root of the RR interval]

Review of ECGs from large populations in Finland (n = 10,822), Japan (n = 12,149), the United States (n = 79,743), and Switzerland (n = 41,676) revealed that a QTc value of 350 ms in males and 365 ms in females was 2.0 standard deviations (SD) below the mean.^8–11 However, a QTc less than the 2.0 SD cutoff did not necessarily equal arrhythmogenic potential. This was illustrated in a 29-year follow-up study of Finnish patients with QTc values as short as 320 ms, in whom no arrhythmias were documented.⁸ Conversely, some patients with purported short QT syndrome had QTc intervals as long as 381 ms.¹²

Similar problems with uncertainty of values have plagued the diagnosis of long QT syndrome.¹³ The lack of reference ranges and the overlap between healthy and affected people called for the development of a scoring system that involves criteria based on ECG and on the clinical evaluation.^14,15

ESTABLISHING THE DIAGNOSIS OF SHORT QT SYNDROME

Clearly, the diagnosis of short QT syndrome can be challenging to establish. The first step is to rule out other causes of a short QT interval.

Differential diagnosis of short QT interval

In addition to genetic channelopathies, other causes of short QT interval must be ruled out before entertaining the diagnosis of short QT syndrome.

• Hypercalcemia is the most important of these: there is usually an accompanying prolonged PR interval and a wide QRS complex¹⁶
• Hyperkalemia¹⁷
• Acidosis¹⁷
• Increased vagal tone¹⁷
• After ventricular fibrillation (thought to be related to increased intracellular calcium)¹⁸
• Digitalis use¹⁹
• Androgen use.²⁰

Interestingly, a shorter-than-expected QT interval was noted in patients with chronic fatigue syndrome.²¹

Which interval to use: QT or QTc?

Unfortunately, most population-based studies that searched for a short QT interval on ECG have used QTc as the main search parameter.^8–11 As already mentioned, in patients with short QT syndrome, the QT interval is, uniquely, not shortened if the heart beats faster. In contrast, the QTc often overestimates the QT interval in patients with short QT syndrome, especially when the heart rate is in the 80s to 90s.¹⁶

In a review of cases of short QT syndrome worldwide, Bjerregaard et al²² found that the QT interval ranged from 210 ms to 340 ms with a mean ± 2 SD of 282 ± 62 ms. On the other hand, the QTc ranged from 248 ms to 345 ms with a mean ± 2 SD of 305 ± 42 ms.

Therefore, correction formulas (such as the Bazett formula) do not perform well in ruling in the diagnosis of short QT syndrome—and they do even worse in ruling it out.^16,22

To establish a diagnosis of short QT syndrome in someone with prior evidence of atrial or ventricular fibrillation, a QT interval less than 340 ms or a QTc less than 345 ms is usually sufficient.²² In borderline cases in which the QT interval is slightly longer, some experts recommend other tests, although strong evidence validating their predictive value does not exist. These tests include genotyping, analysis of T wave morphology, and electrophysiologic studies.¹⁶

Recently, Gollob et al²³ proposed a scoring system for short QT syndrome (Table 1). After reviewing the literature and comparing the diagnostic markers, the investigators determined diagnostic criteria that, when applied to the previously reported cases, were able to identify 58 (95.08%) of 61 patients with short QT syndrome (ie, a sensitivity of 95%).

For patients with intermediate probability, the authors recommended continued medical and ECG surveillance as well as ECGs for first-degree relatives, to further clarify the diagnosis.

Again, a principal caveat about this system is that it relies on the QTc interval rather than the QT interval to diagnose short QT syndrome.

THE SCOPE OF THE DISEASE

In a recent review of the literature, Gollob et al²³ found a total of 61 cases of short QT syndrome reported in English. The cohort was predominantly male (75.4%), and most of the symptomatic patients presented during late adolescence and early adulthood. However, there have been reports of infants (4 and 8 months old), and of a man who presented for the first time at the age of 70. Of note, the authors only considered short QT syndrome types 1, 2, and 3 (see below) in their search for cases.

Whether the syndrome is truly this rare or, rather, whether many physicians are not aware of it is still to be determined. In addition, it is possible that incorrectly measuring the QT interval contributes to the lack of identification of this entity. Both of these factors were implicated in the rarity of reported long QT syndrome early after its discovery.^14,15

MUTATIONS IN CARDIAC ION CHANNELS

Five distinct genetic defects have been associated with short QT syndrome. As in long QT syndrome, these give rise to subtypes of short QT syndrome, which are numbered 1 to 5 (see below).

The cardiac action potential

To understand how the mutations shorten the QT interval, we will briefly review of the cardiac myocyte action potential.²⁴ In nonpacemaker cells of the heart, the activation of the cell membrane initiates a series of changes in ion channels that allow the movement of ions along an electrical gradient. This movement occurs in five phases and is repeated with every cardiac cycle (Figure 2).

In phase 0, the cardiac cell rapidly depolarizes.

Repolarization occurs in phases 1, 2, and 3 and is largely a function of potassium ions leaving the cell. During phase 2, calcium and sodium ions enter the cell and balance the outward potassium flow, creating the “flat” portion of the repolarization curve. Phase 3 is the main phase of repolarization in which the membrane potential rapidly falls back to its resting state (–90 mV). During phases 1 and 2, the cell membrane is completely refractory to stimulation, whereas phase 3 is divided into three parts:

• The effective refractory period: the cell is able to generate a potential that is too weak to be propagated
• The relative refractory period: the cell can respond to a stimulus that is stronger than normal
• The supernormal phase: the last small portion of phase 3, in which a less-than-normal stimulus can yield a response in the cell.

In phase 4, the cell is completely repolarized, and the cycle can start again.

Short QT syndrome 1. In 2004, Brugada et al²⁵ identified the first mutation that causes abnormal shortening of the action potential duration. In contrast to the mutations that underlie long QT syndrome, this mutation actually causes a gain of function in the gene coding the rapidly acting delayed potassium current (IKr) channel proteins KCNH2 or HERG. Potassium leaving at a more rapid rate causes the cell to repolarize more quickly and shortens the QT interval. The clinical syndrome associated with KCNH2 gene gain-of-function mutation is called short QT syndrome 1.

Short QT syndromes 2 and 3. Other IK (potassium channel) proteins have been implicated as well. Gain-of-function mutations in the KCNQ1 and KCNJ2 genes are believed to account for short QT syndromes 2 and 3, respectively. KCNQ1 codes for the IKs protein, and KCNJ2 codes for the IK1 protein.^26,27

Short QT syndromes 4 and 5 were identified by Antzelevitch et al,²⁸ who described several patients who had a combination of channel abnormalities and ECG findings. Their ECGs showed “Brugada-syndrome-like” ST elevation in the right precordial leads, but with a short QT interval. These new syndromes were found to be associated with genetic abnormalities distinct from those of Brugada syndrome and other short QT syndromes. These abnormalities involved loss-of-function mutations in the CACNA1C gene (which codes for the alpha-1 subunit of the L-type cardiac calcium channel) and in the CACNB2 gene (which codes for the beta-2b subunit of the same channel). The two defects correspond to the clinical syndromes short QT syndrome 4 and short QT syndrome 5, respectively.²⁸

MECHANISM OF ARRHYTHMOGENESIS IN SHORT QT SYNDROME

The myocardium is made of different layers: the epicardium, the endocardium, and the middle layer of myocytes composed mainly of M cells. Cells in the different layers differ in the concentration of their channels and can be affected differently in various syndromes. When cells in one or two of the layers repolarize at a rate different from cells in another layer, they create different degrees of refractoriness, which establishes the potential for reentry circuits to form.

It is believed that in short QT syndrome the endocardial cells and M cells repolarize faster than the epicardial cells, predisposing to reentry and arrhythmias. This accentuation of “transmural dispersion of repolarization” accounts for arrhythmogenesis in short QT syndrome as well as in long QT syndrome and the Brugada syndromes. The difference between these syndromes appears to be the layer or area of the myocardium that is affected more by the channelopathy (the M cells in long QT syndrome and the epicardium of the right ventricle in the Brugada syndrome).²⁹

WHEN TO THINK OF SHORT QT SYNDROME

In any survivor of sudden cardiac death, the QT interval should be thoroughly scrutinized, and family members should undergo ECG. Patients in whom a short QT interval is incidentally discovered and for which other reasons are ruled out (see differential diagnosis) should be encouraged to have family members undergo ECG. Other potential patients are young people who develop atrial fibrillation and patients who have idiopathic ventricular fibrillation.⁴

TREATMENT AND PROGNOSIS

Evidence-based recommendations for the management of short QT syndrome do not yet exist, mainly because the number of patients identified to date is small.

Implantable cardioverter-defibrillators

Although placing an implantable cardioverter-defibrillator (ICD) seems to be warranted in patients who experience ventricular fibrillation, ventricular tachycardia, or aborted cardiac death, or in patients who have a family history of the same symptoms, the best management option is less clear for patients who have no symptoms and no family history.³⁰ In addition, some patients may not want an ICD or may even not qualify for this therapy.

A unique problem with ICDs in short QT syndrome stems from one of the syndrome’s main features on ECG: the tall and peaked T wave that closely follows the R wave can sometimes be interpreted as a short R-R interval, provoking an inappropriate shock from the ICD.³¹

For the above reasons, we strongly encourage consulting a center with expertise in QT-interval-related disorders before placing an ICD in a patient suspected of having short QT syndrome.

Antiarrhythmic drugs

Prolongation of the QT interval (and the effective refractory period) with drugs has been an interesting area of research. Gaita et al³² studied the effect of four antiarrhythmics—flecainide (Tambocor), sotalol (Betapace), ibutilide (Corvert), and quinidine—in six patients with short QT syndrome. Only quinidine was associated with significant QT prolongation, from 263 ± 12 ms to 362 ms ± 25 ms. This resulted in a longer ventricular effective refractory period (> 200 ms), and ventricular fibrillation was no longer inducible during provocative testing.

In a recent study of long-term outcomes of 53 patients with short QT syndrome, Giustetto et al³³ noticed that none of the patients taking quinidine, including those with a history of cardiac arrest, had any further arrhythmsic events. On the other hand, the incidence of arrhythmic events during the follow-up was 4.9% per year in patients not taking this drug. Quinidine had a stronger effect on the QT interval in patients with the HERG mutation than in those without.

RESEARCH MAY LEAD TO A BETTER UNDERSTANDING OF OTHER DISEASES

The short QT syndrome is one of the most recently recognized cardiac channelopathies associated with malignant arrhythmias. As with long QT syndrome, research in short QT syndrome may lead to a better understanding of the pathogenesis of more common but still poorly understood arrhythmias such as lone atrial fibrillation and idiopathic ventricular fibrillation.

Sudden cardiac death in a young person is a devastating event that has puzzled physicians for decades. In recent years, many of the underlying cardiac pathologies have been identified. These include structural abnormalities such as hypertrophic cardiomyopathy and nonstructural disorders associated with unstable rhythms that lead to sudden cardiac death.

The best known of these “channelopathies” are the long QT syndromes, which result from abnormal potassium and sodium channels in myocytes. Recently, interest has been growing in a disorder that may carry a similarly grim prognosis but that has an opposite finding on electrocardiography (ECG).

Short QT syndrome is a recently described heterogeneous genetic channelopathy that causes both atrial and ventricular arrhythmias and that has been documented to cause sudden cardiac death.

In 1996, a 37-year-old woman from Spain died suddenly; ECG several days earlier had shown a short QT interval of 266 ms.¹ Two years later, an unrelated 17-year-old American woman undergoing laparoscopic cholecystectomy suddenly developed atrial fibrillation with a rapid ventricular response.¹ Her QT interval was 225 ms. Her brother had a QT interval of 240 ms, and her mother’s was 230 ms. The patient’s maternal grandfather had a history of atrial fibrillation, and his QT interval was 245 ms. These cases led to the description of this new clinical syndrome (see below).²

CLINICAL FEATURES

Short QT syndrome has been associated with both atrial and ventricular arrhythmias. Atrial fibrillation, polymorphic ventricular tachycardia, and ventricular fibrillation have all been well described. Patients who have symptoms usually present with palpitations, presyncope, syncope, or sudden or aborted cardiac death.^3,4

ELECTROCARDIOGRAPHIC FEATURES

The primary finding on ECG is a short QT interval. However, others have been noted (Figure 1):

Short or absent ST segment

This finding is not merely a consequence of the short QT interval. In 10 patients with short QT syndrome, the distance from the J point to the peak T wave ranged from 80 to 120 ms. In 12 healthy people whose QT interval was less than 320 ms, this distance ranged from 150 ms to 240 ms.⁵

Tall and peaked T wave

A tall and peaked T wave is a common feature in short QT syndrome. However, it was also evident in people with short QT intervals who had no other features of the syndrome.⁵

QT response to heart rate

Normally, the QT interval is inversely related to the heart rate, but this is not true in short QT syndrome: the QT interval remains relatively fixed with changes in heart rate.^6,7 This feature is less helpful in the office setting but may be found with Holter monitoring by measuring the QT interval at different heart rates.

BUT WHAT IS CONSIDERED A SHORT QT INTERVAL?

In clinical practice, the QT interval is corrected for the heart rate by the Bazett formula:

Corrected QT (QTc) = [QT interval/square root of the RR interval]

Review of ECGs from large populations in Finland (n = 10,822), Japan (n = 12,149), the United States (n = 79,743), and Switzerland (n = 41,676) revealed that a QTc value of 350 ms in males and 365 ms in females was 2.0 standard deviations (SD) below the mean.^8–11 However, a QTc less than the 2.0 SD cutoff did not necessarily equal arrhythmogenic potential. This was illustrated in a 29-year follow-up study of Finnish patients with QTc values as short as 320 ms, in whom no arrhythmias were documented.⁸ Conversely, some patients with purported short QT syndrome had QTc intervals as long as 381 ms.¹²

Similar problems with uncertainty of values have plagued the diagnosis of long QT syndrome.¹³ The lack of reference ranges and the overlap between healthy and affected people called for the development of a scoring system that involves criteria based on ECG and on the clinical evaluation.^14,15

ESTABLISHING THE DIAGNOSIS OF SHORT QT SYNDROME

Clearly, the diagnosis of short QT syndrome can be challenging to establish. The first step is to rule out other causes of a short QT interval.

Differential diagnosis of short QT interval

In addition to genetic channelopathies, other causes of short QT interval must be ruled out before entertaining the diagnosis of short QT syndrome.

• Hypercalcemia is the most important of these: there is usually an accompanying prolonged PR interval and a wide QRS complex¹⁶
• Hyperkalemia¹⁷
• Acidosis¹⁷
• Increased vagal tone¹⁷
• After ventricular fibrillation (thought to be related to increased intracellular calcium)¹⁸
• Digitalis use¹⁹
• Androgen use.²⁰

Interestingly, a shorter-than-expected QT interval was noted in patients with chronic fatigue syndrome.²¹

Which interval to use: QT or QTc?

Unfortunately, most population-based studies that searched for a short QT interval on ECG have used QTc as the main search parameter.^8–11 As already mentioned, in patients with short QT syndrome, the QT interval is, uniquely, not shortened if the heart beats faster. In contrast, the QTc often overestimates the QT interval in patients with short QT syndrome, especially when the heart rate is in the 80s to 90s.¹⁶

In a review of cases of short QT syndrome worldwide, Bjerregaard et al²² found that the QT interval ranged from 210 ms to 340 ms with a mean ± 2 SD of 282 ± 62 ms. On the other hand, the QTc ranged from 248 ms to 345 ms with a mean ± 2 SD of 305 ± 42 ms.

Therefore, correction formulas (such as the Bazett formula) do not perform well in ruling in the diagnosis of short QT syndrome—and they do even worse in ruling it out.^16,22

To establish a diagnosis of short QT syndrome in someone with prior evidence of atrial or ventricular fibrillation, a QT interval less than 340 ms or a QTc less than 345 ms is usually sufficient.²² In borderline cases in which the QT interval is slightly longer, some experts recommend other tests, although strong evidence validating their predictive value does not exist. These tests include genotyping, analysis of T wave morphology, and electrophysiologic studies.¹⁶

Recently, Gollob et al²³ proposed a scoring system for short QT syndrome (Table 1). After reviewing the literature and comparing the diagnostic markers, the investigators determined diagnostic criteria that, when applied to the previously reported cases, were able to identify 58 (95.08%) of 61 patients with short QT syndrome (ie, a sensitivity of 95%).

For patients with intermediate probability, the authors recommended continued medical and ECG surveillance as well as ECGs for first-degree relatives, to further clarify the diagnosis.

Again, a principal caveat about this system is that it relies on the QTc interval rather than the QT interval to diagnose short QT syndrome.

THE SCOPE OF THE DISEASE

In a recent review of the literature, Gollob et al²³ found a total of 61 cases of short QT syndrome reported in English. The cohort was predominantly male (75.4%), and most of the symptomatic patients presented during late adolescence and early adulthood. However, there have been reports of infants (4 and 8 months old), and of a man who presented for the first time at the age of 70. Of note, the authors only considered short QT syndrome types 1, 2, and 3 (see below) in their search for cases.

Whether the syndrome is truly this rare or, rather, whether many physicians are not aware of it is still to be determined. In addition, it is possible that incorrectly measuring the QT interval contributes to the lack of identification of this entity. Both of these factors were implicated in the rarity of reported long QT syndrome early after its discovery.^14,15

MUTATIONS IN CARDIAC ION CHANNELS

Five distinct genetic defects have been associated with short QT syndrome. As in long QT syndrome, these give rise to subtypes of short QT syndrome, which are numbered 1 to 5 (see below).

The cardiac action potential

To understand how the mutations shorten the QT interval, we will briefly review of the cardiac myocyte action potential.²⁴ In nonpacemaker cells of the heart, the activation of the cell membrane initiates a series of changes in ion channels that allow the movement of ions along an electrical gradient. This movement occurs in five phases and is repeated with every cardiac cycle (Figure 2).

In phase 0, the cardiac cell rapidly depolarizes.

Repolarization occurs in phases 1, 2, and 3 and is largely a function of potassium ions leaving the cell. During phase 2, calcium and sodium ions enter the cell and balance the outward potassium flow, creating the “flat” portion of the repolarization curve. Phase 3 is the main phase of repolarization in which the membrane potential rapidly falls back to its resting state (–90 mV). During phases 1 and 2, the cell membrane is completely refractory to stimulation, whereas phase 3 is divided into three parts:

• The effective refractory period: the cell is able to generate a potential that is too weak to be propagated
• The relative refractory period: the cell can respond to a stimulus that is stronger than normal
• The supernormal phase: the last small portion of phase 3, in which a less-than-normal stimulus can yield a response in the cell.

In phase 4, the cell is completely repolarized, and the cycle can start again.

Short QT syndrome 1. In 2004, Brugada et al²⁵ identified the first mutation that causes abnormal shortening of the action potential duration. In contrast to the mutations that underlie long QT syndrome, this mutation actually causes a gain of function in the gene coding the rapidly acting delayed potassium current (IKr) channel proteins KCNH2 or HERG. Potassium leaving at a more rapid rate causes the cell to repolarize more quickly and shortens the QT interval. The clinical syndrome associated with KCNH2 gene gain-of-function mutation is called short QT syndrome 1.

Short QT syndromes 2 and 3. Other IK (potassium channel) proteins have been implicated as well. Gain-of-function mutations in the KCNQ1 and KCNJ2 genes are believed to account for short QT syndromes 2 and 3, respectively. KCNQ1 codes for the IKs protein, and KCNJ2 codes for the IK1 protein.^26,27

Short QT syndromes 4 and 5 were identified by Antzelevitch et al,²⁸ who described several patients who had a combination of channel abnormalities and ECG findings. Their ECGs showed “Brugada-syndrome-like” ST elevation in the right precordial leads, but with a short QT interval. These new syndromes were found to be associated with genetic abnormalities distinct from those of Brugada syndrome and other short QT syndromes. These abnormalities involved loss-of-function mutations in the CACNA1C gene (which codes for the alpha-1 subunit of the L-type cardiac calcium channel) and in the CACNB2 gene (which codes for the beta-2b subunit of the same channel). The two defects correspond to the clinical syndromes short QT syndrome 4 and short QT syndrome 5, respectively.²⁸

MECHANISM OF ARRHYTHMOGENESIS IN SHORT QT SYNDROME

The myocardium is made of different layers: the epicardium, the endocardium, and the middle layer of myocytes composed mainly of M cells. Cells in the different layers differ in the concentration of their channels and can be affected differently in various syndromes. When cells in one or two of the layers repolarize at a rate different from cells in another layer, they create different degrees of refractoriness, which establishes the potential for reentry circuits to form.

It is believed that in short QT syndrome the endocardial cells and M cells repolarize faster than the epicardial cells, predisposing to reentry and arrhythmias. This accentuation of “transmural dispersion of repolarization” accounts for arrhythmogenesis in short QT syndrome as well as in long QT syndrome and the Brugada syndromes. The difference between these syndromes appears to be the layer or area of the myocardium that is affected more by the channelopathy (the M cells in long QT syndrome and the epicardium of the right ventricle in the Brugada syndrome).²⁹

WHEN TO THINK OF SHORT QT SYNDROME

In any survivor of sudden cardiac death, the QT interval should be thoroughly scrutinized, and family members should undergo ECG. Patients in whom a short QT interval is incidentally discovered and for which other reasons are ruled out (see differential diagnosis) should be encouraged to have family members undergo ECG. Other potential patients are young people who develop atrial fibrillation and patients who have idiopathic ventricular fibrillation.⁴

TREATMENT AND PROGNOSIS

Evidence-based recommendations for the management of short QT syndrome do not yet exist, mainly because the number of patients identified to date is small.

Implantable cardioverter-defibrillators

Although placing an implantable cardioverter-defibrillator (ICD) seems to be warranted in patients who experience ventricular fibrillation, ventricular tachycardia, or aborted cardiac death, or in patients who have a family history of the same symptoms, the best management option is less clear for patients who have no symptoms and no family history.³⁰ In addition, some patients may not want an ICD or may even not qualify for this therapy.

A unique problem with ICDs in short QT syndrome stems from one of the syndrome’s main features on ECG: the tall and peaked T wave that closely follows the R wave can sometimes be interpreted as a short R-R interval, provoking an inappropriate shock from the ICD.³¹

For the above reasons, we strongly encourage consulting a center with expertise in QT-interval-related disorders before placing an ICD in a patient suspected of having short QT syndrome.

Antiarrhythmic drugs

Prolongation of the QT interval (and the effective refractory period) with drugs has been an interesting area of research. Gaita et al³² studied the effect of four antiarrhythmics—flecainide (Tambocor), sotalol (Betapace), ibutilide (Corvert), and quinidine—in six patients with short QT syndrome. Only quinidine was associated with significant QT prolongation, from 263 ± 12 ms to 362 ms ± 25 ms. This resulted in a longer ventricular effective refractory period (> 200 ms), and ventricular fibrillation was no longer inducible during provocative testing.

In a recent study of long-term outcomes of 53 patients with short QT syndrome, Giustetto et al³³ noticed that none of the patients taking quinidine, including those with a history of cardiac arrest, had any further arrhythmsic events. On the other hand, the incidence of arrhythmic events during the follow-up was 4.9% per year in patients not taking this drug. Quinidine had a stronger effect on the QT interval in patients with the HERG mutation than in those without.

RESEARCH MAY LEAD TO A BETTER UNDERSTANDING OF OTHER DISEASES

The short QT syndrome is one of the most recently recognized cardiac channelopathies associated with malignant arrhythmias. As with long QT syndrome, research in short QT syndrome may lead to a better understanding of the pathogenesis of more common but still poorly understood arrhythmias such as lone atrial fibrillation and idiopathic ventricular fibrillation.

Patients with advanced heart failure far outnumber the hearts available for transplantation. Partly as a consequence of this shortage, left-ventricular assist devices (LVADs) are being used more widely.

This article is an update on options for managing severe, advanced heart failure, with special attention to new developments and continuing challenges in heart transplantation and LVADs.

THE PREVALENCE OF HEART FAILURE

About 2.6% of the US population age 20 and older have heart failure—some 5.8 million people. Of these, about half have systolic heart failure.¹ Patients with systolic heart failure can be classified by degree of severity under two systems:

The New York Heart Association (NYHA) classifies patients by their functional status, from I (no limitation in activities) to IV (symptoms at rest). NYHA class III (symptoms with minimal exertion) is sometimes further broken down into IIIa and IIIb, with the latter defined as having a recent history of dyspnea at rest.

The joint American College of Cardiology and American Heart Association (ACC/AHA) classification uses four stages, from A (high risk of developing heart failure, ie, having risk factors such as family history of heart disease, hypertension, or diabetes) to D (advanced heart disease despite treatment). Patients in stage D tend to be recurrently hospitalized despite cardiac resynchronization therapy and drug therapy, and they cannot be safely discharged without specialized interventions. The options for these patients are limited: either end-of-life care or extraordinary measures such as heart transplantation, long-term treatment with inotropic drugs, permanent mechanical circulatory support, or experimental therapies.²

The estimated number of people in ACC/AHA stage D or NYHA class IV is 15,600 to 156,000. The approximate number of heart transplants performed in the United States each year is 2,100.³

WHICH AMBULATORY PATIENTS ARE MOST AT RISK?

The range for the estimated number of patients with advanced heart failure (NYHA class IIIb or IV) is wide (see above) because these patients may be hard to recognize. The most debilitated patients are obvious: they tend to be in the intensive care unit with end-organ failure. However, it is a challenge to recognize patients at extremely high risk who are still ambulatory.

The European Society of Cardiology⁴ developed a definition of advanced chronic heart failure that can help identify patients who are candidates for the transplant list and for an LVAD. All the following features must be present despite optimal therapy that includes diuretics, inhibitors of the renin-angiotensin-aldosterone system, and beta-blockers, unless these are poorly tolerated or contraindicated, and cardiac resynchronization therapy if indicated:

• Severe symptoms, with dyspnea or fatigue at rest or with minimal exertion (NYHA class III or IV)
• Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema) or of reduced cardiac output at rest (peripheral hypoperfusion)
• Objective evidence of severe cardiac dysfunction (at least one of the following): left ventricular ejection fraction less than 30%, pseudonormal or restrictive mitral inflow pattern on Doppler echocardiography, high left or right ventricular filling pressure (or both left and right filling pressures), and elevated B-type natriuretic peptides
• Severely impaired functional capacity demonstrated by one of the following: inability to exercise, 6-minute walk test distance less than 300 m (or less in women or patients who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min
• One or more hospitalizations for heart failure in the past 6 months.

Treadmill exercise time is an easily performed test. Hsich et al⁵ found that the longer patients can walk, the lower their risk of death, and that this variable is about as predictive of survival in patients with systolic left ventricular dysfunction as peak oxygen consumption, which is much more cumbersome to measure.

The Seattle Heart Failure Model gives an estimate of prognosis for ambulatory patients with advanced heart failure. Available at http://depts.washington.edu/shfm/, it is based on age, sex, NYHA class, weight, ejection fraction, blood pressure, medications, a few laboratory values, and other clinical information. The model has been validated in numerous cohorts,⁶ but it may underestimate risk and is currently being tested in clinical trials (REVIVE-IT and ROADMAP; see at www.clinicaltrials.gov).

Recurrent hospitalization is a simple predictor of risk. A study of about 7,000 patients worldwide found that after hospitalization with acute decompensated heart failure, the strongest predictor of death within 6 months was readmission for any reason within 30 days of the index hospitalization (Starling RC, unpublished observation, 2011). Any patient with heart failure who is repeatedly hospitalized should have a consultation with a heart failure specialist.

INOTROPIC THERAPY FOR BRIDGING

Inotropic drugs, which include intravenous dobutamine (Dobutrex) and milrinone (Primacor), are used to help maintain end-organ function until a patient can obtain a heart transplant or LVAD.

Inotropic therapy should not be viewed as an alternative to heart transplantation or device implantation. We inform patients that inotropic therapy is purely palliative and may actually increase the risk of death, which is about 50% at 6 months and nearly 100% at 1 year. A patient on inotropic therapy who is not a candidate for a transplant or for an assist device should be referred to a hospice program.⁷

CARDIAC TRANSPLANTATION: SUCCESSES, CHALLENGES

Survival rates after heart transplantation are now excellent. The 1-year survival rate is about 90%, the 5-year rate is about 70%, but only about 20% survive 20 years or longer.^8,9 The prognosis is not as good as for combined heart-lung transplantation patients.

Age is an important factor and is a contentious issue: some medical centers will not offer transplantation to patients over age 65. Others regard age as just another risk factor, like renal dysfunction or diabetes.

Quality of life after heart transplantation is excellent: patients are usually able to return to work, regardless of their profession.

The leading cause of death after heart transplantation is malignancy, followed by coronary artery vasculopathy, then by graft failure. Some patients develop left ventricular dysfunction and heart failure of unknown cause. Others develop antibody-mediated rejection; in recent years this has been more promptly recognized, but treatment remains a challenge.

Acute rejection, which used to be one of the main causes of death, now has an extremely low incidence because of modern drug therapies. In a US observational study currently being conducted in about 200 patients receiving a heart transplant (details on CTOT-05 at www.clinicaltrials.gov), the incidence of moderate rejection during the first year is less than 10% (Starling RC, unpublished observation). But several concerns remain.

Adverse effects of immunosuppressive drugs continue to be problematic. These include infection, malignancy, osteoporosis, chronic kidney toxicity, hypertension, and neuropathy.

Renal dysfunction is one of the largest issues. About 10% of heart transplant recipients develop stage 4 kidney disease (with a glomerular filtration rate < 30 mL/min) and need kidney transplantation or renal replacement therapy because of the use of calcineurin inhibitors for immunosuppression.¹⁰

Coronary artery vasculopathy was the largest problem when heart transplantation began and continues to be a major concern and focus of research.^11,12 Case 1 (below) is an example of the problem.

Case 1: Poor outcome despite an ideal scenario

A 57-year-old businessman had dilated cardiomyopathy and progressive heart failure for 10 years. He was listed for transplantation in 2008 and was given an LVAD (HeartMate II, Thoratec Corp, Pleasanton, CA) as a bridge until a donor heart became available.

In 2009, he received a heart transplant under ideal conditions: the donor was a large 30-year-old man who died of a gunshot wound to the head in the same city in which the patient and transplant hospital were located. Cardiopulmonary resuscitation was not performed, and the cold ischemic time was just a little more than 3 hours. Immune indicators were ideal with a negative prospective cross-match.

Laboratory results after transplantation included creatinine 1.7 mg/dL (normal 0.6–1.2 mg/dL), low-density lipoprotein cholesterol 75 mg/dL, high-density lipoprotein cholesterol 64 mg/dL, and triglycerides 90 mg/dL.

The patient was given immunosuppressive therapy with cyclosporine (Neoral), mycophenolate (CellCept), and prednisone. Because his creatinine level was high, he was also perioperatively given basiliximab (Simulect), a monoclonal antibody to the alpha chain (CD25) of the interleukin-2 receptor. (In a patient who has poor renal function, basilixumab may help by enabling us to delay the use of calcineurin inhibitors.) He also received simvastatin (Zocor) 10 mg.

Per Cleveland Clinic protocol, he underwent 13 biopsy procedures during his first year, and each was normal (grade 0 or 1R). Evaluation by cardiac catheterization at 1 year showed some irregularities in the left anterior descending artery, but a stent was not deemed necessary. Also, per protocol, he underwent intravascular ultrasonography, which revealed abnormal thickness in the intima and media, indicating that coronary artery disease was developing, although it was nonobstructive.

Two months after this checkup, the patient collapsed and suddenly died while shopping. At autopsy, his left anterior descending artery was found to be severely obstructed.

Coronary artery vasculopathy is still a major problem

This case shows that coronary artery vasculopathy may develop despite an ideal transplantation scenario. It remains a large concern and a focus of research.

Coronary vasculopathy develops in 30% to 40% of heart transplant recipients within 5 years, and the incidence has not been reduced by much over the years. However, probably fewer than 5% of these patients die or even need bypass surgery or stenting, and the problem is managed the same as native atherosclerosis. We perform routine annual cardiac catheterizations or stress tests, or both, and place stents in severely blocked arteries.

THE DONOR SHORTAGE: CHANGING HOW HEARTS ARE ALLOCATED

The number of patients receiving a heart transplant in the United States—about 2,000 per year—has not increased in the past decade. The European Union also has great difficulty obtaining hearts for people in need, and almost every transplant candidate there gets mechanical support for some time. The gap between those listed for transplant and the number transplanted each year continues to widen in both the United States and Europe.

All transplant candidates are assigned a status by the United Network of Organ Sharing (UNOS) based on their medical condition. The highest status, 1A, goes to patients who are seriously ill, in the hospital, on high doses of inotropic drugs (specific dosages are defined) and mechanical circulatory support such as an LVAD, and expected to live less than 1 month without a transplant. Status 1B patients are stable on lower-dose inotropic therapy or on mechanical support, and can be in the hospital or at home. Status 2 patients are stable and ambulatory and are not on inotropic drugs.

In July 2006, UNOS changed the rules on how patients are prioritized for obtaining an organ. The new rules are based both on severity of illness (see above) and geographic proximity to the donor heart—local, within 500 miles (“zone A”) or within 500 to 1,000 miles (“zone B”). The order of priority for donor hearts is:

• Local, status 1A
• Local, status 1B
• Zone A, status 1A
• Zone A, status 1B
• Local, status 2
• Zone B, status 1A
• Zone B, status 1B
• Zone A, status 2.

As a result of the change, donor hearts that become available in a particular hospital do not necessarily go to a patient in that state. Another result is that status 2 patients, who were previously the most common transplant recipients, now have much less access because all status 1 patients within 500 miles are given higher priority. Since the change, only 8% of hearts nationwide go to status 2 patients, which is 67% fewer than before. At the same time, organs allocated to status 1A patients have increased by 26%, and their death rates have fallen.³

The new allocation system is a positive change for the sickest patients, providing quicker access and a reduction in waiting-list mortality.¹³ The drawback is that status 2 patients who are less ill are less likely to ever receive an organ until their condition worsens.

Heart transplant outcomes are publicly reported

The Scientific Registry of Transplant Recipients publicly reports heart transplant outcomes (www.srtr.org). For any transplant center, the public can learn the number of patients waiting for a transplant, the death rate on the waiting list, the number of transplants performed in the previous 12 months, the waiting time in months, and observed and risk-adjusted expected survival rates. A center that deviates from the expected survival rates by 10% or more may be audited and could lose its certification.

Also listed on the Web site is the percentage of patients who receive a support device before receiving a transplant. This can vary widely between institutions and may reflect the organ availability at the transplant center (waiting times) or the preferences and expertise of the transplantation team. We believe that the mortality rate on the waiting list will be reduced with appropriate use of LVADs as a bridge to transplantation when indicated. We have now transitioned to the use of the improved continuous-flow LVADs and rarely maintain patients on continuous inotropic therapy at home to await a donor organ.

MECHANICAL CIRCULATORY SUPPORT: BRIDGE OR DESTINATION?

Mechanical circulatory support devices are increasingly being used to sustain patients with advanced heart failure. Currently at Cleveland Clinic, more LVADs are implanted than hearts are transplanted.

Mechanical circulatory support is indicated for patients who are listed for transplant to keep them functioning as well as possible while they are waiting (bridge to transplant). For others it is “destination therapy”: they are not candidates for a transplant, but a device may improve and prolong the rest of their life.

Case 2: A good outcome despite a poor prognosis

A 71-year-old man was rejected for transplantation by his local hospital because of his age and also because he had pulmonary artery hypertension (78/42 mm Hg; reference range 15–30/5–15 mm Hg) and creatinine elevation (3.0 mg/dL; reference range 0.6–1.5 mg/dL). Nevertheless, he did well on a mechanical device and was accepted for transplantation by Cleveland Clinic. He received a transplant and is still alive and active 14 years later.

Comment. Determining that a patient is not a good transplantation candidate is often impossible. Putting the patient on mechanical support for a period of time can often help clarify whether transplantation is advisable. Probably most patients who receive mechanical support do so as a bridge to decision: most are acutely ill and many have organ dysfunction, pulmonary hypertension, and renal insufficiency. After a period of support, they can be assessed for suitability for transplantation.

LVADs continue to improve

Many devices are available for mechanical circulatory support.¹⁴ In addition to LVADs, there are right-ventricular assist devices (RVADs), and devices that simultaneously support both ventricles (BiVADs). Total artificial hearts are also available, as are acute temporary percutaneous devices. These temporary devices—TandemHeart (CardiacAssist, Pittsburgh, PA) and Impella (Abiomed, Danvers, MD)—can be used before a long-term mechanical device can be surgically implanted.

LVADs are of three types:

• Pulsatile volume-displacement pumps, which mimic the pumping action of the natural heart. These early devices were large and placed in the abdomen.
• Continuous axial-flow pumps, which do not have a “heartbeat.” These are quieter and lighter than the early pumps, and use a turbine that spins at 8,000 to 10,000 rpm.
• Continuous centrifugal-flow pumps. These have a rotor spinning at 2,000 to 3,000 rpm, and most of them are magnetically powered and suspended.

The superiority of LVADs over medical therapy was clearly shown even in early studies that used pulsatile LVADs.¹⁵ The results of such studies and the increased durability of the devices have led to their rapidly expanded use.

The newer continuous-flow pumps offer significant improvements over the old pulsatile-flow pumps, being smaller, lighter, quieter, and more durable (Table 1). A 2007 study of 133 patients on a continuous axial-flow LVAD (HeartMate II) found that 76% were still alive after 6 months, and patients had significant improvement in functional status and quality of life.¹⁶ In a postapproval study based on registry data, HeartMate II was found superior to pulsatile pumps in terms of survival up to 12 months, percentage of patients reaching transplant, and cardiac recovery. Adverse event rates were similar or lower for HeartMate II.¹⁷

Another study compared a continuousflow with a pulsatile-flow LVAD for patients who were ineligible for transplantation. Survival at 2 years was 58% with the continuousflow device vs 24% with the pulsatile-flow device (P = .008).¹⁸ Since then, postmarket data of patients who received an LVAD showed that 85% are still alive at 1 year.¹⁹ This study can be viewed as supporting the use of LVADs as destination therapy.

Quality of life for patients receiving an LVAD has been excellent. When biventricular pacemakers for resynchronization therapy first became available, distances on the 6-minute walk test improved by 39 m, which was deemed a big improvement. LVAD devices have increased the 6-minute walk distance by 156 m.²⁰

Adverse events with LVADs have improved, but continue to be of concern

Infections can arise in the blood stream, in the device pocket, or especially where the driveline exits the skin. As devices have become smaller, driveline diameters have become smaller as well, allowing for a better seal at the skin and making this less of a problem. Some centers report the incidence of driveline infections as less than 20%, but they continue to be a focus of concern.¹⁸

Stroke rates continue to improve, although patients still require intensive lifelong anticoagulation. The target international normalized ratio varies by device manufacturer, ranging from 1.7 to 2.5.

Bleeding. Acquired von Willebrand syndrome can develop in patients who have an LVAD, with the gastrointestinal system being the most frequent site of bleeding.²¹

Device thrombosis occurs very rarely (2%–3%) but is very serious and may require pump exchange.

Mechanical malfunction. As duration of therapy lengthens, problems are arising with aging devices, such as broken wires or short circuits. New-generation pumps have markedly improved durability and reliability.

Good data are kept on device outcomes

The Interagency for Mechanically Assisted Circulatory Support (INTERMACS) maintains a national registry of patients with a mechanical circulatory support device to treat advanced heart failure. It was jointly established in 2006 by the National Heart, Lung, and Blood Institute, Centers for Medicare and Medicaid Services (CMS), the US Food and Drug Administration, and others. Reporting to INTERMACS is required for CMS reimbursement.

The INTERMACS database now has about 4,500 patients at 126 medical centers and is yielding useful information that is published in annual reports.²² The 2011 report focused on the experience with mechanical circulatory support as destination therapy and showed that patients who receive continuousflow pumps have significantly better survival rates than those with pulsatile-flow pumps.²³ An earlier report showed that the level of illness at the time of implantation predicts survival²⁴; this information now drives cardiologists to try to improve patient status with a temporary support device or intra-aortic balloon pump before implanting a durable device. The sickest patients (INTERMACS level 1) have the poorest outcomes, and centers now do fewer implantations in patients in this category. We have learned this important lesson from the INTERMACS registry.

The new devices have received a lot of media attention, and patient accrual has increased steadily as the devices have been approved.

On November 20, 2012, the US Food and Drug Administration approved the HeartWare Ventricular Assist System (HeartWare, Framingham, MA) for heart failure patients awaiting a transplant.

FUTURE DIRECTIONS

PROCEED II is an ongoing global clinical trial comparing the outcomes with donor hearts transported in standard cold storage to those transported in an experimental transport device that pumps the heart under physiologic conditions. If proven effective, this device could allow long-distance transport of donor hearts and expand the donor population.

A prospective, randomized study is now enrolling patients to evaluate induction therapy with rituximab (Rituxan) plus conventional immunosuppression (tacrolimus [Prograf], mycophenolate, steroid taper) vs placebo induction plus conventional immunosuppression. The study will enroll 400 patients (200 to each treatment arm) at 25 sites and will have a 36-month accrual period with 12-month follow-up (see http://clinicaltrials.gov/show/NCT01278745). The study is based on data in primates that found that eliminating B cells with an anti-CD20 drug before transplantation markedly reduced the incidence of coronary artery vasculopathy.

Patients with advanced heart failure far outnumber the hearts available for transplantation. Partly as a consequence of this shortage, left-ventricular assist devices (LVADs) are being used more widely.

This article is an update on options for managing severe, advanced heart failure, with special attention to new developments and continuing challenges in heart transplantation and LVADs.

THE PREVALENCE OF HEART FAILURE

About 2.6% of the US population age 20 and older have heart failure—some 5.8 million people. Of these, about half have systolic heart failure.¹ Patients with systolic heart failure can be classified by degree of severity under two systems:

The New York Heart Association (NYHA) classifies patients by their functional status, from I (no limitation in activities) to IV (symptoms at rest). NYHA class III (symptoms with minimal exertion) is sometimes further broken down into IIIa and IIIb, with the latter defined as having a recent history of dyspnea at rest.

The joint American College of Cardiology and American Heart Association (ACC/AHA) classification uses four stages, from A (high risk of developing heart failure, ie, having risk factors such as family history of heart disease, hypertension, or diabetes) to D (advanced heart disease despite treatment). Patients in stage D tend to be recurrently hospitalized despite cardiac resynchronization therapy and drug therapy, and they cannot be safely discharged without specialized interventions. The options for these patients are limited: either end-of-life care or extraordinary measures such as heart transplantation, long-term treatment with inotropic drugs, permanent mechanical circulatory support, or experimental therapies.²

The estimated number of people in ACC/AHA stage D or NYHA class IV is 15,600 to 156,000. The approximate number of heart transplants performed in the United States each year is 2,100.³

WHICH AMBULATORY PATIENTS ARE MOST AT RISK?

The range for the estimated number of patients with advanced heart failure (NYHA class IIIb or IV) is wide (see above) because these patients may be hard to recognize. The most debilitated patients are obvious: they tend to be in the intensive care unit with end-organ failure. However, it is a challenge to recognize patients at extremely high risk who are still ambulatory.

The European Society of Cardiology⁴ developed a definition of advanced chronic heart failure that can help identify patients who are candidates for the transplant list and for an LVAD. All the following features must be present despite optimal therapy that includes diuretics, inhibitors of the renin-angiotensin-aldosterone system, and beta-blockers, unless these are poorly tolerated or contraindicated, and cardiac resynchronization therapy if indicated:

• Severe symptoms, with dyspnea or fatigue at rest or with minimal exertion (NYHA class III or IV)
• Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema) or of reduced cardiac output at rest (peripheral hypoperfusion)
• Objective evidence of severe cardiac dysfunction (at least one of the following): left ventricular ejection fraction less than 30%, pseudonormal or restrictive mitral inflow pattern on Doppler echocardiography, high left or right ventricular filling pressure (or both left and right filling pressures), and elevated B-type natriuretic peptides
• Severely impaired functional capacity demonstrated by one of the following: inability to exercise, 6-minute walk test distance less than 300 m (or less in women or patients who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min
• One or more hospitalizations for heart failure in the past 6 months.

Treadmill exercise time is an easily performed test. Hsich et al⁵ found that the longer patients can walk, the lower their risk of death, and that this variable is about as predictive of survival in patients with systolic left ventricular dysfunction as peak oxygen consumption, which is much more cumbersome to measure.

The Seattle Heart Failure Model gives an estimate of prognosis for ambulatory patients with advanced heart failure. Available at http://depts.washington.edu/shfm/, it is based on age, sex, NYHA class, weight, ejection fraction, blood pressure, medications, a few laboratory values, and other clinical information. The model has been validated in numerous cohorts,⁶ but it may underestimate risk and is currently being tested in clinical trials (REVIVE-IT and ROADMAP; see at www.clinicaltrials.gov).

Recurrent hospitalization is a simple predictor of risk. A study of about 7,000 patients worldwide found that after hospitalization with acute decompensated heart failure, the strongest predictor of death within 6 months was readmission for any reason within 30 days of the index hospitalization (Starling RC, unpublished observation, 2011). Any patient with heart failure who is repeatedly hospitalized should have a consultation with a heart failure specialist.

INOTROPIC THERAPY FOR BRIDGING

Inotropic drugs, which include intravenous dobutamine (Dobutrex) and milrinone (Primacor), are used to help maintain end-organ function until a patient can obtain a heart transplant or LVAD.

Inotropic therapy should not be viewed as an alternative to heart transplantation or device implantation. We inform patients that inotropic therapy is purely palliative and may actually increase the risk of death, which is about 50% at 6 months and nearly 100% at 1 year. A patient on inotropic therapy who is not a candidate for a transplant or for an assist device should be referred to a hospice program.⁷

CARDIAC TRANSPLANTATION: SUCCESSES, CHALLENGES

Survival rates after heart transplantation are now excellent. The 1-year survival rate is about 90%, the 5-year rate is about 70%, but only about 20% survive 20 years or longer.^8,9 The prognosis is not as good as for combined heart-lung transplantation patients.

Age is an important factor and is a contentious issue: some medical centers will not offer transplantation to patients over age 65. Others regard age as just another risk factor, like renal dysfunction or diabetes.

Quality of life after heart transplantation is excellent: patients are usually able to return to work, regardless of their profession.

The leading cause of death after heart transplantation is malignancy, followed by coronary artery vasculopathy, then by graft failure. Some patients develop left ventricular dysfunction and heart failure of unknown cause. Others develop antibody-mediated rejection; in recent years this has been more promptly recognized, but treatment remains a challenge.

Acute rejection, which used to be one of the main causes of death, now has an extremely low incidence because of modern drug therapies. In a US observational study currently being conducted in about 200 patients receiving a heart transplant (details on CTOT-05 at www.clinicaltrials.gov), the incidence of moderate rejection during the first year is less than 10% (Starling RC, unpublished observation). But several concerns remain.

Adverse effects of immunosuppressive drugs continue to be problematic. These include infection, malignancy, osteoporosis, chronic kidney toxicity, hypertension, and neuropathy.

Renal dysfunction is one of the largest issues. About 10% of heart transplant recipients develop stage 4 kidney disease (with a glomerular filtration rate < 30 mL/min) and need kidney transplantation or renal replacement therapy because of the use of calcineurin inhibitors for immunosuppression.¹⁰

Coronary artery vasculopathy was the largest problem when heart transplantation began and continues to be a major concern and focus of research.^11,12 Case 1 (below) is an example of the problem.

Case 1: Poor outcome despite an ideal scenario

A 57-year-old businessman had dilated cardiomyopathy and progressive heart failure for 10 years. He was listed for transplantation in 2008 and was given an LVAD (HeartMate II, Thoratec Corp, Pleasanton, CA) as a bridge until a donor heart became available.

In 2009, he received a heart transplant under ideal conditions: the donor was a large 30-year-old man who died of a gunshot wound to the head in the same city in which the patient and transplant hospital were located. Cardiopulmonary resuscitation was not performed, and the cold ischemic time was just a little more than 3 hours. Immune indicators were ideal with a negative prospective cross-match.

Laboratory results after transplantation included creatinine 1.7 mg/dL (normal 0.6–1.2 mg/dL), low-density lipoprotein cholesterol 75 mg/dL, high-density lipoprotein cholesterol 64 mg/dL, and triglycerides 90 mg/dL.

The patient was given immunosuppressive therapy with cyclosporine (Neoral), mycophenolate (CellCept), and prednisone. Because his creatinine level was high, he was also perioperatively given basiliximab (Simulect), a monoclonal antibody to the alpha chain (CD25) of the interleukin-2 receptor. (In a patient who has poor renal function, basilixumab may help by enabling us to delay the use of calcineurin inhibitors.) He also received simvastatin (Zocor) 10 mg.

Per Cleveland Clinic protocol, he underwent 13 biopsy procedures during his first year, and each was normal (grade 0 or 1R). Evaluation by cardiac catheterization at 1 year showed some irregularities in the left anterior descending artery, but a stent was not deemed necessary. Also, per protocol, he underwent intravascular ultrasonography, which revealed abnormal thickness in the intima and media, indicating that coronary artery disease was developing, although it was nonobstructive.

Two months after this checkup, the patient collapsed and suddenly died while shopping. At autopsy, his left anterior descending artery was found to be severely obstructed.

Coronary artery vasculopathy is still a major problem

This case shows that coronary artery vasculopathy may develop despite an ideal transplantation scenario. It remains a large concern and a focus of research.

Coronary vasculopathy develops in 30% to 40% of heart transplant recipients within 5 years, and the incidence has not been reduced by much over the years. However, probably fewer than 5% of these patients die or even need bypass surgery or stenting, and the problem is managed the same as native atherosclerosis. We perform routine annual cardiac catheterizations or stress tests, or both, and place stents in severely blocked arteries.

THE DONOR SHORTAGE: CHANGING HOW HEARTS ARE ALLOCATED

The number of patients receiving a heart transplant in the United States—about 2,000 per year—has not increased in the past decade. The European Union also has great difficulty obtaining hearts for people in need, and almost every transplant candidate there gets mechanical support for some time. The gap between those listed for transplant and the number transplanted each year continues to widen in both the United States and Europe.

All transplant candidates are assigned a status by the United Network of Organ Sharing (UNOS) based on their medical condition. The highest status, 1A, goes to patients who are seriously ill, in the hospital, on high doses of inotropic drugs (specific dosages are defined) and mechanical circulatory support such as an LVAD, and expected to live less than 1 month without a transplant. Status 1B patients are stable on lower-dose inotropic therapy or on mechanical support, and can be in the hospital or at home. Status 2 patients are stable and ambulatory and are not on inotropic drugs.

In July 2006, UNOS changed the rules on how patients are prioritized for obtaining an organ. The new rules are based both on severity of illness (see above) and geographic proximity to the donor heart—local, within 500 miles (“zone A”) or within 500 to 1,000 miles (“zone B”). The order of priority for donor hearts is:

• Local, status 1A
• Local, status 1B
• Zone A, status 1A
• Zone A, status 1B
• Local, status 2
• Zone B, status 1A
• Zone B, status 1B
• Zone A, status 2.

As a result of the change, donor hearts that become available in a particular hospital do not necessarily go to a patient in that state. Another result is that status 2 patients, who were previously the most common transplant recipients, now have much less access because all status 1 patients within 500 miles are given higher priority. Since the change, only 8% of hearts nationwide go to status 2 patients, which is 67% fewer than before. At the same time, organs allocated to status 1A patients have increased by 26%, and their death rates have fallen.³

The new allocation system is a positive change for the sickest patients, providing quicker access and a reduction in waiting-list mortality.¹³ The drawback is that status 2 patients who are less ill are less likely to ever receive an organ until their condition worsens.

Heart transplant outcomes are publicly reported

The Scientific Registry of Transplant Recipients publicly reports heart transplant outcomes (www.srtr.org). For any transplant center, the public can learn the number of patients waiting for a transplant, the death rate on the waiting list, the number of transplants performed in the previous 12 months, the waiting time in months, and observed and risk-adjusted expected survival rates. A center that deviates from the expected survival rates by 10% or more may be audited and could lose its certification.

Also listed on the Web site is the percentage of patients who receive a support device before receiving a transplant. This can vary widely between institutions and may reflect the organ availability at the transplant center (waiting times) or the preferences and expertise of the transplantation team. We believe that the mortality rate on the waiting list will be reduced with appropriate use of LVADs as a bridge to transplantation when indicated. We have now transitioned to the use of the improved continuous-flow LVADs and rarely maintain patients on continuous inotropic therapy at home to await a donor organ.

MECHANICAL CIRCULATORY SUPPORT: BRIDGE OR DESTINATION?

Mechanical circulatory support devices are increasingly being used to sustain patients with advanced heart failure. Currently at Cleveland Clinic, more LVADs are implanted than hearts are transplanted.

Mechanical circulatory support is indicated for patients who are listed for transplant to keep them functioning as well as possible while they are waiting (bridge to transplant). For others it is “destination therapy”: they are not candidates for a transplant, but a device may improve and prolong the rest of their life.

Case 2: A good outcome despite a poor prognosis

A 71-year-old man was rejected for transplantation by his local hospital because of his age and also because he had pulmonary artery hypertension (78/42 mm Hg; reference range 15–30/5–15 mm Hg) and creatinine elevation (3.0 mg/dL; reference range 0.6–1.5 mg/dL). Nevertheless, he did well on a mechanical device and was accepted for transplantation by Cleveland Clinic. He received a transplant and is still alive and active 14 years later.

Comment. Determining that a patient is not a good transplantation candidate is often impossible. Putting the patient on mechanical support for a period of time can often help clarify whether transplantation is advisable. Probably most patients who receive mechanical support do so as a bridge to decision: most are acutely ill and many have organ dysfunction, pulmonary hypertension, and renal insufficiency. After a period of support, they can be assessed for suitability for transplantation.

LVADs continue to improve

Many devices are available for mechanical circulatory support.¹⁴ In addition to LVADs, there are right-ventricular assist devices (RVADs), and devices that simultaneously support both ventricles (BiVADs). Total artificial hearts are also available, as are acute temporary percutaneous devices. These temporary devices—TandemHeart (CardiacAssist, Pittsburgh, PA) and Impella (Abiomed, Danvers, MD)—can be used before a long-term mechanical device can be surgically implanted.

LVADs are of three types:

• Pulsatile volume-displacement pumps, which mimic the pumping action of the natural heart. These early devices were large and placed in the abdomen.
• Continuous axial-flow pumps, which do not have a “heartbeat.” These are quieter and lighter than the early pumps, and use a turbine that spins at 8,000 to 10,000 rpm.
• Continuous centrifugal-flow pumps. These have a rotor spinning at 2,000 to 3,000 rpm, and most of them are magnetically powered and suspended.

The superiority of LVADs over medical therapy was clearly shown even in early studies that used pulsatile LVADs.¹⁵ The results of such studies and the increased durability of the devices have led to their rapidly expanded use.

The newer continuous-flow pumps offer significant improvements over the old pulsatile-flow pumps, being smaller, lighter, quieter, and more durable (Table 1). A 2007 study of 133 patients on a continuous axial-flow LVAD (HeartMate II) found that 76% were still alive after 6 months, and patients had significant improvement in functional status and quality of life.¹⁶ In a postapproval study based on registry data, HeartMate II was found superior to pulsatile pumps in terms of survival up to 12 months, percentage of patients reaching transplant, and cardiac recovery. Adverse event rates were similar or lower for HeartMate II.¹⁷

Another study compared a continuousflow with a pulsatile-flow LVAD for patients who were ineligible for transplantation. Survival at 2 years was 58% with the continuousflow device vs 24% with the pulsatile-flow device (P = .008).¹⁸ Since then, postmarket data of patients who received an LVAD showed that 85% are still alive at 1 year.¹⁹ This study can be viewed as supporting the use of LVADs as destination therapy.

Quality of life for patients receiving an LVAD has been excellent. When biventricular pacemakers for resynchronization therapy first became available, distances on the 6-minute walk test improved by 39 m, which was deemed a big improvement. LVAD devices have increased the 6-minute walk distance by 156 m.²⁰

Adverse events with LVADs have improved, but continue to be of concern

Infections can arise in the blood stream, in the device pocket, or especially where the driveline exits the skin. As devices have become smaller, driveline diameters have become smaller as well, allowing for a better seal at the skin and making this less of a problem. Some centers report the incidence of driveline infections as less than 20%, but they continue to be a focus of concern.¹⁸

Stroke rates continue to improve, although patients still require intensive lifelong anticoagulation. The target international normalized ratio varies by device manufacturer, ranging from 1.7 to 2.5.

Bleeding. Acquired von Willebrand syndrome can develop in patients who have an LVAD, with the gastrointestinal system being the most frequent site of bleeding.²¹

Device thrombosis occurs very rarely (2%–3%) but is very serious and may require pump exchange.

Mechanical malfunction. As duration of therapy lengthens, problems are arising with aging devices, such as broken wires or short circuits. New-generation pumps have markedly improved durability and reliability.

Good data are kept on device outcomes

The Interagency for Mechanically Assisted Circulatory Support (INTERMACS) maintains a national registry of patients with a mechanical circulatory support device to treat advanced heart failure. It was jointly established in 2006 by the National Heart, Lung, and Blood Institute, Centers for Medicare and Medicaid Services (CMS), the US Food and Drug Administration, and others. Reporting to INTERMACS is required for CMS reimbursement.

The INTERMACS database now has about 4,500 patients at 126 medical centers and is yielding useful information that is published in annual reports.²² The 2011 report focused on the experience with mechanical circulatory support as destination therapy and showed that patients who receive continuousflow pumps have significantly better survival rates than those with pulsatile-flow pumps.²³ An earlier report showed that the level of illness at the time of implantation predicts survival²⁴; this information now drives cardiologists to try to improve patient status with a temporary support device or intra-aortic balloon pump before implanting a durable device. The sickest patients (INTERMACS level 1) have the poorest outcomes, and centers now do fewer implantations in patients in this category. We have learned this important lesson from the INTERMACS registry.

The new devices have received a lot of media attention, and patient accrual has increased steadily as the devices have been approved.

On November 20, 2012, the US Food and Drug Administration approved the HeartWare Ventricular Assist System (HeartWare, Framingham, MA) for heart failure patients awaiting a transplant.

FUTURE DIRECTIONS

PROCEED II is an ongoing global clinical trial comparing the outcomes with donor hearts transported in standard cold storage to those transported in an experimental transport device that pumps the heart under physiologic conditions. If proven effective, this device could allow long-distance transport of donor hearts and expand the donor population.

A prospective, randomized study is now enrolling patients to evaluate induction therapy with rituximab (Rituxan) plus conventional immunosuppression (tacrolimus [Prograf], mycophenolate, steroid taper) vs placebo induction plus conventional immunosuppression. The study will enroll 400 patients (200 to each treatment arm) at 25 sites and will have a 36-month accrual period with 12-month follow-up (see http://clinicaltrials.gov/show/NCT01278745). The study is based on data in primates that found that eliminating B cells with an anti-CD20 drug before transplantation markedly reduced the incidence of coronary artery vasculopathy.

Patients with advanced heart failure far outnumber the hearts available for transplantation. Partly as a consequence of this shortage, left-ventricular assist devices (LVADs) are being used more widely.

This article is an update on options for managing severe, advanced heart failure, with special attention to new developments and continuing challenges in heart transplantation and LVADs.

THE PREVALENCE OF HEART FAILURE

About 2.6% of the US population age 20 and older have heart failure—some 5.8 million people. Of these, about half have systolic heart failure.¹ Patients with systolic heart failure can be classified by degree of severity under two systems:

The New York Heart Association (NYHA) classifies patients by their functional status, from I (no limitation in activities) to IV (symptoms at rest). NYHA class III (symptoms with minimal exertion) is sometimes further broken down into IIIa and IIIb, with the latter defined as having a recent history of dyspnea at rest.

The joint American College of Cardiology and American Heart Association (ACC/AHA) classification uses four stages, from A (high risk of developing heart failure, ie, having risk factors such as family history of heart disease, hypertension, or diabetes) to D (advanced heart disease despite treatment). Patients in stage D tend to be recurrently hospitalized despite cardiac resynchronization therapy and drug therapy, and they cannot be safely discharged without specialized interventions. The options for these patients are limited: either end-of-life care or extraordinary measures such as heart transplantation, long-term treatment with inotropic drugs, permanent mechanical circulatory support, or experimental therapies.²

The estimated number of people in ACC/AHA stage D or NYHA class IV is 15,600 to 156,000. The approximate number of heart transplants performed in the United States each year is 2,100.³

WHICH AMBULATORY PATIENTS ARE MOST AT RISK?

The range for the estimated number of patients with advanced heart failure (NYHA class IIIb or IV) is wide (see above) because these patients may be hard to recognize. The most debilitated patients are obvious: they tend to be in the intensive care unit with end-organ failure. However, it is a challenge to recognize patients at extremely high risk who are still ambulatory.

The European Society of Cardiology⁴ developed a definition of advanced chronic heart failure that can help identify patients who are candidates for the transplant list and for an LVAD. All the following features must be present despite optimal therapy that includes diuretics, inhibitors of the renin-angiotensin-aldosterone system, and beta-blockers, unless these are poorly tolerated or contraindicated, and cardiac resynchronization therapy if indicated:

• Severe symptoms, with dyspnea or fatigue at rest or with minimal exertion (NYHA class III or IV)
• Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema) or of reduced cardiac output at rest (peripheral hypoperfusion)
• Objective evidence of severe cardiac dysfunction (at least one of the following): left ventricular ejection fraction less than 30%, pseudonormal or restrictive mitral inflow pattern on Doppler echocardiography, high left or right ventricular filling pressure (or both left and right filling pressures), and elevated B-type natriuretic peptides
• Severely impaired functional capacity demonstrated by one of the following: inability to exercise, 6-minute walk test distance less than 300 m (or less in women or patients who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min
• One or more hospitalizations for heart failure in the past 6 months.

Treadmill exercise time is an easily performed test. Hsich et al⁵ found that the longer patients can walk, the lower their risk of death, and that this variable is about as predictive of survival in patients with systolic left ventricular dysfunction as peak oxygen consumption, which is much more cumbersome to measure.

The Seattle Heart Failure Model gives an estimate of prognosis for ambulatory patients with advanced heart failure. Available at http://depts.washington.edu/shfm/, it is based on age, sex, NYHA class, weight, ejection fraction, blood pressure, medications, a few laboratory values, and other clinical information. The model has been validated in numerous cohorts,⁶ but it may underestimate risk and is currently being tested in clinical trials (REVIVE-IT and ROADMAP; see at www.clinicaltrials.gov).

Recurrent hospitalization is a simple predictor of risk. A study of about 7,000 patients worldwide found that after hospitalization with acute decompensated heart failure, the strongest predictor of death within 6 months was readmission for any reason within 30 days of the index hospitalization (Starling RC, unpublished observation, 2011). Any patient with heart failure who is repeatedly hospitalized should have a consultation with a heart failure specialist.

INOTROPIC THERAPY FOR BRIDGING

Inotropic drugs, which include intravenous dobutamine (Dobutrex) and milrinone (Primacor), are used to help maintain end-organ function until a patient can obtain a heart transplant or LVAD.

Inotropic therapy should not be viewed as an alternative to heart transplantation or device implantation. We inform patients that inotropic therapy is purely palliative and may actually increase the risk of death, which is about 50% at 6 months and nearly 100% at 1 year. A patient on inotropic therapy who is not a candidate for a transplant or for an assist device should be referred to a hospice program.⁷

CARDIAC TRANSPLANTATION: SUCCESSES, CHALLENGES

Survival rates after heart transplantation are now excellent. The 1-year survival rate is about 90%, the 5-year rate is about 70%, but only about 20% survive 20 years or longer.^8,9 The prognosis is not as good as for combined heart-lung transplantation patients.

Age is an important factor and is a contentious issue: some medical centers will not offer transplantation to patients over age 65. Others regard age as just another risk factor, like renal dysfunction or diabetes.

Quality of life after heart transplantation is excellent: patients are usually able to return to work, regardless of their profession.

The leading cause of death after heart transplantation is malignancy, followed by coronary artery vasculopathy, then by graft failure. Some patients develop left ventricular dysfunction and heart failure of unknown cause. Others develop antibody-mediated rejection; in recent years this has been more promptly recognized, but treatment remains a challenge.

Acute rejection, which used to be one of the main causes of death, now has an extremely low incidence because of modern drug therapies. In a US observational study currently being conducted in about 200 patients receiving a heart transplant (details on CTOT-05 at www.clinicaltrials.gov), the incidence of moderate rejection during the first year is less than 10% (Starling RC, unpublished observation). But several concerns remain.

Adverse effects of immunosuppressive drugs continue to be problematic. These include infection, malignancy, osteoporosis, chronic kidney toxicity, hypertension, and neuropathy.

Renal dysfunction is one of the largest issues. About 10% of heart transplant recipients develop stage 4 kidney disease (with a glomerular filtration rate < 30 mL/min) and need kidney transplantation or renal replacement therapy because of the use of calcineurin inhibitors for immunosuppression.¹⁰

Coronary artery vasculopathy was the largest problem when heart transplantation began and continues to be a major concern and focus of research.^11,12 Case 1 (below) is an example of the problem.

Case 1: Poor outcome despite an ideal scenario

A 57-year-old businessman had dilated cardiomyopathy and progressive heart failure for 10 years. He was listed for transplantation in 2008 and was given an LVAD (HeartMate II, Thoratec Corp, Pleasanton, CA) as a bridge until a donor heart became available.

In 2009, he received a heart transplant under ideal conditions: the donor was a large 30-year-old man who died of a gunshot wound to the head in the same city in which the patient and transplant hospital were located. Cardiopulmonary resuscitation was not performed, and the cold ischemic time was just a little more than 3 hours. Immune indicators were ideal with a negative prospective cross-match.

Laboratory results after transplantation included creatinine 1.7 mg/dL (normal 0.6–1.2 mg/dL), low-density lipoprotein cholesterol 75 mg/dL, high-density lipoprotein cholesterol 64 mg/dL, and triglycerides 90 mg/dL.

The patient was given immunosuppressive therapy with cyclosporine (Neoral), mycophenolate (CellCept), and prednisone. Because his creatinine level was high, he was also perioperatively given basiliximab (Simulect), a monoclonal antibody to the alpha chain (CD25) of the interleukin-2 receptor. (In a patient who has poor renal function, basilixumab may help by enabling us to delay the use of calcineurin inhibitors.) He also received simvastatin (Zocor) 10 mg.

Per Cleveland Clinic protocol, he underwent 13 biopsy procedures during his first year, and each was normal (grade 0 or 1R). Evaluation by cardiac catheterization at 1 year showed some irregularities in the left anterior descending artery, but a stent was not deemed necessary. Also, per protocol, he underwent intravascular ultrasonography, which revealed abnormal thickness in the intima and media, indicating that coronary artery disease was developing, although it was nonobstructive.

Two months after this checkup, the patient collapsed and suddenly died while shopping. At autopsy, his left anterior descending artery was found to be severely obstructed.

Coronary artery vasculopathy is still a major problem

This case shows that coronary artery vasculopathy may develop despite an ideal transplantation scenario. It remains a large concern and a focus of research.

Coronary vasculopathy develops in 30% to 40% of heart transplant recipients within 5 years, and the incidence has not been reduced by much over the years. However, probably fewer than 5% of these patients die or even need bypass surgery or stenting, and the problem is managed the same as native atherosclerosis. We perform routine annual cardiac catheterizations or stress tests, or both, and place stents in severely blocked arteries.

THE DONOR SHORTAGE: CHANGING HOW HEARTS ARE ALLOCATED

The number of patients receiving a heart transplant in the United States—about 2,000 per year—has not increased in the past decade. The European Union also has great difficulty obtaining hearts for people in need, and almost every transplant candidate there gets mechanical support for some time. The gap between those listed for transplant and the number transplanted each year continues to widen in both the United States and Europe.

All transplant candidates are assigned a status by the United Network of Organ Sharing (UNOS) based on their medical condition. The highest status, 1A, goes to patients who are seriously ill, in the hospital, on high doses of inotropic drugs (specific dosages are defined) and mechanical circulatory support such as an LVAD, and expected to live less than 1 month without a transplant. Status 1B patients are stable on lower-dose inotropic therapy or on mechanical support, and can be in the hospital or at home. Status 2 patients are stable and ambulatory and are not on inotropic drugs.

In July 2006, UNOS changed the rules on how patients are prioritized for obtaining an organ. The new rules are based both on severity of illness (see above) and geographic proximity to the donor heart—local, within 500 miles (“zone A”) or within 500 to 1,000 miles (“zone B”). The order of priority for donor hearts is:

• Local, status 1A
• Local, status 1B
• Zone A, status 1A
• Zone A, status 1B
• Local, status 2
• Zone B, status 1A
• Zone B, status 1B
• Zone A, status 2.

As a result of the change, donor hearts that become available in a particular hospital do not necessarily go to a patient in that state. Another result is that status 2 patients, who were previously the most common transplant recipients, now have much less access because all status 1 patients within 500 miles are given higher priority. Since the change, only 8% of hearts nationwide go to status 2 patients, which is 67% fewer than before. At the same time, organs allocated to status 1A patients have increased by 26%, and their death rates have fallen.³

The new allocation system is a positive change for the sickest patients, providing quicker access and a reduction in waiting-list mortality.¹³ The drawback is that status 2 patients who are less ill are less likely to ever receive an organ until their condition worsens.

Heart transplant outcomes are publicly reported

The Scientific Registry of Transplant Recipients publicly reports heart transplant outcomes (www.srtr.org). For any transplant center, the public can learn the number of patients waiting for a transplant, the death rate on the waiting list, the number of transplants performed in the previous 12 months, the waiting time in months, and observed and risk-adjusted expected survival rates. A center that deviates from the expected survival rates by 10% or more may be audited and could lose its certification.

Also listed on the Web site is the percentage of patients who receive a support device before receiving a transplant. This can vary widely between institutions and may reflect the organ availability at the transplant center (waiting times) or the preferences and expertise of the transplantation team. We believe that the mortality rate on the waiting list will be reduced with appropriate use of LVADs as a bridge to transplantation when indicated. We have now transitioned to the use of the improved continuous-flow LVADs and rarely maintain patients on continuous inotropic therapy at home to await a donor organ.

MECHANICAL CIRCULATORY SUPPORT: BRIDGE OR DESTINATION?

Mechanical circulatory support devices are increasingly being used to sustain patients with advanced heart failure. Currently at Cleveland Clinic, more LVADs are implanted than hearts are transplanted.

Mechanical circulatory support is indicated for patients who are listed for transplant to keep them functioning as well as possible while they are waiting (bridge to transplant). For others it is “destination therapy”: they are not candidates for a transplant, but a device may improve and prolong the rest of their life.

Case 2: A good outcome despite a poor prognosis

A 71-year-old man was rejected for transplantation by his local hospital because of his age and also because he had pulmonary artery hypertension (78/42 mm Hg; reference range 15–30/5–15 mm Hg) and creatinine elevation (3.0 mg/dL; reference range 0.6–1.5 mg/dL). Nevertheless, he did well on a mechanical device and was accepted for transplantation by Cleveland Clinic. He received a transplant and is still alive and active 14 years later.

Comment. Determining that a patient is not a good transplantation candidate is often impossible. Putting the patient on mechanical support for a period of time can often help clarify whether transplantation is advisable. Probably most patients who receive mechanical support do so as a bridge to decision: most are acutely ill and many have organ dysfunction, pulmonary hypertension, and renal insufficiency. After a period of support, they can be assessed for suitability for transplantation.

LVADs continue to improve

Many devices are available for mechanical circulatory support.¹⁴ In addition to LVADs, there are right-ventricular assist devices (RVADs), and devices that simultaneously support both ventricles (BiVADs). Total artificial hearts are also available, as are acute temporary percutaneous devices. These temporary devices—TandemHeart (CardiacAssist, Pittsburgh, PA) and Impella (Abiomed, Danvers, MD)—can be used before a long-term mechanical device can be surgically implanted.

LVADs are of three types:

• Pulsatile volume-displacement pumps, which mimic the pumping action of the natural heart. These early devices were large and placed in the abdomen.
• Continuous axial-flow pumps, which do not have a “heartbeat.” These are quieter and lighter than the early pumps, and use a turbine that spins at 8,000 to 10,000 rpm.
• Continuous centrifugal-flow pumps. These have a rotor spinning at 2,000 to 3,000 rpm, and most of them are magnetically powered and suspended.

The superiority of LVADs over medical therapy was clearly shown even in early studies that used pulsatile LVADs.¹⁵ The results of such studies and the increased durability of the devices have led to their rapidly expanded use.

The newer continuous-flow pumps offer significant improvements over the old pulsatile-flow pumps, being smaller, lighter, quieter, and more durable (Table 1). A 2007 study of 133 patients on a continuous axial-flow LVAD (HeartMate II) found that 76% were still alive after 6 months, and patients had significant improvement in functional status and quality of life.¹⁶ In a postapproval study based on registry data, HeartMate II was found superior to pulsatile pumps in terms of survival up to 12 months, percentage of patients reaching transplant, and cardiac recovery. Adverse event rates were similar or lower for HeartMate II.¹⁷

Another study compared a continuousflow with a pulsatile-flow LVAD for patients who were ineligible for transplantation. Survival at 2 years was 58% with the continuousflow device vs 24% with the pulsatile-flow device (P = .008).¹⁸ Since then, postmarket data of patients who received an LVAD showed that 85% are still alive at 1 year.¹⁹ This study can be viewed as supporting the use of LVADs as destination therapy.

Quality of life for patients receiving an LVAD has been excellent. When biventricular pacemakers for resynchronization therapy first became available, distances on the 6-minute walk test improved by 39 m, which was deemed a big improvement. LVAD devices have increased the 6-minute walk distance by 156 m.²⁰

Adverse events with LVADs have improved, but continue to be of concern

Infections can arise in the blood stream, in the device pocket, or especially where the driveline exits the skin. As devices have become smaller, driveline diameters have become smaller as well, allowing for a better seal at the skin and making this less of a problem. Some centers report the incidence of driveline infections as less than 20%, but they continue to be a focus of concern.¹⁸

Stroke rates continue to improve, although patients still require intensive lifelong anticoagulation. The target international normalized ratio varies by device manufacturer, ranging from 1.7 to 2.5.

Bleeding. Acquired von Willebrand syndrome can develop in patients who have an LVAD, with the gastrointestinal system being the most frequent site of bleeding.²¹

Device thrombosis occurs very rarely (2%–3%) but is very serious and may require pump exchange.

Mechanical malfunction. As duration of therapy lengthens, problems are arising with aging devices, such as broken wires or short circuits. New-generation pumps have markedly improved durability and reliability.

Good data are kept on device outcomes

The Interagency for Mechanically Assisted Circulatory Support (INTERMACS) maintains a national registry of patients with a mechanical circulatory support device to treat advanced heart failure. It was jointly established in 2006 by the National Heart, Lung, and Blood Institute, Centers for Medicare and Medicaid Services (CMS), the US Food and Drug Administration, and others. Reporting to INTERMACS is required for CMS reimbursement.

The INTERMACS database now has about 4,500 patients at 126 medical centers and is yielding useful information that is published in annual reports.²² The 2011 report focused on the experience with mechanical circulatory support as destination therapy and showed that patients who receive continuousflow pumps have significantly better survival rates than those with pulsatile-flow pumps.²³ An earlier report showed that the level of illness at the time of implantation predicts survival²⁴; this information now drives cardiologists to try to improve patient status with a temporary support device or intra-aortic balloon pump before implanting a durable device. The sickest patients (INTERMACS level 1) have the poorest outcomes, and centers now do fewer implantations in patients in this category. We have learned this important lesson from the INTERMACS registry.

The new devices have received a lot of media attention, and patient accrual has increased steadily as the devices have been approved.

On November 20, 2012, the US Food and Drug Administration approved the HeartWare Ventricular Assist System (HeartWare, Framingham, MA) for heart failure patients awaiting a transplant.

FUTURE DIRECTIONS

PROCEED II is an ongoing global clinical trial comparing the outcomes with donor hearts transported in standard cold storage to those transported in an experimental transport device that pumps the heart under physiologic conditions. If proven effective, this device could allow long-distance transport of donor hearts and expand the donor population.

A prospective, randomized study is now enrolling patients to evaluate induction therapy with rituximab (Rituxan) plus conventional immunosuppression (tacrolimus [Prograf], mycophenolate, steroid taper) vs placebo induction plus conventional immunosuppression. The study will enroll 400 patients (200 to each treatment arm) at 25 sites and will have a 36-month accrual period with 12-month follow-up (see http://clinicaltrials.gov/show/NCT01278745). The study is based on data in primates that found that eliminating B cells with an anti-CD20 drug before transplantation markedly reduced the incidence of coronary artery vasculopathy.

Indications that Raynaud phenomenon may be the presenting manifestation of a systemic autoimmune rheumatic disease are older age at onset (ie, over age 30), male sex, asymmetric involvement, and prolonged and painful attacks that can be severe enough to cause ischemic digital ulceration or gangrene (Figure 1).

Hence, chronic and severe digital ischemia causing ulceration or infarction differentiates secondary from primary Raynaud phenomenon and should prompt an investigation for an autoimmune rheumatic process. When taking the history, the clinician should seek clues to an underlying autoimmune condition, such as arthralgia, heartburn, dysphagia, shortness of breath, cough, and should examine the patient for telltale signs such as puffy hands and fingers, sclerodactyly, digital pitting scars, loss of fingertip pulp tissue, telangiectasias, and calcinosis.

CLUES TO PRIMARY VS SECONDARY RAYNAUD PHENOMENON

A diagnostic algorithm of digital ischemia (Figure 2) illustrates the range of presentations and possible causes. In Raynaud phenomenon, cold temperature and emotional stress provoke reversible color changes of the fingers and toes. Intense vasospasm of the digital arteries produces three well-defined phases¹: white (pallor resulting from vasospasm), blue (dusky cyanosis due to deoxygenation of static venous blood) (Figure 1), and red (reactive hyperemia after the restoration of blood flow). However, only about 60% of patients have all three color changes. The attacks are associated with paresthesias, an uncomfortable feeling of coldness in the fingers, and ischemic pain.

Primary Raynaud phenomenon

Primary or idiopathic Raynaud phenomenon is seen in 5% to 10% of the general population. It more commonly affects women ages 15 to 30, is generally mild, involves the digits symmetrically, and is sometimes familial. An increase in alpha-2 adrenergic responses in the digital vessels leads to arterial vasospasm, an exaggerated physiologic response to cold temperatures.² Geographic variability in prevalence likely represents differences in mean outdoor temperatures,³ which is in part why attacks of primary Raynaud phenomenon tend to be worse in the winter months.⁴

Secondary Raynaud phenomenon

Raynaud phenomenon also often occurs in certain autoimmune rheumatic diseases (secondary Raynaud phenomenon): for example, it is seen in scleroderma (90% to 95% of patients), mixed connective tissue disease (85%), systemic lupus erythematosus (40%), antisynthetase syndrome (40%), and sometimes in patients with other autoimmune rheumatic diseases. It may also be seen in hematologic disorders (cryoglobulinemia, cryofibrinogenemia, paraproteinemias, cold agglutinin disease, and polycythemia rubra vera), and it can also result from environmental and occupational exposures (frostbite, use of vibrating tools) and from exposure to certain drugs and toxins, such as polyvinyl chloride (Figure 2).

Acrocyanosis, a benign neurohormonal condition, should be included in the differential diagnosis for Raynaud phenomenon. Raynaud phenomenon is episodic, whereas acrocyanosis leads to persistent cyanosis of the acral body parts (fingers, toes) that is exacerbated by cold temperatures. However, the trophic skin changes, localized pain, and ulceration are not seen in acrocyanosis.

NAILFOLD CAPILLAROSCOPY: A KEY PART OF THE WORKUP

From Chatterjee S. Systemic scleroderma. In: Carey WD, ed. Current Clinical Medicine, 2nd ed. Philadelphia, PA: Saunders/Elsevier; 2010: 1177–1186. Reprinted with permission from Elsevier.

Nailfold capillaroscopy should be part of the evaluation of patients with Raynaud phenomenon (Figure 3), as it is one of the most reliable tests for distinguishing between primary and secondary Raynaud phenomenon.⁵ The sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis increases significantly with the addition of nailfold capillary abnormalities.^6,7

A stereomicroscope or videocapillaroscope is usually recommended to evaluate nailfold capillary morphology,⁵ but if such equipment is not available, a regular ophthalmoscope (with the lens set at 20 diopters or higher for better resolution) can serve the purpose at the bedside.⁸ A drop of mineral oil is placed on the nailfold to improve the image resolution, as it makes the horny layer of the cuticle transparent.

Abnormal patterns include dilated and enlarged capillary loops, disorganized capillaries, “dropouts” (avascular areas), microhemorrhages, and arborized capillaries (Figure 3).⁵ At no additional cost, the presence of these microvascular changes would add to the suspicion of secondary Raynaud phenomenon (negative predictive value of 93%).⁹ In addition, evolving capillaroscopic changes can be seen during follow-up visits, indicating the progressive nature of the microvasculopathy seen in these autoimmune rheumatic diseases.¹⁰

ADDITIONAL TESTING

If an underlying autoimmune rheumatic disease is suspected, laboratory testing should include a complete blood cell count, an erythrocyte sedimentation rate, and an antinuclear antibody (ANA) assay. If the ANA assay is negative, no further testing is usually necessary; however, a positive test should alert the clinician to consider an underlying autoimmune rheumatic process (negative predictive value of 93%).⁹ In a patient presenting with Raynaud phenomenon, a positive ANA test (even in the absence of other symptoms) warrants more frequent follow-up, urinalysis, and perhaps referral to a rheumatologist.

In the case of a positive ANA test, before ordering additional autoantibody tests, it is useful to consider the relevant non-Raynaud clinical manifestations. Indiscriminate ordering of a battery of autoantibodies should be avoided because of significant added cost and because it is not likely to provide additional information to guide management.

On the other hand, these more specific antibody tests may be of value in confirming the diagnosis suggested by the clinical profile of specific autoimmune rheumatic diseases, eg, anti-double-stranded DNA¹¹ and anti-Smith¹² antibodies for lupus, anti-topoisomerase I (Scl-70) and anti-centromere antibodies for scleroderma, ¹³ and anti-synthetase (eg, anti-Jo-1) antibodies for autoimmune myositis.^14,15

Indications that Raynaud phenomenon may be the presenting manifestation of a systemic autoimmune rheumatic disease are older age at onset (ie, over age 30), male sex, asymmetric involvement, and prolonged and painful attacks that can be severe enough to cause ischemic digital ulceration or gangrene (Figure 1).

Hence, chronic and severe digital ischemia causing ulceration or infarction differentiates secondary from primary Raynaud phenomenon and should prompt an investigation for an autoimmune rheumatic process. When taking the history, the clinician should seek clues to an underlying autoimmune condition, such as arthralgia, heartburn, dysphagia, shortness of breath, cough, and should examine the patient for telltale signs such as puffy hands and fingers, sclerodactyly, digital pitting scars, loss of fingertip pulp tissue, telangiectasias, and calcinosis.

CLUES TO PRIMARY VS SECONDARY RAYNAUD PHENOMENON

A diagnostic algorithm of digital ischemia (Figure 2) illustrates the range of presentations and possible causes. In Raynaud phenomenon, cold temperature and emotional stress provoke reversible color changes of the fingers and toes. Intense vasospasm of the digital arteries produces three well-defined phases¹: white (pallor resulting from vasospasm), blue (dusky cyanosis due to deoxygenation of static venous blood) (Figure 1), and red (reactive hyperemia after the restoration of blood flow). However, only about 60% of patients have all three color changes. The attacks are associated with paresthesias, an uncomfortable feeling of coldness in the fingers, and ischemic pain.

Primary Raynaud phenomenon

Primary or idiopathic Raynaud phenomenon is seen in 5% to 10% of the general population. It more commonly affects women ages 15 to 30, is generally mild, involves the digits symmetrically, and is sometimes familial. An increase in alpha-2 adrenergic responses in the digital vessels leads to arterial vasospasm, an exaggerated physiologic response to cold temperatures.² Geographic variability in prevalence likely represents differences in mean outdoor temperatures,³ which is in part why attacks of primary Raynaud phenomenon tend to be worse in the winter months.⁴

Secondary Raynaud phenomenon

Raynaud phenomenon also often occurs in certain autoimmune rheumatic diseases (secondary Raynaud phenomenon): for example, it is seen in scleroderma (90% to 95% of patients), mixed connective tissue disease (85%), systemic lupus erythematosus (40%), antisynthetase syndrome (40%), and sometimes in patients with other autoimmune rheumatic diseases. It may also be seen in hematologic disorders (cryoglobulinemia, cryofibrinogenemia, paraproteinemias, cold agglutinin disease, and polycythemia rubra vera), and it can also result from environmental and occupational exposures (frostbite, use of vibrating tools) and from exposure to certain drugs and toxins, such as polyvinyl chloride (Figure 2).

Acrocyanosis, a benign neurohormonal condition, should be included in the differential diagnosis for Raynaud phenomenon. Raynaud phenomenon is episodic, whereas acrocyanosis leads to persistent cyanosis of the acral body parts (fingers, toes) that is exacerbated by cold temperatures. However, the trophic skin changes, localized pain, and ulceration are not seen in acrocyanosis.

NAILFOLD CAPILLAROSCOPY: A KEY PART OF THE WORKUP

From Chatterjee S. Systemic scleroderma. In: Carey WD, ed. Current Clinical Medicine, 2nd ed. Philadelphia, PA: Saunders/Elsevier; 2010: 1177–1186. Reprinted with permission from Elsevier.

Nailfold capillaroscopy should be part of the evaluation of patients with Raynaud phenomenon (Figure 3), as it is one of the most reliable tests for distinguishing between primary and secondary Raynaud phenomenon.⁵ The sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis increases significantly with the addition of nailfold capillary abnormalities.^6,7

A stereomicroscope or videocapillaroscope is usually recommended to evaluate nailfold capillary morphology,⁵ but if such equipment is not available, a regular ophthalmoscope (with the lens set at 20 diopters or higher for better resolution) can serve the purpose at the bedside.⁸ A drop of mineral oil is placed on the nailfold to improve the image resolution, as it makes the horny layer of the cuticle transparent.

Abnormal patterns include dilated and enlarged capillary loops, disorganized capillaries, “dropouts” (avascular areas), microhemorrhages, and arborized capillaries (Figure 3).⁵ At no additional cost, the presence of these microvascular changes would add to the suspicion of secondary Raynaud phenomenon (negative predictive value of 93%).⁹ In addition, evolving capillaroscopic changes can be seen during follow-up visits, indicating the progressive nature of the microvasculopathy seen in these autoimmune rheumatic diseases.¹⁰

ADDITIONAL TESTING

If an underlying autoimmune rheumatic disease is suspected, laboratory testing should include a complete blood cell count, an erythrocyte sedimentation rate, and an antinuclear antibody (ANA) assay. If the ANA assay is negative, no further testing is usually necessary; however, a positive test should alert the clinician to consider an underlying autoimmune rheumatic process (negative predictive value of 93%).⁹ In a patient presenting with Raynaud phenomenon, a positive ANA test (even in the absence of other symptoms) warrants more frequent follow-up, urinalysis, and perhaps referral to a rheumatologist.

In the case of a positive ANA test, before ordering additional autoantibody tests, it is useful to consider the relevant non-Raynaud clinical manifestations. Indiscriminate ordering of a battery of autoantibodies should be avoided because of significant added cost and because it is not likely to provide additional information to guide management.

On the other hand, these more specific antibody tests may be of value in confirming the diagnosis suggested by the clinical profile of specific autoimmune rheumatic diseases, eg, anti-double-stranded DNA¹¹ and anti-Smith¹² antibodies for lupus, anti-topoisomerase I (Scl-70) and anti-centromere antibodies for scleroderma, ¹³ and anti-synthetase (eg, anti-Jo-1) antibodies for autoimmune myositis.^14,15

Indications that Raynaud phenomenon may be the presenting manifestation of a systemic autoimmune rheumatic disease are older age at onset (ie, over age 30), male sex, asymmetric involvement, and prolonged and painful attacks that can be severe enough to cause ischemic digital ulceration or gangrene (Figure 1).

Hence, chronic and severe digital ischemia causing ulceration or infarction differentiates secondary from primary Raynaud phenomenon and should prompt an investigation for an autoimmune rheumatic process. When taking the history, the clinician should seek clues to an underlying autoimmune condition, such as arthralgia, heartburn, dysphagia, shortness of breath, cough, and should examine the patient for telltale signs such as puffy hands and fingers, sclerodactyly, digital pitting scars, loss of fingertip pulp tissue, telangiectasias, and calcinosis.

CLUES TO PRIMARY VS SECONDARY RAYNAUD PHENOMENON

A diagnostic algorithm of digital ischemia (Figure 2) illustrates the range of presentations and possible causes. In Raynaud phenomenon, cold temperature and emotional stress provoke reversible color changes of the fingers and toes. Intense vasospasm of the digital arteries produces three well-defined phases¹: white (pallor resulting from vasospasm), blue (dusky cyanosis due to deoxygenation of static venous blood) (Figure 1), and red (reactive hyperemia after the restoration of blood flow). However, only about 60% of patients have all three color changes. The attacks are associated with paresthesias, an uncomfortable feeling of coldness in the fingers, and ischemic pain.

Primary Raynaud phenomenon

Primary or idiopathic Raynaud phenomenon is seen in 5% to 10% of the general population. It more commonly affects women ages 15 to 30, is generally mild, involves the digits symmetrically, and is sometimes familial. An increase in alpha-2 adrenergic responses in the digital vessels leads to arterial vasospasm, an exaggerated physiologic response to cold temperatures.² Geographic variability in prevalence likely represents differences in mean outdoor temperatures,³ which is in part why attacks of primary Raynaud phenomenon tend to be worse in the winter months.⁴

Secondary Raynaud phenomenon

Raynaud phenomenon also often occurs in certain autoimmune rheumatic diseases (secondary Raynaud phenomenon): for example, it is seen in scleroderma (90% to 95% of patients), mixed connective tissue disease (85%), systemic lupus erythematosus (40%), antisynthetase syndrome (40%), and sometimes in patients with other autoimmune rheumatic diseases. It may also be seen in hematologic disorders (cryoglobulinemia, cryofibrinogenemia, paraproteinemias, cold agglutinin disease, and polycythemia rubra vera), and it can also result from environmental and occupational exposures (frostbite, use of vibrating tools) and from exposure to certain drugs and toxins, such as polyvinyl chloride (Figure 2).

Acrocyanosis, a benign neurohormonal condition, should be included in the differential diagnosis for Raynaud phenomenon. Raynaud phenomenon is episodic, whereas acrocyanosis leads to persistent cyanosis of the acral body parts (fingers, toes) that is exacerbated by cold temperatures. However, the trophic skin changes, localized pain, and ulceration are not seen in acrocyanosis.

NAILFOLD CAPILLAROSCOPY: A KEY PART OF THE WORKUP

From Chatterjee S. Systemic scleroderma. In: Carey WD, ed. Current Clinical Medicine, 2nd ed. Philadelphia, PA: Saunders/Elsevier; 2010: 1177–1186. Reprinted with permission from Elsevier.

Nailfold capillaroscopy should be part of the evaluation of patients with Raynaud phenomenon (Figure 3), as it is one of the most reliable tests for distinguishing between primary and secondary Raynaud phenomenon.⁵ The sensitivity of the American College of Rheumatology classification criteria for systemic sclerosis increases significantly with the addition of nailfold capillary abnormalities.^6,7

A stereomicroscope or videocapillaroscope is usually recommended to evaluate nailfold capillary morphology,⁵ but if such equipment is not available, a regular ophthalmoscope (with the lens set at 20 diopters or higher for better resolution) can serve the purpose at the bedside.⁸ A drop of mineral oil is placed on the nailfold to improve the image resolution, as it makes the horny layer of the cuticle transparent.

Abnormal patterns include dilated and enlarged capillary loops, disorganized capillaries, “dropouts” (avascular areas), microhemorrhages, and arborized capillaries (Figure 3).⁵ At no additional cost, the presence of these microvascular changes would add to the suspicion of secondary Raynaud phenomenon (negative predictive value of 93%).⁹ In addition, evolving capillaroscopic changes can be seen during follow-up visits, indicating the progressive nature of the microvasculopathy seen in these autoimmune rheumatic diseases.¹⁰

ADDITIONAL TESTING

If an underlying autoimmune rheumatic disease is suspected, laboratory testing should include a complete blood cell count, an erythrocyte sedimentation rate, and an antinuclear antibody (ANA) assay. If the ANA assay is negative, no further testing is usually necessary; however, a positive test should alert the clinician to consider an underlying autoimmune rheumatic process (negative predictive value of 93%).⁹ In a patient presenting with Raynaud phenomenon, a positive ANA test (even in the absence of other symptoms) warrants more frequent follow-up, urinalysis, and perhaps referral to a rheumatologist.

In the case of a positive ANA test, before ordering additional autoantibody tests, it is useful to consider the relevant non-Raynaud clinical manifestations. Indiscriminate ordering of a battery of autoantibodies should be avoided because of significant added cost and because it is not likely to provide additional information to guide management.

On the other hand, these more specific antibody tests may be of value in confirming the diagnosis suggested by the clinical profile of specific autoimmune rheumatic diseases, eg, anti-double-stranded DNA¹¹ and anti-Smith¹² antibodies for lupus, anti-topoisomerase I (Scl-70) and anti-centromere antibodies for scleroderma, ¹³ and anti-synthetase (eg, anti-Jo-1) antibodies for autoimmune myositis.^14,15