Progress in hypertrophic cardiomyopathy has saved lives, but knowledge gaps exist

As the main cause of sudden cardiac death in the developed world for people younger than 35 years, it is perhaps not surprising that hypertrophic cardiomyopathy is most often regarded as a disease that strikes without warning and leaves family members and friends reeling from the loss of a loved one.

However, although unpredictable sudden death is a characteristic of hypertrophic cardiomyopathy (HCM), it does not represent the overall outlook for patients with this disease today, more than 50 years since it was first recognized in a patient.

Barry J. Maron, MD, said despite the complexity and unpredictability of HCM, substantial progress has been made in the diagnosis and treatment of the disease. Photo courtesy of: Barry J. Maron, MD

“After 50 years, we have arrived at a different place, where this is a treatable disease, compatible with a normal life expectancy, and sometimes without the necessity of treatment because probably the vast majority of affected people live their lives without any major complications from HCM and may not even know they have it,” Barry J. Maron, MD, director, Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, told Cardiology Today.

Still, Maron said more must be done to increase the awareness of this disease.

“Time to time, there have been misunderstandings about what [HCM] is and how it’s treated and what patients can expect from a diagnosis,” he said. “So that continues to be an obstacle for the patient population because HCM is relatively uncommon in CV practice, making it easy to understand why rapid developments in this disease may not immediately penetrate the knowledge of everyone practicing cardiology.”

Locating the source of the disease

Despite its first modern description in a patient in 1957, the cause of HCM remained much a mystery for more than 3 decades until Seidman and colleagues began to unravel the genetic foundation of the disease. Their findings showed a mutation in the MYH7 gene in a family with HCM. After this discovery, more than a dozen genes were also implicated in HCM, with MYH7 and MYBPC3 now regarded as the most common causal genes, accounting for approximately 50% of all HCM cases.

Currently, the gene for HCM occurs in at least one of every 500 people. The disease, with complications ranging from angina and dyspnea to arrhythmia, is clinically diagnosed based on the detection of cardiac hypertrophy via an echocardiogram. This detection method, however, is not without shortcomings, as the likelihood of patients with a clinical diagnosis of HCM being misdiagnosed because of phenocopy conditions may be as high as 10%, said A. J. Marian, MD, professor and director, Center for Cardiovascular Genetics with The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston.

“There are conditions, such as storage diseases, that can cause cardiac hypertrophy. Clinically, they may be similar to true HCM, but they have different mechanisms involved,” Marian said, adding that the consequence of mistaking the disease is that the patient will be given the wrong treatment.

James B. Young

Although this discrepancy opens the door for more precise genetic testing, this method too has its share of challenges to overcome, said James B. Young, MD, professor of medicine of the Cleveland Clinic Foundation and Cardiology Today Section Editor.

“Physicians are often unclear on how to use molecular diagnostic tools, when to order genetic and genomic testing, and when to search for various mutations. There is just a lot of confusion out there regarding this strategy,” Young said in an interview, further noting that HCM “often isn’t at the top of somebody’s differential diagnosis. A patient comes in with atypical symptoms, chest discomfort, particularly in a young individual, and [physicians] may not list this high in their differential diagnosis because perhaps we haven’t educated folks enough about the frequency of the problem and the importance of the problem.”

Potential promise, challenges

During the past decade, patients with HCM at high risk for sudden death have benefited from the use of implantable cardioverter defibrillators. One study that tested the device in a high-risk population was conducted by Maron and colleagues and published in a 2007 issue of the Journal of the American Medical Association. According to their results, ICD interventions in 506 patients up to a 17-year interval terminated ventricular fibrillation and ventricular tachycardia in 20% of the study population, with only one sudden cardiac death, which was attributed to an ICD malfunction.

“The importance of the study is that it shows that sudden death [associated with HCM] is preventable, and that the ICD is the only treatment for HCM known to prolong life,” Maron said.

ICD therapy, as well as surgical myectomy surgery, transplantation and alcohol ablation for HF, represent dramatic hits regarding how to approach patients with the disease, but the role of drug treatment in HCM still remains uncertain.

“One persistent problem is how do you treat these patients with medications? We have not had a good clinical trial that has given us insight,” said Robert Roberts, MD, president and CEO of the University of Ottawa Heart Institute and Cardiology Today Editorial Board member. “There are several drugs people use, like beta-blockers, calcium-channel blockers and disopyramide (Norpace, Pfizer), but those are directed more toward the symptomatic patient population rather than patients with HCM having hypertrophy without symptoms.”

Robert Roberts

Currently, Marion said, pharmaceutical treatment in HCM is empiric. “In adults, no treatment has been shown to reverse or prevent the evolution of cardiac hypertrophy or fibrosis in HCM,” he said. “However, prevention of cardiac hypertrophy and fibrosis through pharmacological interventions could possibly reduce the risk of sudden cardiac death and perhaps even eliminate it.”

In addition, Roberts said there have been several animal models that have explained numerous findings of HCM, which may have future consequence in the treatment of this disease. These include studies that have shown use of a statin drug, an ACE inhibitor, an aldosterone inhibitor and N-acetylcysteine in mice and rabbits given the human HCM gene to be able to significantly ameliorate the disease.

“Unfortunately, we have never been able to get funding to do the trial in humans,” Roberts said. “Despite it being a common cause of sudden death, it is still a rare disease. In order to do a clinical trial, you would have to find a large number of centers. But, so far, drug companies have not been keen on doing such a study, in part because they are looking at a small population.”

The role of molecular biology in the treatment of HCM for Maron, however, remains unclear and unlikely to be the ultimate answer. “The whole idea of some sort of molecular ‘cure’ ignores one important point: This is a very powerful and heterogeneous genetic heart disease that will be very difficult to reverse in its entirety. It’s unlikely that it will ever be reversible by molecular biology,” he said.

Nevertheless, obtaining funding for research into HCM to try to answer these questions remains paramount.

“There has been very little if any funding available from NIH for clinical research related to genetic diseases, such as HCM,” Maron said. “In my view, it is unfair that our major granting institutions do not put much weight in these less common diseases. For people with HCM, it’s the most common disease in the world.”

“This is a disease in which we know an awful lot and we’re ready to do clinical trials,” Roberts said. “Given the devastating nature of the disease, it would be most unfortunate if we cannot find funding to do that.”

Athletes and HCM

Every year, the spotlight is focused on sudden cardiac death disorders when young and seemingly healthy athletes collapse and, sometimes, die on the field of play. This, in fact, has been a consistent problem with youth sports for decades, as sudden death occurred more than 1,800 times to young competitive athletes between 1980 and 2006 in the United States alone, according to the US National Registry for Sudden Death in Athletes assembled by Barry J. Maron, MD, at the Minneapolis Heart Institute Foundation. Of these sudden deaths, 36% were the result of HCM, the most common CV cause. The mechanism of sudden death with HCM, Maron said, is ventricular arrhythmias that emanate from an unpredictable substrate. “We’re not exactly sure how it occurs with or without sports. The precise mechanism by which sports as a trigger arrives at these ventricular arrhythmias, given underlying heart disease, is unclear,” he said. At the 36th Bethesda Conference, a consensus conference relating risk to various diseases and sports, recommendations were established that determined eligibility vs. disqualification of competitive athletes with CV abnormalities. According to one of the recommendations, “Athletes with a probable or unequivocal clinical diagnosis of HCM should be excluded from most competitive sports, with the possible exception of those of low intensity.” In Italy, where a national law has required all athletes undergo an annual clinical examination, including an ECG, since 1971, the practice of barring athletes with HCM has produced promising results. During a 17-year period (1979-1996) in the Veneto region of Italy, data from one study indicated that 49 sudden deaths occurred in competitive athletes, with only one death resulting from HCM. However, it is important to keep in mind that there is a lot of variability and unpredictability built into the relationship between vigorous physical activity and risk for an arrhythmia-related event, and participation in sports does not necessarily mean that there is going to be a sudden death event, Maron said. “But it’s fair to say that athletes are at greater risk, and it does make sense to identify HCM in athletes because the general standard recommendation is disqualification from intense sports to reduce risk,” he said.

Directions for future research

In the years ahead, one of the challenges for advancing the field of HCM will be continuing research despite funding limitations to answer the questions that still remain about the disease.

One such question, according to Roberts, involves the lethal final stage of HF when the ventricle dilates rather than hypertrophies, which usually results in a downhill course. “We don’t know why that happens, why the heart goes from the strong or forceful pumping of hypertrophy to a dilated heart and then death. But it emphasizes the importance of understanding the hypertrophy of HF,” he said.

For Maron, even after 50 years, more still needs to be understood about the natural history of the disease. “We just completed a study looking at patients with HCM presenting at 60 years of age or older. Because of the greater availability of imaging and awareness of HCM, we are seeing increasing numbers of patients in this age group that was once believed to be uncommon and is now, in fact, the most rapidly growing age group identified with this disease,” he said. “The study showed that this is a relatively low-risk group with a risk for sudden cardiac death of only 0.2% per year.”

Ultimately, Marian said, understanding the mechanisms that are involved in the pathogenesis of the disease will allow clinical studies to truly test whether it is possible to reverse, prevent or attenuate the phenotype by targeting specific pathways and mechanisms.

“While genetic information is essential, it by itself is not going to solve the problem,” he said. “We need to take the gene and understand the mechanisms, and then block the responsible mechanisms in order to prevent and cure the disease. One day we will get to a point where each specific subtype [of HCM] will be treated differently. But we are not there yet.” – by Brian Ellis

For more information:

• Corrado D. N Engl J Med. 1998;339:364-369.
• Marian A. J Cardiovasc Transl Res. 2009;2:483-492.
• Maron BJ. Circulation. 2009;119:1085-1092.
• Maron BJ. JAMA. 2007;298:405-412.
• Maron BJ. J Am Coll Cardiol. 2005; doi:10.1016/j.jacc.2005.02.002.
• Maron BJ. J Am Coll Cardiol. 2009;54:191-200.
• Seidman CE. Cell. 1990;62:999-1006.

Disclosures: Dr. Maron has received grants from Medtronic and is a consultant for GeneDx. Drs. Marian, Roberts and Young report no relevant financial disclosures.