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.
“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.
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.”
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.”
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.”