BOSTON — For three decades, hypertrophic cardiomyopathy has basically been considered to be a genetic disease. The cause was believed to be variants in individual genes encoding cardiac sarcomere proteins.
But that is changing, however, according to a review published recently in the American Journal of Cardiology.1.
Lead author Bradley A. Maron, MD, of Brigham & Women’s Hospital, Harvard Medical School and the VA Boston Healthcare System, and colleagues suggested that HCM’s varied clinical presentation is not fully explained by single gene variants. To bolster that viewpoint, they cite data from clinical and network medicine analyses and recent genetic studies.
“Despite 60 years of study in thousands of patients of all ages, an uncertainty as to the cause of HCM persists,” the authors wrote. “Recent scientific progress, including studies of tissue from patients, have caused a shift in the conceptual framework explaining this complex disease.”
Background information in the article explained, “Hypertrophic cardiomyopathy (HCM) is a global and relatively common cause of patient morbidity and mortality and is among the first reported monogenic cardiac diseases.”
HCM has an estimated clinical prevalence of 1: 200 to 1: 500 in the general population. It is identified worldwide in at least 125 countries on all continents.
The article pointed out that the new concepts are very different from the “strict traditional dogma tethering HCM to single gene variants (the monogenic hypothesis).”
While this postmonogenic era of HCM opens up the possibility to advance disease etiology into clinically relevant areas, the authors decried the time that has been lost, noting, “Achieving this goal, however, requires acknowledging an uncomfortable realization: that overemphasis on the monogenic determinants of HCM over the past three decades has diverted time away from efforts to discover alternative disease mechanisms.”
They noted that HCM affects patients of both genders and across many cultures and has similar but heterogeneous clinical expression, adding, “Despite its clinical and genetic diversity, HCM has become a highly treatable condition along personalized care pathways, now resulting in the likelihood of low morbidity and mortality and the possibility of normal life expectancy. Nevertheless, even in the current era of effective diagnosis and management using sophisticated clinical tools, understanding the basic mechanisms responsible for HCM at its earliest stages of development remains an important aspiration.”
The article emphasized that while HCM is a complex disease that might be inherited according to an autosomal dominant pattern, it also has “unpredictable expressivity, genotype-phenotype uncoupling, and either variable, low, or no penetrance of clinically overt disease. Dominant transmission of HCM is well documented in some families, sarcomere mutations can precede development of the disease phenotype and left ventricular hypertrophy is an endophenotypic tracking marker of disease inheritance.”
“Therefore, it is undeniable that genetic factors play a role in disease evolution for some patients with HCM, presumably as 1 or several potential triggers for susceptibility pathways,” the study team wrote. “Clinically, genetic context has a crucial role in the development of HCM, including commercial genetic testing and cascade screening of families to identify affected relatives without left ventricular hypertrophy who may ultimately develop and/or transmit the disease.”
The report also detailed emerging evidence that argues for HCM research that integrates genetic context, post-transcriptional events, and acquired determinants of disease.
“These transformative advances place a new focus on possible novel interactions between acquired disease determinants and genetic context to produce complex HCM phenotypes, also offering a measure of caution against overemphasizing monogenics as the principal cause of this disease,” the authors pointed out. “These new perspectives in which HCM is not a uniformly genetic disease but likely explained by multifactorial etiology will also unavoidably impact how HCM is viewed by patients and families in the clinical practicing community going forward, including relevance to genetic counseling and access to healthcare insurance and psychosocial wellness.”
The report concluded, “After 60 years of clinical recognition, definitive understanding of the basic mechanisms responsible for the development and expression of the expansive HCM disease spectrum remains largely elusive. Over the last 30 years, much of what we have learned about this complex and heterogeneous disease has been viewed through the restrictive prism of the monogenic sarcomere hypothesis. From our perspective, we do not de-emphasize the significant role of the genetic context in HCM, that is, the genetic profile of patients, which includes variants but also undoubtedly involves nongenetic factors.”
Regarding HCM as a disease solely of genetic etiology might have been misleading to patients and families, the authors added, suggesting that success in broadening the view will depend on the use of network medicine, functional genetics, and other contemporary methods.
- Maron BA, Wang RS, Carnethon MR, Rowin EJ, Loscalzo J, Maron BJ, Maron MS. What Causes Hypertrophic Cardiomyopathy? Am J Cardiol. 2022 Jul 14:S0002-9149(22)00651-8. doi: 10.1016/j.amjcard.2022.06.017. Epub ahead of print. PMID: 35843734.Circulation
