Affecting one in 500 people, hypertrophic cardiomyopathy is a condition in which the walls of the left ventricle, the heart's main pumping chamber, become abnormally thick. "HCM is one of the primary causes of sudden death among young, apparently healthy patients; it is also a frequent cause of heart failure requiring surgery or a transplant," says Dr. Rafik Tadros, a cardiologist and associate professor in Université de Montréal's Faculty of Medicine.
Although HCM was first identified in the 1950s, recent advances in genomics and increased statistical power have shed new light on the disease. However, many gaps in scientists' understanding of it remain unexplored. Working alongside colleagues from around the world, Tadros took part in a major study focusing on HCM's genetic causes. Capping off a decade of research, the study was published last month in Nature Genetics.
The cause is mostly unknown
Even though HCM has always been regarded as a genetic disorder, a problematic gene is only detected in one-third of cases; in the rest, the cause is unknown. "There is a good deal of variability in the expression of HCM,' said Tadros. "Even among individuals with a recognizable genetic defect, some do not go on to develop the disease."
It's now beginning to be understood that HCM is caused by a combination of genetics and other lifetime risk factors (environment, lifestyle, co-morbidities, and so on). "Evaluation at birth is typically normal, but the disease manifests later on, either during adolescence or in adulthood," Tadros said.
Currently, there is no specific treatment for HCM. "What we're treating are the consequences of the disease," Tadros explained. Patients at risk of blood clots or cardiac arrest are given anticoagulants or fitted with defibrillators. For individuals with thickened ventricle walls and obstructed blood flow, drugs or surgery are the preferred treatments.
Combing through the genetics
To improve the diagnostic process and therapeutic treatments, researchers keep on combing through the genetics. "We now know that HCM stems from what we call complex genetics," said Tadros. "A gene mutation is not the sole cause of the disease. In fact, several regions of the genome boost the development risk."
To determine the key genomic regions, very large cohorts of patients are needed, which is why an international network of researchers is required: in Tadros' study, they were located in major centres in the Netherlands, the U.S., the U.K, Italy and Canada, particularly Toronto and Montreal.
In total, the genomes of some 5,900 patients with HCM were examined and compared to a control group of nearly 69,000 individuals. "It's by far the largest pangenomic association study for this disease," noted Tadros, who holds the Canada Research Chair in Translational Cardiovascular Genetics.
After comparing genetic variants among HCM patients in relation to the rest of the population, the researchers identified 70 genome regions associated with the disease.
To ensure robust results, parallel analyses were carried out in the U.K. and Montreal. Artificial intelligence was used to measure the dimensions and function of the left ventricle, and to evaluate heart function among 36,000 healthy individuals, based on cardiac magnetic resonance results. In addition to providing insight into the genetic determinants of the normal left ventricle's shape and function, additional light was shed on HCM's genetic causes.
A second phase is planned
"This was the first phase; the second, which will likely take many years, will be to determine why each of the identified genome regions is associated with HCM," said Tadros.
The same research team also developed models to predict which individual mutation carriers are at risk of developing the disease or related complications. Their findings were reported in another article published simultaneously in Nature Genetics.
These and future studies will deepen scientists' understanding of the disease with a view to developing new treatments and targeting individuals for whom they would be most beneficial.
Tadros sees another glimmer of hope: "If we have a better way of predicting who will develop HCM or its complications, we will be able to reassure certain patients and avoid unnecessary monitoring if they are not at high risk."
About this study
"Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy," by Rafik Tadros et al., was published Feb. 18, 2025 in Nature Genetics.
