Before the heart thickens: unraveling the early origins of hypertrophic cardiomyopathy

More than hypertrophy

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, affecting approximately 1 in 200 people. In the Netherlands, most patients with a genetic predisposition carry a variant in MYBPC3, the gene for a protein involved in contraction and relaxation of heart muscle cells (cardiomyocytes). Yet the variant does not explain everything. "People with exactly the same gene defect can have very different symptoms," Van den Dolder explains. "One person develops a thickened heart muscle at a young age, while a family member with the same DNA defect has hardly any complaints for years. We wanted to understand why." 

Two complementary models

Van den Dolder studied the early origins of HCM in a mouse model carrying the Mybpc3 c.2373insG Dutch founder variant, and in cardiomyocytes grown from induced pluripotent stem cells (iPSC-CMs) of patients carrying the same variant. "With the mouse model we can study how the whole heart behaves in a living body, and with the patient-derived heart cells we can study what a specific genetic change does in human cells," she says.  

Metabolism comes first

In the mouse model, changes in relaxation of the heart and early adaptations in the mitochondrial energy supply were visible, while the heart muscle was not thickened. The patient-derived iPSC-CMs also showed changes in their energy supply and relaxation. Strikingly, these early changes appeared before a clear reduction of the cMyBP-C protein, also known as haploinsufficiency, a well-established disease mechanism in human patients with advanced disease. "The energy supply and relaxation of the heart cells were already disturbed, while the heart muscle was not yet thickened," Van den Dolder notes. "Even the cMyBP-C haploinsufficiency that we know from patients was not found." This suggests that thickening is not the first problem, but a later consequence of changes that already take place in the cardiomyocyte. 

A multiple-hit story

A central hypothesis was that metabolic stress contributes to the development of HCM. Yet in the mouse model, neither ageing nor a Western diet alone led to clear thickening of the heart muscle, although both did cause changes in metabolism and other processes in the body. This supports a "multiple-hit" model, in which the genetic defect forms a first vulnerability, but multiple factors are needed before the disease fully develops. "The genetic change alone is not enough to cause the disease," Van den Dolder explains. "That is actually a hopeful message, because it means that the course of the disease is not fixed, but at least partly modifiable." 

Towards earlier detection

Her findings support a shift toward earlier detection and monitoring of functional and metabolic changes in people with a genetic predisposition, rather than relying on a thickened heart muscle as the disease marker. "If changes in heart function and metabolism are already present before the heart thickens, we may be able to use them to detect and monitor people with a genetic predisposition earlier," Van den Dolder concludes.