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New Insights Into Molecular Mechanisms of Cardiomyopathy

Researchers at the University of Miami Miller School of Medicine have illuminated molecular imbalances in heart muscle cells that can lead to hypertrophic cardiomyopathy (HCM), a genetic condition that thickens the walls of heart muscles, making it harder for the heart to pump blood.

Danuta Szczesna-Cordary, Ph.D.
Danuta Szczesna-Cordary, Ph.D.

HCM is the most common cause of sudden cardiac death for people under 30, including young athletes in their prime.

Using a variety of sophisticated technologies, the research team showed how anomalies in the contracting filaments that power heart muscle cells can give rise to cardiomyopathies, as well as how specific mutations affect energy distribution. The study was published in the journal PNAS (Proceedings of the National Academy of Sciences).

“Hypertrophic cardiomyopathy is the most common genetically inherited heart disease,” said Danuta Szczesna-Cordary, Ph.D., professor of molecular and cellular pharmacology and senior author on the study. “By investigating this potentially deadly condition on the molecular level, we can better understand the mechanisms that drive it.”

HCM arises in sarcomeres, the basic contractile units in the heart. Sarcomeres are made up of two types of muscle filament molecules, actin and myosin. Myosin, a type of molecular motor, converts chemical energy into mechanical energy that pulls actin filaments along, causing muscle fibers to contract and generating movement.

This process is heavily reliant on the shapes of, and spatial relationships between, these two fibrous molecules. For myosin molecules to function properly, those in the disordered relaxed state (DRX) and the more recently discovered energy-conserving state known as the super-relaxed state (SRX) must be in balanced equilibrium. Imbalances in these relationships can lead to cardiac dysfunction, much as a dropped chain can prevent a bicycle from moving.

Representative fiber diffraction patterns
Representative fiber diffraction patterns of HCM–D166V (Left), WT controls (Middle), and DCM–D94A (Right) models at increasing calcium concentrations
from pCa 8 to 4.

The research team focused on two mutations that affect these muscle processes and can lead to disease. They studied two animal models: one for hypertrophic cardiomyopathy (HCM-D166V) and one for a related condition, dilated cardiomyopathy (DCM-D94A), in which the inside cavity of one or more chambers of the heart is enlarged, weakening the heart’s ability to pump blood. Using methods including a technique called X-ray diffraction, the group assessed structural changes in the sarcomeres of both models.

The DCM model revealed a disproportionate amount of myosin heads in the super-relaxed SRX state. “The lower proportion of myosin heads occupying the DRX state,” said Dr. Szczesna-Cordary, “suggests a reduced ability to enter the force-producing phase and provide mechanical energy to support the heart’s pumping action” – a condition associated with the clinical symptoms of dilated cardiomyopathy.

However, in the HCM model, more myosin heads were in the DRX state and thus excessively contractile, a pathological condition that can lead to life-altering arrhythmias, heart failure, or death. The data support the clinically observed phenotype of hypercontractility associated with hypertrophic cardiomyopathy.

These insights could lead to new therapeutic approaches to ameliorate hypertrophic and/or dilated cardiomyopathy.

“Understanding how we can regulate myosin SRX/DRX equilibrium in a normal heart, and how it is changed in heart disease, may advance new therapeutics for patients suffering from genetic cardiomyopathies,” said Dr. Szczesna-Cordary. “We’re still at the very earliest stages, but we believe we are on the right track.”

Tags: Dr. Danuta Szczesna-Cordary, hypertrophic cardiomyopathy, Miller School of Medicine, molecular and cellular pharmacology, PNAS