Eric Devaney Lab - Research

Cardiomyopathies

Although many pathologies can cause heart failure it is cardiomyopathy that is the most common reason for heart transplant surgery. There are actually five types of cardiomyopathy. The two most common types, however, are hypertrophic and dilated.

Hypertrophic cardiomyopathy (HCM) can involve the left and right ventricle or both. It is a familial disease with autosomal dominant inheritance. HCM often exists sub-clinically for a long period. Young athletes are usually able to compensate for decreases in volume capacity of the left ventricle caused by wall thickening—tragically, it is often diagnosed only after it causes sudden cardiac arrest on the field of play. In dilated cardiomyopathy (DCM) the heart muscle begins to stretch and becomes thinner, thus impairing contraction.

Although the pathogenesis of cardiomyopathy is poorly understood, a genetic etiology has been firmly established in families with hereditary cardiomyopathies. In fact, familial hypertrophic cardiomyopathy occurs in 1 in 500 worldwide and is the most common genetic heart disease in the United States.

Figure 1. The three most common types of cardiomyopathy. (From Nature Reviews Cardiology 10:1038, 2013).


Myosin is the molecular motor protein which drives muscle contraction in the heart, and mutations in myosin are known to cause both HCM and DCM. Myosin is a hexameric protein complex which is composed of two heavy chains and four light chains. An ATP-dependent motor domain is located in each heavy chain and the light chains perform regulatory roles. Myosin thick filaments interdigitate with actin thin filaments in a near-crystalline array in the cardiac sarcomere. The interaction between myosin and actin is regulated in a calcium-dependent fashion by the troponin-tropomyosin complex. In the mammalian heart, there are two heavy chain isoforms, alpha-myosin heavy chain (αMHC) which has a fast ATPase activity and beta-myosin heavy chain (βMHC) which is 2-3 times slower. Healthy humans express a predominance of the slow isoform βMHC in the cardiac ventricles, and αMHC represents only 10% of the total. This small amount of α-MHC expression has disproportionately large impact on cardiac myocyte contractile power production. Thus it is likely that mutations of α-MHC may have functional consequences on overall cardiac performance in patients. Mutations in the MYH7 gene encoding βMHC are the second most common cause of hypertrophic cardiomyopathy.

Figure 2. Myosin crossbridge cycling. (From N Engl J Med 336:775, 1997)


Cardiac performance is critically dependent upon the normal function of myosin, the heart’s molecular motor. The importance of myosin is demonstrated by the high frequency of myosin mutations found in patients with hereditary cardiomyopathy.Although α-MHC is by far the less dominant myosin isoform in the human heart, the presence of these disease-related mutations support its importance in human cardiac function. Sarcomeric gene mutations are thought to trigger the development of cardiomyopathy due to alterations in contractile function. Despite the wealth of genetic information that has accumulated in the analysis of β-MHC mutations, the primary effects of α-MHC gene mutations on cardiac function are unclear.

The Devaney lab is currently determining the effects on contractile function due to α-MHC mutations associated with HCM and DCM in isolated cardiac myocytes.

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