Hypertrophic and dilated cardiomyopathies are the two most common kinds of genetic heart disease. The disease is caused by one or more mutations in the genotype of affected individuals, in genes which code for proteins in the cardiac muscle sarcomere. Hypertrophic diseases are characterized by the enlargement of individual cells making up the tissue or organ, while dilated cardiomyopathies gradually cause heart failure due to an abnormally thin ventricular wall. Although the genetic cause behind these diseases vary, they share the same mutations in sarcomeric protein genes, and are implicated with myosin.
The predisposition to hypertrophic cardiomyopathies is inherited as an autosomal dominant trait. HCM results in an usual enlargement of the ventricular and interventricular septum tissue, causing the individual to be at risk of impaired electrical activity. As the heart relies on precise electrical signalling in order to maintain its homeostatic heartbeat, hypertrophic cardiomyopathies pose a risk of sudden, unexpected death, particularly in athletes.
In contrast to HCM, dilated cardiomyopathies or DCM result in the dilation of the myocardium or heart muscle; this causes the thinning of the ventricular wall, and consequent impairment of systolic function. Furthermore, DCM impounds on one’s health gradually; the impaired heartbeat causes the progressive enlargement of the tissue. As with HCM, the most common pathway of inheriting the DCM phenotype is autosomal dominant; other patterns are also found, including autosomal recessive (Alstrom syndrome), X-linked (Duchenne muscular dystrophy) and mitochondrial inheritance.
Research suggests that when mutations are present in the sarcomeric proteins, the diseased HCM or DCM phenotype occurs; this is due to the altered contractile properties of the mutant myosin, leading to altered contraction and consumption of ATP – thus, the muscle’s abnormal ATP consumption may be the cause behind the diseased phenotype.
Due to ethical reasons, only small biopsies of human muscle have been used to study cardiomyopathies in humans. Alternatively, researchers have turned to transgenic mice to study the effects of myosin mutations on heart function. It was found that mice which were heterozygous for the R403Q gene mutation exhibited a hypertrophic phenotype, featuring a disarray of myocytes. Firstly, this indicates that the mutation is dominant. Secondly, further studies found that this disarray of myocytes was consistent at the cellular level, with actin and myosin attaching at very variable angles, compared to the wild type. Thus, myosin mutations potentially cause a disarray in myocytes at the cellular level, which is reflected at the acto-myosin level.
Studies over the past two decades have found that hypertrophic cardiomyopathy in particular actually has enhanced myosin activity; this may explain the large proportion of athletes who suffer from sudden death due to HCM – the large heart muscle provides them with a physiological advantage. HCM is a double-edged sword, however, and the muscle grows so abnormally large that electrical function is impaired and the individual is at risk of myocardial infarction. It is thus evident that genetic studies in mice support our understanding of diseases in humans, where research is blocked by ethical barriers; an application of this research may be the screening of athletes for HCM.
Moore, J. R; Leinwand, L.; Warshaw, D. M; Understanding Cardiomyopathy Phenotypes Based on the Functional Impact of Mutations in the Myosin Motor. Circulation Research, Vol. 111(3), 20 July 2012, p 375-385. Retrieved 13/10/2012.