Genetic mutations and mechanisms in dilated cardiomyopathy

Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure.In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow.Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere.Many mutations are “private” or rare variants, often unique to families.In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins.DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function.Private mutations account for most DCMs, with few hotspots or recurring mutations.More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM.Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia. Cardiomyopathy: diagnosis and prevalenceCardiomyopathy is defined by a pathologically abnormal myocardium.There are four major classifications of cardiomyopathy: dilated (DCM), hypertrophic (HCM), restrictive (RCM), and arrhythmogenic RV (ARVC).Cardiomyopathy is most commonly diagnosed through in vivo imaging, with either echocardiography or, increasingly, cardiac MRI.DCM refers to enlargement of the heart, which often affects all four chambers, especially late in the disease.Most commonly, DCM is associated with reduced LV function or systolic function, although early in the disease the LV may be dilated, with only minimally reduced function.In contrast, HCM is characterized by increased LV wall thickness, often targeting the septum that separates the LV from the RV (Figure 1).RCM is the most elusive, in part because the heart may appear morphologically close to normal, with only minor increased wall thickness or modestly decreased LV ejection fraction.The infiltrative process underlying RCM is often not readily detectable in vivo with even the most sensitive imaging technique.RCM is characterized by impaired filling of the heart, known as diastolic dysfunction, which reduces cardiac output.ARVC is characterized by reduced function and thinning of the RV with a fibrofatty infiltration that can be seen on MRI.Myocardial ischemia remains a common cause of DCM, accounting for approximately half of DCM.Toxic, metabolic, and immunologic causes have each been linked to DCM, as well as hypertension and valvular disease.Genetic cardiomyopathy, which runs in families, is now more commonly diagnosed, largely because surveillance for and awareness of the condition have improved.It is also now increasingly understood that more than one etiology may contribute to DCM within a given individual.Unlike cardiomyopathy that results from some of the other causes, genetic cardiomyopathy is a progressive disease.The time course is highly dependent on the age of presentation, which relates to