Advances in Cardiovascular Imaging Imaging Phenotype versus Genotype in Hypertrophic Cardiomyopathy State-of-the Art in Genetics of Hcm Sarcomere and Z-disc Protein Gene Mutations State-of-the-art in Imaging in Hcm Assessment of Morphology

H ypertrophic cardiomyopathy (HCM) is a common monogenetic cardiac disease with a prevalence of 0.2% 1 that usually is inherited as an autosomal dominant trait with variable penetrance and expression. Clinically, HCM is defined by the presence of left ventricular (LV) hypertrophy (LVH) unexplained by abnormal loading conditions. 1 The natural history varies from an asymptomatic course to drug-refractory angina/dyspnea, sudden cardiac death (SCD), and end-stage heart failure. The incidence of HCM-related SCD is approximately 1% to 2% in children and adolescents and 0.5% to 1% in adults. 2,3 In this review, we examine the impact of advanced diagnostic imaging technologies on HCM, with particular emphasis on the detection of particular genetic subtypes. In Ϸ60% of cases, HCM is inherited as an autosomal dominant trait caused by mutations in genes coding for cardiac sarcomere proteins (Figure 1). 4 –7 Mutations in genes encoding Z-disc proteins and proteins involved in calcium regulation account for Ͻ5% of cases. The absence of sarco-meric gene mutations can be explained by limitations of current mutation detection techniques or mutations in as yet unidentified genes, but in some cases, hypertrophy is caused by other diseases that mimic the phenotype of sarcomeric protein disease. Table 1 lists genetic disorders associated with HCM. More than 600 different sarcomeric gene mutations are reported in patients with HCM. 8 –16 The majority are missense mutations, but nonsense, frameshift, and in-frame insertion/ deletion mutations also occur. Most mutations are characterized by incomplete penetrance and variable clinical expression likely due to locus heterogeneity and the effect of mutations at different locations within the same gene. Most mutations probably have a dominant negative effect on sarcomere function, but in some cases, haploinsufficiency (ie, only a single functional copy of a gene, the other being inactivated by the mutation) also may be important. It is suggested that hypertrophy results from reduced contractile function, but studies of myocyte function in patients with mutations in sarcomere protein genes are contradictory. Nevertheless, murine models of sarcomeric mutations show increased calcium sensitivity and altered calcium cycling between sarcomere and sarcoplasmic reticu-lum. In vitro studies using purified myosin filaments and skinned papillary muscle have reported increased calcium sensitivity of force development that results in impaired ventricular relaxation in vivo. 17,18 Z-discs are lateral boundaries of the sarcomere that play a fundamental role in mechanical stretch sensing. Several mutations in genes coding for Z-disc proteins have been implicated in HCM, …