Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype.

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Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology, starting from the molecular level and expanding from there. With such insights, there is potential for clinical translation that may transform management of patients and families with inherited cardiomyopathies. If key pathways for disease development can be identified, they could potentially serve as targets for novel disease-modifying or disease-preventing therapies. By utilizing gene-based diagnostic testing, we can identify at-risk individuals prior to the onset of clinical disease, allowing for disease-modifying therapy to be initiated early in life, at a time that such treatment may be most successful. In this section, we review the current application of genetics in clinical management, focusing on hypertrophic cardiomyopathy as a paradigm; discuss state-of-the-art genetic testing technology; review emerging knowledge of gene expression in sarcomeric cardiomyopathies; and discuss both the prospects, as well as the challenges, of bringing genetics to medicine.

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Severe microvascular dysfunction is a potent long-term predictor of adverse LV remodeling and systolic dysfunction in HCM. Our findings indicate microvascular dysfunction as a potential target for prevention of disease progression and heart failure in HCM.

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The R403Q mutation in β-myosin heavy chain was the first mutation to be identified as responsible for familial hypertrophic cardiomyopathy (FHC). In spite of extensive work on the functional sequelae of this mutation, the mechanism by which the mutant protein causes the disease has not been definitely identified. Here we directly compare contraction and relaxation mechanics of single myofibrils from left ventricular samples of one patient carrying the R403Q mutation to those from a healthy control heart. Tension generation and relaxation following sudden increase and decrease in [Ca 2+ ] were much faster in the R403Q myofibrils with relaxation rates being the most affected parameters. The results show that the R403Q mutation leads to an apparent gain of protein function but a greater energetic cost of tension generation. Increased energy cost of tension generation may be central to the FHC disease process, help explain some unresolved clinical observations, and carry significant therapeutic implications. The R403Q mutation in the β-myosin heavy chain was the first mutation to be identified as responsible for familial hypertrophic cardiomyopathy (FHC) (Geisterfer-Lowrance et al. 1990), a primary disease of the cardiac sarcomere that is the most commonly identified cause of cardiac sudden death in young people. The functional sequelae of the R403Q mutation have been extensively investigated using a variety of experimental models and approaches (Cuda et al. 1993;Lankford et al. 1995;Sata & Ikebe, 1996;Geisterfer-Lowrance et al. 1996;Marian et al. 1999;Tyska et al. 2000;Lowey, 2002;Keller et al. 2004) but the cardiac sarcomeres of affected individuals have never been directly examined. Here we compare contraction and relaxation of left ventricular myofibrils from one patient carrying the R403Q mutation to those from a healthy control heart. To investigate sarcomere mechanics we use previously This paper has online supplemental material. published techniques to measure and control the force and length of single myofibrils activated and relaxed by fast solution switching (Tesi et al. 2002;Piroddi et al. 2007). One advantage of this approach was that we could probe the acto-myosin transduction cycle while keeping the native structured sarcomere environment of the mutant protein. Preliminary report of this work has been published in abstract form ). Methods PatientsThe investigation conforms with the principles outlined in the Declaration of Helsinki and had been approved by the local Ethics Committee. Informed consent was given for both mutational analysis and mechanical experiments.A 24-year-old man, with a severe family history of premature cardiac death, diagnosed at 13 with FHC, and

Patients with HCM with sarcomere myofilament mutations are characterized by more severe impairment of microvascular function and increased prevalence of myocardial fibrosis, compared with genotype-negative individuals. These findings suggest a direct link between sarcomere gene mutations and adverse remodeling of the microcirculation in HCM, accounting for the increased long-term prevalence of ventricular dysfunction and heart failure in genotype-positive patients.