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Genetics of Hypertrophic Cardiomyopathy: Advances and Pitfalls in Molecular Diagnosis and Therapy

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Genetics of Hypertrophic Cardiomyopathy: Advances and Pitfalls in Molecular Diagnosis and Therapy The Application of Clinical Genetics Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Genetics of hypertrophic cardiomyopathy: advances and pitfalls in molecular diagnosis and therapy Catarina Roma-Rodrigues1 Abstract: Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle that Alexandra R Fernandes1,2 occurs mainly due to mutations (.1,400 variants) in genes encoding for the cardiac sarcomere. HCM, the most common familial form of cardiomyopathy, affecting one in every 500 people 1UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e in the general population, is typically inherited in an autosomal dominant pattern, and presents Tecnologia da Universidade Nova de variable expressivity and age-related penetrance. Due to the morphological and pathological Lisboa, Campus de Caparica, Caparica, Portugal; 2Centro de Química heterogeneity of the disease, the appearance and progression of symptoms is not straightforward. Estrutural, Instituto Superior Técnico, Most HCM patients are asymptomatic, but up to 25% develop significant symptoms, including Universidade de Lisboa, Lisboa, chest pain and sudden cardiac death. Sudden cardiac death is a dramatic event, since it occurs Portugal without warning and mainly in younger people, including trained athletes. Molecular diagnosis of HCM is of the outmost importance, since it may allow detection of subjects carrying muta- tions on HCM-associated genes before development of clinical symptoms of HCM. However, due to the genetic heterogeneity of HCM, molecular diagnosis is difficult. Currently, there are mainly four techniques used for molecular diagnosis of HCM, including Sanger sequencing, high resolution melting, mutation detection using DNA arrays, and next-generation sequencing techniques. Application of these methods has proven successful for identification of mutations on HCM-related genes. This review summarizes the features of these technologies, highlight- ing their strengths and weaknesses. Furthermore, current therapeutics for HCM patients are correlated with clinically observed phenotypes and are based on the alleviation of symptoms. This is mainly due to insufficient knowledge on the mechanisms involved in the onset of HCM. Tissue engineering alongside regenerative medicine coupled with nanotherapeutics may allow fulfillment of those gaps, together with screening of novel therapeutic drugs and target delivery systems. Keywords: hypertrophic cardiomyopathy, molecular diagnosis, sarcomere, next-generation sequencing, sudden cardiac death Introduction Cardiomyopathies are a heterogeneous group of diseases affecting the heart muscle and frequently lead to progressive heart failure-related disability or cardiovascular death.1,2 According to the morphological and functional phenotype, cardiomyopathies can be Correspondence: Alexandra R Fernandes Departamento de Ciências da Vida, divided in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy, restrictive Faculdade de Ciências e Tecnologia left ventricular cardiomyopathy, arrhythmogenic cardiomyopathy, and left ventricular da Universidade Nova de Lisboa, non-compaction.1,2 A detailed definition and description of the subtypes of cardio- Campus de Caparica, 2829-516 Caparica, Portugal myopathies is outside the scope of this review and may be found elsewhere.1–3 Many Tel +35 12 1294 8530 cardiomyopathies are monogenic disorders due to single gene mutations in germinal Fax +35 12 1294 8530 Email [email protected] cells and thereby are inherited.3 HCM, a primary disease of the cardiac muscle that submit your manuscript | www.dovepress.com The Application of Clinical Genetics 2014:7 195–208 195 Dovepress © 2014 Roma-Rodrigues and Fernandes. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted http://dx.doi.org/10.2147/TACG.S49126 without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Roma-Rodrigues and Fernandes Dovepress occurs mainly due to mutations in genes encoding for the maintenance and regulation of sarcomere structure and cardiac contractile apparatus, is the most common familial function include myosin binding protein (MyBP)-c, titin, and form of cardiomyopathy, as well as the most phenotypically tropomyosin.13 Several mitochondria, which are responsible variable cardiac disease.4–6 Indeed, the pathophysiology of for generation of adenosine triphosphate for contraction, HCM is complex, being characterized by a wide range of dis- are scattered between myofibrils.12 Electrical excitation of ease processes, with varying genetics, clinical manifestations, the myocyte results in a high increase in the intracellular cal- heart morphology, and prognosis.6 Due to the phenotypic cium concentration, an event called excitation-contraction heterogeneity of the disease, the diagnosis of HCM at late coupling, that initiates further release of calcium from the adulthood is frequent, when the morphology and functional sarcoplasmic reticulum.12,13 Contractions of the sarcomere debility of the heart caused by the disease have progressed.7 are then initiated by calcium binding to troponin C, enabling This is of special importance for asymptomatic or mildly projections of the myosin molecules to interact with actin symptomatic young patients with HCM who may experi- molecules, through an adenosine triphosphate-dependent ence ventricular arrhythmias and sudden cardiac death.8 The process.12,13 Relaxation occurs by lowering the calcium molecular diagnosis of HCM allows the detection of subjects concentration in the myocyte and consequent detachment carrying a mutation on genes that cause the disease, even from troponin C.12 In HCM, mutations occurring at the before the development of symptoms.9 This review outlines level of the sarcomere will ultimately result in inefficient the current knowledge about HCM, describing the biochem- or excessive use of adenosine triphosphate and therefore in istry and physiology of HCM, highlighting the genetic and an energy deficiency.7,14 Among other consequences, these allelic heterogeneity underlying HCM, and pointing out the energy requirements compromise calcium homeostasis methods used for molecular diagnosis of HCM, along with and excitation-contraction coupling, in turn compromising their advantages and current limitations. It also emphasizes the relaxation capacity of the cardiomyocytes and conse- the current and new directions in HCM therapy. quently the force of contractibility.7,15 Moreover, mutations in sarcomere proteins seem to trigger an early increase in Hypertrophic cardiomyopathy the synthesis of collagen, which will result in myocardial Physiology and biochemistry of the fibrosis and consequently in overt HCM.16 Myocardial fibro- normal heart – what goes wrong! sis, together with an increase in the size of cardiomyocytes, The mechanical events that allow a cardiac cycle to occur results in myocardial left ventricular hypertrophy (LVH; require an appropriate venous return, regulation of outflow Figure 2).11 resistance, a normal myocardial contractile state, heart rate control, and an adequate supply of oxygenated blood.10 Physiological and morphological Alterations in one of these aspects may lead to cardiac characteristics deficiency.10 In HCM, the myocardial contractile state is Myocardial fibrosis in HCM patients seems to be related to compromised by cardiomyocyte hypertrophy, disarray, the myocyte death caused by stresses imposed by sarcomere and increased myocardial fibrosis.6 In fact, the myocardium mutations.16 Due to the limited division of cardiomyocytes, of a heart affected by HCM is composed of myocytes with maintenance of the structural integrity of the heart is distorted nuclei and disorganized myofibrils.11 This mor- accomplished by accumulation of fibroblasts.17 However, phology have a negative impact on cardiac relaxation and because fibroblasts do not have a contractile capacity, lead to arrhythmias and progression of heart failure.11 a supplementary effort is required from the surviving Despite the limited knowledge of the mechanisms cardiomyocytes and a consequent downward spiral that involved in modification of cardiomyocytes in HCM, it is includes neurohormonal activation, further cardiomyocyte well established that they are related to mutations at the death, and increased fibrosis.17,18 Myocardial fibrosis and level of the sarcomere proteins and other proteins involved further ischemia may result in LVH and predispose patients in muscle contraction and force transduction.6 Sarcomeres, to ventricular arrhythmias and ultimately to sudden car- which are responsible for muscle contraction, are formed by diac death.16 This clinical outcome occurs unexpectedly, contractile myofibrils composed of thick filaments (myosin) mainly in young people, including trained athletes.8,19 LV H and thin filaments (actin and associated regulatory proteins, is highly age-dependent, mainly occurring during or soon ie, tropomyosin and troponins C, I, and T) that slide past after the periods of rapid somatic growth that take place each other
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