2D\n: two-dimensional\n99mTc-DPD\n: 99mTechnetium-3,3-diphosphono- 1,2-propanodi-carboxylic acid\nACE\n: angiotensin-converting enzyme\nAF\n: atrial fibrillation\nAL\n: amyloid light chain\nAR\n: aortic regurgitation\nARB\n: angiotensin receptor blocker\nATTR\n: amyloidosis-transthyretin type\nAV\n: atrioventricular\nBiVAD\n: biventricular assist device\nBNP\n: brain natriuretic peptide\nBPM\n: Beats per minute\nCCS\n: Canadian Cardiovascular Society\nCFC\n: cardiofacialcutaneous\nCHA2DS2-VASc\n: Congestive Heart failure, hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65–74, and Sex (female)\nCMR\n: cardiac magnetic resonance\nCRT\n: cardiac resynchronization therapy\nCRT-D\n: cardiac resynchronization therapy-defibrillator\nCRT-P\n: Cardiac resynchronization therapy with a pacemaker\nCT\n: computed tomography\nDC\n: direct current\nDNA\n: deoxyribonucleic acid\nE/A\n: ratio of mitral peak velocity of early filling (E) to mitral peak velocity of late filling (A)\nE/e’\n: ratio of early transmitral flow velocity (E) to early mitral annulus velocity (e’)\nEACTS\n: European Association for Cardio-Thoracic Surgery\nECG\n: electrocardiogram\nEF\n: ejection fraction\nEPS\n: electrophysiological study\nESC\n: European Society of Cardiology\nFDA\n: (US) Food and Drug Administration\nFHL1\n: four and a half LIM domains 1\nHAS-BLED\n: hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly (>65 years), drugs/alcohol concomitantly\nHCM\n: hypertrophic cardiomyopathy\nhs-cTnT\n: high sensitivity cardiac troponin T\nHTS\n: high throughput sequencing\nICD\n: implantable cardioverter defibrillator\nILR\n: implantable loop recorder\nINR\n: international normalized ratio\nIUD\n: intrauterine device\nLA\n: left atrium\nLAMP-2\n: lysosome-associated membrane protein 2\nLBBB\n: left bundle branch block\nLEOPARD\n: Lentigines, ECG abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, and sensory-neural Deafness\nLGE\n: late gadolinium enhancement\nLV\n: left ventricular\nLVAD\n: left ventricular assist device\nLVH\n: left ventricular hypertrophy\nLVOTO\n: left ventricular outlow tract obstruction\nMADIT-RIT\n: Multicenter Automatic Defibrillator Implantation Trial—Reduce Inappropriate Therapy\nMAPK\n: mitogen activated protein kinase\nMELAS\n: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes\nMERFF\n: myoclonic epilepsy with ragged red fibres\nMRA\n: mineralocorticoid receptor antagonist\nMYBPC3\n: myosin-binding protein C, cardiac-type\nMYH7\n: myosin-7 (s-myosin heavy chain)\nMYL3\n: myosin light chain 3\nNOAC\n: new oral anticoagulants\nNSVT\n: non-sustained ventricular tachycardia\nNT-proBNP\n: N-terminal pro brain natriuretic peptide\nNYHA\n: New York Heart Association\nOAC\n: oral anticoagulants\no.d.\n: omni die (every day)\nPC-CMR\n: phase contrast cardiac magnetic resonance\nPDE5\n: phosphodiesterase type 5\nPET\n: positron emission tomography\nPRKAG2\n: gamma-2 sub-unit of the adenosine monophosphate-activated protein kinase\nRAAS\n: renin angiotensin aldosterone system\nRV\n: right ventricular\nSAM\n: systolic anterior motion\nSCD\n: sudden cardiac death\nSAA\n: septal alcohol ablation\nS-ICD™\n: Subcutaneous lead implantable cardioverter defibrillator\nSPECT\n: single photon emission computed tomography\nSSFP\n: steady-state free precession\nSVT\n: supraventricular tachycardia\nTOE\n: transoesophageal echocardiography\nTNNI3\n: troponin I, cardiac muscle\nTNNT2\n: troponin T, cardiac muscle\nTPM1\n: tropomyosin alpha-1 chain\nTTE\n: transthoracic echocardiography\nTTR\n: transthyretin\nVF\n: ventricular fibrillation\nVKA\n: vitamin K antagonist\nVT\n: ventricular tachycardia\nWHO\n: World Health Organization\n\nGuidelines summarize and evaluate all available evidence at the time of the writing process, on a particular issue with the aim of assisting health professionals in selecting the best management strategies for an individual patient, with a given condition, taking into account the impact on outcome, as well as the risk-benefit-ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help the health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate.\n\nA great number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organisations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC website (http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx). ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated.\n\nMembers of this Task Force were selected by the ESC to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for management (including diagnosis, treatment, prevention and rehabilitation) of a given condition according to ESC Committee for Practice Guidelines (CPG) policy. A critical evaluation of diagnostic and therapeutic procedures was performed including assessment of the risk-benefit-ratio. Estimates of expected health outcomes for larger populations were included, where data exist. The level of evidence and the strength of recommendation of particular management options were weighed and graded according to predefined scales, as outlined in Tables 1 and 2 .\n\nThe experts of …

2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC)

http://www.cardiologia-vigo.com/wp-content/uploads/2011/10/2011_HRS-EHRA_GeneticTesting.pdf

HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies: This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA)

This international consensus statement provides the state of genetic testing for the channelopathies and cardiomyopathies. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the use and role of genetic testing for these potentially heritable cardiac conditions. This document focuses primarily on the state of genetic testing for the 13 distinct entities detailed and the relative diagnostic, prognostic, and therapeutic impact of the genetic test result for each entity. It does not focus on the therapeutic management of the various channelopathies and cardiomyopathies. Treatment/management issues are only discussed for those diseases (i.e., LQTS, HCM, DCM + CCD, RCM) in which the genetic test result could potentially influence treatment considerations.

Writing recommendations for genetic diseases require adaptation of the methodology normally adopted to prepare guidelines for clinical practice. Documents produced by other scientific societies have acknowledged the need to define the criteria used to rank the strength of recommendation for genetic diseases.1

The most obvious difference is that randomized and/or blinded studies do not exist. Instead, most of the available data are derived from registries that have followed patients and recorded outcome information. The authors of this statement have therefore defined specific criteria for Class I, Class IIa or b, and Class III recommendations and have used the conventional language adopted by AHA/ACC/ESC Guidelines to express each class. All recommendations are level of evidence (LOE) C (i.e., based on experts' opinions).

A Class I recommendation ( “is recommended” ) was applied for genetic testing in index cases with a sound clinical suspicion for the presence of a channelopathy or a cardiomyopathy when the positive predictive value of a genetic test is high (likelihood of positive result >40% and signal/noise ratio >10; Table 3), AND/OR when …

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HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies

Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction. It is commonly asymmetrical with the most severe hypertrophy involving the basal interventricular septum. Left ventricular outflow tract obstruction is present at rest in about one third of the patients and can be provoked in another third. The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis. The hypertrophy is also frequently associated with left ventricular diastolic dysfunction. In the majority of patients, HCM has a relatively benign course. However, HCM is also an important cause of sudden cardiac death, particularly in adolescents and young adults. Nonsustained ventricular tachycardia, syncope, a family history of sudden cardiac death, and severe cardiac hypertrophy are major risk factors for sudden cardiac death. This complication can usually be averted by implantation of a cardioverter-defibrillator in appropriate high-risk patients. Atrial fibrillation is also a common complication and is not well tolerated. Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. MYH7 and MYBPC3 , encoding β-myosin heavy chain and myosin-binding protein C, respectively, are the 2 most common genes involved, together accounting for ≈50% of the HCM families. In ≈40% of HCM patients, the causal genes remain to be identified. Mutations in genes responsible for storage diseases also cause a phenotype resembling HCM (genocopy or phenocopy). The routine applications of genetic testing and preclinical identification of family members represents an important advance. The genetic discoveries have enhanced understanding of the molecular pathogenesis of HCM and have stimulated efforts designed to identify new therapeutic agents.

Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy.

Genetics of Hypertrophic Cardiomyopathy After 20 Years: Clinical Perspectives

Background— Hypertrophic cardiomyopathy is an autosomal-dominant disorder in which 10 genes and numerous mutations have been reported. The aim of the present study was to perform a systematic screening of these genes in a large population, to evaluate the distribution of the disease genes, and to determine the best molecular strategy in clinical practice. Methods and Results— The entire coding sequences of 9 genes ( MYH7 , MYBPC3 , TNNI3 , TNNT2 , MYL2 , MYL3 , TPM1 , ACTC , and TNNC1 ) were analyzed in 197 unrelated index cases with familial or sporadic hypertrophic cardiomyopathy. Disease-causing mutations were identified in 124 index patients (≈63%), and 97 different mutations, including 60 novel ones, were identified. The cardiac myosin-binding protein C ( MYBPC3 ) and β-myosin heavy chain ( MYH7 ) genes accounted for 82% of families with identified mutations (42% and 40%, respectively). Distribution of the genes varied according to the prognosis ( P =0.036). Moreover, a mutation was found in 15 of 25 index cases with “sporadic” hypertrophic cardiomyopathy (60%). Finally, 6 families had patients with more than one mutation, and phenotype analyses suggested a gene dose effect in these compound-heterozygous, double-heterozygous, or homozygous patients. Conclusion— These results might have implications for genetic diagnosis strategy and, subsequently, for genetic counseling. First, on the basis of this experience, the screening of already known mutations is not helpful. The analysis should start by testing MYBPC3 and MYH7 and then focus on TNNI3 , TNNT2 , and MYL2 . Second, in particularly severe phenotypes, several mutations should be searched. Finally, sporadic cases can be successfully screened.

Marc Burban

Papers

Hypertrophic Cardiomyopathy Distribution of Disease Genes, Spectrum of Mutations, and Implications for a Molecular Diagnosis Strategy