5/14/2014. How do you evaluate hypertrophic cardiomyopathy? How do you do you diagnose hypertrophic cardiomyopathy?

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1 Hypertrophic Cardiomyopathy: Clinical and Genetic Evaluation Hypertrophic Cardiomyopathy: Clinical and Genetic Evaluation Ray E. Hershberger, MD Professor of Medicine i Director, Division of Human Genetics Joint Appointment, Division of Cardiovascular Medicine Department of Internal Medicine The Ohio State College of Medicine/Wexner Medical Center Columbus, Ohio No conflicts, nothing to disclose Ray.Hershberger@osumc.edu How do you do you diagnose hypertrophic cardiomyopathy? Unexplained LV hypertrophy Non-dilated left ventricle, preserved systolic function No other systemic disease Degree of hypertrophy o Usually >15 mm o May be <15 mm in early disease o Occasionally mm chronically Confounders Athlete s heart, severe HTN, metabolic and/or syndromic disease ECG abnormal 75-85% of cases, even in early disease How do you evaluate hypertrophic cardiomyopathy? Cardiovascular Testing ECG Cardiac Imaging o Usually transthoracic echocardiography o Consider cardiac magnetic resonance imaging (CMR) If suggestion of apical HCM, aneurysm gadolinium helpful for scar, prognosis 24 hour Holter monitor Exercise stress test Consider stress echo o To clarify rest outflow obstruction o Degree of mitral regurgitation Genetic evaluation 1

2 Hypertrophic Cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy is a genetic disease of contractile proteins 6 Seidman, Seidman, Cell 2001;104: Phenotype, Sensitivity of Genetic Testing What do you do when you diagnose a new patient with hypertrophic cardiomyopathy? A genetic evaluation for HCM is always indicated 47% 35% 10% 8% A genetic evaluation may include genetic testing The central purpose of a genetic evaluation is to assess risk sigmoid reverse curve apical neutral o Especially in unaffected at-risk relatives o Especially if history of early sudden death Binder, et al, Mayo Clinic Proceed 2006; 81:

3 If a genetic evaluation is always indicated, what is it and how is it done? Comprehensive family history always Clinical screening of relatives always Counseling about HCM: o That it is considered to be a genetic disease o It may have a variable age of onset o Associated symptoms, outcomes, etc Consider genetic testing Consider referral to CV genetics Periodic clinical screening of at-risk relatives Medical, device therapy as needed Are There Guidelines? Guideline documents: 2011 American College of Cardiology/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy, Gersh, Maron, et al 2009 Heart Failure Society of America Guideline for Genetic Evaluation of Cardiomyopathy, Hershberger, et al Other key documents: 2014 GeneReviews (online at Hypertrophic Cardiomyopathy Overview Cirino, Ho Family History is always first! A careful family history for three or more generations is recommended for all patients with cardiomyopathy. Family History is key Family History is essential to inform clinical or molecular genetic studies, helpful to assess risk of sudden death Frequently requires extra effort from patient, family members Goals of a family history Determine if familial HCM is present Identify unaffected but at-risk relatives Confirm diagnosis Identify pedigree-specific features age of onset early mortality sudden unexplained death other unusual or syndromic features be wary of SCD from heart attack 3

4 Clinical screening for cardiomyopathy in asymptomatic first-degree relatives of persons with cardiomyopathy is recommended. Clinical screening is recommended to consist of: History (HF symptoms, arrhythmias, presyncope, syncope) Exam (attention to cardiac and skeletal muscle systems) Electrocardiogram Echocardiogram Holter monitoring Exercise treadmill stress testing Clinical screening family members Aspects requiring effort or medical decision making Facilitate family member screening Evaluate clinical data, decide if positive Integrate clinical data within pedigree Interpret the pedigree and decide if familial if molecular genetic testing is indicated who should be tested who is at risk frequency of follow up Consider referral if unable to complete Evaluation, genetic counseling, and genetic testing of cardiomyopathy patients are complex processes. Referral to centers expert in genetic et evaluation and family-based management should be considered. Level of Evidence = B Key Aspects of Cardiomyopathy Phenotypes Usually adult onset, age dependent, varies with cardiomyopathy classification Individual phenotypes, even with the same genotype (mutation), vary within and between pedigrees Penetrance is variable Mendelian inheritance usually evident 4

5 Mendelian Inheritance Classic Mendelian Inheritance - Autosomal Dominant Clinical Screening: Recommended at intervals in asymptomatic firstdegree relatives who are known to carry a diseasecausing mutation. Recommended for asymptomatic at-risk first degree relatives when genetic testing has not been performed or has not identified a disease-causing mutation. Age, yrs Screening Guideline <12 Optional unless any of the following are present: Family history of early HCM-related death Early development of LVH, or other adverse complications Competitive athlete in intense training program Symptoms Other clinical findings that suggest early LVH Repeat evaluation every months >18 Repeat evaluation every 3-5 years or with symptoms Guided by late-onset LVH or HCM-related complications Gersh, et al, JACC 2011;58: e Molecular Genetic Testing: Genetic testing should be considered for the one clearly affected person in a family to facilitate family screening and management. Level of Evidence = A 5

6 Rationale for Genetic Testing in Cardiovascular Genetic Medicine Pre-symptomatic diagnoses enables: Improved surveillance for disease presentation Early treatment to decrease morbidity and mortality Key Aspects of Cardiomyopathy Phenotypes Cardiomyopathy types follow genetic themes (ontologies) By: Preventing disease progression (drugs, specific Rx) Improved timing of interventions (drugs, devices) Averting advanced heart failure / arrhythmic events HCM Gene Ontology Genes of the Sarcomere MYH7 MYBPC3 beta myosin heavy chain myosin binding protein C TNNT2 troponin T TNNI3 troponin I TPM1 tropomyosin MYL2 myosin light chain 2 MYL3 myosin light chain 3 ACTC1 cardiac actin Hypertrophic cardiomyopathy is a genetic disease of sarcomeric proteins MYBPC3 (myosin binding protein C) 40% MYH7 (beta myosin heavy chain) 40% TNNT2, TNNI3, TPM % MYL2, MYL3, ACTC1 1-3% Multiple mutations 4-8% 6

7 Key Aspects of Cardiomyopathy Genotypes Allelic Heterogeneity TTNT2 HCM / DCM allelic variation Red Numbers = HCM variants; Blue Letters = DCM variants Relevant rare variants almost always unique to a patient or family - private Most cardiomyopathy genes have mutations scattered throughout coding sequence Hershberger et al, Circ Genetics 2009; 2: Hypertrophic Cardiomyopathy Genetic testing sensitivity ranges 35-50% (63)% Richard, France, / 197 = 63% Mayo Clinic i series, / 389 = 38% Gruner, Toronto series / 471 = 35% Ingles, Australia / 265 = 52% Richard et al, Circ 2003;107: Ackerman, Current Opinion Cardiol 2005;20: Gruner et al, Circ Genetics 2013;6:19-26 Ingles, Semsarian et al, Genetics in Med 2013; epub Factors predictive of positive genetic testing in hypertrophic cardiomyopathy Toronto series of 163 / 471 = 35% positive Linear regression to construct integer weights for clinical, echocardiographic variables Those variables independently predictive: (+) s: female, thicker LV septum to posterior wall, +FH, morphology (-) s: arterial hypertension, age Gruner et al Circ Genetics 2013;6:

8 Factors predictive of positive genetic testing in hypertrophic cardiomyopathy Hypertrophic Phenotype Caused by Metabolic/Infiltrative Disease Australian series of 138 of 265 = 52% positive positive family history (72% vs 29%) positive FH of early sudden death (89% vs 59%) Multivariate analysis earlier age (34 years vs 44 years) female greater LV wall thickness positive FH FH of early sudden death Gene PRKAG2 GLA LAMP2 Protein AMP-activated protein kinase Alpha-galactosidase Lysosome-associated membrane protein-2 Features HCM with WPW Fabry disease X-linked Danon disease X-linked Ingles, Semsarian Genetics in Med 2013; epub 30 HCM Genetic Testing Costs Costs ~ $3000-$4000, several commercial vendors One time cost! Comparable or less than other cardiovascular tests Insurance commonly pays for genetic testing ti with appropriate indications, evaluations, billing codes Cost effectiveness now demonstrated! Ingles J, Semsarian C, et al, A cost effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy. Heart 2012;98: Wordsworth S, et al. DNA testing for hypertrophic cardiomyopathy: a cost-effectiveness model. Eur Heart J 2010;31: Caveats and final comments So bottom line, who should undergo genetic testing? Familial HCM to assess genetic risk in relatives (To clarify etiology and/or inform treatment options, e.g., Fabry s: alpha galactosidase / GLA mutations) What is the sensitivity of HCM molecular genetic testing? HCM 35-50% (higher if familial) 32 8

9 More caveats and comments Are there psychosocial issues with genetic evaluation? Yes. How do you deal with them? Seek a genetic counselor! Do you advise that I start ordering genetic testing? Yes, if you are able to present, discuss and delineate benefits, risks, and uncertainty of testing, select an appropriate test panel (considering insurance coverage and administering the consent). Otherwise seek a genetic counselor (or geneticist) ideally with cardiovascular interest or experience. Hypertrophic Cardiomyopathy: Clinical and Genetic Evaluation Thank you! Are there issues of test interpretation? Yes! Seek expert help and collaboration, or refer out genetic testing while becoming informed. 33 9