Use of Genetics in the Clinical Evaluation and Management of Cardiac Disease
Use of Genetics in the Clinical Evaluation and Management of Cardiac Disease Amy Sturm, MS, CGC Assistant Professor, Clinical Internal Medicine, OSUMC Potential Conflict of Interest Disclaimer: this talk is sponsored by GeneDx Learning Objectives and Content 1. 2. 3. Outline common inherited cardiac conditions Review practice guidelines related to the genetic evaluation of common inherited cardiac conditions Discuss management and screening recommendations Common Inherited CVDs Cardiomyopathies (isolated and syndromic) Hypertrophic cardiomyopathy (HCM) Dilated cardiomyopathy (DCM) Restrictive cardiomyopathy (RCM) Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) Left ventricular noncompaction (LVNC) Arrhythmias (isolated and syndromic) Long QT syndrome (LQTS) Brugada syndrome Catecholaminergic polymorphic ventricular tachycardia (CPVT) Familial atrial fibrillation Aneurysm syndromes Familial thoracic aortic aneurysm and dissection syndromes Marfan, Loeys-Dietz, and other connective tissue disorders Familial coronary artery disease and dyslipidemias General Rules of Thumb Most inherited CVDs Autosomal dominant, BUT Lack a traditional inheritance pattern Incomplete penetrance Lack of additional diagnoses in family due to variable expression of disease and small family size Common At diseases younger ages More severe Context Understanding of the genetic basis of many forms of CVD has advanced significantly in the last 5-10 years There are now professional society guidelines that recommend genetic testing for a variety of hereditary CVDs including LQTS, HCM, and ARVD/C The number of genes associated with CVDs continues to increase The number of clinically available genetic tests for CVDs has expanded rapidly in recent years Cardiomyopathies (CM) Diseases of the myocardium (heart muscle) Causes the heart to become enlarged and dilated, thickened, and/or stiffened As cardiomyopathy worsens, the heart becomes weaker and is less able to pump blood and maintain a normal rhythm This can lead to heart failure, arrhythmia or sudden death Among the leading indications for heart transplantation >26,000 deaths in the United States per year Can affect both adults and children Can be acquired or inherited HFSA recommendations Genetic Evaluation of Cardiomyopathy A Heart Failure Society of America Practice Guideline (Hershberger et al. J Cardiac Fail 2009;15:83-97) 1. 2. 3. 4. 5. A careful family history for >3 generations is recommended for all patients with CM. Clinical screening for CM in asymptomatic first-degree relatives is recommended. Evaluation, genetic counseling, and genetic testing of CM patients are complex processes. Referral to centers expert in genetic evaluation and family-based management should be considered. Genetic testing should be considered for the one most clearly affected person in a family to facilitate family screening and management. Genetic and family counseling is recommended for all patients and families with CM. Hypertrophic Cardiomyopathy (HCM) Prevalence of HCM is 1 in 500 Most common inherited cardiac disorder Major cause of sudden cardiac death (SCD) in the young (<30 years of age) Most common cause of SCD in young athletes Majority of idiopathic forms are genetic Clinical Features of HCM Unexplained left ventricular hypertrophy (LVH) Usually diffuse and maximal in the interventricular septum Localized forms have also been documented Outflow tract obstruction is also possible Clinical spectrum is diverse with variable age of onset Typically includes chest pain, exertion-related dyspnea, or impaired consciousness Others experience progressive exercise intolerance, heart failure or unexpected SCD Majority of individuals remain asymptomatic Annual frequencies of HCM-related SCD ~1-2% in children and adolescents 0.5-1% in adults Normal Heart and Heart with HCM Enlargement of the heart muscle Right ventricle Left ventricle Clinical Diagnosis of HCM Clinical diagnosis is made in most cases with echocardiography and EKG Detection of unexplained LVH Cardiac MRI is also showing potential to become an important tool in the diagnosis of HCM May detect early abnormalities (e.g. myocardial fibrosis) before LVH is present Genetic Basis of HCM Usually autosomal dominant inheritance Extensive genetic heterogeneity A disease of the sarcomere Incomplete penetrance and variable expressivity HCM: A Disease of the Sarcomere The contractile unit within the cardiac myocyte that is comprised of thick and thin filaments Mutations in sarcomeric genes account for ~60% of all cases of HCM Genes Associated with HCM Keren et al. Nature Clin Prac CV Med 2008 HCM Phenocopies J Cardiovasc Trans Res 2009 Genetic Testing for HCM Clinical genetic testing is available Current detection rate quoted 40% for isolated cases 66% for cases with positive family history of HCM or SCD Many private mutations Cardiac testing strategy: start with family member with most severe phenotype Multiple mutations (in the same or different genes) have been reported in 5-10% of cases of HCM, LQTS, and ARVD/C Individuals with 2 or more mutations often have earlier age of onset, more severe presentation, and worse prognosis “Dosage effect”: carriers of one mutation in these families are typically more mildly affected Critical to test at-risk family members for all mutations identified Every effort should be made to identify all mutations present in a family If testing has already been done on a mildly affected family member, or if targeted testing of only a few genes has been done, it may be wise to pursue testing with a comprehensive panel in an affected family member whose phenotype is unusually severe For example, with extreme hypertrophy in infancy in the setting of familial disease with late presentation, searching for two mutations is indicated Dilated Cardiomyopathy (DCM) The heart is enlarged and becomes less effective in pumping blood Left ventricular dilation and systolic dysfunction Leads to symptoms of heart failure and arrhythmias The prevalence of DCM is ~1/2500, although it may be more common Chronic disease with no cure, but current treatments can significantly improve its course Clinical Features of DCM Congestive heart failure Edema (fluid accumulation) Orthopnea (inability to breathe except in an upright position) Paroxysmal nocturnal dyspnea (dyspnea caused by lung congestion, occurring suddenly at night) Reduced cardiac output Fatigue Dyspnea on exertion (shortness of breath which occurs with effort) Arrhythmias and/or conduction system disease Occasionally, some patients may have muscle weakness or dystrophy Some individuals may not have any clinical symptoms and can only be identified by diagnostic testing Clinical Diagnosis of DCM Echocardiography is often the best way to identify DCM and can show: Left ventricle enlargement Decreased ejection fraction (usually <50%) Wall motion abnormalities (usually global hypokinesis) Atrial enlargement Other recommended tests are a physical exam and ECG Origin of DCM Many possible causes of DCM Coronary artery disease Infection Excessive alcohol and other drug use Valvular disease Hypertension Myocarditis Idiopathic DCM ~20-50% of patients with idiopathic DCM have a family history of the disease and are considered to have familial DCM A thorough pedigree should be taken on every individual with idiopathic DCM Toxins Familial DCM Criteria for familial DCM One individual diagnosed with idiopathic DCM, with at least One relative also diagnosed with idiopathic DCM, OR One first-degree relative with an unexplained sudden death <35 years of age Sudden cardiac death in the setting of nonischemic cardiomyopathy is commonly referred to as a “heart attack” by lay persons, and one should not automatically assume that this refers to a myocardial infarction when obtaining a family history Inheritance of DCM Autosomal dominant (~90%) X-linked (~5-10%) Autosomal recessive More common among certain ethnic groups and may be responsible for some cases of especially young (<10 years) onset Mitochondrial Penetrance and Disease Expression Penetrance Incomplete Age-dependent Variable disease expression Both intra- and inter- familial variability Families often demonstrate a wide range of mild to severe disease across all generations Within the same family, the disease may range from subtle clinical symptoms and/or mild arrhythmias to sudden death or DCM leading to heart failure and/or cardiac transplantation Clinical onset is usually in the adult years (30s to 50s) but varies widely, occasionally even presenting in infants, small children, and the elderly Crucial to convey this information in genetic counseling Genes Associated with DCM Hershberger et al J of Cardiac Failure 2009 Genetic Testing for DCM Extensive genetic heterogeneity Mutations in >20 genes have been implicated as causative Relatively low frequency of involvement of any one gene Clinical genetic testing available Current clinical sensitivity of genetic testing is ~25-30% DCM phenotype suggestive of specific disease gene Prominent conduction disease, with or without supraventricular or ventricular arrhythmias, then DCM and heart failure Think about a LMNA gene mutation Pacemakers common Signs of skeletal muscle involvement shown most commonly by elevated creatine kinase Several studies have demonstrated increased risk of sudden cardiac death for individuals with a LMNA mutation Autosomal dominant inheritance Screening and Management Clinical Screening Recommendations Genetic Evaluation of CardiomyopathyA Heart Failure Society of America Practice Guideline (Hershberger et al. J Cardiac Fail 2009;15:83-97) Clinical screening for cardiomyopathy is recommended in Asymptomatic at-risk relatives who are known to carry the disease-causing mutation(s) Asymptomatic at-risk FDRs when genetic testing has not been performed or has not identified a disease-causing mutation Screening Times and Intervals Cardiomyopathy Phenotype If mutation present If genetic testing and/or clinical family screening negative Hypertrophic Every 3 yrs until 30 yrs, except yearly during puberty; every 5 yrs after Every 3 yrs until 30 yrs, except yearly during puberty; after 30 yrs if symptoms develop Yearly in childhood; every 1-3 yrs in adults Every 3-5 yrs beginning in childhood Yearly after age 10 to 50 yrs Every 3-5 yrs after age 10 LVNC Yearly in childhood; every 1-3 yrs in adults Every 3 yrs beginning in childhood Restrictive Yearly in childhood; every 1-3 yrs in adults Every 3-5 yrs beginning in adulthood Dilated ARVD/C Hershberger et al. J Cardiac Fail 2009 Clinical Screening Tests It is recommended that clinical screening consist of: History (with special attention to heart failure symptoms, arrhythmias, presyncope, and syncope) Physical examination (with special attention to the cardiac and skeletal muscle systems) Electrocardiogram Echocardiogram CK-MM (at initial evaluation only) Signal-averaged electrocardiogram (SAECG) in ARVD only Holter monitoring in HCM, ARVD Exercise treadmill testing in HCM Magnetic resonance imaging in ARVD Hershberger et al. J Cardiac Fail 2009 Clinical Screening Caveats Screening should also be initiated at any time signs or symptoms appear At-risk FDRs with any abnormal clinical screening tests (regardless of genotype) should be considered for repeat clinical screening at one year Clinical screening for HCM has also been recommended in “athletic SDRs” when genetic testing has not been performed or has not identified a disease-causing mutation* Hershberger et al. J Cardiac Fail 2009, *Bos et al. JACC 2009 Benefits and Limitations of Screening Screening frequently detects relatives with asymptomatic mild heart disease Early diagnosis and treatment can improve survival and/or enhance quality of life Medical intervention may delay disease presentation and progression May avoid advanced therapies such as cardiac transplantation May avert sudden cardiac death Normal cardiac screening does not exclude the later development of cardiomyopathy in at-risk relatives Management Guidelines for clinical management of HCM and DCM have been developed JACC 2003;42:1687-1713. ACC/ESC Expert Consensus Document on HCM Circ 2010;121:445-456. Strategies for Risk Stratification and Prevention of Sudden Death in HCM. JACC 2005;46:e1-e82 ACC/AHA Guideline for Dx and Management of Chronic Heart Failure J Card Fail 2006;12:10-38. HFSA 2006 Heart Failure Practice Guideline. Risk stratification for sudden cardiac death is imperative HCM Noninvasive predictors of SCD risk include SCD in FDRs, malignant genotype, unexplained syncope, abnormal blood pressure response to exercise, ectopic ventricular activity, and massive septal hypertrophy (>30mm)^ Risk of SCD up to *6%/year in patients 20-30 years Clinical management remains complex Heterogeneous symptoms Marked variability in natural history ^Fowler et al Curr Treat Op Cardiovasc Med 2009, *Maron et al Circulation 2000 Management options Pharmacologic therapy Lifestyle modifications Avoiding competitive sports Healthy lifestyle Mechanical devices Surgical intervention Mechanical Devices – Pacemakers and ICDs Pacemaker Uses electrical pulses to treat heart rhythms that are too slow, fast, or irregular Implantable cardioverter defibrillator (ICD) Sophisticated implanted device that monitors heart rhythm and recognizes and automatically terminates lethal ventricular arrhythmias and restores a normal heartbeat in people who are at high risk of SCD Emphasized need for multidisciplinary evaluation of these patients with electrophysiology experts http://www.heart.org.in Prevention of sudden death Intracardiac electrogram obtained at 1:20 AM in a patient while asleep 5 years after implantation From 35-yo man with HCM who received prophylactic ICD because of family history of SD and marked ventricular septal thickness (31 mm). A. VT begins abruptly B. Defibrillator senses VT and charges C. VT deteriorates into VF, and defibrillator issues 20-J shock (D; arrow), restoring sinus rhythm. Virtually identical sequence occurred 9 years later during sleep; the patient is now 53 years of age and asymptomatic. Circ 2010; 121:445-456. Surgical Intervention Septal myectomy (HCM) Alcohol ablation (HCM) Cardiac transplant Impact of genetic diagnosis on arrhythmia management in CM Some genes associated with familial CM and heart failure are associated with increased risk of arrhythmia LMNA, DES Although some studies have suggested a more benign clinical course for individuals with an MYBPC3 mutation, others have shown that mutations in this gene may result in early-onset CM (both DCM and HCM) ICD implantation should not be overlooked in the setting of an MYBPC3 mutation Individuals with a TNNT2 mutation associated with familial HCM are more likely to have SCD with relatively less severe LVH The recognition of a TNNT2 mutation should lead clinicians to disregard septal wall thickness in ICD implantation recommendation/decision Curr Treat Op Cardiovasc Med 2010 12:566-577. Children and Cardiomyopathy Although cardiomyopathy has been identified in infants and small children, most disease is adolescent (HCM) or adult-onset Pediatric cardiomyopathies, especially those presenting in the 1st year of life, have an increased likelihood of being mitochondrial or metabolic-based HCM of childhood Young children with left ventricular hypertrophy (LVH) may have an underlying mitochondrial or metabolic disease OR have early clinical expression of HCM from a sarcomere gene mutation Children <1 year of age with HCM are usually seen frequently, commonly every 3 months Siblings without clinical features are followed yearly in most cases until reaching puberty DCM of childhood A subgroup of affected children has associated skeletal myopathy and some also have conduction system disease In families with early onset, screening of at-risk relatives should begin earlier Parents should be alert for symptoms in at-risk children and should have a low threshold for evaluation Echocardiograms and ECGs on children should be evaluated by pediatric centers Cardiomyopathy Case Examples Patient M.P. M.P. history Starting at age 15y, had echos every 3-5 yrs Most recent echo showed minimal basilar septal hypertrophy (1.3 cm) Recommendations after initial genetics consult Contact Dr. Ommen at Mayo Clinic to retrieve copy of father’s research genetic testing Mutation was identified via the HCM IRB-approved protocol at Mayo CLIA confirmation of research result with commercial genetic testing confirmed research result IVS30+2T>G mutation in the MYBPC3 gene Genetic testing for M.P. and other at-risk relatives M.P. Follow-up M.P. tests positive Recommend follow-up screening with cardiologist and adding cardiovascular magnetic resonance (CMR) Studies have shown that CMR may identify patients with increased susceptibility to ventricular tachyarrhythmia; this is based on the findings of the presence and extent of myocardial scar and fibrosis* His two daughters are tested and both test positive Referred to cardiogenetics clinic at local Children’s hospital for evaluation by pediatric cardiologist, pediatric geneticist, and pediatric cardiac genetic counselor Echocardiograms to be performed on both girls *JACC 2008; 51. NEJM 2010; 363:552-63. Patient N.H. Patient with possible familial DCM referred by cardiologist in Marietta, OH Met with genetic counselor and medical geneticist in Medical Genetics Program Education regarding familial DCM, inheritance pattern, genetic testing options, including benefits and limitations of testing Informed consent provided and genetic testing ordered N.H. genetic testing results Uninformative results Familial disease but no familial mutation identified We can still provide screening recommendations for relatives Genetic Evaluation of Cardiomyopathy A Heart Failure Society of America Practice Guideline Hershberger et al. J Cardiac Fail 2009;15:83-97 Clinical screening is recommended in Asymptomatic at-risk relatives who are known to carry the disease-causing mutation(s) Asymptomatic at-risk FDRs when genetic testing has not been performed or has not identified a disease-causing mutation Screening times and intervals Clinical screening tests to perform Every 3-5 yrs beginning in childhood Hereditary Arrhythmias Why are They Important? They affect people of all ages They can be easy to recognize They can cause syncope They can cause sudden cardiac death (SCD) They can cause sudden infant death syndrome (SIDS) Genetic testing is available for many hereditary arrhythmia syndromes Mutations in cardiac ion channel genes A recent review of the literature concluded that at least one out of five SIDS victims carries a mutation in a cardiac ion channel gene* Symptoms can be treated SCD can be prevented *Int J Cardiol 2011 Klaver EC et al. Hereditary Arrhythmia Syndromes Long QT syndrome Brugada syndrome Catecholaminergic polymorphic VT (CPVT) ARVD/C Short QT syndrome Familial Wolff-Parkinson-White Syndrome Familial atrial fibrillation Long QT Syndrome (LQTS) Prevalence of 1 in 2,000 – 1 in 5,000 Clinically identified by prolonged QT interval on ECG Presents with syncope and SCD due to ventricular tachyarrhythmias, typically torsades de pointes Torsades can cause seizures due to cerebral anoxia Caused mostly by mutations in ion channel genes (potassium and sodium channels) These mutations can also cause sudden infant death syndrome (SIDS) Acquired vs. Inherited LQTS Important to identify acquired factors that cause QT prolongation through careful history MI, CMs, hypokalemia, hypocalcemia, hypomagnesemia, autonomic influences, drug effects, hypothermia Inherited LQTS Romano-Ward syndrome (autosomal dominant) Jervell and Lange-Nielsen syndrome (autosomal recessive with congenital deafness) A detailed family history is essential in diagnosis! Diagnostic Criteria for LQTS Schwartz Scoring System 1 point, low probability 2 to 3 points, intermediate probability 4 points, high probability Goldenberg and Moss, JACC 2008 Common LQTS Phenotypes Clinical Phenotype %age of cases T-wave pattern Incidence of cardiac events Common cardiac event triggers Sudden death risk LQT1 42-54% Broad 63% Exercise, emotion, 4% KCNQ1 T wave swimming LQT2 35-45% KCNH2 Bifid 46% T wave Emotion, exercise, 4% sleep, startle, postpartum LQT3 SCN5A ~2-8% Late-onset peaked/ 18% Rest or sleep >4% biphasic T wave Vincent GM Genetests.org 2009, Morita et al. Lancet 2008 Auditory (Startle) Stimulus in LQT2 Morita et al. Lancet 2008 Incomplete Penetrance in LQTS Penetrance is incomplete and influenced by age, genotype, gender, environmental factors, therapy, and possibly other modifier genes Many remain without overt cardiac symptoms 37% of LQT1 54% of LQT2 82% of LQT3 Age-Specific Risk Factors for LifeThreatening Cardiac Events in LQTS Goldenberg and Moss, JACC 2008 Genes Associated with LQTS Lancet 2008; 372:750-63. Genetic Testing for LQTS Clinical genetic testing available Current sequencing detection rate ~75% A negative genetic test does not rule out LQTS Large deletions and duplications in LQTS Studies have shown that 5-12% of patients with normal sequencing of the most common LQTS genes had large genomic rearrangements Am J Cardiol 2010, Heart Rhythm 2008 Reflex genetic testing to investigate genomic rearrangements may be of clinical value Up to 10% of patients with LQTS will have two mutations Once pathogenic, causative mutation identified, genetic testing should be offered to all FDRs regardless of QTc interval Management of LQTS Beta-blockers Very effective in LQT1 Should be continued during pregnancy and after delivery (cardiac events increase during first 9 months postpartum) However, residual risk for cardiac events *In cohort of 335 genotyped LQTS patients on beta-blockers, cardiac events occurred in 10% of LQT1 23% of LQT2 32% of LQT3 Patients who remain symptomatic on beta-blockers should be considered for other therapies ^However, important to note that many events “on beta-blockers” may be due to noncompliance *Priori et al. JAMA 2004, ^Vincent et al. Circ 2009 Management of LQTS Implantable cardioverter-defibrillators (ICDs) Highly effective in high-risk LQTS patients International LQTS Registry data* (mean 8 yr fu) 125 ICD patients: 1.3% death rate 161 clinically similar non-ICD patients: 16% death rate Preventive measures Avoidance of adrenergic-type stimuli, alarm clocks, and QT-prolonging drugs (www.qtdrugs.org) Restriction of participation in athletic activity; no participation in competitive sports *Zareba et al. J Cardiovasc Electrophysiol 2003 Clinical Screening Caveats Prolonged QT is a transient finding A normal ECG or Holter monitor does not rule out LQTS in at-risk relatives Patient J.P. 84 ? 61 ? 39 ? 59 20s 81 ? 56 ? 20s ? 27 ? 23 d.8 ? 28 52 ? 26 ? 46 21 19 ? 17 LQTS syncope ? 15 42 ? 13 Genetic Testing for Long QT Syndrome LQTS1 (KCNQ1) ++ Acquired LQT sensitivity (KCNE1) 84 81 Acquired LQT sensitivity (KCNE1) only ++ ? 61 -+ 39 ? ++ 59 20s -+ 56 ? 20s -- 27 -- 23 d.8 ? 28 52 ? 26 -- 46 21 19 -- 17 Acquired LQT sensitivity (KCNE1) only LQTS syncope -- 15 42 -- 13 Value of Genetic Information for this Family Type of LQTS diagnosed Can help determine effectiveness of therapy (beta-blockers are extremely effective in LQT1 and should be administered at diagnosis and ideally before the preteen years) Those who test positive are referred to EP for risk management Those who test negative for both genetic variants have no increased risk nor do their children Acquired LQT sensitivity also diagnosed in this family Individuals with this variant need to avoid QT-prolonging drugs Those who tested positive received counseling from Specialty Practice Pharmacist Large-scale clinical utility of genetic testing and cascade screening to identify Conclusions: (most often asymptomatic) at-risk relatives 1. 100 Cascade screening in families one of tested the main inherited probands with mutation identified,with 509 relatives positive arrhythmia syndromes, based on genetic testing and Treatment initiated and ongoing in relatives 65% ofcardiologic LQTS (199/308) subsequent investigation, resulted in immediate 71% of CPVT (85/120) prophylactic treatment in a substantial proportion of carriers. 6% of Brugada (5/81) Treatment included drug (n=249), pacemaker (n=26) or ICD (n=14) 2. A All large number of carriers are treated presymptomatically; mutation carriers received lifestyle instructions and list of drugs to avoid these patients would have been missed without testing. Important clinical implication specific to LQTS – of all patientsgenetic with a QTc <460 ms, 59% were treated; these patients probably would have been missed if ECG alone was performed without genetic testing In Conclusion… Family History “Red Flags” “Heart attack” in person <50 yrs (cardiomyopathy, arrhythmia, aortic dissection) Two or more closely-related family members on the same side of the family with the same or related conditions (for example, heart disease, stroke, arrhythmia) Sudden death, unexplained (MI, cardiomyopathy, arrhythmia, aortic dissection) Family history of symptoms and procedures suspicious for a hereditary arrhythmia syndrome: syncope, seizures, family members with pacemakers and/or ICDs, sudden death, SIDS An individual who has been diagnosed with a specific type of hereditary heart disease (i.e. HCM, Marfan syndrome, etc.) Coronary heart disease at a young age (male under 55 or female under 65) Two or more closely-related family members with a congenital heart defect Resources Sudden Arrhythmia Death Syndromes Foundation (sads.org) Hypertrophic Cardiomyopathy Association (4hcm.org) Cardiac Arrhythmias Research and Education Foundation, Inc. (longqt.org) The Cardiomyopathy Association (cardiomyopathy.org) Children's Cardiomyopathy Foundation (childrenscardiomyopathy.org) CardioWhat: A Kid’s Guide to Cardiomyopathy (NSGC, Children’s Cardiomyopathy Foundation) Circulation Patient Pages
© Copyright 2024