Hypertrophic Cardiomyopathy

Transcription

1 Hypertrophic Cardiomyopathy A Presentation for the MUD meeting January, 2018 Reviewed by Bill Rooney MD VP/Medical Director 1

2 Agenda Definitions Epidemiology Pathophysiology Making the Diagnosis ECG changes with this diagnosis Treatment Prognosis 2

3 Why this presentation? Hypertrophic Cardiomyopathy Affects 1 in 500 people Is the most prevalent, heritable cardiovascular disease Is the most common cause of sudden cardiac death in young athletes Recent gene editing research is very interesting 3

4 Hypertrophic Cardiomyopathy----A Case Report 4 Case Description What caused the sudden death? What exactly is occurring in the heart that caused the problem? What is the chance other family members might have it? How do you identify those that have it? Is there anything that can be done to cure it or to mitigate the mortality risk? What other clinical problems can occur besides sudden death and do those things cause increased mortality? 4

5 Hypertrophic Cardiomyopathy----Variable Outcomes 5 Patient dx with HCM Sudden Cardiac Event Very early death Symptoms Complications Early death No Symptoms No early death 5

6 HCM is associated with a genetic abnormality which leads to an abnormal production of the contractile apparatus components in the myocardial sarcomere. HCM manifests itself by left ventricular hypertrophy, although the location and severity of the hypertrophy vary. Symptoms include: Chest pain Palpitations Dyspnea/orthopnea Syncope Asymptomatic These symptoms really can be lumped into 3 categories 1. chest pain 2. heart failure 3. arrhythmias Clinical outcomes include: Sudden death CHF Atrial arrhythmias Ventricular arrhythmias CVA No adverse impact 6 6

7 A pump An electrical powerhouse A source for loving emotion Tissue which needs a blood supply for nutrients 7 7

8 Left Atrium Mitral Valve Left Ventricle Outflow Tract Outflow Tract Interventricula r Septum Accessed 12/12/2017 using Googles labeled for reuse with modification feature. 8

9 Cardiomyopathy 9 J Am Coll Cardiol ;54: ; 9

10 Hypertrophic Cardiomyopathy (HCM) 10 The generally accepted definition of HCM is a disease state characterized by unexplained Left Ventricular hypertrophy (LVH) associated with non-dilated ventricular chambers in the absence of another cardiac or systemic disease that itself would be capable of producing the magnitude of hypertrophy evident in a given patient, with the caveat that patients who are genotype positive may be phenotypically negative without overt hypertrophy. * Other terms like, Idiopathic Hypertrophic Subaortic Stenosis (IHSS), Hypertrophic obstructive cardiomyopathy (HOCM) and Asymmetric Septal Hypertrophy (ASH) were used in the past to describe HCM. It is now understood that: any area of the heart can be hypertrophied obstruction to LV outflow is not necessarily related to Sudden Cardiac Death (SCD) from dysrhythmia. *Circulation. 2011;124: ; originally published online November 8,

11 LVH ----is it HCM? 11 HBP Valvular Lesion Athlete s Heart Cause Apparent LVH No Apparent Cause HCM Characteristics: (when cause is apparent) Concentric May reverse with treatment No FH Later onset Characteristics: (when HCM) May be isolated (Asymmetric) Does not reverse +/- Outflow obstruction FH Diastolic dysfunction 11

12 Characteristics of HCM 12 Maximal LV wall thickness 15 mm, (13-14 mm considered borderline), particularly in the presence of other compelling information (e.g., family history of HCM), based on echocardiography. About 2/3 will have some obstruction to the Left Ventricular Outflow Tract (LVOT) Family members who test positive for a genotype, but do not have LVH are said to be subclinical *Circulation. 2011;124: ; originally published online November 8,

13 HCM Epidemiology 13 It occurs in all ethnic groups. There is a morphologic form limited to the LV apex that appears most commonly in Japan. The prevalence is estimated to be between.05 and.2% (1:500) of the population Although most remain unidentified HCM is found in 0.5% of people referred for echocardiography It is often familial with an autosomal dominant inheritance pattern Variable penetrance and expression combined with variation in the age of onset make exact prediction difficult. 13

14 HCM Epidemiology 14 Bimodal age distribution If diagnosed in childhood, there can be dramatic increases in hypertrophy through adolescence Adult form peak incidence is the third decade, but can occur through the 6 th decade of life. In 1 st degree relatives of those affected with HCM, echocardiography shows disease in ~ 25%. ECGs are abnormal in 90% of those with HCM. 14

15 Cellular pathology in HCM 15 Cardiac muscle cells (myocytes) show increased diameter and bizarre shapes. Myocytes are arranged in chaotic patterns. Normally they align parallel to other myocytes, but they form oblique and perpendicular angles in HCM Characteristically, 10% or greater of the ventricle wall is affected by the pathological changes. Intramural coronary arteries show thickened walls and narrowed lumen in 80% at necropsy. Micro vascular (small-vessel) disease often causes clinically silent myocardial ischemia and myocyte death. This is followed by repair and fibrosis. The chaotic architecture and increased fibrosis likely contribute to the increased risk of ventricular dysrhythmia and sudden cardiac death (SCD). 15

16 HCM Morphology 16 Heart Fail Clin April 1; 6(2):

17 Sarcomere 17 Myosin Actin Quick, John, "Potential Application of the Synchronization Modulation Technique on Clinical Aspects" (2011). Outstanding Honors Theses. Paper

18 AUTOSOMAL DOMINANT Monogenic Diseases ~7,000 known Mendelian diseases Topol, Eric Individualized Medicine from Prewomb to Tomb. Cell 157 March 27,2014 Person with no disease HCM patient Autosomal Dominant Genes Disease in homozygous genotypes Disease in heterozygous genotypes A small modification in a single gene When on an autosome the inheritance obeys Mendelian laws Abnormal gene a a A A a A a a aa aa 18

19 Sequence matters Polymer of sugar and phosphate groups Nucleobases Deletions Adenine Thymine Cytosine Guanine Insertions Switches Repeats

20 Abnormal mrna mrna Abnormal Protein Protein Sequence Does Matter! Protein function: Cell Structure Cell Function Cell Regulation Examples of Protein function: Antibodies Enzymes Structural component Transport Protein_primary_structure.svg.png Image downloaded 8/5/16 from Bing free to modify, share, and use commercially se- L2_L3&adlt=strict&id=327BD63212E32BB7A857458B7357B1C1F3E7F31B&selectedIndex=11 &ccid=ft2usk4j&simid= &thid=oip.m16ddae4a4e23e52d43fc31b9b o0&ajaxhist=0 Image downloaded 8/5/16 from Bing free to modify, share, and use commercially

21 Where are those genes exactly Hypertrophic Cardiomyopathy TNNT2 gene 1q32 Hypertrophic Cardiomyopathy MYBPC3 gene 11p11.2 BRCA 2 gene 13q12.3 BRCA 1 gene 17q21 Hypertrophic Cardiomyopathy MYH7 gene 14q12 Hypertrophic Cardiomyopathy TNNI3 gene 19q13.4 AMONG OTHERS 21

22 Genotype versus Phenotype Abnormal gene Disease Variable expressivity Age Mutation type Genetic heterogenity Environmental exposure Genetic modifiers Mosaicism Penetrance Full Incomplete Variable 22

23 >50 mutations identified ~40% of adults <50 with this High penetrance defect have no hypertrophy Genetic Younger causes age at diagnosis of Cardiac Hypertrophy Hypertrophy worse 23 Increased risk of SCD >1500 mutations identified in 15 different genes!! <50% of patients have an identified gene mutation 3-10% have more than 1 genetic mutation! Heart Fail Clin April 1; 6(2): /j.hfc Ingles, J et al. Application of Genetic Testing in Hypertrophic Cardiomyopathy for Preclinical Disease Detection. Circ Cardiovascular Genetics Dec,

24 Genetic causes of Cardiac Hypertrophy Gene Clinical Disease Location Protein Symbol Features Hypertrophic Sarcomere: β-myosin heavy chain MYH7 Variable hypertrophy Cardiomyopathy Thick filament Myosin-binding protein C MYBPC3 Prognosis good Regulatory myosin light chain MYL2 Atrial arrhythmias Essential myosin light chain MYL3 with disease duration Titin TTN Ventricular arrhythmias Thin filament Troponin T TNNT2 uncommon Troponin I TNNT3 Heart failure uncommon α Tropomyosin TPM1 Actin ACTC1 Z-disc Muscle LIM protein CSRP3 Variable Hypertrophy + Skeletal myopathy Telethonin TCAP Variable hypertrophy Myozenin 2 MYOZ2 Variable hypertrophy Intercalated disc Vinculin VCL Variable hypertrophy Metabolic Cytosol Adenosine mono- phosphate- PRKAG2 Variable hypertrophy Cardiomyopathy activated protein kinase, γ2 Atrial arrhythmias; Progressive subunit Conduction System Disease Lysosome Lysosome-associated LAMP2 Massive hypertrophy membrane protein-2 Ventricular arrhythmias common Heart failure common Lysosome α-galactosidase A GLA Variable hypertrophy Ann Intern Med April 20; 152(8): 513 W Renal disease common 24

25 HCM penetrance related to defect 25 Heart Fail Clin April 1; 6(2):

26 Genetic Test Results Category Pathogenic Likely Pathogenic Variants of uncertain significance Likely benign Benign Characteristics Variant previously associated as cause of the disorder Variant expected to cause the disorder Variant that might be causative Variant probably not causative Variant recognized as neutral 26

27 Genetic Testing---Who to test? Mutation found Family member with known disease Test for that specific mutation in family members Unaffected individual Increased chance for inconclusive results If test is negative, is it: Because that gene is not mutated in the family?? or The mutation does exist in the family but the tested person doesn t have it?? 27

28 Hypertrophic Cardiomyopathy Proband = first affected family member seeking attention for a genetic disorder Pathogeni c mutation found Family member genetic screening frequently done Positive test = need for surveillance and imaging Negative test = Highly likely unaffected Proband Variation of Uncertain Significance Usually can t do family genetic screening No Mutation Found No family genetic screening typically Clinical screening for family members 28

29 Interaction of Many Factors Diseases can be a combo of one or more genes, one or more behaviors, and one or more environmental factors, with both good and harmful effects. Behaviors Gene Concept Hypertension Other Diseases Behaviors Behaviors Gene Disease HCM Behaviors Smoking Gene ACE Gene Genotype DD KEY Harmful Beneficial MYH Gene7 Environmental Factors Behaviors

30 From Prewomb To Tomb Topol, Eric Individualized Medicine from Prewomb to Tomb. Cell 157 March 27,

31 Pathophysiology HCM 31 Diastolic Dysfunction Thickened Ventricle Outflow Obstruction Impaired Relaxation Myocardial Ischemia Small vessel disease, myocardial bridging, microvascular dysfunction Supply demand mismatch, thick muscle cannot be supplied by intramural and small vessels Autonomic Dysfunction About 25% will have failure of the BP to rise with exercise (might fall) Mitral Regurgitation Common finding in LVOT obstruction, may be due to distortion of valve leaflets by Systolic Anterior Motion (SAM) *Circulation. 2011;124: ; originally published online November 8,

32 Presentation of HCM 32 32

33 Diagnosis 33 Starts with an ECG and Echocardiogram Once confirmed-suspected 24 hour ambulatory monitor (Holter) CMR if not well seen with echo Stress test reasonable Genotype counseling & screening Coronary angiography in those with chest pain Computed Tomographic Angiography (CTA) in those at low risk for CAD 33

34 Hypertrophic Cardiomyopathy ECG findings However, the ECG changes of HCM are not specific to HCM. An echocardiogram is frequently needed to help establish the diagnosis 34 34

35 Here is an ECG on a 58 y/o with echo proven hypertrophic cardiomyopathy we received during the course of business Hypertrophic recently. Cardiomyopathy 35 35

36 Same disorder, different look 36 36

37 Echocardiography and HCM Mitral Valve LV thickness, Typically evaluated at septum and free wall level Considered abnormal when 15 mm Defined asymmetrical in presence of a septal to free wall thickness ratio between 1.3 and Systolic Anterior Motion (SAM) Characterized by an abrupt anterior movement of the mitral valve reaching its peak before maximum movement of the posterior wall. Severity correlates with LVOT Contact between SAM and the septum usually indicates an obstruction 30 mmhg. Heart Fail Clin April 1; 6(2):

38 LVOT Obstruction in HCM 38 1/3 will have LVOT obstruction > 30 mm Hg at rest* 1/3 with physiologic provocation 1/3 do not have LVOT obstruction *Gradients >= 50 mm HG and symptomatic are considered for myectomy or ablation 38

39 Echo IVS 39 Heart Fail Clin April 1; 6(2):

40 Other Testing 40 Cardiovascular Magnetic Resonance (CMR) Views the entire LV myocardium to see localized hypertrophy Echo missed 6% of HCM patients in one study Identifies apical hypertrophy and apical aneurysms Late Gadolinium Enhancement (LGE) Identifies myocardial fibrosis Correlates with malignant ventricular arrhythmias Trending toward correlating with outcomes (although more study necessary) 1 *Circulation. 2011;124: ; originally published online November 8, UpToDate.com Clinical manifestations, diagnosis, and evaluation of hypertrophic cardiomyopathy. Accessed 2/12/16 3 Hoey, Edward, et al. The role of magnetic resonance imaging in hypertrophic cardiomyopathy. Quantitative Imaging in Medicine and Surgery. Vol 4 No 5 Oct

41 Figure 2. MRI revealed severe hypertrophy confined to left ventricular apex, suggesting apical HCM. Ha J et al. Circulation 2005;112:e49-e50 Copyright American Heart Association 41

42 Figure 6. Causes of sudden death in young competitive athletes, as reported to the Minneapolis Heart Institute Foundation national registry. Maron B J, Pelliccia A Circulation 2006;114: Copyright American Heart Association 42

43 Figure 11. Clinical criteria used to distinguish nonobstructive HCM from athlete s heart when maximal LV wall thickness is within shaded grey area of overlap, consistent with both diagnoses. Maron B J, Pelliccia A Circulation 2006;114: Copyright American Heart Association 43

44 Evaluation and Treatment 44 All patients with HCM should undergo comprehensive sudden cardiac death (SCD) risk stratification at initial evaluation to determine the presence of the following: A personal history for ventricular fibrillation, atrial fibrillation, sustained VT, or SCD events A family history for SCD events, including appropriate ICD therapy for ventricular tachyarrhythmias Unexplained syncope Documented non-sustained ventricular tachycardia (NSVT) defined as 3 or more beats at greater than or equal to 120 bpm on ambulatory (Holter) ECG Maximal LV wall thickness greater than or equal to 30 mm Hypotensive response to exercise Those without any of the above are generally considered low risk and typically are followed longitudinally Circulation. 2000;102: ) *Gersh, B. et al ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Executive Summary. Circulation. Dec 13, 2011;124: ; 44

45 Risk Factors for Sudden Cardiac Death Risk Factors for sudden cardiac death: Cardiac arrest Sustained V tach FH of sudden cardiac death Unexplained syncope LVH >3 cm thickness Abnormal BP response to exercise Non-sustained V tach Possible Risk Factors for sudden cardiac death: LVOT obstruction Abnormal MRI with gadolinium High risk mutation 2013 by Canadian Medical Association Daniel L. Jacoby et al. CMAJ 2013;185:

46 Evaluation and Treatment continued 46 Exercise Low intensity exercise is reasonable High intensity, competitive sports could be dangerous Medications Beta blockers and Calcium channel blockers can be used for symptoms. Vasodilators and diuretics may be harmful in those with LVOT obstruction. Other In symptomatic LVOT obstruction, not controlled with medication, septal reduction therapy might be performed. *Gersh, B. et al ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Executive Summary. Circulation. Dec 13, 2011;124: ; 46

47 Evaluation and treatment continued Atrial Fibrillation (25% will develop this) Ablation or Maze Anticoagulate and Rate control Indication for an Implantable Cardiac Defibrillator (ICD) Prior Cardiac Arrest, Ventricular fibrillation or hemodynamically unstable Ventricular tachycardia. SCD in 1 or more 1 st degree relatives LV wall thickness > 30 mm. 1 or more unexplained syncopal episodes Consider ICD Nonsustained VT, especially in a younger individual Abnormal BP response to exercise 47 Question: How often does the ICD, once implanted, appropriately discharge? ICD complication rate is high (4% per year) and risks versus benefits need to be considered 10% PER YEAR 4% PER YEAR *Gersh, B. et al ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Executive Summary. Circulation. Dec 13, 2011;124: ; 47

48 Age All cause Mortality in Percent per year Heart 2006;92:

49 744 enrolled US and Italy Followed for 23 years 49 Circulation. 2000;102: ) 49

50 Clinical profile of sudden death 50 Severe (Class III NYHA) 29% 29% Mild (Class II NYHA) 32% 29% In bed 16% Moderate-severe exertion 16% Asymptomatic 39% Sedentary Mild exertion 68% Symptomatic state prior to death Activity level at time of death Circulation. 2000;102: ) 50

51 Case to consider Case A 45 year-old man applies for life insurance. Other than a rare bronchitis or sore throat, he does not see a family doctor. In his application it says he is adopted and does not know his FH. BP is normal. This is his ECG: 51

52 Case (cont) 52 He reapplies after seeing a cardiologist. History revealed: Occasional chest pain after eating A light-headed feeling when over-exerting Occasional palpitations Exam revealed: A 2/6 systolic murmur along the lower left sternal border. Echo showed: No left ventricular outflow obstruction. LVPWd of 1.4 cm. IVSd was 1.5 cm. Grade II diastolic dysfunction Left Atrium measured 4.7 cm in diameter. Ejection Fraction was 55%. CTA did not show any significant obstructions in coronary arteries Holter showed 11 episodes of 3-5 beat non-sustained V-tach in the 24 hours, and numerous couplets. Treatment started: Beta blocker and F/u in 3 months to repeat holter. 52

53 In Summary Hypertrophic Cardiomyopathy has many appearances There are many genetic mutations Remember this slide 53 Genetic testing is helpful but not perfect HCM can be asymptomatic or can present in a variety of different ways It can impact mortality Finally, there are several identified risk factors for sudden death 53

54 Question s?????????? 54 Hypertrophic Cardiomyopathy 54

55 Gene Editing 55 Gene editing involves modifying the genetic sequence of DNA There are several techniques Mega-nucleases Zinc finger nucleases (ZFN s) Transcription activator-like effector-based nucleases (TALEN) Clustered regularly interspaced short palindromic repeats (CRISPR-Cas) CRISPR-Cas was Science as 2015 Breakthrough of the Year Ma, H et al, Correction of a pathogenic gene mutation in human embryos. Nature. Published Online 2 August

56 MYBPC3 gene CRSPR-cas and HCM gene editing Accounts for 56 40% of all known HCM genetic defects Study took a male with a known 4 bp GAGT deletion in exon 16 GAGT Ma, H et al, Correction of a pathogenic gene mutation in human embryos. Nature. Published Online 2 August

57 CRSPR-cas and HCM gene editing 57 The CRSPR-cas 9 unzips the DNA with the defect Both strands of the DNA are cut The DNA repairs itself using the homologydirected repair (HDR) type system using the non-mutant homologous chromosome Ma, H et al, Correction of a pathogenic gene mutation in human embryos. Nature. Published Online 2 August

58 Gene correction in S-phase-injected human embryos H Ma et al. Nature 1 7 (2017) doi: /nature