Hypertrophic cardiomyopathy (HCM) is a genetic heart condition characterized by excessive thickening of the heart muscle. It was initially described in the 1950s and causes significant morbidity and mortality due to heart failure, arrhythmias, and sudden cardiac death. The pathophysiology involves left ventricular outflow tract obstruction, diastolic dysfunction, myocardial ischemia, and mitral regurgitation. Treatment involves medications, septal reduction procedures like myectomy or alcohol ablation, and implantable cardioverter-defibrillators in high-risk patients. Prognosis depends on symptom severity and risk factors for sudden cardiac death.

1. Hypertrophic Obstructive Cardiomyopathy Dr KURIAN JOSEPH JOURNAL PRESENTATION

2. Historical Perspective HCM was initially described by Teare in 1958 Found massive hypertrophy of ventricular septum in small cohort of young patients who died suddenly Braunwald was the first to diagnose HCM clinically in the 1960s Many names for the disease Idiopathic hypertrophic subaortic stenosis (IHSS) Muscle subaortic stenosis Hypertrophic obstructive cardiomyopathy (HOCM)

3. Background Prevalence of HCM: 1:500 to 1:1000 individuals This occurrence is higher than previously thought, suggesting a large number of affected but undiagnosed people Men and African-Americans affected by almost 2:1 ratio over women and Caucasians Global disease with most cases reported from USA, Canada, Western Europe, Israel, & Asia

4. Pathophysiology of HCM The pathophysiology of HCM involves 4 interrelated processes: Left ventricular outflow obstruction Diastolic dysfunction Myocardial ischemia Mitral regurgitation

6. Systolic Anterior Motion -SAM Subaortic outflow obstruction is caused by systolic anterior motion (SAM) of the mitral valve - leaflets toward the ventircular septum SAM is generated by Venturi effect A drag effect

7. LV Outflow Obstruction in HCM Physiological Consequences of Obstruction Elevated intraventricular pressures Prolongation of ventricular relaxation Increased myocardial wall stress Increased oxygen demand Decrease in forward cardiac output

10. Maron MS et al. NEJM. 2003;348:295.

11. Pathophysiology of HCM Diastolic Dysfunction Contributing factor in 80% of patients Impaired relaxation High systolic contraction load Ventricular contraction/relaxation not uniform Accounts for symptoms of exertional dyspnea Abnormal diastolic filling  increased pulmonary venous pressure

12. Pathophysiology of HCM Myocardial Ischemia Often occurs without atherosclerotic coronary artery disease Postulated mechanisms Abnormally small and partially obliterated intramural coronary arteries as a result of hypertrophy Inadequate number of capillaries for the degree of LV mass

13. Pathophysiology of HCM Mitral Regurgitation Results from the systolic anterior motion of the mitral valve Severity of MR directly proportional to LV outflow obstruction Results in symptoms of dyspnea, orthopnea in HCM patients

14. Integrated Pathophysiology Braunwald. Atlas of Heart Diseases: Cardiomyopathies, Myocarditis, and Pericardial Disease . 1998.

15. Microscopy The microscopy of HOCM demonstrates Myocyte hypertrophy Myocardial fibre disarry Interstitial and perivascular fibrosis Intimal and medial hypertrophy in intramural arteries. These changes lead to LV diastolic dysfunction by impairing relaxation and reducing compliance and scarring of the myocardium.

16. Massive left ventricular hypertrophy, mainly confined to the septum Histopathology showing significant myofiber disarray and interstitial fibrosis Cell Research. 2003;13(1):10.

17. Genetic Basis of HCM Autosomal dominant trait Mutations usually in B-myosin heavy chain, Myosin binding proteinC and cardiac troponin T. >450 mutations in 13 cardiac sarcomere & myofilament-related genes identified Alcalai et al. J Cardiovasc Electrophysiol. 19(1): Jan 2008.

18. Genetics of HCM Alcalai et al. J Cardiovasc Electrophysiol 2008;19:105.

19. Clinical Presentation Dyspnea on exertion (90%), orthopnea, PND Angina (70-80%) Syncope (20%), Presyncope (50%) outflow obstruction worsens with increased contractility during exertional activities Sudden cardiac death HCM is most common cause of SCD in young people, including athletes

20. Physical Examination Carotid Pulse Bifid – short upstroke & prolonged systolic ejection Jugular Venous Pulse Prominent a wave – decreased ventricular compliance Apical Impulse Double or triple Heart Sounds S4 usually present due to hypertrophy

21. Physical Examination Murmur Medium-pitch crescendo-decrescendo systolic murmur along LLSB without radiation Dynamic maneuvers Murmur intensity increases with decreased preload (i.e. Valsalva) Murmur intensity decreases with increased preload (i.e. squatting, hand grip)

22. Dynamic murmur of HOCM Smaller LV volume brings septum closer to anterior MV leaflet: more obstruction and louder murmur. Larger LV volume separates upper septum from anterior MV leaflet: less obstruction and softer murmur.

23. How to alter LV volume Increase LV volume Squatting Isometric handgrip Beta Blockers Phenylephrine Passive leg lifting Slow heart rate IV volume infusion Decrease LV volume Stand (after squatting) Valsalva maneuver Amyl nitrate Nitroglycerin Increase heart rate Volume depletio n Isoproterenol Exercise

24. Physical Examination in HCM Braunwald E. Atlas of Internal Medicine . 2007.

25. Diagnostic Evaluation Electrocardiogram Echocardiogram Catheterization

26. Electrocardiogram in HCM

27. Echocardiography in HCM

28. Transesophageal Echo

29. Coronary Angiography Hyperdynamic systolic function results in almost complete obliteration of the LV cavity Coronary angiography demonstrate Septal bulge on LV cavity.

30. Cardiac Magnetic Resonance CMR demonstrates myocardial scarring, which differentiate HCM from other LV hypertrophies CMR is indicated when ECHO views are limited due to unusual distribution of hypertrophy, or to detect milder magnitudes of hypertrophy. CMR with gadolinium enhancement imaging will detect myocardial scarring in about two thirds of HOCM patients.

31. Sudden Cardiac Death Unfortunately, SCD can be the first clinical manifestation. Occur in 15% of patients with HOCM SCD is seen more in young patients during and after physical exercise. High SCD association is seen in Prior cardiac arrest First degree relative with HOCM and SCD Multiple syncope associated with syncope Non sustained VT Treatment of choice is ICD. Strenuous sports should be avoided. No evidence that medical Rx reduces the rick of SCD

32. Clinical Course of HCM Heart Failure Only 10-15% progress to NYHA III-IV Only 3% will become truly end-stage with systolic dysfunction Endocarditis 4-5% of HCM patients Usually mitral valve affected Atrial Fibrillation Prevalent in up to 30% of older patients Dependent on atrial kick – CO decreases by 40% if AF present Autonomic Dysfunction 25% of HCM patients Associated with poor prognosis

33. Disease Progression in HCM ACC Consensus Document. J Am Coll Cardiol. 2003;42(9):1693.

34. Treatment of HCM Medical therapy Device therapy Surgical septal myectomy Alcohol septal ablation

35. ACC Consensus Document. J Am Coll Cardiol. 2003;42(9):1693.

36. Medical Therapy Beta-blockers Increase ventricular diastolic filling/relaxation Decrease myocardial oxygen consumption Have not been shown to reduce the incidence of SCD Verapamil Augments ventricular diastolic filling/relaxation Disopyramide Used in combination with beta-blocker Negative inotrope

37. Septal Myectomy In symptomatic patients despite medical Rx With gradient >50mm Hg at rest or provocation After aortic cross-clamping and aortotomy, bar of myocardium is excised from proximal septum. Complications include total AV block and VSD.

38. Surgical Septal Myectomy Nishimura RA et al. NEJM. 2004. 350(13):1320.

39. Alcohol Septal Ablation Braunwald. Atlas of Heart Diseases: Cardiomyopathies, Myocarditis, and Pericardial Disease . 1998.

40. Alcohol Septal Ablation Before After

41. Alcohol Septal Ablation Successful short-term outcomes LVOT gradient reduced from a mean of 60-70 mmHg to <20 mmHg Symptomatic improvements, increased exercise tolerance Long-term data not available yet Complications Complete heart block Large myocardial infarctions No randomized efficacy trials yet for alcohol septal ablation vs. surgical myectomy

42. Circulation. 2008; 18(2): 131-9.

43. Dual-Chamber Pacing Proposed benefit: pacing the RV apex will decrease the outflow tract gradient Several RCTs have found that the improvement in subjective measures provided by dual-chamber pacing is likely a placebo effect Objective measures such as exercise capacity and oxygen consumption are not improved No correlation has been found between pacing and reduction of LVOT gradient

44. Efficacy of Therapeutic Strategies Nishimura et al. NEJM. 2004. 350(13):1323.

45. Implantable Cardioverter Defibrillators in HCM Primary & Secondary Prevention

46. Appropriate discharges in 23% of patients Rate of appropriate discharges of 7% per year Of 21 patients for which intracardiac electrograms were available, 10 shocks for VT, 9 shocks for VF Suggested role for ICDs in primary & secondary prevention of SCD Maron BJ et al. NEJM 2000;342: 365-73.

47. Risk Stratification – ICDs Primary Prevention Risk Factors for SCD Premature HCM-related sudden death in more than 1 relative History of unexplained syncope Multiple or prolonged NSVT on Holter Hypotensive blood pressure response to exercise Massive LVH How many risk factors warrant ICD placement?

48. Multicenter registry study w/ 506 pts from 1986-2003 Mean follow-up 3.7 yrs Average age 41 years old Primary Outcome: appropriate ICD interventions terminating VF/VT JAMA. 2007;298(4): 405-12.

49. JAMA. 2007;298(4): 405-12. J Cardiovasc Electrophysiol 2008;19(10).

50. 3500 asymptomatic elite athletes (75% male), mean age 20.5 +/- 5.8 years, no family hx of HCM 12-lead ECG, 2D-Echo 53 athletes (1.5%) had LVH 3 athletes (0.08%) had ECG and echo features of HCM J Am Coll Cardiol 2008;51(10):1033-9.

51. HCM vs. Athlete’s Heart Circulation 1995;91.

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