Hypertrophic cardiomyopathy

A SUBJECT SEMINAR ON HYPERTROPHIC CARDIOMYOPATHY

1. Hypertrophic cardiomyopathy Dr. DEEPIKA.T FIRST YEAR PG STUDENT DEPARTMENT OF GENERAL MEDICINE RRMCH, BENGALURU MODERATOR Dr. KRISHNA.M.V HOD, DEPARTMENT OF GENERAL MEDICINE RRMCH, BENGALURU

2. CONTENTS Introduction – Cardiomyopathy HCM Definition & Background Historical Perspective Genetic Basis Morphology Pathophysiology Clinical Features Clinical Course Management Screening Strategies DD with Athlete’s heart

3. Cardiomyopathy cardiomyopathy is defined as “disorders characterised by morphologically and functionally abnormal myocardium in the absence of any other disease that is sufficient, by itself, to cause the observed phenotype ” Harrison's Principles of Internal Medicine, 20E (2018) A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality ESC Working Group on Myocardial Pericardial Diseases (Elliott P et al. EHJ 2007)

4. ESC Working Group on Myocardial Pericardial Diseases (Elliott P et al. EHJ 2007)

5. Hypertrophic Cardiomyopathy

6. Definition Hypertrophic cardiomyopathy is defined as left ventricular hypertrophy that develops in the absence of causative hemodynamic factors, such as hypertension, aortic valve disease, or systemic infiltrative or storage diseases Harrison's Principles of Internal Medicine, 2OE (2018)

7. Background Hypertrophic cardiomyopathy is a genetic disorder that is typically inherited in an autosomal dominant fashion with variable penetrance and variable expressivity HCM is the leading cause of sudden cardiac death in preadolescent and adolescent .

8. Background The hallmark of the disorder is myocardial hypertrophy that is inappropriate, often asymmetrical and occurs in the absence of an obvious inciting hypertrophy stimulus This hypertrophy can occur in any region of the left ventricle but frequently involves the IVS , which results in a LVOT obstruction

9. Background Prevalence of HCM: 0.05-0.2% of the population Prevalence in North America, Africa and Asia is about 1:500  This occurrence is higher than previously thought, suggesting a large number of affected but undiagnosed people Approximately 25% of first-degree relatives of patients with HCM show morphological evidence on 2D-echo Men: Women :: 2:1 African-American : Caucasians :: 2:1

10. Historical Perspective First description of HCM by Teare in 1958  Found massive hypertrophy of ventricular septum in small cohort of young patients who died suddenly First clinical diagnosis of HCM by Braunwald in the 1960s Alternative names  Idiopathic hypertrophic subaortic stenosis (IHSS)  Muscle subaortic stenosis  Hypertrophic obstructive cardiomyopathy (HOCM)

11. Genetic Basis Autosomal dominant inheritance with incomplete penetrance More than nine different sarcomere genes with over 1400 mutations have been implicated, although ∼80% of patients have a mutation in either MYH7 or MYBPC3 Genetic basis of ventricular hypertrophy does not directly correlate with prognostic risk stratification

12. At the level of sarcomere, mutations lead to enhanced calcium sensitivity, maximal force generation and ATPase activity Abnormal energetics and impaired relaxation due to mutation and hypertrophy are seen.

13. Morphology Left Ventricular Hypertrophy Mitral Valve Apparatus Histopathology

14. Left Ventricular Hypertrophy Diverse patterns of asymmetric LV hypertrophy are characteristic of HCM. Typically, one or more regions of the LV wall are of greater thickness than other areas. A sharp transitions in thickness between adjacent areas or noncontiguous patterns of segmental hypertrophy, as well as extension into the right ventricle. There is not a single “classic” morphologic form, and virtually all possible patterns of LVH have been reported, including normal LV wall thicknesses

15. Mitral Valve Apparatus There may be diverse alterations in valvular size and shape and represent a primary morphologic abnormality in HCM The valve may be as much as twice normal size from elongation of both leaflets or segmental enlargement of only the anterior leaflet or the midportion of the posterior leaflet.

16. Histopathology Cardiac muscle cells show increased transverse diameter and bizarre shapes, often maintaining intercellular connections with several adjacent cells. Myocytes (and myofilaments ) are arranged in chaotic, disorganized patterns at oblique and perpendicular angles. Abnormal intramural coronary arteries with thickened walls (composed of increased intimal and medial components) and narrowed lumen are present in 80%, most frequently within or close to areas of replacement fibrosis, contributing to microvascular ischemia and angina

17. Disorganized LV architecture with myocyte disarray. Small-vessel disease; remodeled intramural coronary arteriole with thickened media and narrowed lumen. Replacement fibrosis, the consequence of silent myocardial ischemia and myocyte death. Harrison's Principles of Internal Medicine, 19E (2015)

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

19. 1. LV outflow obstruction Long-standing LV outflow obstruction is a major determinant for heart failure symptoms and death in HCM patients Subaortic outflow obstruction is caused by systolic anterior motion (SAM) of the mitral valve – leaflets move toward the septum

20. LV outflow obstruction Explanations for the SAM of the mitral valve Mitral valve is pulled against the septum by contraction of the papillary muscles, which occurs because of the valve's abnormal location and septal hypertrophy altering the orientation of the papillary muscles Mitral valve is drawn toward the septum because of the lower pressure that occurs as blood is ejected at high velocity through a narrowed outflow tract ( Venturi effect)

21. LV outflow obstruction Physiological Consequences of Obstruction  Elevated intraventricular pressures  Prolongation of ventricular relaxation  Increased myocardial wall stress  Increased oxygen demand  Decrease in forward cardiac output

22. 2.Diastolic Dysfunction  Contributing factor in 80% of patients  Impaired relaxation Non uniform ventricular contraction High systolic contraction Diffuse ischemia causing stiffness.  Accounts for symptoms of exertional dyspnea  Increased filling pressures → increased pulmonary venous pressure

23. 3. 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 and increased myocardial oxygen consumption  Increased filling pressures  Resulting in subendocardial ischemia

24. Clinical presentation Dyspnea on exertion (90%), orthopnea , PND Palpitations (PAC, PVC, sinus pauses, AF, A flutter, SVT and VT) Congestive heart failure (2 o to increased filling pressures and myocardial ischemia) Angina (70-80%) Syncope (20%), Presyncope (50%) Outflow obstruction worsens with increased contractility during exertional activities resulting in decrease in cardiac output Conditions of low preload, such as dehydration, and low afterload, such as arterial vasodilatation, may lead to transient hypotension and near-syncope Secondary to arrhythmias

25. Clinical presentation Sudden cardiac death HCM is most common cause of SCD in young people, including athletes Can be the first manifestation Most common cause is arrhythmias esp. VF either denovo or AF degenerated into VF due to 2 o accessory pathway

26. Sudden Cardiac Death - causes Braunwald's Heart Disease- A Textbook of Cardiovascular Medicine 9th Ed

27. Physical Examination Carotid Pulse  Bifid – rises quickly, then declines in midsystole followed by a secondary rise in carotid pulsation during late systole short upstroke & prolonged systolic ejection Jugular Venous Pressure  Prominent a wave – decreased RV compliance Apical Impulse  Double apical impulse - forceful left atrial contraction against a highly noncompliant left ventricle  Triple apical impulse results from a late systolic bulge that occurs when the heart is almost empty and is performing near-isometric contraction

28. Physical Examination Heart Sounds S1 usually normal S2 usually split but in severe cases – paradoxically split S3 indicate heart failure S4 usually present due to hypertrophy

29. Murmur Medium-pitch crescendo-decrescendo systolic murmur along LLSB and apex and radiates to suprasternal notch Dynamic maneuvers  Murmur intensity increases with decreased preload (i.e. Valsalva , standing, nitrates, diuretics)  Murmur intensity decreases with increased preload (i.e. squatting, hand grip)

30. Diagnostic Evaluation Electrocardiogram Echocardiogram Catheterization Cardiac MR

31. ECG LVH with nonspecific ST/T wave abnormalities Left or right axis deviation, LAE, Conduction abnormalities Abnormal and prominent Q wave in the anterior precordial and lateral limb leads A fib with preexitation implies poor prognosis Findings on Holter monitoring include APC’s VPC’s, sinus pauses, wandering atrial pacemaker, atrial tachycardia, AF/flutter and nonsustained ventricular tachycardia.

32. Abnormal ECG patterns are common in HCM patients (up to 90% of probands ) and may be present in advance of the appearance of hypertrophy on imaging. Criteria for LVH are usually present: Increased precordial voltages and non-specific ST segment and T-wave abnormalities (LVH strain). Deep, narrow “dagger-like” Q waves in the lateral and inferior leads. Apical HCM - “giant T Wave Inversion” and no septal Q waves An association exists between Wolf-Parkinson's White and HCM

33. Left ventricular hypertrophy results in increased precordial voltages and non-specific ST segment and T-wave abnormalities. Asymmetrical septal hypertrophy produces deep, narrow (“dagger-like”) Q waves in the lateral (V5-6, I, aVL ) and inferior (II, III, aVF ) leads.

34. There is a subset of patients with phenotypic expression of the disease by echocardiography that has a normal ECG. Among 2,485 patients with an echocardiographic evidence of HCM seen at the Mayo Clinic 135 (5.4%) had a normal ECG. They had less severe phenotypic expression of HCM. (McLeod et al. JACC Vol. 54, No. 3, 2009)

35. 2-D echocardiography Given its wide availability and relatively low cost, 2D echocardiography is the initial imaging modality for the diagnosis and management of HCM.  Abnormal systolic anterior leaflet motion of the mitral valve  LV hypertrophy  Left atrial enlargement  Diastolic dysfunction  Small ventricular chamber size  Septal hypertrophy with septal to free wall ratio greater than 1.4:1 (absolute septal wall thickness >15mm)  Decreased mid aortic flow  Partial systolic closure of the aortic valve in mid systole

36. •Echocardiographic diagnostic criteria for HCM: Unexplained maximal wall thickness (measured at end-diastole) ≥ 15 mm (or >2 standard deviation for age, height and gender) in any myocardial segment Septal /posterior wall thickness ratio of >1.3 in a nondilated ventricle and >1.5 in the setting of systemic hypertension.

37. The different anatomic variants in HCM

38. Braunwald's Heart Disease- A Textbook of Cardiovascular Medicine 9th Ed

39. When to use CMR? CMR should be integrated into the initial evaluation of all patients if available. It is of greatest importance in the “ borderline patient” : LV myocardium is not well visualized by the echocardiogram The echocardiographic data are inconclusive The electrocardiogram is abnormal but the echocardiogram is normal Members of high-risk families with non-diagnostic findings on echocardiogram To differentiate HCM from other conditions including amyloidosis, hypertensive heart disease and athlete’s heart

40. Cardiac MRI Useful when echocardiography is questionable , particularly with apical hypertrophy SAM of the mitral valve is clearly seen on cardiac MRI Improvement in obstruction after septal ablation or myomectomy can be demonstrated, as can the location and size of the associated infarction , which are useful for planning repeat procedures Cardiac MRI tagging identifies abnormal patterns of strain, shear, and torsion in cases of HCM, demonstrating significant dysfunction in hypertrophic areas of the ventricle

41. Braunwald's Heart Disease- A Textbook of Cardiovascular Medicine 9th Ed

42. Gadolinium contrast cardiac MRI - differentiating HCM from other causes of cardiac hypertrophy and other types of cardiomyopathy such as, amyloidosis, athletic heart, and Fabry’s disease Late gadolinium enhancement occurring in HCM represents myocardial fibrosis  The greater the degree of late gadolinium enhancement, the more likely that the particular HCM patient has 2 or more risk factors for sudden death  More likely the patient has or will develop progression of ventricular dilation toward heart failure, thereby indicating a poorer prognosis

43. Management Prevention of sudden cardiac death - ICD Medical Rx of Heart failure & AF Surgery Dual Chamber Pacing Alcohol Septal Ablation

44. Implantable Cardioverter Defibrillators Primary prevention in individuals with risk factors such as Young Age Non-sustained Ventricular Tachycardia Severity of LV wall thickness Family History of Sudden Cardiac Death (age < 40y) Unexplained syncope Left Atrial Diameter Left Ventricular Outflow Tract Obstruction Hypotensive Blood Pressure Response to Exercise

45. Harrison's Principles of Internal Medicine, 19E (2015)

46. Braunwald's Heart Disease- A Textbook of Cardiovascular Medicine 9th Ed

47. Medical Therapy Beta-blockers  Increase ventricular diastolic filling/relaxation  Decrease myocardial oxygen consumption  Have not been shown to reduce the incidence of Sudden Cardiac Death Verapamil  Augments ventricular diastolic filling/relaxation Disopyramide  Used in combination with beta-blocker In the presence of persistent symptoms  Negative inotrope Diuretics in patients with fluid retention

48. Dual Chamber Pacing Proposed benefit:  Pacing the RV apex will decrease the outflow tract gradient by decreasing projection of basal septum into LVOT 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

49. severe medical refractory symptoms develop in about 5% of patients , for whom surgical myectomy or alcohol septal ablation may be effective Neither procedure has shown to improve outcome other than symptoms With both procedures, the most common complication is the development of complete heart block Alcohol Septal Ablation

50. Harrison's Principles of Internal Medicine, 19E (2015)

51. Braunwald's Heart Disease- A Textbook of Cardiovascular Medicine 9th Ed

52. Differentiating from Athlete’s heart Unusual patterns of LVH LV cavity < 45mm Marked LA enlargement Bizzare ECG patterns Abnormal LV diastolic filling Family hostory of HCM LV cavity > 55mm Normal LV diastolic filling Normal LA size Male sex Thickness decreases with deconditioning No Family hostory of HCM Athlete’s heart HCM LV thickness >15 mm LV thickness <13 mm Grey zone 13-15 mm Favours HCM Favours Athlete’s heart

53. REFERENCES: Harrison’s principles of internal medicine ESC guidelines of cardiomyopathy Braunwald’s heart disease

54. thank you