1. Mechanisms and Treatment of Symptoms in Hypertrophic Cardiomyopathy: Septal Reduction Therapy or Nothing? Andrew Wang, MD, FACC, FAHA Associate Professor of Medicine

2. High Impact Journals

4. Clinical Course of HCM JAMA. 1999;281:650-655 N = 234 F/U = 8 years

5. Exercise Capacity in HCM Sharma, AJC 2000;86:162-8.

6. Exercise Capacity in HCM Sharma, AJC 2000;86:162-8.

7. % Mortality Age at Death or Most Recent Evaluation (years) 5-1516-2526-3536-4546-5556-6566-75>75 Mortality in HCM Maron BJ et al. Circulation 2000;102:858-864. *

8. HF Mortality in HCM Predictors of HF death: –NYHA functional class 3 or 4 –LV outflow obstruction  30 mm Hg –LV wall thickness  25 mm Maron et al, Circulation 2000;102:858-864.; Spirito et al. NEJM 2000;342:177801785.

9. Outline: Symptom Management in HCM Should septal reduction therapy be the primary treatment of the masses? Is left ventricular diastolic dysfunction the common mechanism of symptoms? Are there other mechanisms and treatment of diastolic dysfunction in HCM?

10. HF Symptoms in HCM LVOT obstruction Diastolic dysfunction Ischemia Mitral valve disease Atrial fibrillation End-stage disease (dilated CM)

11. Clinical Definition Thickened (>14 mm), non-dilated left ventricle in the absence of associated conditions which could produce that magnitude of hypertrophy

12. Circulation 1961;23;189-194

13. Asymmetric Septal Hypertrophy and Systolic Anterior Motion

14. LVOT Obstruction and Outcome Maron, NEJM 2003:295-303.

15. Symptoms (heart failure, angina, syncope) Non-obstructive Obstructive Pharmacologic therapy Refractory sx Transplantation Myectomy Septal ablation Dual chamber pacing Adapted from Spirito et al. NEJM 1997;336:775-785.

16. Medical Therapy for HOCM Nishimura, NEJM 2004;350:1320-27. Drug Decrease Resting LVOT Gradient Decrease Exercise LVOT Gradient Beta-blockers++++ Calcium channel blocker (verapamil)++++ Disopyramide+++++

17. Retrospective, observational study at 4 centers (N=118) Disopyramide 400 mg daily, duration 3 yrs 66% required no septal reduction therapy –NYHA improved from 2.3 to 1.7 –Peak LVOTG reduced from 75 to 40 mm Hg JACC, 2005.

18. Medical Therapy of Obstruction “None of the pharmacologic agents commonly used to control symptoms of hypertrophic cardiomyopathy (i.e., beta- blockers, calcium-channel blockers, and disopyramide) or amiodarone significantly affected [outcome] when taken for more than 50 percent of the follow-up period.” Maron, NEJM 2003:295-303.

19. Surgical Myectomy

20. Reduces outflow tract gradient in 90% Subjective improvement in ~80% at 5 yrs Operative mortality 1-2%; 5 yr survival 84- 90% Complications –complete heart block 3%, VSD <1%, AI <1%

21. Surgical Myectomy

22. Surgical Myectomy and Survival

23. Alcohol Septal Ablation LA LV

24. Septal Ablation Results 1-2% mortality 10-20% permanent pacemaker Marked reduction in LVOT gradient Improvement in –NYHA functional class and exercise duration –Diastolic function –Mitral regurgitation –LV mass

25. Myectomy vs. Ablation?

26. Mitral Valve: The Other Half of LVOT Obstruction

27. Residual SAM After Ablation Am J Cardiol 2007;100:1691–1695.

28. LVOT Obstruction: A Moving Target? Kizilbash et al, Circulation 1998;97:461-466. RestingProvoked by NTG

29. Classification Hypertrophic Cardiomyopathy (HCM) ~1 per 500 persons (500,000 in US) With obstruction to LV outflow (HOCM, IHSS)  25% No obstruction to LV outflow ~75%

30. A Paradigm Shift? Circulation 2006;114;2232-2239

31. Provocable LVOT Obstruction Circulation 2002;106;454-459;

32. Symptom Management in HCM 1)Search for LVOT obstruction. 2)Find it. 3)Remove it.

33. Is diastolic dysfunction the common mechanism of heart failure symptoms and reduced exercise capacity in HCM?

34. Lele, S. S. et al. Circulation 1995;92:2886-2894 Exercise capacity is related to LV filling rate

35. Doppler Derived LVEDP Correlates with Exercise Capacity and HF Severity Heart 2002;87;247-251 N= 85

36. Dual Chamber Pacing Impairs Diastolic Function in HOCM Nishimura, JACC, 1996;27:421-30. SR Optimal AV=60 ms

37. Diastolic Function Improves After Septal Reduction Therapy Am J Cardiol 2003;91:817–821

38. MRI Post-Ablation

39. Diastolic Function in HCM Doppler measures of diastolic function are abnormal in 2/3. Diastolic dysfunction is not related to severity of LVH (max LV thickness or LV mass index). Exercise capacity is independently associated with diastolic function but not LVH. JACC 1990;16:808-13. Am Heart J 2005;150:144-9.

40. Hypertrophy and LV Filling Circulation 1985;72;310-316

41. HF Severity and Wall Thickness

42. Restrictive phenotype in HCM

43. Histopathology Hypertrophy Myocyte disarray Thickened media of intramural coronary arteries Interstitial fibrosis/collagenInterstitial fibrosis/collagen

44. Fibrosis in HCM % fibrosis Cell diameter

45. Collagen Turnover and Diastolic Function in HCM Circulation. 2003 Sep 23;108(12):1455-60.

46. Delayed-enhanced CMR in HCM

47. Histologic Basis of Hyperenhancement J Am Coll Cardiol 2004;43:2260–4.

48. Clinical Association with Hyperenhancement Progressive diz: ≥ 5 mm decrease in wall thickness and ≥ 5 mm increase in LVIDD over 5 years J Am Coll Cardiol 2003;41:1561–7.

49. Hyperenhancement and Diastolic Function in HCM

50. Overall (n=76)HE + (n=45)HE- (n=31)P value Age54.4 (14.1)51.7 (14.6)58.2 (12.6)0.049 Female40 (53%)19 (42%)21 (68%)0.029 Familial HCM22 (29%)15 (33%)7 (23%)0.31 Symptomatic61 (80%)34 (76%)27 (87%)0.21 NYHA 3 or 436 (47%)22 (49%)14 (45%)0.74 History of syncope11 (15%)5 (11%)6 (19%)0.34 History of atrial fibrillation8 (11%)5 (11%)3 (10%)0.84 Obstructive HCM45 (59%)34 (53%)21 (68%)0.21 Medications Beta-blocker58 (76%)33 (63%)25 (81%)0.46 Verapamil11 (14%)4 (9%)7 (23%)0.09 Disopyramide7 (9%)4 (9%)7 (9%)0.91

51. Overall (n=76)HE+ (n=45)HE- (n=31)P value Septal wall thickness, mm22.8 (6.9)25.3 (7.0)19.1 (5.0)<0.001 Posterior wall thickness, mm10.9 (3.7)11.2 (3.7)10.6 (3.8)0.48 Maximum LV wall thickness, mm23.6 (6.4)26.2 (6.2)19.8 (4.6)<0.001 LV mass, g230.5 (84.2)252.7 (87.8)198.2 (67.9)0.005 LV mass index, g/m2119.6 (43.3)131.4 (46.5)102.5 (31.9)0.002 End-diastolic volume, ml112.7 (28.6)117.8 (32.2)105.2 (20.5)0.040 End-diastolic volume index, ml/ml 2 58.6 (14.0)61.2 (15.9)54.8 (9.7)0.032 End-systolic volume, ml27.3 (16.0)31.3 (19.3)21.6 (6.5)0.003 End-systolic volume index, ml/m 2 14.1 (7.7)16.0 (9.1)11.3 (3.5)0.002 Calculated LV ejection fraction, %76.4 (8.3)74.4 (9.3)79.4 (5.4)0.004 Median HE mass (IQR), g6.4 (2.7, 11.3) % of LV with HE (IQR)2.5 (1.1, 4.7)

52. Overall (n=76) HE + (n=45) HE - (n=31)P value Septal wall thickness, mm20.5 (5.5)21.5 (6.2)19.0 (3.9)0.035 Posterior wall thickness, mm14.5 (3.4)14.9 (3.3)13.9 (3.5)0.20 Maximum wall thickness, mm23.4 (5.7)24.9 (6.2)21.3 (0.42)0.004 LVEDD, mm38.9 (7.2)38.9 (7.7)38.9 (6.6)1.0 LVESD, mm24.9 (6.1)24.6 (6.5)25.3 (5.4)0.63 Left atrial diameter, mm44.3 (8.1)45.5 (8.9)42.6 (6.6)0.123 Peak LVOT gradient at rest, mm Hg48.3 (39.1)48.2 (42.6)48.5 (35.7)0.97 E m velocity, cm/sec91.2 (34.8)96.0 (39.8)84.3 (25)0.12 A m velocity, cm/sec77.5 (31.2)65.8 (28.5)93.2 (27.9)<0.001 E m /A m ratio1.39 (0.97)1.71 (1.15)0.96 (0.31)<0.001 Deceleration time, msec215.5 (70.5)211.8 (78.5)221.0 (57.8)0.58 Isovolumic relaxation time, msec81.7 (37.8)80.0 (41.5)84.3 (31.9)0.63 Pulmonary vein S velocity, cm/sec52.4 (12.8)48.5 (11.8)57.6 (12.4)0.003 Pulmonary vein D velocity, cm/sec44.2 (12.4)46.8 (14.2)40.8 (8.6)0.036 Pulmonary vein S/D ratio1.27 (0.47)1.14 (0.52)1.44 (0.32)0.006 DTI E a velocity, cm/sec5.9 (2.7)6.2 (3.4)5.5 (1.7)0.38 DTI A a velocity, cm/sec7.6 (2.6)6.8 (2.8)8.5 (2.2)0.021 E m /E a ratio18.1 (9.2)18.9 (10.5)17.2 (7.8)0.52 A-Ar-6.2 (34.5)-11.0 (39.6)10.5 (26.7)0.21

54. r= 0.339 p= 0.003

55. r= 0.234 p= 0.042

56. p=0.002 p<0.001 A. B. Diastolic Function Grade

57. Treatment of Diastolic Dysfunction: Verapamil LV Relaxation Chamber stiffness LVEDP, mmHg Bonow, Circulation 1981, 1985 + Hess, EHJ 1983 +00 Tendera, Chest 1983 +-3 TenCate, Circulation 1983 -0+2 Kass, Ann Int Med 1993 00+2.6

58. Negative Inotropic Therapy Does Not Improve Diastolic Function Propranolol found to have no effect or worsen diastolic function (peak filling rate) in HCM. Disopyramide worsens LVEDP, cardiac index and tau in non-obstructive HCM Bonow et al. Circ 1981;64:787-96. Hess et al. EHJ 1983;4 Supp F:47-56. Mastubara. JACC 1995;26:768.

59. Comparison of Beta-Blocker and Verapamil on Exercise Capacity RCT (4 wk crossover design) comparing nadolol, verapamil, and placebo N=18 pts (10 non-obstructive HCM) with NYHA class 1 or 2 sx No difference in peak VO 2 between treatments Gilligan et al. JACC 1993;21:1672-9.

60. Increased myocardial aldosterone and aldosterone synthase mRNA in human HCM Tsybouleva et al. Circ 2004;109:1284-91.

61. Profibrotic Effects of Aldosterone Tsybouleva et al. Circ 2004;109:1284-91.

62. RAAS Antagonism in HCM Am J Cardiol 2005;96:1563–1567.

63. Summary Most patients with HCM have evidence of LVOT obstruction. Septal reduction therapies improve heart failure symptoms in HCM. LV diastolic dysfunction is present in majority of HCM pts and is the common pathway for HF symptoms and impaired exercise capacity in HCM. Other mechanisms of diastolic dysfunction may exist, but their proven pharmacologic therapies are lacking.

65. Exercise Capacity and LVOT Gradient Am J Cardiol 2000;86:162–168.

66. Nishimura, NEJM 2004;350:1320-27.

67. Lele, S. S. et al. Circulation 1995;92:2886-2894 Exercise capacity is related to stroke volume index and LV filling

68. BNP in HCM Circulation 2004;109;984-989;

69. BNP in HCM Am J Cardiol 2007;100:712–714)

70. Determinants of BNP in HCM Grade of diastolic function Age Gender Septal thickness RVSP Am J Cardiol 2007;100:712–714)

71. HF Severity and Wall Thickness

72. LVOT Gradient

73. Non-invasive vs. Invasive Measurement of LV Filling Pressure Circulation 2007;116;2702-2708