1. Heart Failure Current Concepts Howard M. Weinberg, D.O. F.A.C.C.

2. Cardiac Architecture Ultrastructure 1. 75% total volume of the heart is made up of cardiomyocyte 2. Contractile proteins lie within the cardiomyocyte A. Ventricular and atrial myocytes B. Myofibrils form myocytes(contractile elements) C. Myofibers are groups of myocytes. Ultrastructure 1. 75% total volume of the heart is made up of cardiomyocyte 2. Contractile proteins lie within the cardiomyocyte A. Ventricular and atrial myocytes B. Myofibrils form myocytes(contractile elements) C. Myofibers are groups of myocytes.

5. Contractile Proteins 1. Actin and Myosin 2. Calcium interacts with Troponin C relieves the inhibition caused by Troponin I

7. Cardiac Cycle Three Phases: 1) LV Contraction 2) LV Relaxation 3) LV Filling The Cardiac Cycle LV CONTRACTION Isovolumic contraction(b) Isovolumic contraction(b) Maximal Ejection © Maximal Ejection © LV Relaxation Start of relaxation and Start of relaxation and reduced ejection (d) reduced ejection (d) Isovolumic relaxation(e) Isovolumic relaxation(e) LV Filling: rapid phase (f) LV Filling: rapid phase (f) Slow LV Filling (g) Slow LV Filling (g) Atrial systole( a) Atrial systole( a) See Wiggers Diagram

9. Frank-Starling Relationship A. Preload: Load before contraction(venous return) B. Afterload: Load which the LV contracts against

10. Starling Curve

11. HF Defined “Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood with an increase in intracardiac chamber pressure” Hunt SA et al. Circulation. 2001;104:2996

12. Clinical Aspects of Heart Failure Backward Heart Failure Backward Heart Failure LVEDP and LVEDV increase LVEDP and LVEDV increase LAP and LAV increase(atria contracts for C.O.) LAP and LAV increase(atria contracts for C.O.) Venous and PCWP increase Venous and PCWP increase Transudation of fluid from capillary bed Transudation of fluid from capillary bed

13. Clinical Aspects of Heart Failure Forward Heart Failure Forward Heart Failure Decrease C.O.= decrease perfusion to vital organs Decrease C.O.= decrease perfusion to vital organs Increase Na and Water retention Increase Na and Water retention

14. Symptoms of Heart Failure Exertional Dyspnea Exertional Dyspnea Orthopnea-Sx in the recumbent position Orthopnea-Sx in the recumbent position Paroxysmal Nocturnal Dyspnea Paroxysmal Nocturnal Dyspnea Theory: 1. Slow resorption of interstial fluid 2. Reduced adrenergic support at night 2. Reduced adrenergic support at night 3. Normal nocturnal depression of the respiratory center 3. Normal nocturnal depression of the respiratory center

15. Framingham Criteria for CHF

16. Cardiac vs Pulmonary Dyspnea Frequent coughing Frequent coughing Cough production Cough production Fever Fever Diaphoresis Diaphoresis Response to Tx Response to Tx

17. Adaptive Mechanisms Increase preload Increase preload Myocardial Hypertrophy Myocardial Hypertrophy Neurohormonal Activation: NE, RAS, BNP, Enothelin, etc Neurohormonal Activation: NE, RAS, BNP, Enothelin, etc

18. Diastolic Heart Failure 1. 1/3 of pts. have primary diastolic HF (normal or near normal LV function) 2. 1/3 combined systolic and diastolic HF 3. Altered ventricular relaxation(inactivation of contraction) 4. Alteration of ventricular filling 5. Some causes: myocardial ischemia, restrictive cardiomyopathy,pericardial disease

19. Diastolic Heart Failure Impaired ability to accept blood and relax during diastole Impaired ability to accept blood and relax during diastole Both types increase with age, African Americans Both types increase with age, African Americans 40-70% incidence more often female, obese, older HTN and less likely to have CAD 40-70% incidence more often female, obese, older HTN and less likely to have CAD Less symptomatic and lower morbidity and mortality Less symptomatic and lower morbidity and mortality

20. High Output Failure  Usually occurs with some underlying heart disease  Clinical conditions:  Anemia  Systemic Ateriovenous Fistula-dialysis/trauma  Hyperthyroidism  Beriberi  Pagets  Multiple myeloma/Pregnancy/Carcinoid/ renal disease  Obesity/polycythemia vera

23. Yancy CW, Strong M. Prim Care Spec Ed. 2002;6:15 High Risk: Hypertension, coronary artery disease, diabetes, family history of cardiomyopathy Asymptomatic LVD: Previous MI, LV systolic dysfunction, asymptomatic valvular disease Symptomatic HF: Known structural heart disease, shortness of breath and fatigue, reduced exercise tolerance Refractory End-Stage HF: Marked symptoms at rest despite maximal medical therapy A B C D Disease Progression of HF: ACC/AHA HF Stages

24. Epidemiology Only major cardiovascular disorder increasing in incidence and prevalence Only major cardiovascular disorder increasing in incidence and prevalence Leading cause of hospitalization in >65 Leading cause of hospitalization in >65 1/3 hospitalized patients readmitted in 90 days 1/3 hospitalized patients readmitted in 90 days 5% of all hospital admissions 5% of all hospital admissions

26. Heart Failure is a Major and Growing Public Health Problem in the U.S.   Approximately 5 million patients in this country have HF   Over 550,000 patients are diagnosed with HF for the first time each year   Primary reason for 12 to 15 million office visits and 6.5 million hospital days each year   In 2001, nearly 53,000 patients died of HF as a primary cause

28. Mortality/Morbidity Despite therapeutic advances, the 1 year mortality for NYHA class IV approaches 40% Despite therapeutic advances, the 1 year mortality for NYHA class IV approaches 40% Impaired Quality of life. Impaired Quality of life. Psychological distress Psychological distress Reduced social functioning Reduced social functioning 49% admitted after an emotional event 49% admitted after an emotional event

31. Prevalence of HF Increases With Age US, 1988–1994 AHA. Heart Disease and Stroke Statistics—2004 Update 0 2 4 6 8 10 20–2425–3435–4445–5455–6465–7475+ Age (yr) Population (%) Males Females

33. Number of Patients With HF Increasing 1979–2001 1979–2001 Hospital discharges from HF rose 164% from 377,000 to 995,000 Hospital discharges from HF rose 164% from 377,000 to 995,000 Deaths increased 155% Deaths increased 155% As US population ages, number of patients with HF expected to double in 30 yr As US population ages, number of patients with HF expected to double in 30 yr AHA. Heart Disease and Stroke Statistics—2004 Update Massie BM et al. Am Heart J. 1997;133:703

34. Natural History of HF Survival (%) LV Dysfunction and Symptoms Mechanism of Death Sudden death40% Worsened HF40% Other20% Progression Annual Mortality 0% 100% Asymptomatic MildModerateSevere <5% 10%20%–30%30%–80%

35. Treatment of Heart Failure Non-surgical Specialty Clinics Lifestyle Modification Pharmacological Non-surgical Specialty Clinics Lifestyle Modification Pharmacological Surgical Surgical

36. Contributing Factors to ADHF Cardiovascular Factors Cardiovascular Factors Superimposed ischemia or infarction Superimposed ischemia or infarction Uncontrolled hypertension Uncontrolled hypertension Unrecognized primary valvular disease Unrecognized primary valvular disease Worsening secondary mitral regurgitation Worsening secondary mitral regurgitation New onset or uncontrolled atrial fibrillation New onset or uncontrolled atrial fibrillation Excessive tachycardia or bradycardia Excessive tachycardia or bradycardia Pulmonary embolism Pulmonary embolism Stevenson LW et al. Am Heart J. 1998;135:293

37. Contributing Factors to ADHF cont'd Systemic Factors Systemic Factors Inappropriate medications Inappropriate medications Superimposed infection Superimposed infection Anemia Anemia Uncontrolled diabetes Uncontrolled diabetes Thyroid dysfunction Thyroid dysfunction Electrolyte abnormalities Electrolyte abnormalities Pregnancy Pregnancy Stevenson LW et al. Am Heart J. 1998;135:293

38. Contributing Factors to ADHF cont'd Patient-Related Factors Patient-Related Factors Medication nonadherence Medication nonadherence Dietary indiscretion Dietary indiscretion Alcohol consumption Alcohol consumption Substance abuse Substance abuse Stevenson LW et al. Am Heart J. 1998;135:293

42. Proven Outcomes for HF Therapies Improve Survival Improve Survival ACE inhibitor ACE inhibitor ARB ARB Beta blocker Beta blocker Aldosterone receptor antagonist Aldosterone receptor antagonist Hydralazine/long- acting nitrates Hydralazine/long- acting nitrates Reduce Hospitalization Reduce Hospitalization ACE inhibitor ARB Beta blocker Aldosterone receptor antagonist Hydralazine/long-acting nitrates Digoxin

43. Surgical/Interventional Therapy Cardiac Resynchronization Therapy Cardiac Resynchronization Therapy Revascularization Revascularization Value repair/replacement Value repair/replacement Cardiomyoplasty Cardiomyoplasty Ventricular Reduction Ventricular Reduction Left Ventricular Assist Devices Left Ventricular Assist Devices Transplant Transplant

44. Ventricular Remodeling Ventricular Remodeling After Acute Infarction Ventricular Remodeling in Diastolic and Systolic HF Initial infarct Expansion of infarct (hours to days) Global remodeling (days to months) Normal heart Hypertrophied heart (diastolic HF) Dilated heart (systolic HF) Jessup M et al. N Engl J Med. 2003;348:2007

45. Yancy CW, Strong M. Prim Care Spec Ed. 2002;6:15 PLUS inotropes, transplant, ventricular assist device Treat hypertension and lipids, smoking cessation, exercise, limit alcohol, ACE inhibitors in appropriate populations PLUS ACE inhibitors, beta blockers in appropriate populations PLUS ACE inhibitors, beta blockers, diuretics, digoxin, aldosterone receptor antagonists, dietary salt restriction HF Therapy

47. Approach to the Patient with CHF

49. Neurohormonal Activation in Heart Failure

50. Background on Remodelling Acute infarction (hours) Infarct expansion (hours to days) Global remodelling (days to months) Improvement of LV remodelling has been associated with improvement in mortality and morbidity outcomes in CHF

54. B-Adrenergic Receptor Blockers Improve survival Improve survival Improve ejection fraction Improve ejection fraction Remodeling Remodeling Quality of life Quality of life Reduce SCD Reduce SCD Inhibiting adverse effects of the sympathetic nervous system Inhibiting adverse effects of the sympathetic nervous system Diminish RAAS activation Diminish RAAS activation

57. All-Cause Mortality: MERIT-HF MERIT-HF Study Group. Lancet. 1999;353:2001 P=0.0082 (adjusted) P=0.00009 (nominal) Placebo Metoprolol CR/XL 0 5 10 15 20 036912151821 Follow-up (mo) Cumulative Mortality (%)

58. Cumulative Mortality in Patients With Severe HF: COPERNICUS Packer M et al. N Engl J Med. 2001;344:1651 Placebo1133937703580446286183114 Carvedilol1156947733620479321208142 No. of Patients at Risk Carvedilol (n = 1156) Placebo (n = 1133) 0 60 80 90 100 0 Months Survival (% of Patients) 36912151821 70 P=0.0014 (adjusted) P=0.00013 (unadjusted)

60. Angiotensin-Converting Inhibitors Decrease conversion of angiotensin I-II Decrease conversion of angiotensin I-II Improve survival Improve survival Decrease rate of hospitalization Decrease rate of hospitalization Improve symptoms Improve symptoms Inhibit neurohormonal activation Inhibit neurohormonal activation Reverse remodeling Reverse remodeling Decrease incidence of SCD? Decrease incidence of SCD?

62. Cumulative Mortality in Patients With Symptomatic HF: SOLVD P=0.0036 for comparison between groups by log-rank test SOLVD Investigators. N Engl J Med. 1991;325:293 Enalapril (n = 1285) (n = 1284) Placebo P=0.0036 0 10 20 30 40 50 0612182430364248 Months Mortality (%) Placebo1284115910851005939819669487299 Enalapril12851195112710691010891697526333 No. of Patients at Risk

64. DIGOXIN NEUROHORMONAL EFFECTS Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone Normalizes arterial baroreceptors Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone Normalizes arterial baroreceptors

65. % WORSENING OF CHF % WORSENING OF CHF p = 0.001 DIGOXIN: 0.125 - 0.5 mg /d (0.7 - 2.0 ng/ml) EF < 35% Class I-III (digoxin+diuretic+ACEI) Also significantly decreased exercise time and LVEF. DIGOXIN: 0.125 - 0.5 mg /d (0.7 - 2.0 ng/ml) EF < 35% Class I-III (digoxin+diuretic+ACEI) Also significantly decreased exercise time and LVEF. DIGOXIN EFFECT ON CHF PROGRESSION RADIANCE N Engl J Med 1993;329:1 RADIANCE N Engl J Med 1993;329:1 Placebo n=93 DIGOXIN Withdrawal Placebo n=93 DIGOXIN Withdrawal DIGOXIN n=85 30 10 0 0 20 100 80 20 0 0 40 60 Days

66. All-Cause Mortality: Digoxin DIG Investigation Group. N Engl J Med 1997;336:525 P=0.80 Placebo Digoxin 0 10 20 30 40 50 0481216202428323640444852 Mortality From Any Cause (%) Months Placebo340332393105297628682758265225512205188115061168734339 Digoxin339732693144301928822759264425312184184014751156737335 No. of Patients at Risk

67. ARB in Heart Failure (meta-analysis) 17 Trials, 12,469pts (JACC Feb 2002) 17 Trials, 12,469pts (JACC Feb 2002) No superiority of ARBs in reducing all-cause mortality or hospitalizations for heart failure No superiority of ARBs in reducing all-cause mortality or hospitalizations for heart failure Poss. benefit with combination ace inhibition Poss. benefit with combination ace inhibition Beneficial for pts intolerant to ace inhibition Beneficial for pts intolerant to ace inhibition

69. ALDOSTERONE Retention Na + Retention H 2 O Excretion K + Excretion Mg 2+ Retention Na + Retention H 2 O Excretion K + Excretion Mg 2+ Collagen deposition Fibrosis - myocardium - vessels Spironolactone Edema Arrhythmias Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) ALDOSTERONE INHIBITORS

70. RALES: All-Cause Mortality 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0 3 6 9 12 15 18 21 24 27 30 33 36 Risk Reduction 30% 95% Cl (18%-40%) P<0.001 Spironolactone + standard therapy Standard therapy (ACE inhibitor + loop diuretic ± digoxin) Probability of survival Months Pitt B, Zannad F, Remme WJ, et al. N Engl J Med, 1999;341:709-717.

72. 0 20 40 60 80 >4 cm/m 2 <4 cm/m 2 LV Index 2-Year Mortality (%) P = 0.004 Lee TH et al. Am J Cardiol 1993 Relation Between LV Size and Outcome in CHF M-mode echocardiography was performed on 382 patients with class III or IV HF (mean LVEF=20%) LV End-Diastolic Dimension Estimated Body Surface Area =

73. Cardiac Resynchronization Therapy Cardiac resynchronization therapy (CRT) has emerged as a promising new treatment for heart failure patients with intraventricular conduction delays or ventricular dysynchrony Cardiac resynchronization therapy (CRT) has emerged as a promising new treatment for heart failure patients with intraventricular conduction delays or ventricular dysynchrony Studies of CRT have demonstrated improvement in patient symptoms and exercise capacity, quality of life, NYHA class(69% vs. 34% at 6 mnths). Studies of CRT have demonstrated improvement in patient symptoms and exercise capacity, quality of life, NYHA class(69% vs. 34% at 6 mnths).

74. Ventricular Dysynchrony Abnormal ventricular conduction resulting in a mechanical delay Abnormal ventricular conduction resulting in a mechanical delay Wide QRS (IVCD); typically LBBB morphology Wide QRS (IVCD); typically LBBB morphology Poor systolic function Poor systolic function Impaired diastolic function Impaired diastolic function

75. Abraham WT, et al. MIRACLE Trial Results; ACC 2001

78. Conclusions In NYHA Class III and IV systolic heart failure patients with intraventricular conduction delays, CRT is safe and well tolerated is safe and well tolerated improves Quality of Life, functional class, and exercise capacity improves Quality of Life, functional class, and exercise capacity improves cardiac structure and function improves cardiac structure and function improves heart failure composite response improves heart failure composite response

79. Thank You