1. Heart Failure

2. Case 1
A 56 year old man with known CAD with NSTEMI x2 and stents in the LAD and LCx presents with 2 months of progressive DOE, LE edema and

3. Question #1
Which of the following therapies will improve this patient’s mortality?
A. Lasix
B. Carvedilol
C. Spironolactone
E. Digoxin
D. All of the above

4. Question #2
PVCs are noted in the hospital. An echocardiogram has moderatey-severely decreased systolic function (EF 28%). What should you do next?
Increase the lisinopril and carvedilol dose
Implant and AICD
Start amiodarone
Put the defibrilator patches on him
D/C telemetry

5. Heart Failure Is a Big Problem
Prevalence: >5,000,000
Incidence: >650,000 new cases/year in the US
Most common discharge diagnosis
Most common cause of readmission < 60 days
Cost: > 34.8 billion annualy
FIGURE 25-1 Prevalence rates of heart failure by gender and age in the United States between 1988 and 1994—the Third National Health and Nutrition Examination Survey (NHANES III). Among men (blue), the prevalence increased from 18 cases per 1000 in those aged 45 to 54 years to 98 cases per 1000 in those aged 75 years and older. Among women (purple), the prevalence increased from 13 cases per 1000 in those aged 45 to 54 years to 97 cases per 1000 in those aged 75 years and older.  (Data from American Heart Association: Heart Disease and Stroke Statistics—2003 Update. Dallas, American Heart Association, 2002.)
Rosamond. Circulation, 2008.
Braunwald

6. Heart Failure Incidence Has Increased, But No By Much
Levy. NEJM, 2002.

7. Survival has improved, but not dramatically
10,311 patients enrolled
Temporal Trends in Age-Adjusted Survival after the Onset
of Heart Failure among Men (Panel A) and Women (Panel B).
Values were adjusted for age (<55, 55 to 64, 65 to 74, 75 to 84,
and »85 years). Estimates are shown for subjects who were 65
to 74 years of age.
Levy. NEJM, 2002.

8. What is Heart Failure?
Definition: Any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.
Cardinal manifestations: Dyspnea, fatigue, fluid retention

9. LV Dysfunction Is Necessary But Not Sufficient For Heart Failure

10. Acute Compensatory Mechanisms Cause Long Term Damage
Activation of renin-angiotensin-aldosterone
Salt and water retention
Myocyte hypertrophy, death and myocardial fibrosis
Sympathetic nervous system stimulation
Increase contractility

11. Cardiac Remodeling Following Injury
McMurray. NEJM, 2010.

12. Activation of the RAS Leads to Remodeling
Renin, excreted in response to adrenergic stimulation of the juxtaglomerular (J-g) cells of the kidney, cleaves plasma angiotensinogen to produce angiotensin I (Ang I). Angiotensin II (Ang II) is formed through the cleavage of Ang I by angiotensin-converting enzyme (ACE). Most of the known biological effects of Ang II are mediated by the type 1 angiotensin receptor (AT1). In general, the AT2 receptor appears to counteract the effects of Ang II mediated by activation of the AT1 pathway. Ang II also may be formed through ACE-independent pathways. These pathways, and possibly incomplete inhibition of tissue ACE, may account for persistence of angiotensin in patients treated with ACE inhibitors. AT1 receptor antagonists have been postulated to provide more complete blockade of the renin-angiotensin-aldosterone system than ACE inhibition alone. ACE inhibition reduces bradykinin degradation, thus enhancing its levels and biological effects, including the production of nitric oxide (NO) and prostaglandin I2 (PGI2). Bradykinin may mediate some of the biological effects of ACE inhibitors.

13. Etiologies of Heart Failure
Depressed LV Function
CAD (2/3 of cases of HF)
Pressure overload: HTN, AS
Volume overload: AI, MR, intra/extra cardiac shunt
NICM: Genetic, infiltrative, toxin/drug, metabolic, viral, Chagas’
Arrythmias
Preserved LV Function
Hypertrophy: HCM, HTN
Aging
Restrictive: Infiltrative (amyloid, sarcoid), storage dz (hemochromatosis)
Fibrosis
Endomyocardial disorders
Pulmonary vascular disease
High-Output States
Metabolic: Thyrotoxicosis, nutrititional (beriberi)
Excessive flow requirements: AV shunt, anemia

14. Clinical Classification of Heart Failure
Gheorghiade. JACC, 2007.

15. Initial Evaluation Decreased exercise tolerance Volume overload
Asymptomatic or other complaints

16. Symptoms To Ask About Major Symptoms Minor Symptoms Dyspnea Orthopnea
PND
Ankle edema
Pulmonary edema
Fatigue
Exercise intolerance
Cachexia
Minor Symptoms
Weight loss
Cough
Nocturia
Palpitations
Peripheral cyanosis
Depression

17. Physical Exam Findings To Look For
JVP
Crackles
Pulmonary edema
Displaced PMI, S3 and S4,

18. Measurement of the JVP 5 cm Clinical Methods. Walker. 1990.

19. How To Measure JVP Clinical Methods. Walker. 1990.

20. CXR: Pulmonary Edema
CXR findings: heart size, congestion, pleural effusion

21. Brain Natriuretic Peptide
Natriuretic peptides
ANP- atrium, BNP- ventricles, CNP- endothelial cells
Increased well stress -> pre-proBNP-> pro-BNP-> BNP+NTproBNP (longer t1/2, higher levels,slower fluctuation)
From the heart
Induce vasodilation, natriuresis and diuresis
Useful and systolic and diastolic heart failure
Daniels. JACC, 2007.

22. Differential Diagnosis BNP Elevation
LV dysfunction
Previous CHF
Advanced age
Renal dysfunction
ACS
Pulmonary disease PE
High output AF
Lower then expected
Obesity
Flash pulmonary edema
Heart failure upstream from the LV
Cardiac tamponade
Pericardial constriction

23. BNP Can Help Differentiate Causes of Dyspnea
Maisel. NEJM, 2002.

24. Higher BNP Is Associated With Higher Mortality
FIGURE 23-2 Plasma brain natriuretic peptide (BNP) was measured before randomization and during follow-up in approximately 4300 patients in the Valsartan Heart Failure Trial. The baseline values for BNP in quartiles were less than 41, 41 to less than 97, 97 to less than 238, and greater than or equal to 238pg/ml. Kaplan-Meier curves show a significant quartile-dependent increase in mortality and first morbid events.  (From Anand IS, Fisher LD, Chiang YT, et al: Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 107:1278, 2003.)
Braunwald

25. New York Heart Association Functional Classification
Class I: No symptoms with ordinary activity
Class II: Some symptoms with ordinary activity
Class III: Symptoms with minimal activity
ClassIV: Symptoms at rest

26. Drugs That May Worsen Heart Failure: Na Retention, Cardiotoxicity, Negative Inotropy
NSAIDS
Calcium channel blockers- non-dihydropyridine
Metformin
Thiazolidinediones
PDE-3 inhibitors
Antiarrhythmic drugs
Chemotherapy
THF alpha inhibitors
Na Containing drugs
Supplements

27. Goals Of Therapy Heart Failure
Relieve symptoms
Slow or reveres deterioration of myocardial function
Decrease mortality

28. Heart Failure Therapy: A Timeline
William Harvey describes circulation
1628
William Withering describes medical use of digoxin
1785
Thiazide Diuretics
1950s
Furosemide
1967
First Heart Transplant
Nitroprusside
1974
Hydralazine
1976
Enalapril reduces mortality
1987
Bisoprolol reduces mortality
1994

29. Dietary and Lifestyle Modification: No Randomized Trials
Sodium Restriction 2-3 gm daily
Weight loss
Smoking cessation
Restriction of alcohol
Daily weight monitoring

30. Diuretics Used to manage volume status Dosing is based on response
Intravenous versus oral therapy
Agents can be combined for better efficacy
No effect on mortality
Libby. Braunwald’s Heart Disease

31. Digoxin In Heart Failure
Inhibits the Na-K-ATPase pump-> increased Ca-> inc LV function
Inhibition of sympathetic outflow

32. Digoxin Does Not Improve Mortality
EF < dig, 3403 placebo
Digitalis Investigation Group. NEJM, 1997.

33. Digoxin Improves Heart Failure Symptoms and Reduces Hospitalization
Digitalis Investigation Group. NEJM, 1997.

34. Digoxin Level > 1.2 ng/ml Is Associated With Increased Mortality
Figure 2 Plot of the adjusted point estimates and 95% confidence intervals of women and men for the hazard ratio for death on digoxin versus placebo at various serum digoxin concentrations (ng/ml) with concentration modeled as a continuous variable. The 95% confidence intervals for the women are offset to allow better depiction of results.
Adams. JACC, 2005.

35. Enalapril Reduces Mortality in NYHA Class IV Heart Failure
253 patients randomized double blind
Consensus trial study group. NEJM, 1987.

36. Meta Analysis: ACE-I Improve Mortality After MI
23% ACE vs 26.9% control
Flather. Lancet, 2000.

37. Candesartan Is An Reasonable Substitute In Patients Who Cannot Tolerate ACE-I
Granger.Lancet, 2003.

38. Mortality Benefit With Hydralazine+ Isordil vs Placebo or Prazosin
642 men, on dig and diuretics, cardiac enlargement or EF < 45%
Cohn. NEJM, 1986.

39. Bidil Improved Survival In Blacks With Heart Failure Taking ACE-I
1050 blacks, NYHA III or IV, on standard therapy
Taylor. NEJM, 2004.

40. Beta Blockers
Metoprolol: NYHA II-IV, EF <40%, metop succinate 200 daily
All cause mortality dec by 34% independent of age, sex etiology of CHF or EF
Merit-HF study group. Lancet, 1999.

41. Carvedilol Is Superior to Short Acting Metoprolol
1511 patients NYHA II-IV carvedilol 25 BID, metop 50 BID
Poole-Wilson. L:ancet, 2000.

42. Improvement of Systolic Function is Related to Beta Blocker Dose
Bristow. Circulation, 1996.

43. Rales Trial: Spironolactone Improves Mortality In Severe Heart Failure
1663 patients ACE, loop, dig, EF < 35%,
46 vs 35% death, RRR 30%, NYHA III or IV at enrollment, NYHA IV within 6 months
Pitt. NEJM, 1999.

44. Ephesus: Epleronone Improves Mortality In Heart Failure Following AMI
6642 After AMI with EF < 40%
Pitt. NEJM, 2003.

45. Treat With Proven Dosages
McMurray. NJEM, 2010.

46. Oral Milrinone Causes A 28% Increase In Mortality
Class III or IV symptoms 1088 patients randomized
Packer. NEJM, 1991.

47. Take Home Messages About Medical Management of CHF
Use proven therapies
Treat with proven dosages

48. How Do I Start These Drugs?
Diuretic
ACE Inhibitor or ARB
Beta Blocker
Hydralazine and Nitrates
Spironolactone or eplerenone
Digoxin

49. AICD For Primary Prevention Of Sudden Cardiac Death In Patients With Heart Failure
Ischemic cardiomyopathy
EF<30%, prior MI
Non-ischemic cardiomyopathy
EF < 35%, NYHA II or III
EF<35%, NYHA III or IV and QRS>120 AICD with CRT
Survival of sudden death or with VT

50. Mortality Reduction In Patients Post MI: MADIT II
Moss. NEJM, 2002.

51. Reduction in Mortality in NICM With ICD: ScD Heft
Bardy. NEJM, 2005.