• Information
  1. Treatment Overview for Systolic CHF
  2. Overview of Medications
  3. Step Therapy for Chronic Systolic CHF
  4. Arrhythmia Therapy in CHF
  5. Decompensated CHF
  6. Endstage CHF
  7. Therapy of Diastolic CHF
  8. Experimental and Emerging Therapeutics
• Resources

A. Treatment Overview for Systolic CHF [1,2]

1. Goals of Therapy
   [Figure] "Therapy of Systolic CHF"
   1. Short Term: relieve symptoms and improve quality of life (QOL)
   2. Long Term: reduce mortality
   3. Improvement in QOL is critical to pharmacologic compliance
   4. Aggressive therapy is required if mortality and morbidity are to be impacted
   5. Using BNP levels in acute and sub-acute setting should improve management [3]
2. Types of Agents
   1. Angiotensin Converting Enzyme Inhibitors (ACE-I)
   2. Angiotensin II Receptor Blocker (ARB)
   3. ß-Adrenergic Receptor Blocker (ß-blocker)
   4. Aldosterone Receptor Antagonist
   5. Diuretics
   6. Nitrates
   7. Inotropic Agents
   8. Lipid Lowering (Statin) Therapy [83]
   9. Aspirin
   10. Oxygen Therapy
3. General Considerations [2]
   [Figure] "Fluid Retention in CHF"
   1. Stepped therapy is used based on disease severity
   2. All patients should receive angiotensin blockade (ACE-I and/or ARB, see below)
   3. ARB added to ACE-I (and other optimal therapies) may be beneficial [18]
   4. ß-blockers should be used in all patients with symptoms and/or HTN
   5. Aldosterone antagonists should be added in symptomatic patients
   6. Exercise training as tolerated (see below)
   7. Low Salt Diet - 3gm/d initially; lower to 2gm/d if continued fluid retention
   8. Diuretics for early symptomatic disease
   9. Fluid Restriction for advanced CHF 2-3L per day depending on symptoms
   10. EtOH restricted to 30mL/day in Advanced CHF
   11. Cardiac resynchronization in symptomatic patients with widened QRS complex
   12. Home based intervention with frequent monitoring can improve morbidity, mortality [4]
   13. Oxygen as needed, improves survival in CHF
   14. TEDs stockings - very effective
   15. Compliance with medications in CHF patients associated with ~35% mortality reduction [19]
4. Evaluation of Patient
   1. Must insure that patient has systolic and not diastolic heart failure
   2. Diastolic dysfunction is treated with anti-inotropic and rate slowing agents
   3. Sytolic failure is harder to treat since cardiac muscle is not able to contract
   4. Treatment of diastolic dysfunction is covered at the end of this outline
   5. Patients with cardiogenic shock require intensive, emergent therapy
   6. BNP levels correlate well with cardiac function [3,5,6]
5. Home Treatment Plans
   1. Home treatment reduces morbidity, readmissions
   2. Key to lifestyle modifications improves relapse free survival, possibly mortality
   3. Frequent monitoring of diet, weight, symptoms is critical to success
   4. Continuous positive airway pressure (CPAP) for patients with CHF and sleep apnea [7]
   5. Nonpharmacologic interventions discussed elsewhere
6. Invasive Treatments
   1. Biventricular pacing in CHF with intraventricular conduction delay (IVCD)
   2. ICD beneficial with LVEF<35% [12,13,14]; reduced death ~20% [88]
   3. LV Assist Device (LVAD)
   4. Cardiomyoplasty
   5. Angioplasty (PCI) or Bypass Surgery (CABG) - for CAD
   6. Heart Transplantation
7. CHF with IVCD (Cardiac Dyssynchrony) [8,9,10,11]
   1. Biventricular pacing is used to promote cardiac resynchronization
   2. IVCD occurs in ~30% of patients with CHF
   3. Delay in atrial-ventricular timing ("dyssynchrony") likely contributes to symptoms
   4. Marked benefit In NYHA Class 3 and 4 CHF and IVCD [8,32]
   5. Clearly improves cardiac function, reduces hospitalizations, symptoms and shows mortality benefit (± ICD) [8,12,32]
   6. Resynchronization in CHF patients with normal (<120ms) QRS complex of no benefit [90]

B. Overview of Medications [3,16]

1. Summary of Agents [16]
   1. Afterload reduction with ACE-I and/or ARB
   2. ß-adrenergic blockers - reduces sympathetic overdrive
   3. Aldosterone receptor blockade - spironolactone, eplerenone
   4. Diuretics - preload reduction (symptomatic only)
   5. Vasodilators - calcium channel blockers, hydralazine, nitrates
   6. Inotropic Agents - mainly digitalis
   7. Anti-ischemics - improves oxygenation in failing heart
   8. Theophylline - adenosine receptor blocker
   9. Lipid lowering with statins associated with ~25% reduction in death or hospitalization in patients with CHF not previously on statins [83]
2. Afterload Reduction
   1. ACE-I and ARB reduce mortality, hospitalizations, recurrent MI in CHF [17,18]
   2. ARB are as effective as ACE-I in CHF or post-MI [17]
   3. Enalapril (ACE-I) reduces mortality more than combination of hydralazine and nitrates
   4. Hydralazine+nitrates - third line (see below)
   5. Amlodipine (Norvasc®) is fourth line therapy for CHF; good anti-anginal activity
3. ACE-I in CHF
   1. Standard of care first line therapy in CHF
   2. Reduce mortality ~25-30% and CHF-related hsopitalizations ~25%
   3. Patients with lowest ejection fraction (EF) have the greatest benefit
   4. Captopril and valsartan similar benefit in CHF and/or LV dysfunction [18]
   5. ACE-I have also been shown to improve overall mortality, reduce the incidence of new diabetes, and improve renal function
   6. Serum BNP levels can be used to follow ACE-I effects [6]
   7. Bisoprolol (ß-blocker) or enalapril used as initial treatment are equally effective [15]
4. ARB
   1. Losartan, candesartan, valsartan are all effective in CHF [18,20,21]
   2. ACE-I and ARB are first line [17]
   3. Valsartan as effective as captopril in CHF or LV dysfunction post-MI [18]
   4. Candesartan added to optimal therapy including ACE-I beneficial in Class II-IV CHF [19]
   5. ARB are used in patients with cough or angioedema on ACE-I
   6. ARB are no safer than ACE-I in severe renal failure (creatinine >3mg/dL)
5. ß-Blocking Agents [22,23,24]
   1. Overall mean EF increases and hospital admissions decrease, symptoms improve
   2. Initiate low doses of ß-blockers in patients with systolic dysfunction [24]
   3. Escalate ß-blocker doses slowly in presence of CHF
   4. Permit remodelling and prevent sudden cardiac death
   5. Improves cardiac response to sympathetic drive
   6. Reduces angiotensin I and II levels in patients on ACE-I [25]
   7. Carvidilol, metoprolol, bisoprolol, metoprolol reduce mortality and improve symptoms
   8. Bisoprolol (ß-blocker) or enalapril used as initial treatment are equally effective [15]
6. Aldosterone Blockade [16]
   1. Spironolactone added to ACE-I + loop diuretic reduced mortality from CHF
   2. Spironolactone is now considered a standard addition for systolic dysfunction
   3. Spironolactone should be added to loop diuretics prior to adding thiazides
   4. Aldosterone blockade increases risk of hyperkalemia significantly [26]
   5. Spironolactone dose 25mg maximum in combination of ACE-I or ARB [27]
7. Diuretics
   1. Symptomatic relief and acute therapy, also as anti-hypertensive
   2. In elderly with HTN and MI, chlorthalidone therapy reduced CHF development ~80%
   3. For chronic CHF, first line is loop diuretic, usually furosemide (Lasix®)
   4. Open label study of torsemide versus furosemide suggests torsemide may be preferred in treatment of CHF [28]
   5. Metolazone 1.25mg/d given 30 minutes before loop diuretic for diuretic resistance
   6. Hydrochlorothiazide (HCTZ) 25-100mg/d 30 min before loop diuretic may also be used
   7. Depletion of potassium (K+) magnesium (Mg2+) is a major problem for thiazides
   8. Loop and thiazide diuretics may increase the risk of sudden (arrhythmic) death
   9. Serum K+, Na+, Mg2+, Ca2+ MUST always be monitored in patients on diuretics
   10. Hyperkalemia can occur in patients on ACE-I or ARB, particularly with volume depletion
   11. Caution with K+ supplements on patients on concommitant ACE-I
   12. Diuretics long term may also deplete thiamine, leading to poorer LV function
   13. Supplementation with thiamine in such patients may improve LV dysfunction (~4%) and diuresis (~500mL/day)
8. Natriuretic Peptides and Agonists [30]
   1. Nesiritide (Natrecor®), a synthetic natriuretic peptide, caused dose-dependent improvements in patients with severe, acute decompensated CHF
   2. Nesiritide improved CHF symptoms versus [31] or combined with [30] nitroglycerin
   3. May be associated with ~1.7X increased risk of death at 30 days (p~0.06) compared with acutely decompensated patients treated with non-inotrope based therapy [79]
   4. Associated with increase in serum creatinine levels and increased risk of death in both inpatients and outpatients in overall reviews [80]
9. Vasodilators
   1. If ACE-I and ARB intolerant (see below), use high dose hydralazine+isosorbide
   2. Isosorbide dinitrate (40mg tid) and hydralazine (75mg tid) is clearly beneficial in black CHF patients with full ACE-I or ARB blockade [29]
   3. Amlodopine, a calcium blocker, does not worsen mortality in CHF
   4. In idiopathic dilated cardiomyopathy with CHF, amlodipine may improve survival
10. Digoxin (Lanoxin®) [35,36]
    1. In CHF patients with reduced EF, digoxin increased risk of death in women but not men [37]
    2. In a prospective study, digoxin reduced hospitalizations but not overall mortality [36]
    3. Most effective in patients with lowest EF and in Class III or IV CHF
    4. Digoxin + ACE-I more effective than ACE-I therapy alone in EF <35% Class II or III CHF [36]
    5. Should be avoided in elderly, in women [87], with diastolic dysfunction, or on quinidine
    6. Caution when using in combination with other drugs to avoid digoxin toxicity
    7. Consider in men with severe systolic CHF, maintain levels 0.5-0.8ng/mL [35,37]
11. Other Inotropic Agents
    1. Dobutamine is most commonly used in severe CHF or cardiac shock
    2. Milrinone - inotropic agent; increases morbidity and mortality in severe CHF
    3. Amrinone - inotropic agent with substantial hypotensive (ß2-agonist) effects
    4. Vesnarinone, an oral agent for chronic use, increased mortality in CHF
    5. Ibopamine - dopamine agonist, increased mortality in Class III/IV CHF
    6. All inotropic agents except digitalis have increased mortality in CHF
12. Anti-Coagulation
    1. Many experts recommend anti-coagulation for EF <15-20%
    2. However, no compelling data support empiric anticoagulation in CHF in normal sinus rhythm
    3. Patients with known clots or in atrial fibrillation should be anti-coagulated
13. Vasopeptidase Inhibitors [38]
    1. Block neutral endpopeptidase (NEP) which metabolizes endogenous vasodilator peptides
    2. These vasodilators included natriuretic eptides, adrenomedullin, and bradykinin
    3. Omapatrilat, an NEP, is as at least as good as, and may be superior to, lisinopril in CHF [38]
14. Theophylline [39]
    1. Blocks adenosine receptors to improve central breathing, oxygenation
    2. May also induce mild diuresis and improved cardiac output
    3. Improves oxygen saturation and abnormal breathing in short study in severe CHF
15. Growth Hormone [39]
    1. Recombinant human GH was given to dilated heart failure patients for 12 weeks
    2. R-hGH increases LV mass in patients with dilated heart failure
    3. R-hGH also increased serum levels of insulin-like growth factor 1 (IGF1)
    4. R-hGH had no effect on NYHA functional class, LV EF, or 6 minute walking test
    5. Longer term treatment may be required to observe clinical effects of R-hGH
16. Coenzyme Q10 supplements have no benefit as adjunctive treatment of CHF [40]
17. Darusentan, an endothelin blocker, had no benefit in chronic CHF on standard therapy [41]

C. Step Therapy for Chronic Systolic CHF [16]

1. Specific agents are discussed in referenced Outlines
2. Adherence to CHF therapy (assessed in randomized trial) reduces risk of mortality ~35% [19]
3. ACE-I and ARB [17]
   1. All CHF patients should be on an ACE-I if tolerated; ARB if ACE-I not tolerated
   2. Afterload reduction and remodeling
   3. ACE-I most effective at maximal doses
   4. ACE-I prevent weight loss associated with CHF (cardiac cachexia) [42]
   5. Losartan (Cozaar®) is as efficacious and better tolerated than captopril in CHF [43]
   6. Candesartan (Atacand®) improves mortality across all CHF ± ACE-I [21,44,45]
   7. Valsartan (Diovan®) added to ACE-I reduces CHF related hospitalizations [20]
   8. ACE-I + aspirin is safe and effective and is not contraindicated [46]
   9. ACE-I + ARB may be given together cautiously with close monitoring
   10. Renal function and K+ should be monitored closely at initiation of ACE-I or ARB
   11. Enalapril or ß-blocker bisoprolol as initial CHF therapy are equally effective [15]
4. Other Afterload Reducing Agents
   1. Only for patients intolerant of both ACE-I and ARB
   2. Combination of hydralazine with nitrates is third line therapy
   3. Hydralazine 25mg po tid initially, up to 150mg po qid as tolerated by blood pressure
   4. Isosorbide dinitrate (Isordil®) 10mg po tid initially, up to 80mg po tid
   5. Hydralazine/isosorbide dinitrate (20mg/37.5mg) fixed dose single pill (BiDil®) is approved (1-2 tabs tid) as adjunctive treatment for black patients with CHF [81]
   6. Tezozosentan, an endothelin receptor blocker, had no benefit in acute CHF [89]
   7. Amlodipine (Norvasc®) may be considered in systolic CHF for blood pressure control
   8. Amlodipine may be used in idiopathic dilated cardiomyopathy
   9. Other calcium channel blockers (CCB) are generally avoided in systolic CHF
   10. Concern for development of lupus-like syndrome with hydralazine
5. ß-Adrenergic Blockers [23,48,49]
   1. Initiate at low dose, increase slowly with monitoring [50,51]
   2. Reduce morbidity and mortality in patients up to 85 years [52]
   3. ß-blockers should only be used in Class II/III CHF and not in unstable patients
   4. Carvidilol (see below)
   5. Metoprolol CR/XL initially 12.5mg po qd, up to 200mg qd
   6. Bisoprolol 1.25mg qd initially, up to 10mg qd
   7. Up to 50% of patients feel somewhat worse during first few months
   8. Patients with systolic dysfunction may decompensate when ß-blockermtherapy is initiated
   9. Therefore, patients with low LV function beginning ß-blockers should be monitored carefully
6. Carvedilol (Coreg®) [50,53,54]
   1. Approved for treatment of CHF, reduces mortality, hospitalizations, improves LV EF
   2. Appears more effective than metoprolol in CHF patients
   3. Effective in combination with ACE-I and diuretics, ± digoxin
   4. Effective in both black and non-black patients with CHF [55]
   5. Initially 3.125mg po bid then titrate up to 50mg po bid [50]
   6. Within first 8 weeks of treatment, carvidilol showed benefits versus placebo [56]
7. Aldosterone Receptor Antagonists [57,58]
   1. Spironolactone (Aldactone®) and eplerenone (Inspra®)
   2. Reduce mortality in Class III/VI CHF patients
   3. Should be added to standard therapy in Class III/IV patients
   4. Spironolactone is initiated at 25mg po qod up to 25mg po bid
   5. Eplerenone 25-50mg po qd, added to standard medical therapy in post-MI patients with EF<40% reudces mortality 15% [58]
   6. Caution with aldosterone antagonists added to ACE-I or ARB due to risk of hyperkalemia
8. Diuretic Resistance [60]
   1. Very common in advanced (Class III and IV) CHF particularly with renal insufficiency
   2. Mechanisms include prerenal azotemia, counterregulatory hormones, reduced delivery of loop diuretics to active site
   3. Fluid restriction to <1.5L per day is critical
   4. Large doses of IV diuretics and combination agents are required in resistance
   5. Spironolactone may be added to loop diuretics for additional efficacy in Class III/IV
   6. Avoid nephrotoxic medications including NSAIDs (including COX-2 specific agents)
   7. Combined loop and thiazide diuretics or metolazone often effective
   8. Metolazone (2.5-10mg/d) is preferred agent since it blocks proximal and distal sites
   9. If spironolactone is used, then K+ levels must be monitored closely
   10. Tolvaptan, an oral vasopressin V2 antagonist, effective in hyponatremic CHF [34,85]
9. Digitalis (Digoxin, Lanoxin®)
   1. Relatively weak inotropic agent for use in patients with low EF (<35%)
   2. Titrate to therapeutic levels and monitor carefully
   3. Avoid hypokalemia in patients on digoxin as arrhythmias are more likely
   4. Should be avoided in hypertrophic cardiomyopathy and diastolic dysfunction
   5. Many drug interactions and narrow therapeutic window
   6. See above for risks versus benefits
10. Nitrates
    1. Preload reduction likely responsible for major effect
    2. Provide rapid symptomatic relief
    3. May reduce ischemia induced cardiac dysfunction
    4. Inhaled NO improves ventilatory function more than oral nitrates in CHF
    5. NO may worsen CHF caused by diastolic dysfunction or aortic stenosis (preload reduction)
    6. Oral nitrates are effective when combined with hydralazine in CHF [29]
11. Oxygen Therapy
    1. For any patient with resting O2 saturation <90% or pO2 <60mm
    2. May provide benefit following exertion in severe patients as well
12. CHF and Renal Insufficiency [61]
    1. Renal insufficiency defined as glomerular filtrationrate (GFR) <60mL/min/1.73m2
    2. ACE-I acceptable for GFR >30mL/min/1.73m2 with close monitoring
    3. Increased risk of hyperkalemia with renal insufficiency and aldosterone blockers
    4. ß-adrenergic blockers are safe and probably effective in CHF with renal insufficiency
    5. Hydralazine-nitrates can be used for afterload reduction with GFR<30mL/min/1.73m2
    6. Digoxin may be beneficial for GFR<60mL/min/1.73m2

D. Arrhythmia Therapy in CHF

1. High risk of suddent cardiac / arrhythmia associated death with CHF, cardiomyopathy
2. Patients with CHF and frequent ventricular arrhythmias have mortality ~15% per year
3. Potassium wasting diuretics (loop, thiazides) may increase risk of sudden cardiac death
   1. Hypokalemia precipitates malignant ventricular arrhythmias in these patients
   2. Hypomagesemia also likely contributes
4. Treatment of Ventricular Arrhythmias
   1. ICD for symptomatic ventricular arrhythmias, particularly with LV EF <35% [11,12,13,14]
   2. ICD but not amiodarone showed mortality benefit in Class II/III CHF with LVEF <35% [77]
   3. Amiodarone may provide some benefit in patients with non-ischemic dilated cardio- myopathy and asymptomatic ventricular arrhythmias [62]
   4. Dronedarone (an amiodarone analog) 400mg bid arrhythmia prophylaxis given to hospitalized patients with severe CHF increased mortality, mainly with worsening CHF [59]
   5. ß-blockers may provide some benefit (low doses) in CHF with arrhythmias
5. Atrial Fibrillation (AFib) in CHF
   1. Common in CHF and dilated cardiomyopathy
   2. Rate control and anti-coagulation for AFib is one option
   3. Conversion to normal sinus rythym (NSR) may improve symptoms in CHF
   4. High dose ß-blockers are generally not well tolerated
   5. Digoxin may slightly improve rate control and inotropy in CHF, but is NOT first line
   6. Consider cardioversion and low dose amiodarone to maintain NSR
   7. Ibutilide is also safe and effective in CHF
   8. CHF patients with AFib have a worse prognosis than those without AFib
   9. Converting AFib to NSR and maintaining NSR improves QOL

E. Decompensated CHF (Intensive Care Unit Setting)

1. Presents as acute cardiogenic pulmonary edema (ACPE)
2. Preload Reduction
   1. Acute preload reduction with nitroglycerin as blood pressure permits
   2. Aggressive diuresis with frequent electrolyte monitoring required
   3. Furosemide 20-40mg IV is usually used as diuretic
   4. Nesiritide (BNP, Natrecor®) recommended for suboptimal response to standard diuretics and nitroglycerin (Class IV CHF) [63] but may increase mortality [79,80]
   5. Nesiritide lead to reduced wedge pressures and dyspnea at 3 hours compared with nitroglycerin or placebo [31]
   6. Morphine 1-10mg IV may be very effective to reduce preload, dyspnea, sympathetic drive
   7. Tolvaptan, oral V2 antagonist, increases water loss without hypokalemia or blood pressure reduction and improves most syptoms of CHF [33,64,85]
   8. Tolvaptan for acute CHF had no effect on long-term mortality or morbidity [34]
3. Inotropic Support
   1. Dobutamine increases inotropy (ß1-agonist) and reduces afterload (ß2-agonist)
   2. Dobutamine causes increased heart rate (chronotropy) through ß1-agonist
   3. If accelerated heart rate not tolerated, substitute amrinone or milrinone for dobutamine
   4. Milrinone did not reduce hospitalization and did increase complications in patients with severe exacerbations of CHF [65]
   5. Intravenous or oral digitalis is not recommended in the acute care setting
   6. Milrinone is not recommended for routine use in severe CHF exacerbations [65]
4. Inotropic and Blood Pressure Support
   1. Dobutamine and milrinone tend to lower blood pressure due to vasodilation
   2. In severe CHF, blood pressure may be too low to support organ function
   3. Dopamine >5µg/kg/min provides inotropic support and some vasoconstriction
   4. Norepinephrine provides inotropic and marked vasocontrictive support
5. Levosimendan (LSM; Simdax®) [74,86]
   1. Increases calcium sensitivity, vasodilates (opens ATP-sensitive K+ channels)
   2. 203 patients with decompensated CHF given dobutamine or LSM
   3. LSM superior to dobutamine on hemodynamics and mortality
   4. Increased side effects, no benefit on mortality at 6 months versus dobutamine [86]
6. Aortic balloon pump - see below
7. Magnesium levels should be maintained high
8. Ventilatory Support [47,66,82]
   1. Non-invasive modes of mechanical ventilation strongly preferred: CPAP or NIPPV [47]
   2. CPAP is continuous positive airway pressure (CPAP)
   3. NIPPV is non-invasive positive pressure ventilation
   4. Pressure support with positive end expiratory pressure is called Bilevel PAP or BiPAP
   5. All of these methods use an airtight facemask sealed over face
   6. CPAP and Bilevel NIPPV showed reduced mortality and reduced need for mechanical ventilation in patients with acute cardiogenic pulmonary edema (ACPE) [47]
   7. CPAP and NIPPV are similarly effective for ACPE with educed risk for mechanical ventilation and reduced length of hospital stay [82]
   8. CPAP and NIPPV similarly effective versus oxygen therapy alone with reduced dyspnea and acidosis, but no effect on length of hospital stay in ACPE [91]
   9. Endotracheal (or nasal) intubation may be required in patients failing non-invasive modes
9. Dopamine Agonists [67,78]
   1. Low dose dopamine (<5µg/kg/minute) also called "renal range" dopamine
   2. Renal range dopamine has no beneficial clinical effect in intensive care unit (ICU) patients
   3. Renal range dopamine will NOT prevent renal deterioration in ICU patients
   4. Fenoldopam (Corlepam®), a dopamine DA1 receptor agonist, may provide some benefit
   5. Nesiritide causes diuresis in diuretic-resistant patients and is usually preferred [63]
10. Revascularization [68]
    1. Revascularization for acute severe CHF following myocardial infarction is critical
    2. Emergent revascularization for cardiogenic shock has higher 1 year survival (~47%) compared with medical stabilization followed by elective revascularization (~34%)

F. Endstage CHF

1. Left Ventricular Assist Device (LVAD)
   1. Mechanical assist devices that take over function of damaged LV
   2. Used for patients to allow heart to rest and recover function
   3. Also with patients as a bridge to heart transplantation (FDA approved)
   4. Generally for short term use
   5. Longer term use (>300 days) successful: improves mortality and QOL [5]
   6. HeartMate® and Novacor® are the major LVADs used
   7. Pulsatile flow up to 10L/min provided, connect from LV to output to aorta
   8. A transcutaneous drive line connects pump to skin hole to external battery pack
   9. Early complications: bleeding, RV heart failure, air embolism, sepsis syndrome
   10. Later complications: infection (such as candida), thromboembolism, device failure
   11. Patients usually on aspirin (rather than warfarin) after device is used
   12. Levels of abnormal dystrophin reduced in patients responding to LVAD therapy [70]
   13. LVAD with aggressive drug therapy lead to reversal of idiopathic dilated cardiomyopathy, explanation of LVAD, and return to normal function in 11 of 15 severe patients [62]
   14. Continuous-flow pumps may be better tolerated and show good efficacy to 12 months [69]
2. Coronary Artery Bypass Graft (CABG) Surgery [71]
   1. CABG may improve function in ischemic disease
   2. Risk of surgery greatly increases as EF declines; EF~10% carries ~30% mortality risk
   3. Angioplasty can be considered in patients with moderate-severe LV dysfunction and CAD
   4. CABG or angioplasty may be effective in cardiogenic shock
   5. Intra-aortic balloon pumps are used as bridges to surgery in patients with CAD
3. Heart Transplantation
   1. Lifesaving for many patients with endstage CHF
   2. Limited by number of donor organs: ~3500 worldwide, 2500 USA per year
   3. Survival about 50% at 10 years
4. Permanent implantation of artificial heart (Jarvik 2000) has now been accomplished [4]

G. Therapy of Diastolic CHF [72]

1. May present with acute pulmonary edema and marked hypertension (HTN) [73]
2. Treat underlying HTN aggressively
   1. ACE-I or ARB, especially in diabetics or with accompanying systolic dysfunction
   2. ACE-I or ARB preferred agents because they may inhibit hypertrophy
   3. ARB no better than standard therapy in treatment of patients with HTN and diastolic dysfunction [87]
3. Slow Heart Rate
   1. ß-Blockers are highly preferred by most cardiologists (high dose if tolerated)
   2. Verapamil or diltiazem calcium blockers also effective
   3. Anti-inotropic agents are recommended to improve diastolic relaxation
   4. Nodal blocking agents are very useful atrial fibrillation associated with diastolic CHF
   5. Slowing heart rate allows longer diastolic filling times, reduces ischemia
4. Other
   1. Low dose diuretics for symptomatic improvement
   2. Low dose nitrates for ischemia (which may worsen diastolic dysfunction)
   3. Limit use of preload reducting agents (venodilators, diuretics)
   4. Reason: diastole in LVH is highly dependent on adequate preload for filling
   5. Digoxin and other inotropes are contraindicated in diastolic CHF patients

H. Experimental and Emerging Therapeutics

1. Angiogenic factors
2. Etomoxir [75]
   1. Inhibitor of carnitine palmitoyltransferase I (CPT-1)
   2. CPT-1 involved in transport of long chain acyl CoA compounds to mitochondria
   3. Etomoxir thus inhibits fatty acid metabolism but promotes glucose utilization
   4. Initial noncontrolled studies show promise in improving heart in Class II/III CHF
3. Meta-analysis of Hawthorne Extract in randomized CHF NYHA Classes I-III trials (692 patients) showed significant benefits on symptoms and exercise capacity [76]

Resources

Cardiac Output (Fick)

References

1. Jessup M and Brozena S. 2003. NEJM. 348(20):2007
2. McMurray JJV and Pfeffer MA. 2005. Lancet. 365:1877
3. Maisel AS, Krishnaswamy P, Nowak RM, et al. 2002. NEJM. 347(3):161
4. Westaby S, Banning AP, Jarvik R, et al. 2000. Lancet. 356(9233):900
5. Rose EA, Gelijns AC, Moskowitz AJ, et al. 2001. NEJM. 345(20):1435
6. Yoshimura M, Mizuno Y, Nakayama M, et al. 2002. Am J Med. 112(9):716
7. Kaneko Y, Floras JS, Usui K, et al. 2003. NEJM. 348(13):1233
8. McAlister FA, Ezekowitz J, Hooton N, et al. 2007. JAMA. 297(22):2502
9. McAlister FA, Ezekowitz JA, Wiebe N, et al. 2004. Ann Intern Med. 141(5):381
10. Bradley DJ, Bradley EA, Baughman KL, et al. 2003. JAMA. 289(6):730
11. Young JB, Abraham WT, Smith AL, et al. 2003. JAMA. 289(20):2685
12. Bristow MR, Saxon LA, Boehmer J, et al. 2004. NEJM. 350(21):2140
13. DiMarco JP. 2003. NEJM. 349(19):1836
14. Kadish A, Dyer A, Daubert JP, et al. 2004. NEJM. 350(21):2151
15. Willenheimer R, van Veldhuisen DJ, Silke B, et al. 2005. Circulation. 112:2426
16. Yan AT, Yan RT, Liu PP. 2005. Ann Intern Med. 140(2):132
17. Lee VC, Rhew DC, Dylan M, et al. 2004. Ann Intern Med. 141(9):693
18. Pfeffer MA, McMurray JJV, Velazquez EJ, et al. 2003. NEJM. 349(20):1893
19. Granger BB, Swedberg K, Ekman I, et al. 2005. Lancet. 366(9502):2005
20. Cohn JN and Tognoni G. 2001. NEJM. 345(23):1667
21. Pfeffer MA, Swedberg K, Granger CB, et al. 2003. Lancet. 362(9386):759
22. Dargie HJ. 2003. Lancet. 362(9377):2
23. Foody AM, Farrell MH, Krumholz HM. 2002. JAMA. 287(7):883
24. Brophy JM, Joseph L, Rouleau JL. 2001. Ann Intern Med. 134(7):550
25. Campbell DJ, Aggarwal A, Esler M, Kaye D. 2001. Lancet. 358(9293):1609
26. Juurlink DN, Mamdani MM, Lee DS, et al. 2004. NEJM. 351(6):543
27. Palmer BF. 2004. NEJM. 351(6):585
28. Murray MD, Deer MM, Ferguson JA, et al. 2001. Am J Med. 111(7):513
29. Taylor AL, Ziesche S, Yancy C, et al. 2004. NEJM. 351(20):2049
30. Nesiritide Study Group. 2000. NEJM. 343(4):246
31. Publication Committee for VMAC Investigators. 2002. JAMA. 287(12):1531
32. Cleland JGF, Daubert JC, Erdmann E, et al. 2005. NEJM. 352(15):1539
33. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. 2007. JAMA. 297(12):1319
34. Gheorghiade M, Konstam MA, Burnett JC Jr, et al. 2007. JAMA. 297(12):1332
35. Rathore SS, Curtis JP, Wang Y, et al. 2003. NEJM. 289(7):871
36. Digitalis Intervention Group. 1997. NEJM. 336(8):525
37. Rathore SS, Wang Y, Krumholz HM. 2002. NEJM. 347(18):1403
38. Rouleau JL, Pfeffer MA, Stewart DJ, et al. 2000. Lancet. 356(9230):615
39. Javaheri S, Parker TJ, Wexler L, et al. 1996. NEJM. 335(8):562
40. Khatta M, Alexander BS, Krichten CM, et al. 2000. Ann Intern Med. 132(8):636
41. Anand I, McMurray J, Cohn JN, et al. 2004. Lancet. 364(9431):347
42. Anker SD, Negassa A, Coats AJS, et al. 2003. Lancet. 361(9363):1077
43. Pitt B, Poole-Wilson PA, Segal R, et al. 2000. Lancet. 355(9215):1582
44. McMurray JJV, Ostergren J, Swedberg K, et al. 2003. Lancet. 362(9386):767
45. Granger CB, McMurray JJV, et al. 2003. Lancet. 362(9386):772
46. Teo KK, Yusef S, Pfeffer M, et al. 2002. Lancet. 360(9339):1037
47. Peter JV, Moran JL, Phillips-Hughes J, et al. 2006. Lancet. 367(9517):1155
48. Which beta-Blocker. 2001. Med Let. 43(1097):9
49. Farrell MH, Foody JM, Krumholz HM. 2002. JAMA. 287(7):890
50. Packer M, Coats AJS, Fowler MB, et al. 2001. NEJM. 344(22):1651
51. Stevenson LW. 2002. NEJM. 346(18):1347
52. Sin DD and McAlister FA. 2002. Am J Med. 113(8):650
53. Cleland JGF, Pennell DJ, Ray SG, et al. 2003. Lancet. 362(9377):14
54. Poole-Wilson PA, Swedberg K, Cleland JGF, et al. 2003. Lancet. 362(9377):7
55. Yancy CW, Fowler MB, Colucci WS, et al. 2001. NEJM. 344(18):1358
56. Krum H, Roecker EB, Mohacsi P, et al. 2003. JAMA. 289(6):712
57. Weber KT. 2001. NEJM. 345(23):1689
58. Pitt B, Remme W, Zannad F, et al. 2003. NEJM. 348(14):1309
59. Kober L, Torp-Pedersen C, McMurray JJ, et al. 2008. NEJM. 358(25):2678
60. Matsumoto A, Momomura SI, Sugiura S, et al. 1999. Ann Intern Med. 130(1):40
61. Shlipak MG. 2003. Ann Intern Med. 138(11):917
62. Singh SN, Fletcher RD, Fisher SG, et al. 1995. NEJM. 333(2):77
63. Nesiritide. 2001. Med Let. 43(1118):99
64. Gheorghiade M, Gattis WA, O'Connor CM, et al. 2004. JAMA. 291(16):1963
65. Cuffe MS, Califf RM, Adams KF Jr., et al. 2002. JAMA. 287(12):1541
66. Masip J, Betbese AJ, Paez J, et al. 2000. Lancet. 356(9248):2126
67. ANZICS Clinical Trials Group. 2000. Lancet. 356(9248):2139
68. Hochman JS, Sleeper LA, White HD, et al. 2001. JAMA. 285(2)190
69. Miller LW, Pagani FD, Russell SD, et al. 2007. NEJM. 357(9):885
70. Vatta M, Stetson SJ, Perez-Verdia A, et al. 2002. Lancet. 359(9310):936
71. Hasdai D, Topol EJ, Califf RM, et al. 2000. Lancet. 356(9232):749
72. Aurigemma GP and Gaasch WH. 2004. NEJM. 351(11):1097
73. Gandhi SK, Powers JC, Nomeir AM, et al. 2001. NEJM. 344(1):17
74. Follath F, Cleland JGF, Just H, et al. 2002. Lancet. 360(9328):196
75. Bristow M. 2000. Lancet. 356(9242):1621
76. Pittler MH, Schmidt K, Ernst E. 2003. Am J Med. 114(8):665
77. Bardy GH, Lee KL, Mark DB, et al. 2005. NEJM. 352(3):225
78. Friedrich JO, Adhikari N, Herridge MS, Beyene J. 2005. Ann Intern Med. 142(7):510
79. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. 2005. JAMA. 293(15):1900
80. Topol EJ. 2005. NEJM. 353(2):113 (Perspective)
81. BiDil for Heart Failure. 2005. Med let. 47(1218):77
82. Masip J, Roque M, Sanchez B, et al. 2005. JAMA. 294(24):3124
83. Go AS, Lee WY, Yang J, et al. 2006. JAMA. 296(17):2105
84. Birks EJ, Tansley PD, Hardy J, et al. 2006. NEJM. 355(18):1873
85. Schrier RW, Gross P, Gheorghiade M, et al. 2006. NEJM. 355(20):2099
86. Mebazaa A, Nieminen MS, Packer M, et al. 2007. JAMA. 297(17):1883
87. Solomon SD, Janardhanan R, Verma A, et la. 2007. Lancet. 369(9579):2079
88. Ezekowitz JA, Rowe BH, Dryden DM, et al. 2007. Ann Intern Med. 147(4):251
89. McMurray JJ, Teerlink JR, Cotter G, et al. 2007. JAMA. 298917):2009
90. Beshai JF, Grimm RA, Nagueh SF, et al. 2007. NEJM. 357(24):2461
91. Gray A, Goodacre S, Newby DE, et al. 2008. NEJM. 359(2):142