Chronic heart failure (CHF) is a major public health problem in industrialized societies with an incidence approaching 10 per 1,000 population after age 65 and an age-dependent prevalence of less than 1% between ages 45-55, 2-5% between ages 65-75, and approximately 10% for patients aged 80 years or more.Thus, HF is primarily a condition of the elderly and approximately 80% of patients hospitalized with HF are more than 65 years old. Underlying causes are numerous and include cardiac brady- or tachyarrhythmias, systolic dysfunction due to coronary artery disease, dilated cardiomyopathy, or myocarditis, as well as diastolic dysfunction due to hypertension, pericardial disease, or restrictive cardiomyopathy, and finally volume or pressure overload due to valvular heart disease, cardiac defects, hypertrophic obstructive cardiomyopathy, and arterial or pulmonary hypertension.
HF is a complex clinical syndrome characterized by the inability of the heart to provide the cardiac output needed by the organism at normal end-diastolic ventricular pressures. Ventricular dysfunction limits exercise tolerance and may impair the quality of life of affected individuals. Clinically, forward failure of the heart leads to low blood pressure and fatigue, while backward failure results in dyspnoe and fluid retention, which may lead to pulmonary congestion, pleural effusions, peripheral edema, as well as impairment of hepatic, gastric, and renal function. Complications of HF include thromboembolic events, arrhythmias, pulmonary edema, cardiogenic shock, and death. Diagnosis of HF is based on history, physical examination, and echocardiography, while additional tests such as 12-lead electrocardiogram, chest radiography, cardiac magnetic resonance imaging, cardiac catheterization, and laboratory testing including brain natriuretic peptide (BNP) levels can provide useful information about the etiology, severity, and prognosis.
In general, HF is a progressive process in which predisposing conditions eventually lead to structural heart damage and asymptomatic ventricular dysfunction before the development of overt HF with clinical symptoms.The hallmark of this progression is cardiac remodeling with changes in left-ventricular geometry and structure that decrease mechanical performance, increase wall stress, and augment atrioventricular regurgitation. Pathophysiologically, major contribution to cardiac remodeling and thereby to the progression of HF stems from the activation of endogenous neurohormonal systems with elevated plasma and/or tissue levels of norepinephrine, angiotensin II, aldosterone, endothelin, vasopressin, and various cytokines.
To describe the development and progression of HF, two classification systems—the New York Heart Association (NYHA) functional classification and the ABCD staging of the American College of Cardiology (ACC)/American Heart Association (AHA)—have been established that complement each other and distinguish between four characteristic stages of HF (see Table 1).The NYHA and ABCD classification systems allow for an assessment of prognosis (two-year mortality: NYHA stage I 10%, II 20%, III 30-40%, IV 40-50%) and specific therapy of HF at each stage of the disease. This article summarizes current strategies for the treatment of patients with HF.
General measures include counseling patients with HF and their families on the cause of the disease, its signs and symptoms, the natural course, the prognosis, therapeutic measures, dietary and social habits including travelling and sexual activity. In general, patients with advanced HF should limit their fluid intake to 1-2 l/day dependent on the individual fluid status and in adaptation to special situations (i.e. fever, diarrhea, vomitus). Patients should perform daily measurements of weight as part of a regular daily routine (i.e. after the morning toilet). Sodium intake should be moderately restricted and body weight should be normalized if patients are overweight or obese. Smoking should be discouraged and excessive alcohol intake should be limited to moderate levels or discontinued where alcohol-toxic cardiomyopathy is suspected. Cardiovascular risk factors such as hyperlipidemia, arterial hypertension, and diabetes mellitus should be controlled. Immunization with influenza and pneumococcal vaccines may reduce the risk of respiratory infections that may lead to a deterioration of HF. Drugs that can exacerbate HF should be avoided, examples being:
- antiarrhythmic agents with the exemption of amiodarone and dofetilide;
- calcium channel blockers such as verapamil, diltiazem, and first generation dihydropyridines;
- non-steroidal anti-inflammatory drugs, coxibs, and corticosteroids; and
- tricyclic anti-depressants and lithium.
In unstable patients, passive mobilization should be carried out while in stable phases of HF a moderate exercise training without strenuous or isometric stress is recommended to prevent muscle de-conditioning. Reversible causes for a worsening of HF such as poor patient compliance, myocardial ischemia, tachy- or bradyarrhythmias, valvular regurgitation, pulmonary embolism, infection, or renal dyfunction should be identified and corrected.
Pharmacological Treatment of HF
Angiotensin-converting Enzyme Inhibitors
In all patients with reduced left ventricular (LV) systolic function (ejection fraction (EF) = 35-40%), angiotensin-converting enzyme inhibitors (ACEIs) are recommended as first-line therapy independent of clinical symptoms (NYHA I-IV) unless there are contraindications. Data from a recent meta-analysis of 12,763 patients enrolled in several large clinical HF trials show that ACEIs improve survival, symptoms, functional capacity, and decrease the rate of hospitalizations. In patients who develop HF after the acute phase of myocardial infarction (MI),ACEIs have been shown to improve survival and to reduce re-infarctions and hospitalizations.
In asymptomatic patients with LV dysfunction, ACEI therapy reduces the incidence of symptomatic HF and hospitalizations. Importantly, ACEIs should be up-titrated to the target dosages used in the large, placebo-controlled HF trials, otherwise to the maximal dose that is tolerated. Therapy should be carefully monitored by regularly assessing blood pressure, renal function, and serum electrolyte levels (especially potassium).
Angiotensin II Type I Receptor Blockers
The ELITE-II trial directly compared the efficacy of angiotensin II type I receptor blockers (ARBs) and ACEI to reduce morbidity and mortality in 3152 patients with HF (NYHA II-III, LVEF ≤40%), and found no significant difference in the benefit mediated by losartan or captopril. In symptomatic patients with LV systolic dysfunction intolerant to ACEIs, ARBs can be used as an alternative to ACEIs to improve morbidity and mortality. In acute MI with signs of HF or LV dysfunction, both ARBs and ACEIs equipotently reduce mortality. ARB administration on top of ACEIs leads to an additive reduction in morbidity and mortality in HF patients remaining symptomatic despite optimal medical therapy including ACEIs. The combination of ARBs and ACEIs shows a higher rate of hypotension, renal dysfunction, and hyperkalemia therefore warranting close monitoring of these parameters.
Beta-adrenergic Receptor Blockers
In patients with symptomatic stable systolic HF (NYHA II-IV) receiving a standard therapy including ACEIs and diuretics, additional therapy with selected beta-adrenergic receptor blockers should be initiated unless there are contraindications. Data from a meta-analysis including results from 22 clinical trials on 10,135 patients show that the beta-adrenergic receptor blockers carvedilol, bisoprolol, and metoprolol succinate decrease mortality, hospitalizations, and improve symptoms and functional class. Moreover, the SENIORS trial showed that in HF patients aged ≥70 years, the beta-blocker nebivolol reduces mortality and cardiovascular hospital admissions.13 In patients with asymptomatic or symptomatic LV systolic dysfunction after MI, long-term beta-blocker treatment in addition to ACEIs has been shown to improve survival. In stable HF patients without signs of fluid retention, beta-blocker treatment should be initiated at very small doses and up-titrated to the target doses used in the large clinical HF trials, otherwise to the maximal dose that is tolerated. Therapy should be carefully monitored for evidence of HF symptoms, fluid retention, hypotension, and bradycardia.
In HF patients with fluid overload (peripheral edema, pulmonary congestion) or a history of such, diuretics are indicated for symptomatic improvement of dyspnoe and exercise tolerance. If tolerated, diuretics should always be co-administered with inhibitors of the renin-angiotensin system and beta-adrenergic receptor blockers. In mild to moderate HF, thiazide diuretics are generally effective while advanced HF usually requires the use of loop diuretics or a combination therapy of loop diuretics and thiazides (sequential nephron blockade).
Aldosterone Receptor Antagonists
In addition to therapy with ACEIs, beta-adrenergic receptor blockers, and diuretics, patients with advanced HF (EF Ôëñ35-40%, NYHA III-IV) should be treated with aldosterone receptor antagonists unless patients have contraindications. Results from the RALES and EPHESUS trials show that aldosterone receptor antagonists decrease mortality and morbidity in this patient collective. Following MI, aldosterone receptor antagonists are indicated in addition to ACEIs and beta-blockers in patients with LV systolic dysfunction and signs of HF or diabetes to reduce mortality and morbidity. During therapy careful monitoring of serum potassium levels, renal function, and fluid status is warranted. Spironolactone treatment should also be monitored for gynaecomastia.
In patients with symptomatic HF (NYHA I-IV) and tachyarrhythmic atrial fibrillation, cardiac glycosides are indicated for heart rate control unless there are contraindications,. Combining cardiac glycosides with beta-adrenergic receptor blockers seems to be more effective than either agent alone in limiting heart rate.While it has no effect on mortality, digoxin may improve symptoms and reduce hospitalizations at low serum levels (i.e. 0.5-0.8ng/ml) in patients with LV systolic dysfunction (EF ≤35-40%) and sinus rhythm who remain symptomatic under a therapy with ACEI, beta-adrenergic receptor blockers, diuretics, and aldosterone receptor antagonists. During therapy, heart rate, atrio-ventricular conduction, potassium and cardiac glycoside serum levels should be monitored. Renal function should be regularly assessed in case of digoxin, which is eliminated by renal excretion.
Cardiac Resynchronization Therapy and Implantable Cardioverter Defibrillators
Cardiac resynchronization therapy (CRT) using biventricular pacing is indicated in patients with reduced LV function (EF ≤35%), sinus rhythm, left bundle branch block or echocardiographic signs of ventricular dyssynchrony and QRS width ≥120ms remaining symptomatic (NYHA III-IV) despite optimal medical therapy. In the Care-HF and COMPANION trials, CRT has been shown to improve survival, symptoms, exercise capacity, and to decrease hospitalizations in this patient group.20-21 Implantation of pacemakers should be based on conventional indications for the treatment of bradyarrhythmias. Conventional right ventricular (RV) pacing may yield detrimental effects on LV function, and results from the recently conducted HOBIPACE trial show that biventricular stimulation is superior to RV pacing with regard to LV function, exercise capacity, and quality of life in patients with LV dysfunction (EF =40%) and standard indication for ventricular pacing. In a recent meta-analysis of four trials looking at secondary prevention of sudden cardiac death (SCD), ICD implantation improved survival in patients who survived cardiac arrest and in patients with sustained clinically significant ventricular tachyarrhythmias. Moreover, several trials have established the indication for ICD therapy in selected HF patients with optimal pharmacological treatment for primary prevention of SCD. In the MADIT II trial, patients with LVEF ≤30% after MI (>1 month) were randomized to ICD implantation or not, and the trial was prematurely stopped after a mean follow-up of 20 months because of a significant reduction of mortality in the ICD group.
In the SCD-HeFT trial, patients with ischemic and non-ischemic symptomatic HF (NYHA II-III) with LVEF ≤35% were randomized to placebo, amiodarone or ICD implantation, and after a mean follow-up of 45.5 months there was a significant decrease in mortality in the ICD group while there was no difference in survival between placebo and amiodarone. In the COMPANION trial, symptomatic patients (NYHA III-IV) with LVEF ≤35% and QRS width ≥120ms were randomized to receive optimal pharmacological therapy alone, in combination with CRT or in combination with CRT and implantable cardioverter defibrillator (ICD). Survival was improved in both the CRT and the CRT/ICD arms as compared to optimal pharmacological therapy alone. The lack of significant differences in mortality between both device arms seems to indicate that ICDs can be safely used in combination with CRT based on the indications for ICD therapy.3
Heart transplantation and Ventricular Assist Devices
In selected patients with severe HF, heart transplantation (HTx) is indicated to improve exercise capacity, quality of life, and survival compared with conventional treatment and has been shown to have five-year survival rates of 70–80% in patients receiving a triple immunosuppressive therapy.1-3,26 Selection criteria for HTx include severe hemodynamic compromise due to HF (refractory cardiogenic shock, continued dependence on intravenous inotropic support for maintenance of adequate organ perfusion, peakVO2 less than 10ml/kg/min with achievement of anaerobic metabolism), refractory severe cardiac ischemia consistently limitating routine activity, and recurrent refractory life-threatening ventricular arrhythmias.3 Contraindications include current drug or alcohol abuse, lack of compliance, serious uncontrollable mental disease, severe comorbidity (i.e. treated malignancy with remission and <5 years follow-up, systemic infection, significant renal or hepatic failure), and fixed pulmonary hypertension.1-2 Immunosuppressive therapy is mandatory for prevention of allograft rejection, but may lead to complications including infections, renal failure, malignancies, and transplant vasculopathy that limited long-term prognosis.1-3 Unfortunately, transplantation is not an option for all HF patients with HTx indications due to a limited number of donor hearts. Therfore, such patients have been ‘bridged’ to transplantation using ventricular assist devices (VADs) or total artificial hearts, both of which have been shown to improve survival-to-transplantation, post- transplant survival, and quality of life.1-3,27-28 In the REMATCH trial, patients with end-stage HF (LVEF ≤25%, NYHA IV, peak VO2 <12-14ml/kg/min or inotropic dependence) ineligible for HTx were randomized to optimal pharmacological therapy or permanent VAD implantation.29 Importantly, patients in the VAD group had significant improvements in one- and two-year survival rates, as well as in quality of life, and these results have established the use of VADs as an alternative to transplantation (destination therapy). Complications associated with assist devices include infections, bleeding, thromboembolism, and device failure.
The treatment of CHF includes general measures, stage-adapted pharmacotherapy, device therapy, and heart transplantation. Mortality is decreased by starting pharmacological therapy with ACEI or ARB in stage NYHA I, beta-blockers in NYHA II, and aldosterone antagonists in NYHA III, while symptomatic relief is effected by diuretics, digitalis, anti-arrhythmics, and inotropics. In selected patients, survival is increased by ICD implantation, CRT, VADs, and heart transplantation