The trusted source for
healthcare information and
Medical Advances in the Evaluation and Treatment of Heart Failure
This article originally appeared in the February 2010 issue of Primary Care Reports.
All emergency physicians are comfortable caring for the patient in acute pulmonary edema. Initial treatment of this emergency condition has changed little in the past decade. However the treatment of less acute patients with congestive heart failure (CHF) has changed dramatically in the recent past. This article will emphasize the management of a patient with congestive heart failure. The ED physician increasingly is part of the health care team, working with the primary care physician. As America "grays," the ED physician will be increasingly involved in the care of these patients and their chronic care as well as emergency stabilization.
Sandra M. Schneider, MD, FACEP, Editor
Heart failure is a clinical syndrome that is characterized by the inability of the heart to meet the body's metabolic demands. This is attributed to either a functional or structural impairment of ventricular filling or ejection of blood. Patients manifest clinically with symptoms of low exercise tolerance and fluid retention.
Heart failure is a major public health problem in the western world. In the United States alone there are about 5 million Americans living with the diagnosis of heart failure. It is also estimated that another 550,000 Americans are diagnosed with this condition every year.1 Heart failure accounts for about 15 million physician office visits every year.2 It is the most common Medicare discharge diagnosis, accounting for more healthcare costs than any other condition in the United States.3 The overall prevalence of heart failure is increasing. This increase has been attributed to the aging population and the advances in the treatment of coronary artery disease (CAD) that have led to more people surviving initial events of acute myocardial infarction.4 Heart failure is primarily a disease of the elderly, as evidenced by the fact that 80% of the patients admitted with heart failure are older than 65 years.5 The incidence of heart failure among people aged 65 years and older is about 10 per 1000 population.1 The estimated direct and indirect cost of heart failure in the United States is $37.2 billion.6
Hypertension is the most common risk factor for heart failure, followed by antecedent acute myocardial infarction (AMI).7 Other risk factors include diabetes, metabolic syndrome, and dilated cardiomyopathy. (See Table 1.) Diabetes mellitus substantially increases the risk of developing heart failure, especially among post-menopausal women with established CAD. Heart failure incidence increases with each additional risk factor. For example, the annual incidence of heart failure among nondiabetic women with no risk factors is 0.4%. This risk increases to 3.4% in nondiabetic women with at least three risk factors. Among diabetic patients with no additional risk factors, the annual incidence of heart failure is 3.0%, compared with 8.2% among diabetics with at least three additional risk factors.8 Dilated cardiomyopathy accounts for a substantial number of cases of heart failure. About one-third of patients with cardiomyopathy may have a genetic predisposition.9
Classification of Heart Failure
There are numerous ways of classifying heart failure and, in many cases, these categories overlap and may be ambiguous. The basis of these definitions has varied widely and has ranged from anatomical (right- vs left-sided heart failure), physiological (diastolic vs systolic), and, in some instances, clinical considerations (acute vs chronic). The World Health Organization (WHO) classification is based on myocardial disorder, i.e., dilated, hypertrophic, restrictive, arrhythmogenic right ventricular, and unspecified cardiomyopathies.10 In recognition of the fact that heart failure is a progressive disorder, the American Heart Association (AHA) and American College of Cardiology (ACC) societies in collaboration have developed the staging criteria that take into account the development and progression of the disease. (See Table 2.) This classification has four stages: A through D. Stage A identifies patients who are at high risk for developing heart failure but have no structural abnormalities of the heart and have no symptoms of heart failure. These are patients who might have risk factors for developing heart failure, such as hypertension, diabetes, CAD, history of alcohol abuse, or exposure to cardiotoxins.
Stage B includes patients with structural heart abnormalities but with no overt symptoms of heart failure. Patients in this stage might have left ventricular hypertrophy (LVH), reduced left ventricular ejection fraction (LVEF), valvular disease, and prior AMI but are asymptomatic.
Stage C includes patients who have all the factors in stages A and B, and in addition have symptoms of clinical heart failure. They not only have structural abnormality of the heart but also manifest clinical symptoms and signs of heart failure.
Stage D includes patients who are refractory to standard treatment of heart failure. These patients may require intravenous pressor agents, mechanical assist devices, heart transplant, or hospice care. In the ACC/AHA classification, patients can progress from one lower stage to a higher stage but never the reverse (i.e., from stage A to B, but never from B to A).
Another more clinically based classification is the New York Heart Association (NYHA) classification. This classification uses the presence or absence of symptoms of heart failure on functional capacity to classify severity of heart failure.11 There are four classes in this classification: I through IV. (See Table 3.)
Causes of Heart Failure
The most common cause of heart failure in the Western world is attributed CAD and often may be secondary to an AMI. CAD accounts for about 70% of the cases heart failure.12 Heart failure also can result from nonischemic causes such as hypertension, cardiomyopathies, valvular disorders, pericardial disorders, or arrhythmias. See Table 4 for comprehensive list of etiologies of heart failure.
Numerous conceptual models have been proposed to explain heart failure; however, no single model effectively explains the complexity of the heart failure syndrome. Earlier models conceived heart failure as a result of excessive salt and water retention leading to poor renal flow (cardiorenal model).13 Following this was the hemodynamic model that conceived heart failure as a problem of "pump failure" with resultant excessive peripheral vasoconstriction.14 These models could not, however, explain the progression of heart failure once the original insult causing heart failure was removed.
More recently, the neuro-hormonal model has attempted to explain the progression of heart failure as resulting from the effects of biochemical molecules released in response to injury of the heart.15 These biomedical chemicals include catecholamines, through the activation of the adrenergic nervous system (ANS); and angiotensin II and aldosterone through the activation of the rennin-angiotensin-aldosterone system (RAAS). With a reduction in cardiac output resulting from an insult on the heart (index event), compensatory mechanisms are set in motion with the goal of maintaining adequate cardiac output for tissue perfusion. An activated ANS and RAAS results in the over-expression of catecholamines, angiotensin II, and aldosterone, respectively. These biochemical molecules have profound maladaptive effects on myocardial cells. Some of these effects include loss of myocytes, hypertrophy, and fibrosis of the myocardium (also known as remodeling). The overall result is that the heart configuration changes from the elliptical shape to a more spherical shape, which is hemodynamically less efficient for pumping out blood. Patients may be asymptomatic after the index event, but with persistence of these maladaptive changes, patients develop overt symptoms of heart failure.
Therapeutic agents such as beta-blockers and angiotensin-converting enzyme inhibitors (ACEI) have been shown to improve survival in heart failure by ameliorating the effects of these maladaptive changes through directly acting on the ANS and RAAS, respectively.16-18 This conceptual framework helps to explain the changes in the development of systolic dysfunction (heart failure with depressed ejection faction, less than 45%). However, the maladaptive changes in diastolic dysfunction (heart failure with preserved ejection fraction) are not very well understood.
Evaluation of patients with heart failure begins with a thorough history and physical examination. A detailed history should elicit patients' risk factors or behaviors associated with the development and progression of heart failure. Direct inquiry about past or current history of CAD, congenital heart disease, valvular diseases, and illicit drug use may help point to etiology of heart failure. It is also important to establish the baseline functional status using the NYHA classification for future monitoring of therapy and progression of the disease.
Many tests routinely are used to evaluate patients with heart failure. Diagnostic tests usually are better at detecting heart failure with systolic dysfunction than heart failure with preserved systolic function. Laboratory evaluation should include tests that reveal disorders that will lead to or cause progression of heart failure. Initial studies should include urinalysis, complete blood count, ECG, and basic metabolic profile. (See Table 5.)
Chest X-ray (CXR) allows the physician to assess pulmonary congestion as well as rule out other respiratory causes of shortness of breath. In chronic heart failure, about 20% of patients may not have pulmonary markings of congestion on CXR because of compensatory increase in lymphatic drainage of fluid.19 One of the most useful diagnostic tests in evaluating heart failure is the 2-dimension echocardiogram (2-D echo). This test noninvasively assesses the functional capacity of the cardiac chambers and the presence of structural abnormalities. It also establishes a baseline reference point for future comparison of heart failure progression. In special situations in which myocardial disease is suspected, such as myocarditis, cardiac magnetic resonance imaging (MRI) can be done to evaluate for this disorder.20 Myocardial biopsy is reserved for patients with acute fulminant heart failure of unknown etiology with ventricular arrhythmias and/or atrioventricular conduction delays, or in patients suspected of having infiltrative processes such as amyloid, hemochromatosis, and restrictive cardiomyopathy of unknown etiology.
Serum assays of brain natriuretic peptide (BNP) and N-terminal pro BNP (NT-proBNP) have been shown to correlate highly with symptoms of heart failure, particularly in systolic dysfunction.21 BNP is released from distended heart muscle as occurs in volume overload states. A number of patient factors besides heart failure can cause elevated levels. Factors that can elevate these serum assays include advanced age, obesity, liver cirrhosis, tachycardia, hypoxemia, and renal function.22 A normal level of BNP in a patient not receiving treatment has a high negative predictive value for heart failure.
Treatment of HF is linked to the ACC/AHA staging guidelines.
Stage A. The goal of management of stage A heart failure is the prevention of progression of disease by treating risk factors. Adequately treated hypertension can lead to profound reduction in the incidence of heart failure. In some studies, optimally treating hypertension translated to as much as a 30-50% reduction in the development of left ventricular hypertrophy and heart failure.23 Blood pressure readings may be falsely high in the ED and a single elevated reading should not be used to initiate treatment. However, individuals with elevated pressures should be referred to their primary care provider for further evaluation and possible treatment. Patients who smoke, drink alcohol, or use drugs are counseled to abstain from these risky behaviors.
Stages B, C, D. The goal of therapy for patients with these stages of heart failure is to decrease the progression of disease, improve symptoms, and minimize the risk factors for the development and progression of the disease. Some of the interventions include salt restrictions and avoidance of nonsteroidal anti-inflammatory drugs (which can cause fluid retention and worsening of heart failure).24 There are also specific therapeutic agents that have been shown to have improved outcomes in patients with heart failure that should be considered. (See Table 6.)
The use of ACEIs is recommended for most patients with stages B, C, and D. These classes of medications have been shown to confer survival benefit to patients with heart failure, after myocardial infarction, and improve heart failure symptoms and reverse remodeling by blunting the activity of the RAAS.25-27 The effects of these medications are not dose-dependent. The effects of low-dose ACEI on mortality have not been any different than in those patients taking high-dose regimens in most randomized clinical trials.28-31 A common adverse side effect of ACEIs is angioedema.
Beta-blockers have been shown to confer clinical benefits in patients with all stages of heart failure. The benefits that beta-blockers confer include improved survival, reduced morbidity, improved quality of life, reduced rate of hospitalizations, improvement in remodeling, and reduced incidence of sudden cardiac death.32-33 Studies have shown improvements in the systolic function and reversal of remodeling with just 3-4 months of treatment with beta-blockers.34-36 In some cases the improvement in mortality and hospitalization was seen as early as 14-21 days after initiation of therapy.37 Beta-blockers should be initiated when the patient is hemodynamically stable at low doses and titrated slowly over 2-4 weeks. Patients often have difficulty with hypotension and fatigue after starting beta-blockers and may present to the ED. Every effort should be made to continue this medication, as symptoms will decrease with time. Caution should be exercised in patients with hyperactive airways disease, bradyarrhythmias, and in patients known to be diabetics with frequent hypoglycemic episodes.
Angiotensin Receptor Blockers (ARBS)
ARBs block the effects of angiotensin II at the angiotensin II type 1 receptor site. ARBs are comparable but not superior to ACE inhibitors.38-40 There are reports of increased adverse events in patients who were receiving a combination of ACEIs and ARBs.41-42 ARBs, therefore, generally are recommended in patients who are not able to tolerate ACEIs due to cough and angioedema.
Aldosterone antagonists are another class of medications that have a beneficial role in heart failure.43 Patients with heart failure have elevated levels of aldosterone, leading to salt and water retention. Aldosterone also works locally on the heart muscle to induce myocardial fibrosis and hypertrophy. Aldosterone antagonists counteract these effects, thereby inhibiting the remodeling process.44 The addition of these agents in patients with advanced heart failure (NYHA class III or IV) has been shown in randomized controlled studies to improve mortality outcomes and hospital admissions for heart failure.45 Patients on aldosterone antagonists must be monitored closely for serum potassium and creatinine. These medications generally are not started if the serum potassium is more than 5.0 mmol/L or the serum creatinine is more than 2.5 mg/dL.
Diuretics are usually the initial medications administered to patients who are symptomatic (stage C and D heart failure). These medications are effective at reducing the pulmonary congestion and cardiac afterload.46 The combination of loop diuretics with thiazide can be effective in optimizing diuresis in advanced cases.47-48
Digoxin can be used in symptomatic patients with low ejection fraction. It has been shown in randomized controlled studies to reduce hospitalization and improve heart failure symptoms. It does not affect survival outcomes, however.49 It is important to monitor electrolytes and renal function in patients receiving digoxin to prevent toxicity. Low serum digoxin concentration (lower than 0.09 ng per milliliter) can be as effective as higher therapeutic ranges previously recommended in maintaining therapeutic response.50 Digoxin also is beneficial in patients with concomitant atrial fibrillation and systolic dysfunction, as it can be used to control ventricular rate in patients with atrial fibrillation. Contraindications for digoxin include second- or third-degree heart block (without a permanent pacemaker), pre-excitation syndromes, and previous evidence of digoxin intolerance.
Hydralazine and Isosorbide Dinitrate
In patients with heart failure and systolic dysfunction who are unable to tolerate ACEIs or ARBs, a combination of hydralazine and isosorbide dinitrate could be considered. This combination therapy has been shown to reduce mortality and hospitalization and to improve quality of life.51-53 Evidence of benefit is strongest in African-Americans. The medications must be titrated over a period of 2-4 weeks. This combination is contraindicated in patients with symptomatic hypotension, lupus syndrome, and severe renal failure.
Diastolic Heart Failure
Diastolic heart failure deserves special mention because of the high prevalence of this disorder; yet, there is still a paucity of outcome data from long-term randomized placebo-controlled trials. Most of the available data on the therapeutic interventions have been in heart failure with systolic dysfunction. Diastolic heart failure is defined by the presence of heart failure symptoms in a patient with normal left ventricular ejection fraction and no valvular abnormalities on echocardiography.54 Approximately 50% of patients with a diagnosis of heart failure have normal or preserved left ventricular function.55 The prevalence of diastolic heart failure is highest in patients older than 75 years, and most often in women.56
The preeminent problem in diastolic heart failure is the impaired ability of the ventricles to relax, leading to increased end-diastolic ventricular pressures in relation to a given ventricular blood volume. Thus with just a slight increase in blood volume, blood pressure, or even the presence of tachycardia in a patient with impaired ventricular relaxation could lead to substantial elevation of left atrial pressures and pulmonary edema. Treatment in the acute setting involves diuresis as well as aggressively treating hypertension and controlling heart rate. Current long-term treatment recommendations have been generally extrapolated from the interventions used in the treatment of heart failure with systolic dysfunction. The use of beta-blockers, ACEIs, and calcium channel blockers generally is recommended in diastolic heart failure.57-60 In the CHARM-preserved study, an angiotensin receptor blocker was associated with lower hospitalization and a non-statistically significant trend toward lower mortality.61
There are nonpharmacological approaches to treatment of some patients with heart failure. All patients with heart failure must be evaluated and treated for CAD. Angioplasty and surgical revascularization can lead to improvement of ischemic symptoms and ejection fraction, and can reduce the incidence of sudden death.62 Some patients with stage C and D heart failure may benefit from bypass surgery. Some studies are looking at the role of surgical procedures designed for the treatment of heart failure. Some of these procedures include mitral valve repair, mechanical devices to reduce wall stress, and surgical excision of infarcted tissue.63-65
Mechanical devices for stage D patients may provide a bridging gap modality in patients awaiting heart transplantation or even those patients who are not candidates for transplant surgery.65 Cardiac resynchronization therapy with biventricular pacers has been shown to be effective in the treatment of patients with heart failure and left bundle-branch blocks on a 12-lead electrocardiogram. These devices have been shown to improve exercise tolerance and quality of life and to reduce the rate of hospitalizations. Resynchronization therapy also been to shown to reverse the remodeling effects and improve the ejection fraction of the heart.66-69
Sudden Cardiac Death
Patients with heart failure are at an increased risk of sudden cardiac death.70 Sudden death usually results from ventricular tachyarrhythmias. Sudden death resulting from cardiac causes accounts for about 50% of all cardiovascular deaths.71 Patients with advanced heart disease such as those with systolic dysfunction and NYHA class III or IV may have up to 50% one-year mortality, with half of these deaths being sudden.72 Patients with severe systolic dysfunction presenting with syncope, for instance, may need to be referred for electrophysiological testing for inducible arrhythmias and possible insertion of mechanical devices.
Heart failure is a debilitating progressive disease that has severe morbidity and mortality. The prevalence of heart failure is increasing because of the aging population. All patients who present with CHF should be referred to their primary care physician for chronic therapy. Many patients recently started on treatment may experience side effects of fatigue, hypotension, and even worsening dyspnea. When possible, treatment should be continued or slowly tapered as these treatments lead to remodeling of the heart and better long-term outcomes. A promising report from the Framingham study showed that there was increased survival with the diagnosis of heart failure.73 Despite this, evidence shows that treatment of heart failure is less than optimal.74
1. American Heart Association. Heart Disease and Stroke Statistics: 2005 Update. Dallas, TX: American Heart Association; 2005.
2. O'Connell JB, Bristow MR. Economic impact of heart failure in the United States: Time for a different approach. J Heart Lung Transplant 1994;13:S107-S112.
3. Massie BM, Shah NB. Evolving trends in the epidemiologic factors of heart failure: Rationale for preventive strategies and comprehensive disease management. Am Heart J 1997;133:703-712.
4. Senni M, Tribouilloy CM, Rodeheffer RJ, et al. Congestive heart failure in the community: Trends in incidence and survival in a 10-year period. Arch Intern Med 1999;159:29-34.
5. Masoudi FA, Havranek EP, Krumholz HM. The burden of chronic congestive heart failure in older persons: Magnitude and implications for policy and research. Heart Fail Rev 2002;7:9-16.
6. Centers for Medicare & Medicaid Services. Health Care Financing Review: Medicare & Medicaid Statistical Supplement. Table 5.5: Discharges, Total Days of Care, and Program Payments for Medicare Beneficiaries Discharged from Short-Stay Hospitals, by Principal Diagnoses Within Major Diagnostic Classifications (MDCs): Calendar Year 2006. Baltimore, MD: Centers for Medicare and Medicaid Services; 2005. Available at: http://www.cms.hhs.gov/MedicareMedicaidStatSupp.
7. Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heart failure. JAMA 1996;275:1557-1562.
8. Bibbins-Domingo K, Lin F, Vittinghoff E, et al. Predictors of heart failure among women with coronary disease. Circulation 2004;110:1424-1430.
9. Francis GS, Pierpont GL. Pathophysiology of congestive heart failure secondary to congestive and ischemic cardiomyopathy. Cardiovasc Clin 1988;19:57-74.
10. Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies. Circulation 1996;93:841-842.
11. Gibelin P. An evaluation of symptom classification of systems used for the assessment of patients with heart failure in France. Eur J Heart Fail 2001;3:739.
12. Fox KF, Cowie MR, Wood DA, et al. Coronary artery disease as the cause of incident heart disease in the population. Eur Heart J 2001;22;228-236.
13. Packer M. The neurohormonal hypothesis: A theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 1992;20:248-254.
14. Mann D, Bristow MR. Mechanisms and models in heart failure: The biomechanical model and beyond. Circulation 2005;111:2837-2849.
15. Bristow MR. The adrenergic nervous system in heart failure. N Engl J Med 1984; 311:850-851.
16. Currie PJ, Kelly MJ, McKenzie A, et al. Oral beta-adrenergic blockade with metoprolol in chronic severe dilated cardiomyopathy. J Am Coll Cardiol 1984;3:203-209.
17. Ikram H, Fitzpatrick D. Double-blind trial of chronic oral beta blockade in congestive cardiomyopathy. Lancet 1981;2:490-493.
18. Foult JM, Tavolaro O, Antony I, et al. Coronary vasodilation induced by intracoronary enalaprilat: An argument for the role of a local renin-angiotensin system in patients with dilated cardiomyopathy. Eur Heart J 1989;10(suppl F):97-100.
19. Stevenson LW, Perloff JK. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA 1989;261:884-888.
20. De Cobelli F, Pieroni,M, Esposito A. Delayed gadolinium-enhanced cardiac magnetic resonance in patients with chronic myocarditis presenting with heart failure or recurrent arrhythmias. J Am Coll Cardiol 2006;47:1649-1654.
21. Maisel A. B-type natriuretic peptide levels.a potential novel "white count" for congestive heart failure. J Card Failure 2001;7:183-193.
22. Weinfeld MS,Chertow GM, Stevenson LW. Aggravated renal dysfunction during intensive therapy for advanced chronic heart failure. Am Heart J 1999;138:285-290.
23. Mosterd A, D'Agostino RB, Silbershatz H, et al. Trends in the prevalence of hypertension, antihypertensive therapy, and left ventricular hypertrophy from 1950 to 1989. N Engl J Med 1999;340:1221-1227.
24. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: An underrecognized public health problem. Arch Intern Med 2000;160:777-784.
25. Munzel T, Keaney JF Jr. Are ACE inhibitors a "magic bullet" against oxidative stress? Circulation 2001;104:1571-1574.
26. Khalil ME, Basher AW, Brown EJ Jr, et al. A remarkable medical story: Benefits of angiotensin-converting enzyme inhibitors in cardiac patients. J Am Coll Cardiol 2001;37:1757-1764.
27. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273:1450-1456. [Erratum, JAMA 1995;274:462.]
28. Gullestad L, Aukrust P, Ueland T, et al.Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure. J Am Coll Cardiol 1999;34:2061-2067.
29. Nanas JN, Alexopoulos G, Anastasiou-Nana MI, et al. Outcome of patients with congestive heart failure treated with standard versus high doses of enalapril: A multicenter study. J Am Coll Cardiol 2000;36:2090-2095.
30. Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999;100:2312-2318.
31. Tang WH, Vagelos RH, Yee YG, et al. Neurohormonal and clinical responses to high- versus low-dose enalapril therapy in chronic heart failure. J Am Coll Cardiol 2002;39:70-78. [Erratum, J Am Coll Cardiol 2002;39:746.]
32. Foody JM, Farrell MH, Krumholz HM. Beta-blocker therapy in heart failure: Scientific review. JAMA 2002;287:883-889.
33. Farrell MH, Foody JM, Krumholz HM. Beta-blockers in heart failure: Clinical applications. JAMA 2002;287:890-897.
34. Bristow M. Beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000;101;558-569.
35. Groenning B, Nilsson J, Sondergaard L, et al. Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol 2000,36:2072-2080.
36. Hall S, Cigarroa C, Marcoux L, et al. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol 1995;25;1154-1161.
37. Krum H, Roecker EB, Mohacsi P, et al. Effects of initiating carvedilol in patients with severe chronic heart failure:results from the COPERNICUS study. JAMA 2003;289:712-718.
38. Cohn J N, Tognoni G; Valsartan heart failure trial investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-1675.
39. McMurray JJ, Pfeffer MA, Swedberg K, et al. Which inhibitor of the rennin angiotensin system should be used in chronic heart failure and left ventricular systolic dysfunction:results of the CHARM low left ventricular ejection fraction trials. Circulation 2004;110:2618-2626.
40. Pitt B, Poole-Wilson PA, Segal R, et al. Effects of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised trial the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582-1587.
41. Baruch L, Anand I, Cohen IS, et al. Augmented short- and long-term hemodynamic and hormonal effects of an angiotensin receptor blocker added to angiotensin converting enzyme inhibitor therapy in patients with heart failure. Vasodilator Heart Failure Trial (V-HeFT) Study Group. Circulation 1999;99:2658-2664.
42. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: The CHARM-Added trial. Lancet 2003;362:767-771.
43. McMurray JJ, O'Meara E. Treatment of heart failure with spironalactone-trial and tribulations. N Eng J Med 2004;351:526-528.
44. Weber KT. Aldosterone in congestive heart failure. N Eng J Med 2001;345:1689-1697.
45. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-717.
46. Faris R, Flather M, Purcell H, et al. Current evidence supporting the role of diuretics in heart failure: A meta analysis of randomized control trials. Int J Cardiol 2002;82:149-158.
47. Ellison D. Diuretic drugs and the treatment of edema: From clinic to bench and back again. Am J Kidney Dis 1994;23:623-43.
48. Brater DC. Diuretic therapy. N Engl J Med 1998;339:387-395.
49. [No authors listed.] The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-533.
50. Adams KF, Gheorghiade M, Uretsky BF, et al. Clinical benefits of low serum digoxin concentrations in heart failure. J Am Coll Cardiol 2002;39:946-953.
51. Cohn JN, Johnson G, Ziesche, et al. A comparison of enalpril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310.
52. Taylor AL, Ziewsche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-2057.
53. Loeb HS, Johnson G, Henrick A, et al. Effect of enalapril, hydralazine plus isosorbide dinitrate and prazosin on hospitalization in patients with chronic congestive heart failure. The V-Heft VA cooperative studies group. Circulation 1993;87(6suppl):V178-V187.
54. Hunt SA, Baker DW, Chin MH, et al. Guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001;38:2101-2113. Accessed August 16, 2004, at www.acc.org/clinical/guidelines/failure/VI_diastolic.htm.
55. Vasan R, Benjamin E, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: An epidemiologic perspective. J Am Coll Cardiol 1995;26:1565-1574.
56. Gaasch WH, Zile MR. Left ventricular diastolic dysfunction and diastolic heart failure. Ann Rev Med 2004;55:373-394.
57. Aronow WS, Kronzon I. Effect of enalapril on congestive heart failure treated with diuretics in elderly patients with prior myocardial infarction and normal left ventricular ejection fraction. Am J Cardiol 1993;71:602-604.
58. Aronow WS, Ahn C, Kronzon I. Effect of propranolol versus no propranolol on total mortality plus nonfatal myocardial infarction in older patients with prior myocardial infarction, congestive heart failure, and left ventricular ejection fraction > or = 40% treated with diuretics plus angiotensin-converting enzyme inhibitors. Am J Cardiol 1997;80:207-209.
59. Setaro JF, Zaret BL, Schulman DS, et al. Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance. Am J Cardiol 1990;66:981-986.
60. Warner JG, Metzger DC, Kitzman DW, et al. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol 1999;33:1567-1572.
61. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARM-Preserved Trial. Lancet 2003;362:777-781.
62. Baumgartner WA. What's new in cardiac surgery. J Am Coll Surg 2001;192:345-355.
63. Raman JS, Hata M, Storer M, et al. The mid-term results of ventricular containment (ACORN WRAP) for end-stage ischemic cardiomyopathy. Ann Thorac Cardiovasc Surg 2001;7:278-281.
64. Bishay ES, McCarthy PM, Cosgrove DM, et al. Mitral valve surgery in patients with severe left ventricular dysfunction. Eur J Cardiothorac Surg 2000;17:213-221.
65. Starling RC, McCarthy PM, Buda T, et al. Results of partial left ventriculectomy for dilated cardiomyopathy: Hemodynamic, clinical, and echocardiographic observations. J Am Coll Cardiol 2000;36:2098-2103.
66. Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001;344:873-880.
67. Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. Circulation 1999;99:2993-3001.
68. Kerwin WF, Botvinick EH, O'Connell JW, et al. Ventricular contraction abnormalities in dilated cardiomyopathy: Effect of biventricular pacing to correct interventricular dyssynchrony. J Am Coll Cardiol 2000;35:1221-1227.
69. Stellbrink C, Breithardt O-A, Franke A, et al. Impact of cardiac resynchronization therapy using hemodynamically optimized pacing on left ventricular remodeling in patients with congestive heart failure and ventricular conduction disturbances. J Am Coll Cardiol 2001;38:1957-1965.
70. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: Epidemiology, transient risk, and intervention assessment. Ann Intern Med 1993;119:1187-1197.
71. Myerburg RJ, Interian A Jr, Mitrani RM, et al. Frequency of sudden cardiac death and profiles of risk. Am J Cardiol 1997;80:10F-19F.
72. Pye MP, Cobbs SM. Mechanisms of ventricular arrhythmias in cardiac failure and hypertrophy. Cardiovas Res 1992;26:740-750.
73. Levy D, Kenchaiah S, Lasron M, et al. Long-term trends in the incidence of and survival with heart failure. N Eng J Med 2002;347:1397-1402.
74. Cleland JG, Cohen-Solal A, Aguilar JC, et al; IMPROVEMENT of Heart Failure Programme Committees and Investigators. Improvement programme in evaluation and management; Study Group on Diagnosis of the Working Group on Heart Failure of The European Society of Cardiology. Management of heart failure in primary care (the IMPROVEMENT of heart failure programme): An international survey. Lancet 2002;360:1631-1639.