2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults

A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation

3.1.1 Identification of Patients (UPDATED)

In general, patients with LV dysfunction or HF present to the healthcare provider in 1 of 3 ways:

• 1. With a syndrome of decreased exercise tolerance.Most patients with HF seek medical attention with complaints of a reduction in their effort tolerance due to dyspnea and/or fatigue. These symptoms, which may occur at rest or during exercise, may be attributed inappropriately by the patient and/or healthcare provider to aging, other physiological abnormalities (e.g., deconditioning), or other medical disorders (e.g., pulmonary disease). Therefore, in a patient whose exercise capacity is limited by dyspnea or fatigue, the healthcare provider must determine whether the principal cause is HF or another abnormality. Elucidation of the precise reason for exercise intolerance can be difficult because several disorders may coexist in the same patient. A clear distinction can sometimes be made only by measurements of gas exchange or blood oxygen saturation or by invasive hemodynamic measurements during graded levels of exercise (see ACC/AHA 2002 Guideline Update for Exercise Testing [33]).

• 2. With a syndrome of fluid retention.Patients may present with complaints of leg or abdominal swelling as their primary (or only) symptom. In these patients, the impairment of exercise tolerance may occur so gradually that it may not be noted unless the patient is questioned carefully and specifically about a change in activities of daily living.

• 3. With no symptoms or symptoms of another cardiac or noncardiac disorder.During their evaluation for a disorder other than HF (e.g., abnormal heart sounds or abnormal electrocardiogram or chest x-ray, hypertension or hypotension, diabetes mellitus, an acute myocardial infarction (MI), an arrhythmia, or a pulmonary or systemic thromboembolic event), patients may be found to have evidence of cardiac enlargement or dysfunction.

A variety of approaches have been used to quantify the degree of functional limitation imposed by HF. The most widely used scale is the NYHA functional classification (34), but this system is subject to considerable interobserver variability and is insensitive to important changes in exercise capacity. These limitations may be overcome by formal tests of exercise tolerance. Measurement of the distance that a patient can walk in 6 minutes may have prognostic significance and may help to assess the level of functional impairment in the very sick, but serial changes in walking distance may not parallel changes in clinical status. Maximal exercise testing, with measurement of peak oxygen uptake, has been used to identify appropriate candidates for cardiac transplantation, to determine disability, and to assist in the formulation of an exercise prescription, but its role in the general management of patients with HF has not been defined.

3.1.2 Identification of a Structural and Functional Abnormality (UPDATED)

A complete history and physical examination are the first steps in evaluating the structural abnormality or cause responsible for the development of HF. Direct inquiry may reveal prior or current evidence of MI, valvular disease, or congenital heart disease, whereas examination of the heart may suggest the presence of cardiac enlargement, murmurs, or a third heart sound. Although the history and physical examination may provide important clues about the nature of the underlying cardiac abnormality, identification of the structural abnormality leading to HF generally requires invasive or noninvasive imaging of the cardiac chambers or great vessels.

The single most useful diagnostic test in the evaluation of patients with HF is the comprehensive 2-dimensional echocardiogram coupled with Doppler flow studies to determine whether abnormalities of myocardium, heart valves, or pericardium are present and which chambers are involved. Three fundamental questions must be addressed: 1) Is the LV ejection fraction (EF) preserved or reduced? 2) Is the structure of the LV normal or abnormal? 3) Are there other structural abnormalities such as valvular, pericardial, or right ventricular abnormalities that could account for the clinical presentation? This information should be quantified with a numerical estimate of EF, measurement of ventricular dimensions and/or volumes, measurement of wall thickness, and evaluation of chamber geometry and regional wall motion.

Right ventricular size and systolic performance should be assessed. Atrial size should also be determined semiquantitatively and left atrial dimensions and/or volumes measured. All valves should be evaluated for anatomic and flow abnormalities to exclude the presence of primary valve disease. Secondary changes in valve function, particularly the severity of mitral and tricuspid valve insufficiency, should be determined.

Noninvasive hemodynamic data acquired at the time of echocardiography are an important additional correlate for patients with preserved or reduced EF. Combined quantification of the mitral valve inflow pattern, pulmonary venous inflow pattern, and mitral annular velocity provides data about characteristics of LV filling and left atrial pressure. Evaluation of the tricuspid valve regurgitant gradient coupled with measurement of inferior vena caval dimension and its response during respiration provides an estimate of systolic pulmonary artery pressure and central venous pressure. Stroke volume may be determined with combined dimension measurement and pulsed Doppler in the LV outflow tract (35). However, abnormalities can be present in any of these parameters in the absence of HF. No single parameter necessarily correlates specifically with HF; however, a totally normal filling pattern argues against clinical HF.

A comprehensive echocardiographic evaluation is important, because it is common for patients to have more than 1 cardiac abnormality that contributes to the development of HF. Furthermore, the study may serve as a baseline for comparison, because measurement of EF and the severity of structural remodeling can provide useful information in patients who have had a change in clinical status or who have experienced or recovered from a clinical event or received treatment that might have had a significant effect on cardiac function.

Other tests may be used to provide information regarding the nature and severity of the cardiac abnormality. Radionuclide ventriculography can provide highly accurate measurements of LV function and right ventricular EF, but it is unable to directly assess valvular abnormalities or cardiac hypertrophy. Magnetic resonance imaging or computed tomography may be useful in evaluating chamber size and ventricular mass, detecting right ventricular dysplasia, or recognizing the presence of pericardial disease, as well as in assessing cardiac function and wall motion (36).

Magnetic resonance imaging may also be used to identify myocardial viability and scar tissue (37). Chest radiography can be used to estimate the degree of cardiac enlargement and pulmonary congestion or to detect the presence of pulmonary disease. A 12-lead electrocardiogram may demonstrate evidence of prior MI, LV hypertrophy, cardiac conduction abnormality (e.g., left bundle-branch block), or a cardiac arrhythmia. However, because of their low sensitivity and specificity, neither the chest x-ray nor the electrocardiogram should form the primary basis for determining the specific cardiac abnormality responsible for the development of HF.

3.1.3 Evaluation of the Cause of Heart Failure

Identification of the condition responsible for the cardiac structural and/or functional abnormalities may be important, because some conditions that lead to LV dysfunction are potentially treatable and/or reversible. Efforts to identify a cause frequently allow the detection of coexistent conditions that may contribute to or exacerbate the severity of symptoms. However, it may not be possible to discern the cause of HF in many patients presenting with this syndrome, and in others, the underlying condition may not be amenable to treatment. Hence, clinicians should focus their efforts on diagnoses that have implications for therapy.

3.2.1 Assessment of Functional Capacity

During the initial and subsequent visits, healthcare providers should inquire about the type, severity, and duration of symptoms that occur during activities of daily living and that may impair the patient's functional capacity. Questions regarding the ability to perform specific tasks may provide greater insight than general inquiries about what symptoms the patient is experiencing, because many patients curtail their activities to limit discomfort. Patients with modest limitations of activity should be asked about their participation in sports or their ability to perform strenuous exercise, whereas patients with substantial limitations of activity should be asked about their ability to get dressed without stopping, take a shower or bath, climb stairs, or perform specific routine household chores. A useful approach is to ask patients to describe activities that they would like to do but can no longer perform, because changes in the ability to perform specific tasks are generally related to important changes in clinical status or course. Ideally, these inquiries should be coupled with direct observations of the patient during a walk around the clinic or up the stairs.

A variety of approaches have been used to quantify the degree of functional limitation imposed by HF. The most widely used scale is the NYHA functional classification (34), but this system is subject to considerable interobserver variability and is insensitive to important changes in exercise capacity. These limitations may be overcome by formal tests of exercise tolerance. Measurement of the distance that a patient can walk in 6 minutes may have prognostic significance and may help to assess the level of functional impairment in the very sick, but serial changes in walking distance may not parallel changes in clinical status. Maximal exercise testing, with measurement of peak oxygen uptake, has been used to identify appropriate candidates for cardiac transplantation, to determine disability, and to assist in the formulation of an exercise prescription, but its role in the general management of patients with HF has not been defined.

3.2.2 Assessment of Volume Status

It is critically important for healthcare providers to evaluate the fluid or volume status of patients with HF during the initial visit and each follow-up examination. This assessment plays a pivotal role in determining the need for diuretic therapy and in detecting sodium excesses or deficiencies that may limit efficacy and decrease the tolerability of drugs used to treat HF. The physical examination is the primary step in evaluating the presence and severity of fluid retention in patients with HF. At each visit, healthcare providers should record the patient's body weight and sitting and standing blood pressures and determine the degree of jugular venous distension and its response to abdominal pressure, the presence and severity of organ congestion (pulmonary rales and hepatomegaly), and the magnitude of peripheral edema in the legs, abdomen, presacral area, and scrotum, as well as ascites in the abdomen.

The most reliable sign of volume overload is jugular venous distention (59–61). Right-sided filling pressures are elevated in the basal state or with abdominal compression (hepatojugular reflux) in many patients with chronically elevated elevated left-sided filling pressures (62). Most patients with peripheral edema should also be considered to have volume overload, but the possibility of noncardiac causes for edema may limit the utility of this sign in some patients. In contrast, most patients with chronic HF do not have rales. This is true even in patients with end-stage disease who have markedly elevated left-sided filling pressures. The presence of rales generally reflects the rapidity of onset of HF rather than the degree of volume overload. Indeed, many patients with chronic HF have elevated intravascular volume in the absence of peripheral edema or rales. Studies using ¹³¹I-tagged albumin have demonstrated plasma volume expansion in more than 50% of patients in whom clinical volume overload was not recognized (63). Short-term changes in fluid status are best assessed by measuring changes in body weight; however, changes in body weight may be less reliable during long periods of follow-up, because many patients may gain nonfluid weight and others may lose skeletal muscle mass and body fat as HF progresses due to the development of cardiac cachexia.

The majority of patients with clinical evidence of volume overload do not exhibit hypoperfusion, even though cardiac performance may be severely depressed. Clinical signs of hypoperfusion become most apparent when cardiac output declines markedly or abruptly. Clues that suggest the presence of such a marked reduction in cardiac output include narrow pulse pressure, cool extremities, altered mentation, Cheyne-Stokes respiration, resting tachycardia, and a disproportionate elevation of blood urea nitrogen relative to serum creatinine. Renal dysfunction in HF is poorly understood and appears to be mediated by interactions between the heart and kidney beyond those primarily due to depressed cardiac output (41).

3.2.3 Laboratory Assessment (UPDATED)

Serum electrolytes and renal function should be monitored routinely in patients with HF. Of particular importance is the serial measurement of serum potassium concentration, because hypokalemia is a common adverse effect of treatment with diuretics and may cause fatal arrhythmias and increase the risk of digitalis toxicity, whereas hyperkalemia may complicate therapy with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and aldosterone antagonists. Worsening renal function may require adjustment of the doses of diuretics, renin-angiotensin-aldosterone system antagonists, digoxin, and noncardiac medications. Development of hyponatremia or anemia may be a sign of disease progression and is associated with impaired survival.

Serum BNP levels have been shown to parallel the clinical severity of HF as assessed by NYHA functional class in broad populations. Levels are higher in hospitalized patients and tend to decrease during aggressive therapy for decompensation (see Section 3.1.3.2, Laboratory Testing) (42). Indeed, there is an increasing body of evidence demonstrating the power of the addition of BNP (or NT-proBNP) levels in the assessment of prognosis in a variety of cardiovascular disorders. However, it cannot be assumed that BNP levels can be used effectively as targets for adjustment of therapy in individual patients. Many patients taking optimal doses of medications continue to show markedly elevated levels of BNP, and some patients demonstrate BNP levels within the normal range despite advanced HF. The use of BNP measurements to guide the titration of drug doses has not been shown conclusively to improve outcomes more effectively than achievement of the target doses of drugs shown in clinical trials to prolong life (64). Ongoing trials will help to determine the role of serial BNP (or other natriuretic peptides) measurements in both diagnosis and management of HF.

Serial chest radiographs are not recommended in the management of chronic HF. Although the cardiothoracic ratio is commonly believed to reflect the cardiac dilatation that is characteristic of HF, enlargement of the cardiac silhouette primarily reflects changes in right ventricular volume rather than LV function, because the right ventricle forms most of the border of dilated hearts on radiographs. Similarly, changes in the radiographic assessment of pulmonary vascular congestion are too insensitive to detect any but the most extreme changes in fluid status (65).

Repeat assessment of EF may be most useful when the patient has demonstrated a major change in clinical status. Both improvement and deterioration may have important implications for future care, although the recommended medical regimen should be continued in most cases. Improvement may reflect recovery from a previous condition, such as viral myocarditis or hypothyroidism, or may occur after titration of recommended therapies for chronic HF. Thus, it is appropriate to obtain a repeat EF after some period of optimal medical therapy, typically 4 to 6 months, to decide about the implantation of an implantable cardioverter-defibrillator (ICD). Deterioration may reflect gradual disease progression or a new event, such as recurrent MI. Routine assessment of EF at frequent, regular, or arbitrary intervals is not recommended.

There has been no established role for periodic invasive or noninvasive hemodynamic measurements in the management of HF. Most drugs used for the treatment of HF are prescribed on the basis of their ability to improve symptoms or survival rather than their effect on hemodynamic variables. Moreover, the initial and target doses of these drugs are selected on the basis of experience in controlled trials and are not based on the changes they may produce in cardiac output or pulmonary wedge pressure. Nevertheless, invasive hemodynamic measurements may assist in the determination of volume status and in distinguishing HF from other disorders that may cause circulatory instability, such as pulmonary diseases and sepsis. Measurements of cardiac output and pulmonary wedge pressure through a pulmonary artery catheter have also been used in patients with refractory HF to assess pulmonary vascular resistance, a determinant of eligibility for heart transplantation. Cardiac output can also be measured by noninvasive methods.

3.2.4 Assessment of Prognosis (UPDATED)

Although both healthcare providers and patients may be interested in defining the prognosis of an individual patient with HF, the likelihood of survival can be determined reliably only in populations and not in individuals. However, some attempt at prognostication in HF may provide better information for patients and their families to help them appropriately plan for their futures. It also identifies patients in whom cardiac transplantation or mechanical device therapy should be considered.

Multivariate analysis of clinical variables has helped to identify the most significant predictors of survival, and prognostic models have been developed and validated (66). Decreasing LVEF, worsening NYHA functional status, degree of hyponatremia, decreasing peak exercise oxygen uptake, decreasing hematocrit, widened QRS on 12-lead electrocardiogram, chronic hypotension, resting tachycardia, renal insufficiency, intolerance to conventional therapy, and refractory volume overload are all generally recognized key prognostic parameters, although the actual prognostic models incorporating them are not widely used in clinical practice (66,67). Although elevated circulating levels of neurohormonal factors have also been associated with high mortality rates, the routine assessment of neurohormones such as norepinephrine or endothelin is neither feasible nor helpful in clinical management. Likewise, elevated BNP (or NT-proBNP) levels predict higher risk of HF and other events after MI, whereas marked elevation in BNP levels during hospitalization for HF may predict rehospitalization and death. Nonetheless, the BNP measurement has not been clearly shown to supplement careful clinical assessment for management.

Because treatment of HF has improved over the past 10 years, the older prognostic models need to be revalidated (68), and newer prognostic models may have to be developed. Outcomes have been improved for most high-risk patients, which has resulted in a shift in the selection process for patients referred for heart transplantation (68). Routine use of ambulatory electrocardiographic monitoring, T-wave alternans analysis, heart rate variability measurement, and signal-averaged electrocardiography have not been shown to provide incremental value in assessing overall prognosis, although ambulatory electrocardiographic monitoring can be useful in decision making regarding placement of ICDs (69).

Class I

• 1. In patients at high risk for developing HF, systolic and diastolic hypertension should be controlled in accordance with contemporary guidelines. (Level of Evidence: A)

• 2. In patients at high risk for developing HF, lipid disorders should be treated in accordance with contemporary guidelines. (Level of Evidence: A)

• 3. For patients with diabetes mellitus (who are all at high risk for developing HF), blood sugar should be controlled in accordance with contemporary guidelines. (Level of Evidence: C)

• 4. Patients at high risk for developing HF should be counseled to avoid behaviors that may increase the risk of HF (e.g., smoking, excessive alcohol consumption, and illicit drug use). (Level of Evidence: C)

• 5. Ventricular rate should be controlled or sinus rhythm restored in patients with supraventricular tachyarrhythmias who are at high risk for developing HF. (Level of Evidence: B)

• 6. Thyroid disorders should be treated in accordance with contemporary guidelines in patients at high risk for developing HF. (Level of Evidence: C)

• 7. Healthcare providers should perform periodic evaluation for signs and symptoms of HF in patients at high risk for developing HF. (Level of Evidence: C)

• 8. In patients at high risk for developing HF who have known atherosclerotic vascular disease, healthcare providers should follow current guidelines for secondary prevention. (Level of Evidence: C)

• 9. Healthcare providers should perform a noninvasive evaluation of LV function (i.e., LVEF) in patients with a strong family history of cardiomyopathy or in those receiving cardiotoxic interventions. (Level of Evidence: C)

Class IIa

• 1. Angiotensin converting enzyme inhibitors can be useful to prevent HF in patients at high risk for developing HF who have a history of atherosclerotic vascular disease, diabetes mellitus, or hypertension with associated cardiovascular risk factors. (Level of Evidence: A)

• 2. Angiotensin II receptor blockers can be useful to prevent HF in patients at high risk for developing HF who have a history of atherosclerotic vascular disease, diabetes mellitus, or hypertension with associated cardiovascular risk factors. (Level of Evidence: C)

Class III

• 1. Routine use of nutritional supplements solely to prevent the development of structural heart disease should not be recommended for patients at high risk for developing HF. (Level of Evidence: C)

Table 3describes cardiovascular medications useful for treatment of various stages of HF. Many conditions or behaviors that are associated with an increased risk of structural heart disease can be identified before patients show any evidence of structural abnormalities. Because early modification of many of these factors can reduce the risk of HF, the recommendation of appropriate medical interventions to patients with these risk factors provides the earliest opportunity to reduce the impact of HF on public and individual health.

4.1.1 Control of Risk

4.1.2 Early Detection of Structural Abnormalities

Asymptomatic patients with ventricular dilatation and reduced LVEF carry substantially higher risk for subsequent morbidity and mortality than the general population. It would be desirable to construct cost-effective strategies to identify such patients in the interest of reducing their subsequent risk.

Limited information is available to support the cost-effectiveness of broad population screening. Brain natriuretic peptide levels represent a potential tool for this purpose (112). An analysis of the implications of elevated BNP has suggested that the screening of asymptomatic people over the age of 60 years with this blood test could yield cost-effective improvement in clinical outcomes across the population (113). Certain patients are appropriate targets for more aggressive screening on the basis of characteristics that denote an increase in the risk for structural heart disease. Healthcare professionals should perform echocardiographic evaluation in selected patients without apparent structural heart disease who are at very high risk of a cardiomyopathy (e.g., those with a strong family history of cardiomyopathy or those receiving cardiotoxic interventions) (114,115). Routine periodic assessment of LV function in other patients is not recommended.

Class I

• 1. All Class I recommendations for Stage A should apply to patients with cardiac structural abnormalities who have not developed HF. (Levels of Evidence: A, B, and C as appropriate)

• 2. Beta blockers and ACEIs should be used in all patients with a recent or remote history of MI regardless of EF or presence of HF (seeTable 3). (Level of Evidence: A)

• 3. Beta blockers are indicated in all patients without a history of MI who have a reduced LVEF with no HF symptoms (seeTable 3and text). (Level of Evidence: C)

• 4. Angiotensin converting enzyme inhibitors should be used in patients with a reduced EF and no symptoms of HF, even if they have not experienced MI. (Level of Evidence: A)

• 5. An ARB should be administered to post-MI patients without HF who are intolerant of ACEIs and have a low LVEF. (Level of Evidence: B)

• 6. Patients who have not developed HF symptoms should be treated according to contemporary guidelines after an acute MI. (Level of Evidence: C)

• 7. Coronary revascularization should be recommended in appropriate patients without symptoms of HF in accordance with contemporary guidelines (see ACC/AHA/ACP-ASIM Guidelines for the Management of Patients With Chronic Stable Angina [712]). (Level of Evidence: A)

• 8. Valve replacement or repair should be recommended for patients with hemodynamically significant valvular stenosis or regurgitation and no symptoms of HF in accordance with contemporary guidelines. (Level of Evidence: B)

Class IIa

• 1. Angiotensin converting enzyme inhibitors or ARBs can be beneficial in patients with hypertension and LVH and no symptoms of HF. (Level of Evidence: B)

• 2. Angiotensin II receptor blockers can be beneficial in patients with low EF and no symptoms of HF who are intolerant of ACEIs. (Level of Evidence: C)

• 3. Placement of an ICD is reasonable in patients with ischemic cardiomyopathy who are at least 40 days post-MI, have an LVEF of 30% or less, are NYHA functional class I on chronic optimal medical therapy, and have reasonable expectation of survival with a good functional status for more than 1 year. (Level of Evidence: B)

Class IIb

• 1. Placement of an ICD might be considered in patients without HF who have nonischemic cardiomyopathy and an LVEF less than or equal to 30% who are in NYHA functional class I with chronic optimal medical therapy and have a reasonable expectation of survival with good functional status for more than 1 year. (Level of Evidence: C)

Class III

• 1. Digoxin should not be used in patients with low EF, sinus rhythm, and no history of HF symptoms, because in this population, the risk of harm is not balanced by any known benefit. (Level of Evidence: C)

• 2. Use of nutritional supplements to treat structural heart disease or to prevent the development of symptoms of HF is not recommended. (Level of Evidence: C)

• 3. Calcium channel blockers with negative inotropic effects may be harmful in asymptomatic patients with low LVEF and no symptoms of HF after MI (see text in Stage C). (Level of Evidence: C)

Patients without HF symptoms but who have had an MI or who have evidence of LV remodeling are at considerable risk of developing HF (116,117). In such patients, the incidence of HF can be decreased by reducing the risk of additional injury and by retarding the evolution and progression of LV remodeling. Initial appropriate measures include those listed as Class I recommendations for patients in Stage A (also see Section 5).

As is the case with patients who have no structural heart disease, there is no evidence that the use of nutritional supplements can prevent the development of HF in patients with a recent or remote MI with or without LV remodeling. The aldosterone antagonist eplerenone has been shown to reduce morbidity and mortality in a population of patients with low EF and HF after MI that has already been treated with ACEIs and beta blockers (118,119). Other preventive measures have been addressed in related guidelines (120).

4.2.1 Prevention of Cardiovascular Events

4.2.2 Early Detection of Heart Failure

As noted, the symptoms and signs of HF are often difficult to identify because they are frequently confused with other disorders or are attributed to aging, obesity, or lack of conditioning. Limitations of exercise tolerance can occur so gradually that patients may adapt their lifestyles (consciously or subconsciously) to minimize symptoms and thus fail to report them to healthcare providers. Hence, patients at risk should be advised to inform their healthcare providers about limitations of exercise tolerance or unexplained fatigue, and healthcare providers should intensify their vigilance for the signs and symptoms of HF in such individuals.

4.3.1 Patients With Reduced Left Ventricular Ejection Fraction (UPDATED)

Changes in this section focused on 3 areas: recommendations about electrical device therapy (e.g., cardiac resynchronization therapy [CRT] and ICDs), the use of a fixed dose combination of hydralazine and isosorbide dinitrate in self-identified African Americans, and the management of atrial fibrillation in patients with HF. The previous version of the guidelines had a number of possibly confusing recommendations about selection of patients for ICD implantation. The writing group has tried to simplify the recommendations, and keep them concordant with the most recent guidelines covering the same issue (69,144). Updated trial information has led to the change in the recommendations about the use of hydralazine/isosorbide dinitrate and about the management of atrial fibrillation (Table 3).

Recommendations

4.3.2 Patients With Heart Failure and Normal Left Ventricular Ejection Fraction

Recommendations

Class I

• 1. Meticulous identification and control of fluid retention is recommended in patients with refractory end-stage HF (279,282,527–532). (Level of Evidence: B)

• 2. Referral for cardiac transplantation in potentially eligible patients is recommended for patients with refractory end-stage HF (533). (Level of Evidence: B)

• 3. Referral of patients with refractory end-stage HF to a HF program with expertise in the management of refractory HF is useful (534–537). (Level of Evidence: A)

• 4. Options for end-of-life care should be discussed with the patient and family when severe symptoms in patients with refractory end-stage HF persist despite application of all recommended therapies. (Level of Evidence: C)

• 5. Patients with refractory end-stage HF and implantable defibrillators should receive information about the option to inactivate the defibrillator. (Level of Evidence: C)

Class IIa

• 1. Consideration of an LV assist device as permanent or “destination” therapy is reasonable in highly selected patients with refractory end-stage HF and an estimated 1-year mortality over 50% with medical therapy (538,539). (Level of Evidence: B)

Class IIb

• 1. Pulmonary artery catheter placement may be reasonable to guide therapy in patients with refractory end-stage HF and persistently severe symptoms (533,540). (Level of Evidence: C)

• 2. The effectiveness of mitral valve repair or replacement is not well established for severe secondary mitral regurgitation in refractory end-stage HF (141 541,542). (Level of Evidence: C)

• 3. Continuous intravenous infusion of a positive inotropic agent may be considered for palliation of symptoms in patients with refractory end-stage HF (543,544). (Level of Evidence: C)

Class III

• 1. Partial left ventriculectomy is not recommended in patients with nonischemic cardiomyopathy and refractory end-stage HF. (Level of Evidence: C)

• 2. Routine intermittent infusions of vasoactive and positive inotropic agents are not recommended for patients with refractory end-stage HF (545,546). (Level of Evidence: A)

Most patients with HF due to reduced LVEF respond favorably to pharmacological and nonpharmacological treatments and enjoy a good quality of life and enhanced survival; however, some patients do not improve or experience rapid recurrence of symptoms despite optimal medical therapy. Such patients characteristically have symptoms at rest or on minimal exertion, including profound fatigue; cannot perform most activities of daily living; frequently have evidence of cardiac cachexia; and typically require repeated and/or prolonged hospitalizations for intensive management. These individuals represent the most advanced stage of HF and should be considered for specialized treatment strategies, such as mechanical circulatory support, continuous intravenous positive inotropic therapy, referral for cardiac transplantation, or hospice care.

Before a patient is considered to have refractory HF, physicians should confirm the accuracy of the diagnosis, identify any contributing conditions, and ensure that all conventional medical strategies have been optimally employed. Measures listed as Class I recommendations for patients in stages A, B, and C are also appropriate for patients in end-stage HF (see also Section 5). When no further therapies are appropriate, careful discussion of the prognosis and options for end-of-life care should be initiated (see Section 7).

4.4.1 Management of Fluid Status

Many patients with advanced HF have symptoms that are related to the retention of salt and water and thus will respond favorably to interventions designed to restore sodium balance. Hence, a critical step in the successful management of end-stage HF is the recognition and meticulous control of fluid retention.

In most patients with chronic HF, volume overload can be treated adequately with low doses of a loop diuretic combined with moderate dietary sodium restriction; however, as HF advances, the accompanying decline in renal perfusion can limit the ability of the kidneys to respond to diuretic therapy (263,275). In such patients, the control of fluid retention may require progressive increments in the dose of a loop diuretic and frequently the addition of a second diuretic that has a complementary mode of action (e.g., metolazone) (283,285). If the patient continues to exhibit evidence of volume overload despite these measures, hospitalization is generally required for further adjustment of therapy (282,527), possibly including intravenous dopamine or dobutamine. This strategy can elicit a marked increase in urine volume, but such a diuresis is frequently accompanied by worsening azotemia, especially if patients are also being treated with an ACEI. Provided that renal function stabilizes, small or moderate elevations of blood urea nitrogen and serum creatinine should not lead to efforts to minimize the intensity of therapy; however, if the degree of renal dysfunction is severe or if the edema becomes resistant to treatment, ultrafiltration or hemofiltration may be needed to achieve adequate control of fluid retention (547,548). The use of such mechanical methods of fluid removal can produce meaningful clinical bene fits in patients with diuretic-resistant HF and may restore responsiveness to conventional doses of loop diuretics.

In general, patients should not be discharged from the hospital until a stable and effective diuretic regimen is established, and ideally, not until euvolemia is achieved. Patients who are sent home before these goals are reached are at high risk of recurrence of fluid retention and early readmission (549), because unresolved edema may itself attenuate the response to diuretics (278–280). Once euvolemia is achieved, the patient's dry weight can be defined and used as a continuing target for the adjustment of diuretic doses. Many patients are able to modify their own diuretic regimen in response to changes in weight that exceed a predefined range. The restriction of dietary sodium (to 2 g daily or less) can greatly assist in the maintenance of volume balance.

Patients with persistent or recurrent fluid retention despite sodium restriction and high-dose diuretic use may benefit from review of fluid intake and restriction to 2 liters daily. The ongoing control of fluid retention may be enhanced by enrollment in an HF program, which can provide the close surveillance and education needed for the early recognition and treatment of volume overload (258–261).

4.4.2 Utilization of Neurohormonal Inhibitors

Controlled trials suggest that patients with advanced HF respond favorably to treatment with both ACEIs and beta blockers in a manner similar to those with mild to moderate disease (155,158,162–165,297,298,300–302,305,310–321,336–343,550). However, because neurohormonal mechanisms play an important role in the support of circulatory homeostasis as HF progresses, neurohormonal antagonism may be less well tolerated by patients with severe symptoms than by patients with mild symptoms. Patients who are at the end stage of their disease are at particular risk of developing hypotension and renal insufficiency after the administration of an ACEI and of experiencing worsening HF after treatment with a beta blocker. As a result, patients with refractory HF may tolerate only small doses of these neurohormonal antagonists or may not tolerate them at all.

Consequently, physicians should exercise great care when considering the use of both ACEIs and beta blockers in patients with refractory HF. Treatment with either type of drug should not be initiated in patients who have systolic blood pressures less than 80 mm Hg or who have signs of peripheral hypoperfusion. In addition, patients should not be started on a beta blocker if they have significant fluid retention or if they recently required treatment with an intravenous positive inotropic agent. Treatment with an ACEI or beta blocker should be initiated in very low doses, and patients should be monitored closely for signs or symptoms of intolerance. If low doses are tolerated, further dosage increments may be considered but may not be tolerated. However, clinical trials with lisinopril and carvedilol suggest that even low doses of these drugs may provide important benefits (174,551).

Alternative pharmacological treatments may be considered for patients who cannot tolerate ACEIs or beta-blockers. A combination of nitrates and hydralazine has been reported to have favorable effects on survival in patients with mild to moderate symptoms who were not taking an ACEI or a beta blocker (238), but the utility of this vasodilator combination in patients with end-stage disease who are being given these neurohormonal antagonists remains unknown. In addition, many patients experience headaches or gastrointestinal distress with these direct-acting vasodilators, which can prevent patients from undergoing long-term treatment. Spironolactone has been reported to prolong life and reduce the risk of hospitalization for HF in patients with advanced disease (256); however, the evidence supporting the use of the drug has been derived in patients who have preserved renal function, and the drug can produce dangerous hyperkalemia in patients with impaired renal function. Finally, although ARBs (325) are frequently considered as alternatives to ACEIs because of the low incidence of cough and angioedema with these medications, it is not clear that ARBs are as effective as ACEIs, and they are as likely as ACEIs to produce hypotension or renal insufficiency (297,552).

4.4.3 Intravenous Peripheral Vasodilators and Positive Inotropic Agents (UPDATED)

Patients with refractory HF are hospitalized frequently for clinical deterioration, and during such admissions, they commonly receive infusions of both positive inotropic agents (dobutamine, dopamine, or milrinone) and vasodilator drugs (nitroglycerin, nitroprusside, or nesiritide) in an effort to improve cardiac performance, facilitate diuresis, and promote clinical stability. Some physicians have advocated the placement of pulmonary artery catheters in patients with refractory HF, with the goal of obtaining hemodynamic measurements that might be used to guide the selection and titration of therapeutic agents (540). However, the logic of this approach has been questioned, because many useful drugs for HF produce benefits by mechanisms that cannot be evaluated by measuring their short-term hemodynamic effects (352,553). Regardless of whether invasive hemodynamic monitoring is used, once the clinical status of the patient has stabilized, every effort should be made to devise an oral regimen that can maintain symptomatic improvement and reduce the subsequent risk of deterioration. Assessment of the adequacy and tolerability of orally based strategies may necessitate observation in the hospital for at least 48 hours after the infusions are discontinued (554).

Patients who cannot be weaned from intravenous to oral therapy despite repeated attempts may require placement of an indwelling intravenous catheter to allow for the continuous infusion of dobutamine or milrinone or, as has been used more recently, nesiritide. Such a strategy is commonly used in patients who are awaiting cardiac transplantation, but it may also be used in the outpatient setting in patients who otherwise cannot be discharged from the hospital. The decision to continue intravenous infusions at home should not be made until all alternative attempts to achieve stability have failed repeatedly, because such an approach can present a major burden to the family and health services and may ultimately increase the risk of death. However, continuous intravenous support may provide palliation of symptoms as part of an overall plan to allow the patient to die with comfort at home (543,544). The use of continuous intravenous support to allow hospital discharge should be distinguished from the intermittent administration of infusions of such agents to patients who have been successfully weaned from inotropic support (536). Intermittent outpatient infusions of either vasoactive drugs such as nesiritide or positive inotropic drugs have not shown to improve symptoms or survival in patients with advanced HF (536,545,546).

4.4.4 Mechanical and Surgical Strategies

Cardiac transplantation is currently the only established surgical approach to the treatment of refractory HF, but it is available to fewer than 2500 patients in the United States each year (555,556). Current indications for cardiac transplantation focus on the identification of patients with severe functional impairment or dependence on intravenous inotropic agents (Table 10).Less common indications for cardiac transplantation include recurrent life-threatening ventricular arrhythmias or angina that is refractory to all currently available treatments (557).

Alternative surgical and mechanical approaches for the treatment of end-stage HF are under development. Clinical improvement has been reported after mitral valve repair or replacement in patients who have a clinically important degree of mitral regurgitation that is secondary to LV dilatation (141). However, no controlled studies have evaluated the effects of this procedure on ventricular function, clinical status, or survival. One recent single-center report of a nonrandomized series of patients considered appropriate candidates for mitral valve repair did not demonstrate a survival advantage (541).

Although both cardiomyoplasty and left ventriculectomy (Batista procedure) at one time generated considerable excitement as potential surgical approaches to the treatment of refractory HF (558,559), these procedures failed to result in clinical improvement and were associated with a high risk of death (560). A variant of the aneurysmectomy procedure is now being developed for the management of patients with ischemic cardiomyopathy (458), but its role in the management of HF remains to be defined. None of the current surgical reconstruction techniques offer “rescue therapy” to patients with critical hemodynamic compromise.

The use of mechanical circulatory assist devices in endstage HF is an area of intense investigation. Extracorporeal devices can be used for short-term circulatory support in patients who are expected to recover from a major cardiac insult (e.g., myocardial ischemia, postcardiotomy shock, or fulminant myocarditis). Left ventricular assist devices provide similar degrees of hemodynamic support; many are implantable and thus allow for long-term support, patient ambulation, and hospital discharge (561). Most clinical experience with these devices has been derived from their use in patients being “bridged” to transplant. The completion of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial investigated the use of these devices as permanent or “destination” therapy in selected non–transplant-eligible patients.

This trial enrolled 129 patients, for whom 2-year survival was 23% in the 68 patients treated with the device and 8% in the 61 patients who received medical therapy (562). Device-related adverse events were numerous and included bleeding, infection, thromboembolic events, and device failure. This trial established the efficacy of device therapy for end-stage HF. Improvements in newer generations of devices will hopefully permit even further prolongation of survival. Presently, destination device therapy is anticipated to benefit those patients predicted to have a 1-year survival of less than 50%. One such group could be the population of non–transplant-eligible patients requiring continuous intravenous inotropic infusions. Some reports have suggested that prolonged mechanical decompression of the failing heart may occasionally be followed by sufficient recovery of myocardial function to allow explantation of the device (563). Improvements in ventricular mechanics, myocardial energetics, histology, and cell signaling have been reported with LV assist device support. However, the frequency and duration of myocardial recovery have been variable (564), and sufficient recovery to permit device explantation is rare except in a few patients with acute onset of HF and the absence of coronary artery disease. Coupling of device therapy with cell transplantation and a variety of angiogenesis or myocardial growth factors are approaches planned for future investigation.

Many patients with HF are members of subpopulations who are likely to exhibit unique responses that accelerate the development or progression of HF or complicate the management of HF.

Class I

• 1. The diagnosis of HF is primarily based on signs and symptoms derived from a thorough history and physical examination. Clinicians should determine the following:

  • a. adequacy of systemic perfusion;

  • b. volume status;

  • c. the contribution of precipitating factors and/or comorbidities;

  • d. if the heart failure is new onset or an exacerbation of chronic disease; and

  • e. whether it is associated with preserved ejection fraction.

• Chest radiographs, electrocardiogram, and echocardiography are key tests in this assessment. (Level of Evidence: C)

• 2. Concentrations of B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) should be measured in patients being evaluated for dyspnea in which the contribution of HF is not known. Final diagnosis requires interpreting these results in the context of all available clinical data and ought not to be considered a stand-alone test (565,566). (Level of Evidence: A)

• 3. Acute coronary syndrome precipitating HF hospitalization should be promptly identified by electrocardiogram and cardiac troponin testing, and treated as appropriate to the overall condition and prognosis of the patient. (Level of Evidence: C)

• 4. It is recommended that the following common potential precipitating factors for acute HF be identified as recognition of these comorbidities is critical to guide therapy:

  • a. acute coronary syndromes/coronary ischemia;

  • b. severe hypertension;

  • c. atrial and ventricular arrhythmias;

  • d. infections;

  • e. pulmonary emboli;

  • f. renal failure; and

  • g. medical or dietary noncompliance. (Level of Evidence: C)

• 5. Oxygen therapy should be administered to relieve symptoms related to hypoxemia. (Level of Evidence: C)

• 6. Whether the diagnosis of HF is new or chronic, patients who present with rapid decompensation and hypoperfusion associated with decreasing urine output and other manifestations of shock are critically ill and rapid intervention should be used to improve systemic perfusion. (Level of Evidence: C)

• 7. Patients admitted with HF and with evidence of significant fluid overload should be treated with intravenous loop diuretics. Therapy should begin in the emergency department or outpatient clinic without delay, as early intervention may be associated with better outcomes for patients hospitalized with decompensated HF (32,567,568). (Level of Evidence: B) If patients are already receiving loop diuretic therapy, the initial intravenous dose should equal or exceed their chronic oral daily dose. Urine output and signs and symptoms of congestion should be serially assessed, and diuretic dose should be titrated accordingly to relieve symptoms and to reduce extracellular fluid volume excess. (Level of Evidence: C)

• 8. Effect of HF treatment should be monitored with careful measurement of fluid intake and output; vital signs; body weight, determined at the same time each day; clinical signs (supine and standing) and symptoms of systemic perfusion and congestion. Daily serum electrolytes, urea nitrogen, and creatinine concentrations should be measured during the use of IV diuretics or active titration of HF medications. (Level of Evidence: C)

• 9. When diuresis is inadequate to relieve congestion, as evidenced by clinical evaluation, the diuretic regimen should be intensified using either:

  • a. higher doses of loop diuretics;

  • b. addition of a second diuretic (such as metolazone, spironolactone, or intravenous chlorothiazide); or

  • c. continuous infusion of a loop diuretic. (Level of Evidence: C)

• 10. In patients with clinical evidence of hypotension associated with hypoperfusion and obvious evidence of elevated cardiac filling pressures (e.g., elevated jugular venous pressure; elevated pulmonary artery wedge pressure), intravenous inotropic or vasopressor drugs should be administered to maintain systemic perfusion and preserve end-organ performance while more definitive therapy is considered. (Level of Evidence: C)

• 11. Invasive hemodynamic monitoring should be performed to guide therapy in patients who are in respiratory distress or with clinical evidence of impaired perfusion in whom the adequacy or excess of intracardiac filling pressures cannot be determined from clinical assessment. (Level of Evidence: C)

• 12. Medications should be reconciled in every patient and adjusted as appropriate on admission to and discharge from the hospital. (Level of Evidence: C)

• 13. In patients with reduced ejection fraction experiencing a symptomatic exacerbation of HF requiring hospitalization during chronic maintenance treatment with oral therapies known to improve outcomes, particularly ACEIs or ARBs and beta-blocker therapy, it is recommended that these therapies be continued in most patients in the absence of hemodynamic instability or contraindications. (Level of Evidence: C)

• 14. In patients hospitalized with HF with reduced ejection fraction not treated with oral therapies known to improve outcomes, particularly ACEIs or ARBs and beta-blocker therapy, initiation of these therapies is recommended in stable patients prior to hospital discharge (569,570). (Level of Evidence: B)

• 15. Initiation of beta-blocker therapy is recommended after optimization of volume status and successful discontinuation of intravenous diuretics, vasodilators, and inotropic agents. Beta-blocker therapy should be initiated at a low dose and only in stable patients. Particular caution should be used when initiating beta blockers in patients who have required inotropes during their hospital course (569,570). (Level of Evidence: B)

• 16. In all patients hospitalized with HF, both with preserved (see Section 4.3.2, Patients With Heart Failure and Normal Left Ventricular Ejection Fraction) and low EF, transition should be made from intravenous to oral diuretic therapy with careful attention to oral diuretic dosing and monitoring of electrolytes. With all medication changes, the patient should be monitored for supine and upright hypotension, and worsening renal function and HF signs/symptoms. (Level of Evidence: C)

• 17. Comprehensive written discharge instructions for all patients with a hospitalization for HF and their caregivers is strongly recommended, with special emphasis on the following 6 aspects of care: diet; discharge medications, with a special focus on adherence, persistence, and uptitration to recommended doses of ACEI/ARB and beta-blocker medication; activity level; follow-up appointments; daily weight monitoring; and what to do if HF symptoms worsen. (Level of Evidence: C)

• 18. Postdischarge systems of care, if available, should be used to facilitate the transition to effective outpatient care for patients hospitalized with HF (215,571–577). (Level of Evidence: B)

Class IIa

• 1. When patients present with acute HF and known or suspected acute myocardial ischemia due to occlusive coronary disease, especially when there are signs and symptoms of inadequate systemic perfusion, urgent cardiac catheterization and revascularization is reasonable where it is likely to prolong meaningful survival. (Level of Evidence: C)

• 2. In patients with evidence of severely symptomatic fluid overload in the absence of systemic hypotension, vasodilators such as intravenous nitroglycerin, nitroprusside or nesiritide can be beneficial when added to diuretics and/or in those who do not respond to diuretics alone. (Level of Evidence: C)

• 3. Invasive hemodynamic monitoring can be useful for carefully selected patients with acute HF who have persistent symptoms despite empiric adjustment of standard therapies, and

  • a. whose fluid status, perfusion, or systemic or pulmonary vascular resistances are uncertain;

  • b. whose systolic pressure remains low, or is associated with symptoms, despite initial therapy;

  • c. whose renal function is worsening with therapy;

  • d. who require parenteral vasoactive agents; or

  • e. who may need consideration for advanced device therapy or transplantation. (Level of Evidence: C)

• 4. Ultrafiltration is reasonable for patients with refractory congestion not responding to medical therapy (578). (Level of Evidence: B)

Class IIb

• 1. Intravenous inotropic drugs such as dopamine, dobutamine or milrinone might be reasonable for those patients presenting with documented severe systolic dysfunction, low blood pressure and evidence of low cardiac output, with or without congestion, to maintain systemic perfusion and preserve end-organ performance. (Level of Evidence: C)

Class III

• 1. Use of parenteral inotropes in normotensive patients with acute decompensated HF without evidence of decreased organ perfusion is not recommended (579). (Level of Evidence: B)

• 2. Routine use of invasive hemodynamic monitoring in normotensive patients with acute decompensated HF and congestion with symptomatic response to diuretics and vasodilators is not recommended (580). (Level of Evidence: B)

A patient may develop acute or progressive symptoms of HF and require hospitalization. In general, there are 3 clinical profiles that describe the hospitalized patient with HF: 1) the patient with volume overload, manifested by pulmonary and/or systemic congestion, frequently precipitated by an acute increase in chronic hypertension; 2) the patient with profound depression of cardiac output manifested by hypotension, renal insufficiency, and/or a shock syndrome, and 3) the patient with signs and symptoms of both fluid overload and shock. Irrespective of the presenting clinical picture, there have been a confusing variety of terms in the literature used to describe these patients, including acute HF syndrome, acute decompensated HF, or cardiogenic shock. However different these 3 groups of patients may be in outcome, they can all be characterized as having a change in HF signs and symptoms resulting in a need for urgent therapy. Patients with HF and preserved LVEF (see Section 4.3.2, Patients With Heart Failure and Normal Left Ventricular Ejection Fraction) are just as likely to be admitted to hospital as those with HF and low LVEF (581). Admission with HF is often triggered by a concomitant cardiovascular event such as a symptomatic tachyarrhythmia, unstable coronary syndrome, or a cerebrovascular event; often the admission is related to medical or dietary noncompliance. The threshold for admission may also be lowered when HF exacerbation is accompanied with a noncardiac condition such as pneumonia or newly diagnosed anemia. Indeed, it is important to note that concurrent conditions and comorbidities such as coronary artery disease, hypertension, valvular heart disease, arrhythmias, renal dysfunction, diabetes, thromboembolism, and anemia are often present, more so than has usually been described in clinical trials, and may precipitate or contribute to the pathophysiology of the syndrome. Unfortunately, the precipitating event leading to hospitalization is not always readily apparent.

 Common Factors That Precipitate Hospitalization for Heart Failure

• • Noncompliance with medical regimen, sodium and/or fluid restriction

• • Acute myocardial ischemia

• • Uncorrected high blood pressure

• • Atrial fibrillation and other arrhythmias

• • Recent addition of negative inotropic drugs (e.g., verapamil, nifedipine, diltiazem, beta blockers)

• • Pulmonary embolus

• • Nonsteroidal anti-inflammatory drugs

• • Excessive alcohol or illicit drug use

• • Endocrine abnormalities (e.g., diabetes mellitus, hyperthyroidism, hypothyroidism)

• • Concurrent infections (e.g., pneumonia, viral illnesses)

HF hospitalizations account for a substantial portion of the overall costs of caring for patients with HF and may be associated with a staggering degree of morbidity and mortality, particularly in the elderly population. It is evident that the prognosis after an index hospitalization for HF is ominous, with a 50% rate of readmission at 6 months and a 25% to 35% incidence of death at 12 months (582–586). Indeed, many HF trials now incorporate the need for hospitalization as an important endpoint with which to evaluate a new therapy; government agencies and insurance companies are increasingly interested in understanding the frequency of repeat HF hospitalizations. Thus, it is important to outline what should occur in the hospital for the HF patient requiring therapy. The scope of these recommendations are based on evidence from the few available randomized trials evaluating management strategies in the acute decompensated HF patient (461,578–580,587), analyses of large registries, and consensus opinion. Additional and more comprehensive information on this subject may be found in the guidelines from the Heart Failure Society of America and the European Society of Cardiology (588,589,589a).

4.5.1 Diagnostic Strategies

The diagnosis of HF in the hospitalized patient should be based primarily on signs and symptoms, as discussed in Section 3.1., Initial Evaluation of Patients. Clinicians need to determine as accurately and as quickly as possible 1) the volume status of the patient, 2) the adequacy of circulatory support or perfusion, and 3) the role or presence of precipitating factors and/or comorbidities. In the patient with previously established HF, efforts should likewise be directed toward understanding what has caused the apparent acute worsening of clinical symptoms. Many of the steps in this investigation are identical to those used in the initial evaluation of HF (see Sections 3.1.3, Evaluation of the Cause of Heart Failure and 3.2, Ongoing Evaluation of Patients). When the diagnosis of HF is uncertain, determination of plasma BNP or NT-proBNP concentration should be considered in patients being evaluated for dyspnea who have signs and symptoms compatible with HF. The natriuretic peptide concentration should not be interpreted in isolation but in the context of all available clinical data bearing on the diagnosis of HF.

An important cause of worsening HF, and for new-onset HF, is an acute MI. Because many patients admitted with acute HF have coronary artery disease, troponins are typically evaluated at admission for acute exacerbation. Actual criteria for an acute coronary event that may indicate the need for further intervention may be present in up to 20% of patients (590,591). However, many other patients may have low levels of detectable troponins not meeting criteria for an acute ischemic event but typical of chronic HF with an acute exacerbation (592). Registry data have suggested that the use of coronary angiography is low for patients hospitalized with decompensated HF and opportunities to diagnose important coronary artery disease may be missed. Symptoms of HF or cardiogenic shock associated with an ischemic event are covered in other guidelines (10,593) and are beyond the scope of this update. For the patient with newly discovered HF, clinicians should be aware of the important role of coronary artery disease in causing HF and should be certain that coronary structure and function are well delineated (see Section 3.1.2, Identification of a Structural and Functional Abnormality) while simultaneously beginning treatment. Coronary visualization may be an important part of the evaluation of patients hospitalized with HF.

Often, patients with chronic HF are admitted with acute decompensation from a number of possible precipitating causes. Clinicians should carefully review the patient's maintenance HF medications and decide whether adjustments should be made as a result of the hospitalization. The large majority of patients with HF admitted to the hospital, especially those with concomitant hypertension, should have their oral therapy continued, or even uptitrated, during hospitalization. It is important to note that it has been shown that continuation of beta blockers for most patients is well tolerated and results in better outcomes (569,570). Withholding of or reduction in beta-blocker therapy should be considered only in patients hospitalized after recent initiation or increase in beta-blocker therapy or with marked volume overload. Patients admitted with worsening azotemia should be considered for a reduction in or temporary discontinuation of their ACEIs, ARBs, and/or aldosterone antagonists until renal function improves. Patients with marked volume overload will require intravenous diuretic therapy with uptitration of diuretic dose and/or addition of synergistic diuretic agents. It should be noted that uptitration of ACEIs or beta blockers during decompensation may reduce the efficacy of the acute interventions to relieve congestion. Although it is important to ensure that evidence-based medications are instituted prior to the patient leaving the hospital, it is equally as critical to reassess medications on admission and to adjust their administration in light of the worsening HF.

4.5.2 Treatment in the Hospital

4.5.3 The Hospital Discharge

To ensure safe, high-quality, and efficient care for patients following hospitalization for HF, the consistent use of clinical practice guidelines developed by the ACCF, the AHA, and the Heart Failure Society of America should be promoted during and after the hospital stay. One critical performance measure for care coordination and transition is that of written discharge instructions or educational material given to patient and/or caregiver at discharge to home or during the hospital stay addressing all of the following: activity level, diet, discharge medications, follow-up appointment, weight monitoring, and what to do if symptoms worsen (616). Education of HF patients and their families is critical and often complex. Failure of these patients to understand how best to comply with physician's and other healthcare providers' instructions is often a cause of HF exacerbation leading to subsequent hospital readmission.

Large registries of hospitalized HF patients suggest that many patients are discharged before optimal volume status is achieved, or sent home without the benefit of life-saving therapies such as ACE/ARB and beta-blocker medications. Among hospitals providing care for patients with HF, there is significant individual variability in conformity to quality-of-care indicators and clinical outcomes and a substantial gap in overall performance (617). Patients are discharged without adequate control of their blood pressure or the ventricular response to atrial fibrillation. Often, the treating clinician fails to appreciate the severity of the HF process or delays diagnostic testing until the patient is seen as an outpatient. These problems, and others, may account for the high rate of HF rehospitalizations seen in the United States.

It is, therefore, incumbent on healthcare professionals to be certain that patients and their families have an understanding of the causes of HF, prognosis, therapy, dietary restrictions, activity, importance of compliance, and signs and symptoms of recurrent HF. Thorough discharge planning that includes a special emphasis on ensuring compliance with an evidence-based medication regimen (571) is associated with improved patient outcomes (572,618,619).

Several studies have examined the effect of providing more intensive delivery of discharge instructions coupled tightly with subsequent well-coordinated follow-up care for patients hospitalized with HF, many with positive results (215,573–575). Comprehensive discharge planning plus postdischarge support for older patients with HF can significantly reduce readmission rates and may improve health outcomes such as survival and quality of life without increasing costs. A meta-analysis (576) of 18 studies representing data from 8 countries randomized 3304 older inpatients with HF to comprehensive discharge planning plus postdischarge support or usual care. During a mean observation period of 8 months, fewer intervention patients were readmitted compared with controls. Analysis of studies reporting secondary outcomes found a trend toward lower all-cause mortality, length of stay, hospital costs, and improvement in quality-of-life scores for patients assigned to an intervention compared with usual care. One other important study (577) focusing on hospital discharge for patients with HF demonstrated that the addition of a 1-hour, nurse educator–delivered teaching session at the time of hospital discharge using standardized instructions resulted in improved clinical outcomes, increased self-care measure adherence, and reduced cost of care. Patients receiving the education intervention had a lower risk of rehospitalization or death and lower costs of care.

The importance of patient safety for all patients hospitalized with HF cannot be overemphasized. Meaningful evidence has facilitated a much better understanding of the systems changes necessary to achieve safer care. This includes the adoption by all U.S. hospitals of a standardized set of 30 “Safe Practices” endorsed by the National Quality Forum (620), which overlap in many ways with the National Patient Safety Goals espoused by The Joint Commission (621). Improved communication between physicians and nurses, medication reconciliation, transitions between care settings, and consistent documentation are examples of patient safety standards that should be ensured for patients discharged from the hospital with HF. Care information, especially changes in orders and new diagnostic information, must be transmitted in a timely and clearly understandable form to all of the patient's current healthcare providers who need that information to provide follow-up care.

Hospitalization is in and of itself an independent risk factor for shortened survival in patients with chronic HF. Hence, appropriate levels of symptomatic relief, support, and palliative care for patients with chronic HF should be addressed as an ongoing key component of their plan of care, especially when hospitalized with acute decompensation (622). Fortunately, most US hospitals today have direct access to palliative care services (623). Good evidence exists for the critical importance of delivering comprehensive supportive care to these patients, including the assessment and treatment of dyspnea and physiological issues including anxiety and depression (624,625,625a,625b).

6.1.1 Hypertension, Hyperlipidemia, and Diabetes Mellitus

Approximately two thirds of patients with HF have a past or current history of hypertension, and approximately one third have diabetes mellitus (674). Both disorders can contribute to the development of systolic or diastolic dysfunction (675,676), either directly or by contributing (together with hyperlipidemia) to the development of coronary artery disease (677,678). Long-term treatment of both hypertension and hyperlipidemia decreases the risk of developing HF (72,73,679,680). In a large-scale trial, the administration of a lipid-lowering agent to patients with hypercholesterolemia and a history of MI reduced all-cause mortality and the risk of developing HF (679). In 2 large-scale multicenter studies, the treatment of hypertension reduced both the risk of death and the risk of HF; this was true regardless of whether the elevation of blood pressure was primarily systolic or diastolic (72,73,680). The benefits of lowering blood pressure may be particularly marked in patients with diabetes mellitus (80,82,681).

Heart failure may complicate the management of both hypertension and diabetes mellitus. Some antihypertensive agents should be avoided in patients with HF because of their ability to depress cardiac function or to lead to salt and water retention. In addition, HF itself is associated with resistance to the actions of insulin (682,683), and the resulting hyperinsulinemia may promote both cardiac and vascular hypertrophy (684–686) and thus may hasten the progression of HF. These mechanisms may compound the deleterious effects of accelerated atherosclerosis and altered energy metabolism on cardiac function and may help to explain why diabetic patients with HF have a worse prognosis than their nondiabetic counterparts (92).

Thiazolidinediones have been associated with increased peripheral edema and symptomatic HF in patients with underlying risk factors or known cardiovascular disease. The risk of developing edema with thiazolidinediones is dose related and is higher in diabetic patients who are taking concomitant insulin therapy. However, the incidence of thiazolidinedione-related fluid retention is low in patients with NYHA functional class I to II symptoms, in whom these drugs can be administered safely with careful monitoring for fluid retention. Initiation of these drugs is not recommended in patients with NYHA functional class III to IV symptoms of HF. Clinical experience has shown that one side effect of newer oral agents of the thiazolidinedione class is weight gain, which is due in part to fluid retention. This effect may have the potential to precipitate or exacerbate HF in patients with reduced cardiac reserve. Thiazolidinediones probably should be used with caution in such patients (687,688).

 Recommendations Concerning Management.Little is known about the benefits of treating hypertension, hypercholesterolemia, or diabetes mellitus in patients with established reduced LVEF and symptoms of HF. The lack of such data is noteworthy, both because the progression of HF is frequently associated with decreases in blood pressure (due to deterioration of cardiac performance) and decreases in serum lipids (due to development of cardiac cachexia) (679) and because the benefits of drugs used to lower blood pressure or blood lipids may be seen only during prolonged periods of treatment (i.e., those that exceed the expected life span of many patients with HF) (72,73,679,680). Nevertheless, it is prudent to manage hypertension, hypercholesterolemia, and diabetes mellitus in patients with HF as if the patients did not have HF. This may be particularly true in patients with HF and preserved LVEF, whose symptoms may respond particularly well to treatments that lower blood pressure (689,690). Renal artery stenosis should be considered in patients with hypertension and HF, because renal artery stenting can treat both conditions.

Drugs that can both control blood pressure and treat HF should be preferred in patients with both conditions; this includes the use of diuretics, ACEIs, and beta blockers. In contrast, physicians should avoid the use of most calcium channel blockers, because of their cardiodepressant effects, or potent direct-acting vasodilators such as minoxidil, because of their sodium-retaining effects.

The drugs routinely used in the management of HF in nondiabetic patients should be administered to those with diabetes mellitus. Angiotensin converting enzyme inhibitors and beta blockers prevent the progression of HF in diabetic and nondiabetic patients (157,162,691). Physicians should not avoid the use of beta blockers in diabetic patients despite fears that these drugs may mask symptoms of hypoglycemia produced by antidiabetic therapy or may exacerbate glucose intolerance or insulin resistance.

6.1.2 Coronary Artery Disease

Approximately two thirds of patients with HF have underlying coronary artery disease, which may limit exercise tolerance by causing angina pectoris or may lead to further myocardial injury by causing an MI. Therefore, physicians should manage both the symptomatic and prognostic consequences of the patient's underlying coronary artery disease in accordance with contemporary guidelines.

Recommendations Concerning Management of Patients With Angina Pectoris.In general, patients who have both angina pectoris and HF should be given drugs that relieve angina along with drugs that are appropriate in the management of HF (692). Both nitrates and beta blockers can improve anginal symptoms and may produce hemodynamic and clinical benefits in patients with reduced LVEF, and thus, they are preferred if these conditions coexist (158,162,164,693,694). Yet, the combination of the 2 drugs may produce little improvement in anginal pain unless fluid retention is adequately controlled with diuretics. It is therefore noteworthy that the decrease in ventricular volume and pressures produced by diuretics may exert independent antianginal effects (695).

Some have suggested that the systemic and coronary vasodilator actions of calcium channel blockers might improve cardiac performance and relieve myocardial ischemia, but these theoretical advantages have not been translated into clinical benefits in controlled clinical trials in HF (696–698). These drugs have not improved symptoms of HF or enhanced exercise tolerance (695–699), and short- and long-term treatment with these drugs (even the use of sustained-release or vasoselective preparations) has increased the risk of worsening HF and death in patients with LV dysfunction (135,700–708). Therefore, most calcium channel blockers should be avoided in patients with HF, even when used for the treatment of angina or hypertension. Of available agents, only amlodipine has been shown not to adversely affect survival, although experience with the drug exists largely in patients who are not taking beta blockers (242).

In patients with both HF and angina pectoris, strong consideration should be given to the use of coronary revascularization. Coronary revascularization can relieve symptoms of myocardial ischemia (709,710), and coronary artery bypass surgery has been shown to lessen angina and reduce the risk of death in patients who have multivessel disease, reduced LVEF, and stable angina (711) (see the ACC/AHA/ACPASIM Guidelines for the Management of Patients With Chronic Stable Angina [712] or the ACC/AHA 2004 Guideline Update for Coronary Artery Bypass Graft Surgery [16]).

Recommendations Concerning Management of Patients Without Angina.In patients with a prior MI but without HF or angina, 4 types of interventions have been used to reduce the risk of reinfarction and death: neurohormonal antagonists such as ACEIs and beta blockers (83,123,124,129); drugs to address dyslipidemia, such as statins; antiplatelet drugs such as aspirin and clopidogrel (310,312); and coronary revascularization (709). In patients who have had an MI and who have HF but not angina, the use of ACEIs and beta blockers can also decrease the risk of reinfarction and death (126–128,713,714), but it is less clear whether such patients benefit from the use of aspirin or revascularization.

Aspirin has been shown to reduce the risk of major ischemic events in patients without HF. The role of aspirin in patients with HF has not been established (709), and concerns have been raised that it may attenuate the hemodynamic and survival benefits of ACEIs (303,306,307). For these reasons, the role of aspirin in preventing ischemic events in patients with chronic HF is controversial (see Section 4.3.1.2.2.1). Alternative antiplatelet agents (e.g., clopidogrel) may not interact adversely with ACEIs (305) and may have superior effects in preventing clinical events (312), but their ability to favorably affect outcomes in HF has not been demonstrated (see Section 4.3.1.2.2.1).

Surgical revascularization has been recommended for a certain subset of patients in other guidelines (715). Some physicians recommend the use of coronary revascularization in patients with HF and coronary artery disease who do not have symptoms of angina. Advocates of this approach have suggested that surgical reperfusion can improve cardiac function and relieve symptoms of HF in patients with myocardium that appears on imaging to be viable but not contracting normally (716–718) and may also reduce the risk of a fatal coronary occlusion in patients with established multivessel disease (717). Despite these theoretical possibilities, however, coronary revascularization has not been shown to improve cardiac function or symptoms or to prevent reinfarction or death in patients with HF and no angina (15,719).

6.1.3 Supraventricular Arrhythmias (UPDATED)

There have been additional trials investigating the appropriate management of atrial fibrillation in patients with HF. The text has been modified to reflect the lessons learned from these trials (see Section 4.3.1, Patients With Reduced Left Ventricular Ejection Fraction). There is also an ACC/AHA/ESC guideline on the management of atrial fibrillation (720).

The course of patients with HF is frequently complicated by supraventricular tachyarrhythmias, which may occur when the myocardial disease process affects the atria or when the atria are distended as a result of pressure or volume overload of the right or left ventricles. The most common treatable atrial arrhythmia is atrial fibrillation, which affects 10% to 30% of patients with chronic HF and is associated with a reduction in exercise capacity and a worse long-term prognosis (721–723).

Supraventricular tachyarrhythmias may exert adverse effects via 4 different mechanisms: 1) the loss of atrial enhancement of ventricular filling may compromise cardiac output; 2) the rapid heart rate may increase demand and decrease coronary perfusion (by shortening ventricular filling time); 3) the rapidity of ventricular response may diminish both cardiac contraction (by aggravating abnormalities of the force-frequency relation) (724,725) and cardiac relaxation (726,727); and 4) the stasis of blood in the fibrillating atria may predispose patients to pulmonary or systemic emboli. In most patients with an ischemic or nonischemic dilated cardiomyopathy, the rapidity of ventricular response is more important than the loss of atrial support, because restoration of sinus rhythm does not result in predictable clinical benefits (728). Rapid supraventricular arrhythmias may actually cause a cardiomyopathy (even in patients without an underlying contractile abnormality) or may exacerbate a cardiomyopathy caused by another disorder (136,137). Hence, the control of ventricular rate and the prevention of thromboembolic events are essential elements of treatment of HF in patients with an underlying supraventricular arrhythmia (729,730). Specific care and initially low doses should be used when beta blockers are instituted to control heart rate in patients with clinical evidence of HF decompensation. The agent previously used in clinical practice to slow the ventricular response in patients with HF and atrial fibrillation is digoxin, but the cardiac glycoside slows atrioventricular conduction more effectively at rest than during exercise (365,731). Hence, digitalis does not block the excessive exercise-induced tachycardia that may limit the functional capacity of patients with HF (363–365,731). Beta blockers are more effective than digoxin during exercise (363,365) and are preferred because of their favorable effects on the natural history of HF (158,162,164). The combination of digoxin and beta blockers may be more effective than beta blockers alone for rate control. Although both verapamil and diltiazem can also suppress the ventricular response during exercise, they can depress myocardial function and increase the risk of worsening HF, especially in patients with HF and low EF, in whom these drugs should be avoided (703,705). If beta blockers are ineffective or contraindicated in patients with atrial fibrillation and HF, amiodarone may be a useful alternative (732). Atrioventricular nodal ablation may be needed if tachycardia persists despite pharmacological therapy (387). Catheter ablation for pulmonary vein isolation has been most effective in patients without structural heart disease; the benefit for patients with established HF is not known (733–735). Regardless of the intervention used, every effort should be made to reduce the ventricular response to less than 80 to 90 bpm at rest and less than 110 to 130 bpm during moderate exercise. Anticoagulation should be maintained in all patients with HF and a history of atrial fibrillation, regardless of whether sinus rhythm is achieved, because of the high rate of silent recurrence of atrial fibrillation with its attendant embolic risk, unless a contraindication exists (730).

Should patients with HF and atrial fibrillation be converted to and maintained in sinus rhythm? The efficacy and safety of restoring and maintaining sinus rhythm in patients with atrial fibrillation were evaluated in a total of 5032 patients in 4 separate trials (736). Both strategies for the management of atrial fibrillation, either to restore and maintain sinus rhythm by electrical or pharmacologic conversion, or to control ventricular rate in atrial fibrillation, have been shown to have equivalent outcomes. These results were confirmed in 2007 with the conclusion of a large trial of patients with both atrial fibrillation and HF (226,227, 730). Most patients revert to atrial fibrillation within a short time unless they are treated with a Class I or III antiarrhythmic drug (721). However, patients with HF are not likely to respond favorably to Class I drugs and may be particularly predisposed to their cardiodepressant and proarrhythmic effects (193,247), which can increase the risk of death (191,192,388). Class III antiarrhythmic agents (e.g., sotalol, dofetilide, and amiodarone) can maintain sinus rhythm in some patients, but treatment with these drugs is associated with an increased risk of organ toxicity (amiodarone) (737,738) and proarrhythmia (dofetilide) (248). Most patients who had thromboembolic events, regardless of the strategy used, were in atrial fibrillation at the time of the event and either were not undergoing anticoagulation therapy or were undergoing therapy at subtherapeutic levels. Thus, it is reasonable to treat HF patients with atrial fibrillation with a strategy of either scrupulous rate control or an attempt at rhythm control.

6.1.4 Prevention of Thromboembolic Events

Patients with chronic HF are at increased risk of thromboembolic events due to stasis of blood in dilated hypokinetic cardiac chambers and in peripheral blood vessels (739,740) and perhaps due to increased activity of procoagulant factors (741). However, in large-scale studies, the risk of thromboembolism in clinically stable patients has been low (1% to 3% per year), even in those with very depressed EFs and echocardiographic evidence of intracardiac thrombi (742–746). These rates are sufficiently low to limit the detectable benefit of anticoagulation in these patients.

In several retrospective analyses, the risk of thromboembolic events was not lower in patients with HF taking warfarin than in patients not treated with antithrombotic drugs (742,744,745). The use of warfarin was associated with a reduction in major cardiovascular events and death in patients with HF in one retrospective analysis but not in another (747–749). A randomized trial comparing the outcome of patients with HF and low EF assigned to aspirin, warfarin, or clopidogrel was completed recently.

Unfortunately, low enrollment in the trial precluded definitive conclusions about efficacy, but no therapy appeared to be superior. Another trial is currently under way comparing aspirin with warfarin in patients with reduced LVEF and may provide more definitive data upon which to base recommendations.

 Recommendations Concerning Management.In the absence of definitive trials, it is not clear how anticoagulants should be prescribed in patients with HF. Despite the lack of supportive data, some physicians prescribe anticoagulants to all patients with markedly depressed EFs and dilated hearts (739). Others would advocate the use of warfarin in patients who are known to harbor a cardiac thrombus (740), even though many thrombi detected by echocardiography do not embolize and many embolic events are probably related to thrombi that are not visualized (293,750). Anticoagulation with warfarin is most justified in patients with HF who have experienced a previous embolic event or who have paroxysmal or persistent atrial fibrillation (730). Anticoagulation should also be considered in patients with underlying disorders that may be associated with an increased thromboembolic risk (e.g., amyloidosis or LV noncompaction) and in patients with familial dilated cardiomyopathy and a history of thromboembolism in first-degree relatives.

6.2.1 Patients With Renal Insufficiency

Patients with HF frequently have impaired renal function as a result of poor renal perfusion, intrinsic renal disease, or drugs used to treat HF. Patients with renal hypoperfusion or intrinsic renal disease show an impaired response to diuretics and ACEIs (275,751) and are at increased risk of adverse effects during treatment with digitalis (370). Renal function may worsen during treatment with diuretics or ACEIs (274,527), although the changes produced by these drugs are frequently short-lived, generally asymptomatic, and reversible. Persistent or progressive renal functional impairment often reflects deterioration of the underlying renal disease process and is associated with a poor prognosis (41,752). The symptoms of HF in patients with end-stage renal disease may be exacerbated by an increase in loading conditions produced both by anemia (753) and by fistulas implanted to permit dialysis. In addition, toxic metabolites and abnormalities of phosphate, thyroid, and parathyroid metabolism associated with chronic renal insufficiency can depress myocardial function.

Despite the potential for these adverse interactions, most patients with HF tolerate mild to moderate degrees of functional renal impairment without difficulty. In these individuals, changes in blood urea nitrogen and serum creatinine are generally clinically insignificant and can usually be managed without the withdrawal of drugs needed to slow the progression of HF. However, if the serum creatinine increases to more than 3 mg per dL, the presence of renal insufficiency can severely limit the efficacy and enhance the toxicity of established treatments (275,370,751). In patients with a serum creatinine greater than 5 mg per dL, hemofiltration or dialysis may be needed to control fluid retention, minimize the risk of uremia, and allow the patient to respond to and tolerate the drugs routinely used for the management of HF (548,754).

6.2.2 Patients With Pulmonary Disease

Because dyspnea is the key symptom in both HF and pulmonary disease, it is important to distinguish the 2 diseases and to quantify the relative contribution of cardiac and pulmonary components to the disability of the patient when these disorders coexist. Exercise testing with simultaneous gas exchange or blood gas measurements may be helpful in this regard, particularly when used in conjunction with right heart catheterization (755).

Some drugs used to treat HF can produce or exacerbate pulmonary symptoms. Angiotensin converting enzyme inhibitors can cause a persistent nonproductive cough that can be confused with a respiratory infection, and conversely, ACEIs may be inappropriately stopped in patients with pulmonary causes of cough. Therefore, physicians should seek a pulmonary cause in all patients with HF who complain of cough, whether or not they are taking an ACEI. The cough should be attributed to the ACEI only if respiratory disorders have been excluded and the cough disappears after cessation of ACEI therapy and recurs after reinstitution of treatment. Because the ACEI-related cough does not represent any serious pathology, many patients can be encouraged to tolerate it in view of the important beneficial effects of ACEIs.

Beta blockers can aggravate bronchospastic symptoms in patients with asthma; however, many patients with asymptomatic or mild reactive airways disease tolerate beta-blockers well. Also, most patients with chronic obstructive pulmonary disease do not have a bronchospastic component to their illness and remain reasonable candidates for beta-blockade (756). Of note, both metoprolol tartrate and bisoprolol may lose their beta-1 selectivity when prescribed in doses that have been associated with an improvement in survival in patients with HF.

6.2.3 Patients With Cancer

Patients with cancer are particularly predisposed to the development of HF as a result of the cardiotoxic effects of many cancer chemotherapeutic agents, especially the anthracyclines (757), high-dose cyclophosphamide (758–762), and trastuzumab (763). Trastuzumab is a monoclonal antibody recently approved for therapy of metastatic breast cancer (764) that has a significant potential to cause HF, especially when combined with anthracyclines. Mediastinal radiation can also cause acute and chronic injury to the pericardium, myocardium, cardiac valves, and coronary arteries, particularly when used in conjunction with cardiotoxic chemotherapy (765).

Patients undergoing potentially cardiotoxic treatments for cancer should be monitored closely for the development of cardiac dysfunction. Heart failure may appear many years after anthracycline exposure, particularly in association with another stress, such as tachycardia. Although noninvasive assessments of LV function and endomyocardial biopsy have been advocated by some investigators (766), many cases escape early detection despite close surveillance.

Dexrazoxane may confer some cardioprotection in patients undergoing anthracycline-based chemotherapy and may allow for higher doses of the chemotherapy to be given (767,768). Heart failure due to chemotherapeutic agents is managed similarly to HF due to other causes, although it is not clear whether patients with cancer respond similarly to patients with other causes of HF. Nevertheless, because most patients with anthracycline-induced cardiomyopathy have striking degrees of tachycardia, many experts believe that beta blockers play a particularly important role in the management of these patients. Although once thought to progress inexorably, HF related to chemotherapy often improves in response to therapy, even when it appears late after exposure.

6.2.4 Patients With Thyroid Disease

Patients with both hyperthyroidism and hypothyroidism are prone to develop HF. Special vigilance is required for patients who are taking amiodarone, who may develop either hyperthyroidism or hypothyroidism. New atrial fibrillation or exacerbation of ventricular arrhythmias should trigger reevaluation of thyroid status.

6.2.5 Patients With Hepatitis C and Human Immunodeficiency Virus

Hepatitis C viral infection can be a cause of cardiomyopathy and myocarditis. It appears that the virus can cause both dilated cardiomyopathy and hypertrophic cardiomyopathy (514,515). The relatively high prevalence of this virus in Japanese populations compared with those in North America and Europe suggests that there may be a genetic predisposition to this type of viral myocarditis (516,769). A small study showed that hepatitis C virus myocarditis might respond favorably to immunosuppressive therapy with prednisone and azathioprine (770,771). Preliminary data also suggest that this type of myocarditis might respond well to interferon therapy (515), although there is concern that interferon can also depress myocardial function.

Human immunodeficiency virus has been recognized as a probable occasional cause of dilated cardiomyopathy. The presence of reduced LVEF in patients with HIV infection appears to correlate with decreased survival (772). Reduced LVEF is often seen in association with a significantly reduced CD4 count, although progression of cardiomyopathy does not appear to be related to falling CD4 levels (773). Drug therapy for HIV with zidovudine has also been implicated as a cause of cardiomyopathy, possibly through its effect on cardiac myocyte mitochondrial function (774). Heart failure in patients with HIV infection may also be caused or exacerbated by pericardial effusion or pulmonary hypertension. Interferon-alpha therapy for HIV-related Kaposi's sarcoma has also been associated with reversible reduction in LVEF. Because of the occurrence of complex opportunistic infections, autoimmune responses to the viral infection, and drug cardiotoxicity, it is difficult to determine how therapies influence the development and control of cardiomyopathy with HIV (775).

6.2.6 Patients With Anemia

Anemia is seldom the cause of HF in the absence of underlying cardiac disease. To be the sole cause of high-output HF, anemia must be severe (e.g., hemoglobin levels less than 5 g per deciliter). On the other hand, patients with HF frequently have anemia for a variety of reasons. The severity of anemia may contribute to the increasing severity of HF. Several studies have demonstrated worse outcomes in patients with HF and anemia (776,777). It is unclear whether anemia is the cause of decreased survival or a result of more severe disease.

Several small studies have suggested benefit from use of erythropoietin and iron for treatment of mild anemia in HF (778–780). There is concern, however, that thromboembolic events may be increased. This therapy is undergoing further investigation.