Diagnosis and Management of Heart Failure: Introduction In the classic text Diseases of the Heart published in 1933,1 Sir

Thomas Lewis identified the diagnosis and management of chronic heart failure as the cardinal problem in clinical cardiology. This observation is relevant today, because heart failure represents one of the most rapidly growing and costly forms of cardiovascular disease. As discussed in Chap. 25, both the incidence and prevalence of heart failure are substantial and rising, because heart failure remains a principal complication of virtually every form of heart disease. Moreover, heart failure is associated with high rates of morbidity, mortality, and economic cost. For example, it is estimated that at any time 30 to 40 percent of heart failure patients are judged to be in New York Heart Association (NYHA) functional class III or IV, indicating an advanced degree of disability.2 Readmission rates for heart failure remain high, and 5-year mortality ranges from 15 percent for those with asymptomatic disease to more than 50 percent in patients with advanced heart failure.36 A sound understanding of the pathophysiology of the disease (as reviewed in Chap. 24) along with a systematic approach to the evaluation and management of heart failure (presented in this chapter) results in improved patient outcomes. The current evaluation and management of patients with chronic systolic heart failure has a large evidence base. Recommendations for its treatment are supported by numerous randomized controlled trials or by substantial clinical and observational experience. Several national and international guidelines directing the evaluation and management of chronic systolic heart failure in adults have been published.710 In contrast, the treatment of diastolic heart failure remains largely empirical and is directed toward controlling symptoms by reducing ventricular filling pressures without reducing cardiac output. The treatment of acute, worsening, or rapidly decompensated heart failure has been inadequately studied. Although published guidelines address the management of decompensated heart failure, recommendations are generally based on consensus expert opinion rather than randomized controlled trials.711 General Principles of Management Heart failure should be prevented through the early treatment of risk factors and, when present, asymptomatic left ventricular (LV) dysfunction. The first revision to the 1995 American College of Cardiology/American Heart Association Guideline for the Evaluation and Management of Heart Failure developed a framework for heart failure prevention.12 This guideline, published in November 200112 and updated in September 2005,7 views heart failure as a continuum beginning with risk factors and culminating in end-stage or refractory disease. According to these guidelines, there are known risk factors and structural prerequisites leading to the development of LV systolic and/or diastolic dysfunction and the clinical syndrome of heart failure. The guideline proposes four stages describing the progression of heart failure (Table 26 1).7 Stage A describes patients who exhibit one or more risk factors for the development of heart failure. If inadequately treated, these risk factors, such as hypertension, diabetes, and coronary artery disease, frequently lead to the development of a structural abnormality of the heart. Stage B is defined by the development of such a structural abnormality of the heart but no symptoms of heart failure. This is the true asymptomatic or never been

symptomatic stage of cardiovascular disease progression to heart failure. Examples of progression from stage A to stage B include the development of LV hypertrophy in the hypertensive subject or the onset of a LV wall motion abnormality and reduced ejection fraction (EF) in the coronary artery disease patient following myocardial infarction (MI). Stage C is heralded by the onset of symptoms related to heart failure, including shortness of breath, fatigue, and exercise intolerance. By definition, stage C patients have current or prior symptoms of heart failure. Thus, even if made asymptomatic with treatment, stage C patients are not considered to have regressed to stage B. Finally, stage D defines the patient with marked heart failure symptoms at rest despite maximal medical therapy. These patients are generally in need of heroic measures, such as cardiac transplantation or mechanical assistance, or referral into a program focused on end-of-life care. Table 261 American College of Cardiology/American Heart Association Stages of Heart Failure

Stage Definition A High risk for developing heart failure (HF)

Patient Description Hypertension Coronary artery disease Diabetes mellitus Family history of cardiomyopathy

Asymptomatic HF Previous MI LV hypertrophy or systolic dysfunction Asymptomatic valvular disease

Symptomatic HF Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance

Refractory end-stage HF

Marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions

LV, left ventricular; MI, myocardial infarction. The treatment of patients with risk factors (stage A) and asymptomatic LV dysfunction (stage B) is extensively reviewed elsewhere in this textbook and briefly in this chapter. Once LV dysfunction and symptomatic heart failure ensue (stages C and D), treatment should ideally be directed at improving the function of the heart as a pump. This both increases cardiac output and decreases venous hypertension, improving both the low-output and congestive signs and symptoms of the disease. The goal of improving the functional performance of the heart as a pump is often difficult to accomplish. Moreover, the chronic use of positive inotropic agents to improve contractility consistently increases mortality when compared to standard heart failure therapy.1315 At the present time, standard pharmacologic management of heart failure is aimed at reducing ventricular preload and afterload and at diminishing, inhibiting, and/or antagonizing neurohormonal vasoconstrictor activation, rather than directly increasing cardiac contractility. Prevention of Heart Failure Typically, stage A and B patients have one or more of the following risk factors for the development of heart failure: advanced age, hypertension, diabetes mellitus, obesity, metabolic syndrome, coronary artery disease, prior MI, and LV hypertrophy.16,17 Other risks for heart failure include anemia, dyslipidemia, sleep disordered breathing, valvular heart disease, family history of cardiomyopathy, exposure to various cardiotoxins (e.g., anthracyclines), skeletal myopathies, and other less common disorders (Table 262). Table 262 Risk Factors for the Development of Heart Failure

Hypertension Diabetes Dyslipidemia Coronary artery disease Valvular heart disease Obesity Metabolic syndrome Smoking Aging

Rheumatic fever Mediastinal irradiation Sleep disordered breathing Collagen vascular disease Anemia Nutritional deficiencies Skeletal myopathies Thyroid disorders Family history of cardiomyopathy

Excessive alcohol consumption Exposure to cardiotoxic agents

Advancing age is one of the most prominent risk factors for heart failure. Data from the Framingham Study indicate that heart failure is present in approximately 1 percent of adults in their 50s and in as many as 10 percent of those in their 80s.16 This association between

advanced age and heart failure is most likely the result of decades of inadequate treatment of underlying risk factors, rather than to aging alone. Obesity acts directly or indirectly by being associated with dyslipidemia, hypertension, insulin resistance, diabetes, and LV hypertrophy, thus promoting heart failure.18 In this regard the metabolic syndrome may represent one of the most prevalent unifying risk factors for heart failure. Obesity may also contribute to the prevalence of obstructive sleep apnea, another independent risk factor for the development of hypertension and heart failure.19,20 Hypertension as a Risk Factor for Heart Failure As noted in Chap. 68, approximately 25 percent of the U.S. population is hypertensive, and the lifetime risk of developing hypertension among Americans exceeds 75 percent.21 Elevated levels of systolic and/or diastolic blood pressure are major risk factors for the development of heart failure.22,23 Information from the Framingham Study suggests that hypertension precedes the onset of heart failure in 91 percent of cases.22 Thus, it is not surprising that long-term treatment of both systolic and diastolic hypertension has been shown to reduce the risk of heart failure.24,25 Numerous randomized, controlled trials have consistently demonstrated that optimal blood pressure control decreases the risk of newonset heart failure by approximately half.26 In other populations hypertension is a less common cause of heart failure and usually associated with coronary heart disease. Hypertension may lead to structural heart disease and cardiac failure through at least two pathways, first the development of LV hypertrophy resulting in heart failure associated with a preserved LV ejection fraction (LVEF) and second MI usually resulting in a regional wall motion abnormality and reduced LVEF (Fig. 261). LV hypertrophy is a strong and independent risk factor for heart failure.27 However, in most instances, heart failure associated with a history of hypertension is mediated by atherosclerotic coronary artery disease rather than or in addition to LV hypertrophy. In this circumstance, hypertension may be seen as a contributor to rather than a direct cause of the LV dysfunction, which may be primarily attributed to myocardial ischemia/infarction. However, the role of hypertension leading to heart failure in post-MI subjects should not be underestimated, because the benefits of treating hypertension in heart attack survivors are dramatic with an 81 percent reduction in the incidence of heart failure.24 Figure 261.

In general, hypertension may lead to heart failure via one of two major pathways, coronary artery disease leading to a reduced EF or LV hypertrophy resulting in heart failure with a preserved EF. EF, ejection fraction; LV, left ventricular. To prevent heart failure and other cardiovascular events in hypertensive subjects, both systolic and diastolic blood pressure should be lowered using evidence-based therapies

recommended in guidelines. Recommendations for the treatment of hypertension are reviewed in Chap. 70 and in the current version of the guideline from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.28 Goal blood pressure and the selection of an antihypertensive regimen depend, in part, on the absence or presence of comorbidity. Data support a lower ideal or target blood pressure goal in patients with associated major cardiovascular risk factors, particularly those with diabetes mellitus.2931 Although treatment to target blood pressure should remain the primary goal of antihypertensive treatment, the choice of specific agent(s) may be determined by the particular comorbidity present (e.g., diabetes, coronary artery disease, or LV dysfunction). Various antihypertensive agents reduce the incidence of heart failure, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, and blockers.28,3234 Calcium

channel blockers and blockers appear to be less effective in preventing the onset of heart failure. In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the -receptor blocking agent doxazosin was associated with an increase in the incidence of new-onset heart failure.35 Although the mechanism of increased heart failure risk with -receptor blockade remains unknown, unopposed

stimulation of -adrenergic receptors is a likely possibility. In any event, blockade should be discouraged in the treatment of hypertension, unless in combination with other agents, particularly blockers. Finally, as noted in the European Society of Cardiology 9 heart failure guideline, the applicability of ALLHAT to the European community is uncertain because the trial enrolled a substantial number of African Americans. Like ACE inhibitors, angiotensin receptor blockers (ARBs) significantly reduce the incidence of heart failure. In this regard, ARBs have been most well-studied in diabetic hypertensives.36,37 However, recent controversy has arisen regarding a so-called ARB paradox describing an apparent increase in MI risk associated with ARB treatment.38,39 While this debate plays out, the totality of currently available data support the safety and efficacy of ARBs in the treatment of hypertension. Most hypertensive subjects require treatment with two or more agents, to achieve target blood pressure control. With this in mind, the authors of the American College of Cardiology/American Heart Association (ACC/AHA) heart failure guidelines recommend the use of agents proven to be useful for the treatment of hypertension and heart failure, particularly diuretics, ACE inhibitors, and blockers, for the treatment of stage A and 7 stage B hypertensive subjects. Likewise, the European Society of Cardiology endorses the use of ACE inhibitors, ARBs, diuretics, and blockers in the prevention of heart 9 failure. Finally, the guideline from the Heart Failure Society of America emphasizes the

use of an ACE inhibitor in stage A patients and the addition of a subjects, particularly those with a prior MI.8

blocker in stage B

Obesity, Diabetes, and the Metabolic Syndrome as Risk Factors for Heart Failure Obesity and insulin resistance are powerful risk factors for the development of heart failure.40,41 Obesity alone has been shown to be an independent risk factor for incident heart failure.41 There are many ways by which obesity may contribute to the development of structural heart disease and heart failure. Many of these mechanisms seem to be mediated by the proliferative milieu associated with insulin resistance/hyperinsulinemia and diabetes. Thus, the metabolic syndrome may also play a major role in increasing the risk of heart failure.42 Approximately 40 percent of the U.S. population older than age 40 years meets the criteria for the diagnosis of the metabolic syndrome.43 Moreover, roughly 21 percent of U.S. adults are obese as defined by a body mass index (BMI) of at least 30.44 This includes 20.8 percent of adult women and 21 percent of adult men for a total of 44.3 million obese adult Americans. Since 1991 the percentage of overweight adults (defined as a BMI 25) increased from 45 percent to 58 percent,44 so that more than one-half of the U.S. adult population is now considered overweight. In other developed societies such as those in Europe, the prevalence of obesity is also on the rise. Thus, the contribution of obesity, diabetes, and the metabolic syndrome to the incidence of heart failure is likely to increase worldwide. The presence of diabetes mellitus substantially increases the risk of heart failure in patients without preexisting structural heart disease.45 Diabetes only modestly increases the risk of heart failure in men but substantially increases the chance of heart failure in women.22 Although diabetes is a risk factor for coronary heart disease, many diabetic patients and especially female diabetics with or without hypertension exhibit angiographically normal epicardial coronary arteries in association with dilated cardiomyopathy. This observation has lead to the proposal of a diabetic cardiomyopathy. The exact nature of this form of heart muscle disease is unknown, but small vessel coronary disease and/or endothelial dysfunction may play a role. Alternatively, hyperinsulinemia, hyperglycemia, and other growth-promoting hormones may mediate pathologic myocyte remodeling subsequently leading to cardiomyopathy in these patients. The management of diabetes and the metabolic syndrome/obesity in the prevention of cardiovascular disease is discussed in Chaps. 90 and 91, respectively. In general, treatment of the metabolic syndrome is limited by the poor success associated with available weight loss therapies and programs. A downward trend in physical activity over decades associated with an upward trend in caloric consumption and the lack of truly effective drug therapies challenge progress in effectively reversing the obesity epidemic.46 When successful, however, weight loss can effectively reduce the risk of diabetes in obese subjects. In the Diabetes Prevention Program (DPP), intensive lifestyle change, defined as a 7 percent reduction in body weight and at least 150 minutes of exercise weekly, was more effective than placebo or drug therapy with metformin in reducing the onset of diabetes mellitus.47 Lifestyle intervention decreased the incidence of diabetes by 58 percent compared to

placebo, whereas metformin diminished the chance of diabetes by 31 percent. In patients with overt diabetes, every effort should be made to control hyperglycemia, but such control has not yet been shown to reduce the subsequent risk of heart failure. Of note, thiazolidinediones (TZDs), commonly prescribed for the treatment of diabetes, have been associated with increased peripheral edema and new-onset heart failure in patients with underlying risk factors or known cardiovascular disease.48 The risk of developing edema with TZDs is dose related and higher in diabetic patients on concomitant insulin therapy. Thus, these agents should be used with caution in at-risk patients, and such patients should be monitored closely for fluid retention. Coronary Artery Disease as a Risk Factor for Heart Failure Coronary artery disease appears to account for 60 percent to 70 percent of the incidence of systolic heart failure. Annually in the United States, approximately 1.1 million individuals suffer a MI and approximately 40 percent of them may be left with a reduced LVEF.49 Data from the Studies of Left Ventricular Dysfunction (SOLVD) Registry, which enrolled subjects in the United States and Canada, provide the following breakdown on the etiology of heart failure: ischemic heart disease, 68.5 percent; idiopathic heart disease, 12.9 percent; hypertension, 7.2 percent; and other causes, 11.3 percent.50 This observation is supported by findings from randomized controlled trials of systolic heart failure that also demonstrate a preponderance of ischemic heart failure. However, these studies generally enrolled mostly middle-aged white men and may not have been representative of the broader heart failure population, including women and minorities. In this context, a recent trial of AfricanAmerican subjects (approximately half women) with systolic heart failure demonstrated a very different distribution of risk factors for heart failure, with only a minority of patients having ischemic heart disease and most exhibiting nonischemic heart failure in association with hypertension, diabetes, and obesity.51 The Acute Decompensated Heart Failure National Registry (ADHERE), which includes unselected patients admitted to the hospital with worsening heart failure, evaluated the prevalence of risk factors in more than 100,000 cases.52 Half of the cases were women. The following predominant risk factors were noted: coronary artery disease, 57 percent; prior MI, 35 percent; hypertension, 73 percent; dyslipidemia, 36 percent; chronic renal insufficiency, 30 percent; and diabetes mellitus, 44 percent.52 It is important to note that approximately 46 percent of ADHERE cases are comprised of patients with preserved LV systolic function (i.e., EF > 40 percent). However, even in patients with reduced LVEF, multiple comorbidities are common and ischemic heart disease is listed as the primary cause of the heart failure in approximately 60 percent of cases. MI is a common cause of heart failure. Following a MI, the development of LV systolic dysfunction and dilation are the most potent predictors of subsequent heart failure and allcause mortality.5355 Once LV injury has occurred, progressive LV dysfunction and dilation ensues unless attenuated by medical and/or surgical therapy. The pathophysiology and management of coronary artery disease is extensively reviewed in Part 8 of this textbook. A consensus statement on preventing atherosclerotic heart disease

provides additional guidelines for management.56 In this context, ACE inhibitors play a major role in the prevention of cardiovascular events and heart failure in subjects with established atherosclerotic vascular disease based on the results of randomized controlled trials.32 Revascularization strategies, either percutaneous or surgical, may also reduce the incidence of heart failure in such patients, but this is less well-studied in contemporary large-scale randomized controlled trials. Coronary revascularization can relieve symptoms of myocardial ischemia, and coronary artery bypass surgery has been shown to lessen angina and reduce the risk of death in patients who have multivessel disease, reduced LVEFs, and stable angina.57 Whether or not surgical revascularization improves the natural history of ischemic heart failure is under evaluation in the National Institutes of Health sponsored Surgical Therapies for Ischemic Heart Failure (STICH) trial. Other Preventive Measures in Heart Failure Other primary and secondary preventive strategies have also been shown to reduce the risk of incident heart failure. For example, lipid lowering therapy results in a significant reduction in new-onset heart failure.58,59 In a large-scale trial, the administration of a lipidlowering agent to patients with hypercholesterolemia and a prior MI reduced all-cause mortality and the risk of developing HF.59 The role of other therapies such as continuous positive airway pressure breathing in obstructive sleep apnea to prevent new-onset heart failure remains to be fully elucidated. Other therapies resulting in reverse remodeling in patients with established (stage C) heart failure (e.g., cardiac resynchronization therapy) are being evaluated in asymptomatic or minimally symptomatic patients, as preventive measures. In this regard, pathological LV remodeling has become a major target for heart failure intervention in stages B through D of the heart failure continuum. Pathologic Remodeling as a Target for Heart Failure Prevention As noted in practice guidelines, in the stage B patient preventive therapies should be directed at improving LV structure and function. Typically, adverse or pathological remodeling is defined in the context of LV dilation and systolic dysfunction as an increase in ventricular volumes (both systolic and diastolic), a decrease in EF, a loss of the normal elliptical geometry of the ventricle, and the onset of functional mitral regurgitation. LV hypertrophy should also be considered as a form of pathological ventricular remodeling and as a target for preventive intervention. The regression of LV hypertrophy in hypertensive subjects appears to improve outcomes.60,61 Thus, therapies that promote either regression of LV hypertrophy or reverse remodeling of the dilated failing heart may be viewed as essential in the prevention or attenuation of heart failure in stage B. Pathological ventricular remodeling within the heart can be considered as ventricular, cellular, or molecular. Ventricular remodeling is defined above. Cellular remodeling may take one of two predominant forms, involving either concentric or eccentric hypertrophy of the myocyte.62 (Figure 262). In the case of concentric myocyte remodeling, the heart cells have thickened but not increased in length so that the longitudinal to transverse ratio of the cell is diminished. With eccentric hypertrophy, the cell is elongated and the longitudinal to transverse ratio is increased. Other cellular changes accompanying pathological remodeling include changes in constituent cardiac proteins, an increase in the amount of cytoskeletal

elements (these are disorganized), an increase in the number of nonmyocytes (many are activated [e.g., fibroblasts] or dysfunctional [e.g., endothelium]), and an increase in the volume and structure of the extracellular matrix. At the molecular level, there is a general reversion to the fetal pattern of gene expression in the dilated failing human heart.63,64 These changes appear to be related to increased wall stress and mediated by a variety of mechanisms, including increases in local and circulating neurohormones.65 Figure 262.

Cartoon of myocyte cellular remodeling in response to pressure overload (hypertension) leading to concentric remodeling of the heart cell and cardiac failure resulting in eccentric myocyte remodeling. A, length of cell; B, width of cell. Source: From Wang X, Li F, Gerdes AM.62 With permission. Many drug therapies and some device-base treatments promote an improvement in cardiac structure and function. Most antihypertensive medications promote regression of LV hypertrophy, but some appear more potent than others when indexed to the degree of blood pressure lowering.66 In subjects with asymptomatic LV systolic dysfunction, the use of ACE inhibitors and blockers has been shown to be particularly effective in promoting reverse remodeling and attenuating clinical events.67,68 ARBs and aldosterone antagonists may also be useful, in this regard. These two classes of drugs have largely been studied in symptomatic patients with reduced EFs and in patients after MI.69,70 Despite the lack of randomized controlled trials evaluating ARBs or aldosterone antagonists in truly asymptomatic LV dysfunction, ARBs represent acceptable alternatives in ACE inhibitor intolerant patients, and the addition of an aldosterone antagonist to an ACE inhibitor/ blockerbased regimen may optimize the reverse remodeling process. As mentioned above, mechanical interventions such as coronary revascularization following MI, cardiac resynchronization therapy or LV assist devices may also improve heart function and thus attenuate heart failure. In summary, the prevention of heart failure is best achieved by an aggressive approach to the treatment of major risk factors, including hypertension, diabetes, obesity, metabolic syndrome, and coronary artery disease, according to published guidelines. The treatment of other comorbid risk factors, such as dyslipidemia, should not be neglected as incremental reduction in heart failure risk may be seen. Once these risk factors progress to LV hypertrophy or dysfunction, risk factor modification should continue and therapies that promote regression of LV hypertrophy or reverse remodeling of the dilated failing heart should be employed, if not already prescribed. Evaluation and Management of Symptomatic Heart Failure

Evaluation of Chronic Heart Failure Tables 263 and 264, taken from the European Society of Cardiology heart failure guideline,9 recommends a routine assessment to establish the diagnosis and likely cause of heart failure. Once the diagnosis of heart failure has been made, the first step in evaluating heart failure is to determine the severity and type of cardiac dysfunction, by measuring EF through two-dimensional echocardiography and/or radionuclide ventriculography. Measurement of EF is the gold standard for differentiating between the two forms of heart failure, systolic and diastolic, and is particularly important given that the approaches to therapy for each syndrome somewhat differ. The history and physical examination should include assessment of symptoms, functional capacity, and fluid retention. Common symptoms of heart failure are dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, lower extremity edema, cough (usually worse at night), abdominal complaints (nausea, vomiting, right upper quadrant pain, abdominal swelling), fatigue, nocturia, sleep disorders, and anorexia. Common physical findings include elevated jugular venous pressure, hepatojugular reflux, pulmonary crackles, sustained and displaced apical impulse, S3 gallop, hepatomegaly, ascites, and peripheral edema. Table 263 Assessments to Be Performed Routinely to Establish the Presence and Likely Cause of Heart Failure

Assessments

Diagnosis of Heart Failure Necessary Supports for

Suggests Alternative Opposes or Additional Diagnosis +++ (If absent)

Appropriate symptoms Appropriate signs Cardiac dysfunction on imaging (usually echocardiography) Response of symptoms or signs to therapy ECG Chest x-ray

+++ +++ +++

+ (If absent) +++ (If absent)

+++

+++ (If absent) +++ (If normal)

If pulmonary congestion or cardiomegaly

+ (If normal)

Pulmonary disease

Full blood count Biochemistry and

Anemia/secondary polycythemia Renal or hepatic

urinalysis Plasma concentration of natriuretic peptides in untreated patients (where available) + (If elevated) +++ (If normal)

disease/diabetes Can be normal in treated patients

+, of some importance; +++, of great importance. Table 264 Additional Tests to Be Considered to Support the Diagnosis of Heart Failure or Suggest an Alternative Diagnosis

Tests

Diagnosis of Heart Failure Supports Opposes

Suggests alternative or additional diagnoses Pulmonary disease Thyroid disease Coronary artery disease, ischemia

Exercise test Pulmonary function tests Thyroid function tests Invasive investigation and angiography Cardiac output

+ (If impaired) +++ (If normal)

+++ (If depressed at rest) +++ (If elevated at rest)

+++ (If normal; especially during exercise) +++ (If normal; in absence of therapy)

Left atrial pressure (pulmonary capillary wedge pressure)

+, of some importance; +++, of great importance. Functional capacity is assessed from the clinical history or preferably measured by an exercise test.71,72 Analysis of expired air during exercise offers a precise measure of the patient's physical limitations. This test is not commonly performed outside of cardiac transplant centers. The NYHA has classified heart failure into four functional classes that may be determined by history taking:73 Class I: no limitations of physical activity, no symptoms with ordinary activities Class II: slight limitation, symptoms with ordinary activities Class III: marked limitation, symptoms with less than ordinary activities Class IV: severe limitation, symptoms of heart failure at rest For example, patients who can walk several blocks without symptoms but have difficulty climbing two flights of stairs may have class II heart failure, whereas those who cannot

walk several blocks easily or become winded while walking up a short flight of stairs might be considered class III. The NYHA functional classification should not be confused with the aforementioned stages of heart failure described in the ACC/AHA heart failure guidelines. The NYHA classification describes functional limitation and is applicable to stages B through D patients, whereas the staging system describes disease progression somewhat independently of functional status. Assessment of fluid retention through measurement of jugular venous pressure, auscultation of the lungs, and examination for peripheral edema is central to the physical examination of heart failure patients. The physical examination alone, however, is relatively insensitive for measuring extracellular fluid volume excess.74,75 A thorough appraisal of symptoms is essential. Even in the absence of perceptible volume excess by physical examination, mild congestive symptoms can indicate volume excess. In addition, the chest radiograph, particularly in a patient with relatively new onset heart failure, is a relatively sensitive measure of volume overload but in the setting of chronic heart failure, the chest radiograph may not reliably help to estimate ventricular filling pressure.76 Given the limitations of physical signs and symptoms in evaluating heart failure clinical status, a number of noninvasive and invasive tools are under development for the assessment of heart failure. One such tool that has proven useful in determining the diagnosis and prognosis of heart failure is the measurement of plasma B-type natriuretic peptide (BNP) levels. Multiple studies, including the Breathing Not Properly Multinational Study,77 demonstrate the usefulness of BNP measurement in the diagnosis of heart failure. In this study 1586 patients who came to the emergency department with acute dyspnea underwent bedside measurement of plasma BNP concentration. The clinical diagnosis of congestive heart failure was adjudicated by two independent cardiologists, who were blinded to the results of the BNP assay. The final diagnosis was dyspnea caused by worsening heart failure in 744 patients (47 percent), dyspnea caused by noncardiac causes in 72 patients with a history of LV dysfunction (5 percent), and no finding of congestive heart failure in 770 patients (49 percent). BNP levels by themselves were more accurate than any historical or physical findings or laboratory values in identifying worsening heart failure as the cause of dyspnea. The diagnostic accuracy of BNP at a cutoff of 100 pg/mL was 83.4 percent. The negative predictive value of BNP was excellent. At levels of less than 50 pg/mL, the negative predictive value of the assay was 96 percent. In the B-Type Natriuretic Peptide for Acute Shortness of Breath Evaluation study, from Mueller and coworkers,78 patients presenting to the emergency department with acute dyspnea were randomly assigned to undergo either a single measurement of BNP or not. Based largely on the findings of the BNP Multinational Study, clinicians were advised that a plasma BNP concentration <100 pg/mL made the diagnosis of congestive heart failure unlikely, whereas a level >500 pg/mL made it highly likely. For BNP levels between 100 pg/mL and 500 pg/mL, the use of clinical judgment and additional testing was encouraged. In this single-blind trial of 452 patients, measurement of BNP in the emergency department resulted in a 10 percent decrease in the rate of hospital admission. Moreover, the median length of stay was reduced by three days and the mean total cost of treatment by approximately $1800. These reductions in rate of hospitalization, length of stay, and cost did not result in any negative effects on mortality or the rate of subsequent hospitalization.

Additionally, plasma BNP is useful in predicting prognosis in heart failure patients. However, serial measurement of plasma BNP as a guide to heart failure management has not yet been proven useful in the management of acute or chronic heart failure. The recommended role of BNP testing at the various stages of heart failure differs a bit among the major heart failure guidelines. The ACC/AHA heart failure guideline suggests that "measurement of BNP can be useful in the evaluation of patients presenting in the urgent care setting in whom the diagnosis of heart failure is uncertain."7 Although the Heart Failure Society of America guideline discourages the use of BNP testing in at risk patients, it more strongly recommends "that BNP or N-terminal-proBNP (NT-proBNP) be assessed in all patients suspected of having heart failure when the diagnosis is not certain"8 (emphasis added). The heart failure guideline from the European Society of Cardiology emphasizes the use of BNP or NT-pro-BNP "as 'rule out' tests to exclude significant cardiac disease," particularly in primary care but also in settings such as the emergency department.9 Approach to Systolic Heart Failure Table 265 presents a general approach to evaluating and managing patients with current or prior symptoms of heart failure and chronic LV systolic dysfunction. This schema is consistent with published clinical practice guidelines.710 In addition to pharmacologic and device-based approaches to treatment, these guidelines stress the importance of dietary counseling, patient education, lifestyle changes, and other nonpharmacologic strategies for the treatment of chronic heart failure. Many of these nonpharmacologic strategies recommended for the management of systolic heart failure also are applicable to the treatment of heart failure associated with a preserved LVEF. Table 265 General Therapeutic Approach to Chronic Heart Failure

Determine the etiology Look for precipitating factors and correct them Nonpharmacologic treatment Sodium restriction ( Aerobic exercise Weight loss in obese patients Treat hypertension and other comorbidities vigorously Pharmacologic treatment Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers Aldosterone antagonists 2 g/d)

Blockers Vasodilators (long-acting nitrates and hydralazine) Diuretics Digoxin Device therapies Cardiac resynchronization therapy Implantable cardioverter defibrillators Left ventricular assist devices (discussed in Chap. 26) When a patient presents with symptomatic heart failure, it is important to determine the underlying cause as some forms of heart failure may be reversible. It is also essential to understand those factors precipitating the transition from stage B to stage C heart failure, as well as subsequent episodes of decompensation. Therapy may then logically follow from an understanding of these factors and an appreciation for evidence-based, guidelinesrecommended treatments. Determine the Etiology of the Heart Failure All patients presenting with new heart failure should be rigorously evaluated to determine the etiology of the disease. Routinely performing such an evaluation is important because there are several surgically correctable forms of heart failure and some potentially reversible forms of inflammatory heart disease and cardiomyopathy associated with systemic diseases or cardiotoxins. For example, some patients with heart failure caused by ischemic heart disease may realize an improvement in the LV dysfunction and chronic heart failure following revascularization with either angioplasty or coronary artery bypass surgery.7986 This may be the case in as much as 20 percent of patients with heart failure in the context of ischaemia, and as mentioned above, is being prospectively evaluated in the STICH trial. The presence or absence of obstructive coronary artery disease should be determined in heart failure patients and, in general, myocardial viability should be assessed in patients with ischemic cardiomyopathy. Viable myocardium and the presence of adequate target vessels for bypass predict a favorable outcome following revascularization for ischemic heart failure, so serious consideration should be given to surgical intervention in such cases. Perhaps the most classic examples of surgically correctable heart failure are those associated with valvular heart disease. For instance, patients with critical aortic stenosis may exhibit severe LV dysfunction and advanced signs and symptoms of chronic heart failure, which may be completely reversible on replacement of the stenotic aortic valve. Severe mitral stenosis is also a cause of acutely reversible heart failure where percutaneous balloon valvuloplasty now represents a feasible and, in many cases, preferred approach to therapy.87 Severe mitral regurgitation is another valvular etiology of left heart failure. Although early mitral valve repair or replacement may prevent the development of chronic heart failure, the presence of advanced LV dilation and severe LV dysfunction at the time

of presentation often precludes surgical intervention. Newer, percutaneous approaches to mitral valve repair may represent a viable alternative to ongoing medical therapy in such patients. The treatment of myocarditis remains controversial. Anecdotal experience suggests that some patients may benefit from therapy directed at the immune system. However, controlled trials of immunosuppressant therapy, immune globulin, and other forms of immunomodulatory therapy in myocarditis have been disappointing.88,89 Thus, current guidelines do not recommend the routine use of immune-based drug therapies for myocarditis. Despite these recommendations many heart failure experts recommend immunosuppressant drug therapy (usually consisting of corticosteroids) for biopsy-proven myocarditis associated with rapidly worsening heart failure signs and symptoms and/or LV function. In this regard the role of endomyocardial biopsy in the evaluation of heart failure remains controversial. None of the guidelines recommend the routine use of heart biopsies in the diagnosis of new or worsening heart failure. However, in suspected cases of myocarditis, endomyocardial biopsy can provide useful information establishing the diagnosis and distinguishing lymphocytic from eosinophilic and giant cell myocarditis. This is important because eosinophilic myocarditis is often exquisitely sensitive to treatment with corticosteroids, whereas giant cell myocarditis seems resistant to immunosuppressant treatment exhibiting a relapsing course despite such medications. Cardiomyopathies related to alcohol or cocaine abuse may respond to discontinuation of the offending agent.90,91 Heart muscle disease associated with chemotherapeutic agents may respond to or be prevented by treatment with ACE inhibitors and/or blockers.92,93 Heart failure related to systemic illness such as hypothyroidism may respond to treatment of the underlying disease. Although few specific therapies exist, the diagnosis of an infiltrative cardiomyopathy may influence subsequent evaluation for systemic disease and inform the natural history of the disease. A further discussion of these less common causes of cardiomyopathy is included in Chaps. 30 and 31. Look for Factors Precipitating Symptoms and Correct Them One of the most important strategies for reducing morbidity and mortality in chronic heart failure is understanding and correcting the precipitating causes of clinical worsening and disease progression (Table 266). Dietary and/or pharmacologic noncompliance appear to be major causes of decompensation in patients with chronic heart failure. Thus, dietary counseling and patient education represent two major goals in the management of chronic heart failure. This may be accomplished through referral to the Dietitian, distribution of patient education materials, office or hospital-based patient education programs, heart failure telemanagement, and home health cardiac specialists. While a great first step, it is clear that education delivered in the hospital alone is inadequate and this educational message must be reinforced on an outpatient basis. Table 266 Precipitating Causes of Worsening Heart Failure

Dietary and/or Pharmacologic Noncompliance Negative inotropes Antiarrhythmics First-generation calcium channel antagonists Increased renal salt and water retention and/or worsening renal function Nonsteroidal antiinflammatory drugs Further damage to the myocardium Adriamycin Alcohol and/or cocaine Myocardial infarction Myocarditis Increased myocardial workload Anemia Hypoxia Infection Pulmonary embolism Worsened valvular dysfunction Arrhythmias The prescription of negative inotropes, such as most antiarrhythmics and the firstgeneration calcium channel antagonists, may also precipitate symptomatic or worsening heart failure and probably worsen outcome in chronic heart failure patients. Because renal perfusion in heart failure patients is largely dependent on vasodilating prostaglandins, the prescription or over-the-counter use of nonsteroidal antiinflammatory drugs may result in worsening renal function and increased renal sodium and water retention.94 In addition, the onset of acute anuric renal failure may occur following the administration of nonsteroidal antiinflammatory drugs to patients with advanced heart failure.95 Thus, some patients may make the transition from stage B to stage C heart failure as a consequence of inappropriate drug therapy. Anything that further damages the myocardiumsuch as a new MIor places an increased workload on the heartsuch as hypoxia, anemia, pulmonary embolism, or infectionmay result in worsening of heart failure. Finally, worsened valvular dysfunction and arrhythmias are occasionally implicated as precipitants of symptomatic heart failure. Nonpharmacologic Treatment of Chronic Heart Failure The nonpharmacologic management of heart failure includes reduced sodium intake,

reduced physical (particularly isometric) exertion, and weight loss in obese patients. In general, sodium intake should be limited to approximately 2 g/d. In advanced heart failure, further dietary sodium restriction may be necessary to attenuate expansion of extracellular fluid volume and the development of edema. Hyponatremia should not discourage compliance with a restricted sodium diet, because the hyponatremia is usually dilutional and associated with total body sodium and water excess. Sodium repletion therefore should only be considered in overt cases of severe excessive diuresis or dehydration. Salt substitutes may be used to improve the palatability of food. However, some agents substitute potassium chloride for sodium chloride and should be used in moderation given the potential risk of hyperkalemia, especially in patients treated with ACE inhibitors, ARBs, and/or aldosterone antagonists. Although dietary sodium restriction may attenuate the development of edema, it cannot prevent it because the kidneys are capable of reducing urinary sodium excretion to less than 10 mmol/d. Thus, diuretics (discussed below) play a key role in the management of symptomatic heart failure. Although vigorous isometric exercise has been poorly evaluated in chronic heart failure, it is currently discouraged in symptomatic patients given the marked increase in myocardial work seen with weight training. Increased LV wall stress during isometric exercise would be expected to have an unfavorable influence on ventricular remodeling. On the other hand, a role has emerged for monitored cardiac rehabilitation and aerobic exercise in patients with stable compensated chronic heart failure. In these patients, aerobic exercise training has been shown to consistently improve functional capacity while inconsistently improving LV function, suggesting that the benefits of aerobic training in chronic heart failure are mostly peripheral.96101 The effect of such training on heart failure outcomes is being evaluated in a large multinational National Institutes of Health randomized controlled trial. All patients with heart failure should receive flu immunization each year. Treat Hypertension and Other Comorbidities Vigorously Although many patients with chronic heart failure have normal or low blood pressures, a large subset of patients remains hypertensive. Because blood pressure is a component of ventricular afterload and it increases the workload of the heart, it should be treated vigorously in patients with chronic heart failure. Some patients with cardiomyopathy on the basis of hypertensive heart disease may recognize a marked improvement with treatment of hypertension alone. This may be accomplished with standard heart failure treatment such as an ACE inhibitor or with various antihypertensive therapies, which appear to be safe to use in patients with LV systolic dysfunction (e.g., vascular-selective calcium channel blockers). Other comorbidities, such as those mentioned earlier in this chapter, should also be treated and may modify disease progression as discussed above.