Julie L. Rosenthal
W. H. Wilson Tang
Heart Failure with Systolic Dysfunction
I.Introduction. Heart failure (HF) is a complex clinical syndrome characterized by impaired myocardial performance and progressive maladaptive neurohormonal activation of the cardiovascular and renal systems leading to circulatory insufficiency and congestion. Currently, acute heart failure syndromes (AHFS) constitute the most common indication for hospitalization in adults over age 65. With the increasing age of the population, improved patient survival with acute coronary syndrome, and reduced mortality from other diseases, the incidence and attendant cost of managing patients with HF will inevitably continue to increase.
A.Terminology
1.Based on the hemodynamic model, systolic HF (or heart failure with reduced ejection fraction, HFrEF) has been defined by the presence of impaired contractility of the left ventricle, most commonly conveyed by an ejection fraction (EF) of ≤40%. This drop in contractility may be associated with chamber dilation and decreased stroke volume (Fig. 8.1). There is a growing appreciation for the limitations of this classification. The threshold for systolic dysfunction is arbitrary, and it is now clear that patients with HF with preserved EF (HFpEF) suffer similar morbidity and mortality. There is substantial variability in EF determinations made by different imaging modalities. Most importantly, EF correlates poorly with symptoms, cardiac indices, and potential response to medical intervention.
FIGURE 8.1 Pressure–volume loops in normal (dashed line) and heart failure (HF; solid line) patients. A: Pressure–volume loops in HF with impaired ejection fraction typically demonstrate a reduction in the end-systolic pressure–volume relationship (ESPVR; i.e., the end-systolic elastance), a representation of contractility. This is typically accompanied by an increase in end-diastolic volume and a reduction in stroke volume (SV) and stroke work (SW; shaded area). At a given ESPVR, a reduction in end-systolic pressure results in an increased SV and reduction in the left ventricular (LV) elastic potential energy (PE; speckled area). B: In contrast, patients with HF with preserved ejection fraction have a normal or elevated ESPVR with a left and upward shift in the end-diastolic pressure–volume relationship reflecting decreased myocardial compliance.
2.In practice, HF is a bedside diagnosis that is defined by clinical assessment. Patients may have cardiac dysfunction without symptoms, often referred to as asymptomatic left ventricular (LV) dysfunction.
3.Others may have preserved LV systolic function with typical signs and symptoms of HF, best referred to as HFpEF (see Chapter 9).
4.The major pathophysiologic process in the progression of HF is cardiac remodeling, progressive chamber enlargement with an obligatory reduction in EF. From a histopathologic standpoint, this is associated with myocyte hypertrophy, fibrosis, apoptosis, and necrosis. Molecular alterations including reexpression of a fetal gene program and alterations in excitation–contraction coupling and regulatory proteins occur.
5.In some cases, myocardial recovery or reverse remodeling is possible with pharmacologic and device therapy.
6.The term congestive HF is overused and nonspecific, often being applied to states of hypervolemia unrelated to cardiac dysfunction. Conversely, not all patients with HF have signs and symptoms of congestion or low output.
7.The term right HF is used to describe patients with predominantly peripheral signs and symptoms of congestion with a relative paucity of pulmonary congestion.
8.Acute decompensated HF or AHFS refer to episode(s) of acute or subacute deterioration because of a wide range of precipitants. The vast majority of these events are marked by systemic and pulmonary congestion.
II.Pathogenesis. HF is a progressive disorder initiated by some form of injury. This injury may range from acute disruptions in myocardial function to one of a number of chronic derangements including familial, infiltrative, metabolic cardiomyopathies, or chronic volume or pressure overloading states related to valvulopathies, intracardiac shunts, systemic/pulmonary hypertension, or conduction abnormalities. Regardless of the initial insult, the acute beneficial compensatory mechanisms ultimately become maladaptive.
A.Neurohormonal activation
1.Activation of the sympathetic nervous system. Chronic activation of the sympathetic nervous system ultimately results in decreased β-adrenergic receptor responsiveness, decreased norepinephrine stores, and sympathetic innervation of the myocardium. Chronically, these changes contribute to myocyte hypertrophy, fibrosis, and necrosis. Extracardiac effects include increased tubular reabsorption of sodium, activation of the renin–angiotensin–aldosterone system (RAAS), neurogenic and systemic vasoconstriction, and vascular hypertrophy.
2.Activation of the RAAS. As HF progresses, renal hypoperfusion and sympathetic stimulation of the kidneys result in increased production of renin by the juxtaglomerular apparatus. Renin cleaves circulating angiotensinogen into the biologically inactive angiotensin I, which is subsequently cleaved by angiotensin-converting enzyme (ACE) to the biologically active angiotensin II. Importantly, renin and ACE-independent pathways can generate angiotensin II. In addition to direct cardiovascular effects, angiotensin II stimulates aldosterone production by the zona glomerulosa within the adrenal cortex, which in turn promotes reabsorption of sodium in exchange for potassium in the distal tubule and collecting ducts of the nephron. Over time, increased aldosterone levels result in the promotion of vascular and myocardial hypertrophy and fibrosis, endothelial dysfunction, and inhibition of norepinephrine uptake.
3.Other neurohormonal derangements. Inappropriate production of arginine vasopressin has an antidiuretic effect and augments systemic vasoconstriction. Endothelin, neuropeptide Y, and other peripheral vasoconstrictors further enhance vascular tone.
A.The American College of Cardiology and the American Heart Association (ACC/AHA) guidelines currently classify HF on the basis of the evolution of the disease across a continuum (always progressive, no reversal):
1.Stage A: patients at high risk for developing HF without structural heart disease or symptomatic HF
2.Stage B: patients with structural heart disease who have not yet developed symptoms of HF
3.Stage C: patients with structural heart disease with prior or current symptoms of HF
4.Stage D: patients with refractory end-stage HF who require specialized advanced treatment
B.The New York Heart Association (NYHA) functional classification, although subjective and vague, remains the most commonly used standard by which the severity of functional impairment is graded (Table 8.1).
TABLE 8.1 New York Heart Association Functional Classification |
|
Class |
Description |
I |
Patients have cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitations, dyspnea, or anginal pain |
II |
Patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain |
III |
Patients have cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitations, dyspnea, or anginal pain |
IV |
Patients have cardiac disease resulting in an inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased |
C.The Killip classification grades the severity of acute decompensated HF in the post–acute coronary syndrome setting and is predictive of 30-day mortality.
1.Killip I: patients with no clinical evidence of HF
2.Killip II: patients with mild signs of HF: S3, elevated jugular venous pressure (JVP), or pulmonary crackles
3.Killip III: patients with acute pulmonary edema
4.Killip IV: patients with cardiogenic shock
IV.Etiology. It is essential to make every effort to identify the specific etiology of HF because it may have implications for management and prognosis. Whereas ischemic cardiomyopathy is by far the most common cause of systolic HF, a diverse array of disease states can culminate in this phenotype (Table 8.2).
TABLE 8.2 Etiologies of Heart Failure |
Ischemic cardiomyopathy |
Idiopathic cardiomyopathy |
Familial cardiomyopathy |
Hypertrophic cardiomyopathy |
Restrictive cardiomyopathy |
Arrhythmogenic heart disease |
Valvular heart disease |
Hypertension |
Inflammatory (lymphocytic, eosinophilic, giant cell myocarditis) |
Amyloidosis |
Sarcoidosis |
Infectious (Chagas disease, Lyme disease, HIV, enterovirus, adenovirus, CMV, bacterial or fungal infections) |
Toxins (alcohol, catecholamines, cocaine, anthracyclines, chloroquine, and other chemotherapeutics, radiation) |
Endocrine (thyroid diseases, adrenal insufficiency, pheochromocytoma, acromegaly, diabetes mellitus) |
Stress-induced cardiomyopathy |
Peripartum cardiomyopathy |
LV noncompaction |
Mitochondrial cardiomyopathy |
Fibroelastosis |
Familial storage disease (hemochromatosis, glycogen storage disease, Hurler syndrome, Anderson–Fabry disease) |
Electrolyte deficiency syndromes (hypokalemia, hypomagnesemia) |
Nutritional deficiencies (L-carnitine, iron, thiamine, and selenium deficiency) |
Familial Mediterranean fever |
Systemic diseases |
Connective tissue disorders (SLE, polyarteritis nodosa, rheumatoid arthritis, scleroderma, dermatomyositis, polymyositis, sarcoidosis) |
Muscular dystrophies (Duchenne, Becker, myotonic, limb girdle) |
Neuromuscular (Friedreich ataxia, Noonan disease) |
CMV, cytomegalovirus; HIV, human immunodeficiency virus; LV, left ventricular; SLE, systemic lupus erythematosus.
A.Ischemic cardiomyopathy accounts for almost half of the cases of systolic HF in industrialized countries. It is defined as cardiomyopathy in the presence of prior extensive myocardial infarction, hibernating myocardium, or severe coronary artery disease. However, the mere presence of obstructive coronary artery disease does not equal ischemic cardiomyopathy because it is possible to have coronary artery disease superimposed with a nonischemic etiology of HF. A careful assessment of the coronary anatomy, ischemic burden, and the presence of infarcted and viable myocardium must be made and an assessment of the proportionality of these findings to the degree of myocardial dysfunction should be determined. The risks and benefits of percutaneous or surgical revascularization should be assessed in all patients with ischemic cardiomyopathy. Extensive observational data have suggested a benefit for coronary artery bypass grafting (CABG) compared with medical therapy alone in moderate to severe LV systolic dysfunction. Registry data suggest that CABG is superior to percutaneous coronary intervention in patients with reduced EF. Recently released 10-year follow-up data from the Surgical Treatment for Ischemic Heart Failure trial demonstrated a significant reduction in all-cause mortality, cardiovascular death, and HF hospitalization in the CABG plus medical therapy cohort compared with the medical therapy alone in patients with an EF <35%. Notably, patients with left main trunk disease and severe angina were excluded from the study and these patients should continue to be treated aggressively with revascularization.
B.Dilated cardiomyopathy. Heterogenous cohort of patients with systolic dysfunction not related to underlying coronary artery disease. In 20% to 30% of HFrEF cases, the precise etiology is not established and a diagnosis of nonischemic, dilated, or idiopathic cardiomyopathy is made. Patients with dilated cardiomyopathy typically have a better prognosis than their ischemic counterparts.
1.Subclinical viral myocarditis can progress to dilated cardiomyopathy. Endomyocardial biopsy sensitivity remains poor but molecular techniques like reverse transcription polymerase chain reaction analysis demonstrates amplification of viral genomes in approximately two-thirds of cases and should be considered when benefits outweigh the risks (see Chapter 11). Any virus can cause myocarditis, but, owing to its ubiquity, coxsackie B virus is the most epidemiologically important.
2.Familial dilated cardiomyopathy. It is now recognized that 25% to 50% of cases of dilated cardiomyopathy may have a genetic etiology. Conditions are typically autosomal dominant and show variable penetrance. A detailed three-generation family history is essential at the time of initial evaluation. If the family history suggests a genetic predisposition, clinical screening of family members is appropriate and genetic testing can be performed following referral to a genetic counselor. Importantly, only 40% of presumed familial dilated cardiomyopathies have identifiable genetic alterations.
3.Hypertensive and diabetic cardiomyopathy are seldom considered as stand-alone diagnoses. Progression from LV hypertrophy to overt dysfunction in hypertensive patients (the so-called burnt-out hypertensive heart) most likely results from progressive microvascular ischemia. Hypertension and diabetes mellitus also contribute significantly to the development of coronary artery disease and ischemic cardiomyopathy.
4.Cardiotoxic agents. The list of toxins that can produce cardiomyopathy is extensive. Identification of the toxin and removal of the offending agent may halt the progression of or even reverse LV dysfunction.
a.Chemotherapeutic agents. Anthracycline (doxorubicin, epirubicin, mitoxantrone) toxicity can cause myocyte destruction and cardiomyopathy. Patients who receive a cumulative doxorubicin equivalent dose of <400 mg/m2 are at low risk for this syndrome, whereas those receiving a cumulative dose >700 mg/m2 have an approximately 20% lifetime risk of developing cardiomyopathy. However, cardiotoxicity can occur at any dose. Doxorubicin is the most cardiotoxic. In an attempt to minimize doxorubicin cardiotoxicity, the agent should be administered via a continuous infusion, not bolus, as a means to lower the peak plasma level and via a liposomal formulation to minimize cardiotoxicity. Alongside standard cardioprotective HF medications, dexrazoxane has been approved for patients receiving doxorubicin therapy to minimize cardiotoxicity. Other cardiotoxic drugs that require careful cardiac monitoring include cyclophosphamide and trastuzumab. Trastuzumab (Herceptin) is now frequently used in the treatment of human epidermal growth factor receptor 2–positive breast cancer and has been associated with cardiotoxicity in 8% to 30% cases, which is reversible following drug cessation in approximately 60% cases and can be rechallenged with close monitoring. Antiangiogenic drugs such as sunitinib can also cause cardiotoxicity and uncontrolled hypertension. 5-Fluorouracil has been associated with both cardiomyopathy and severe coronary vasospasm.
b.Alcohol consumption (>5 drinks per day) is thought to represent a common cause of toxin-mediated cardiomyopathy. However, there is limited observational data on the actual incidence of the cardiomyopathy or the volume of alcohol consumption necessary to induce it. Total abstinence from alcohol may result in complete resolution, whereas continued use is associated with a 3- to 6-year mortality exceeding 50%.
c.Stimulant drugs including cocaine and methamphetamines may result in the development of HF via multiple derangements including progressive concentric hypertrophy and recurrent myocardial infarction.
d.Toxin exposures including lead, arsenic, and cobalt can result in progressive myocardial dysfunction. Iron overload from primary or secondary hemochromatosis may present with restrictive cardiomyopathy; it typically progresses to a mixed or dilated form. Treatment with chelating agents or phlebotomy may improve cardiac function in both primary and secondary forms.
5.Inflammatory cardiomyopathy (i.e., myocarditis) is discussed in detail in Chapter 11.
6.Tachyarrhythmia-induced cardiomyopathy can complicate the course of atrial fibrillation, atrial flutter, ectopic atrial tachycardia, and even occult sustained ventricular tachycardia and frequent premature ventricular contractions (>10% to 20% of beats). In general, it is thought that persistent tachycardia in excess of 110 beats/min is required to induce LV dysfunction. This is a critical diagnosis to make, because treatment of the underlying tachyarrhythmia generally results in complete resolution of the cardiomyopathy.
7.Peripartum cardiomyopathy is defined as a dilated cardiomyopathy occurring between the last month of pregnancy and up to 5 months postpartum. Approximately 50% of peripartum cardiomyopathy patients improve with standard HF pharmacotherapy but the morbidity and mortality continues to be high for those patients who do not demonstrate myocardial recovery. Risk factors include age >30, multiparity, African American, and hypertension or history of preeclampsia.
8.Valvular disorders are common causes of HF secondary to volume or pressure overload or both. Aortic and mitral valve pathology can lead to progressive LV dysfunction (see Chapters 15 and 16). When appropriate, surgical correction is the preferred management of severe valvular lesions, or high-risk candidates could consider a percutaneous approach, for example, transcatheter aortic valve replacement, balloon valvuloplasty, or MitraClip.
9.Miscellaneous disorders: Thyroid disorders: Hypothyroidism is common in patients with HF. Severe hypothyroidism (i.e., myxedema) may cause decreased cardiac output and HF. Bradycardia and pericardial effusion can develop in extreme cases of hypothyroidism. Hyperthyroidism can also lead to AHFS, which can be especially problematic in elderly patients with low ventricular reserve. Atrial fibrillation is a common accompanying arrhythmia, occurring in 9% to 22% of patients with thyrotoxicosis. Nonspecific symptoms such as fatigue, weight loss, and insomnia may predominate. Previously stable angina may also become unstable. Patients treated with amiodarone may develop a wide range of thyroid disorders ranging from abnormal thyroid function tests to overt amiodarone-induced thyrotoxicosis or hypothyroidism. Both conditions can occur in otherwise normal thyroid glands.
Thiamine deficiency (beriberi): Although rare in industrialized countries, thiamine deficiency is still prevalent in the developing world. It can also occur in alcoholics or individuals observing fad diets. Wet beriberi includes features of high-output cardiac failure such as marked edema, peripheral vasodilatation, and pulmonary congestion. The signs and symptoms of dry beriberi include glossitis, hyperkeratosis, and peripheral neuropathy. The laboratory diagnosis is made by assessing erythrocyte transketolase and 24-hour urine thiamine levels. Severe cases can present with lactic acidosis. Intravenous (IV) therapy with 100 mg of thiamine followed by daily oral supplementation can result in dramatic clinical improvement. Chronic use of high-dose diuretics may be complicated by subclinical thiamine deficiency of unknown significance.
Other nutritional deficiencies: Carnitine and selenium deficiency may result in dilated cardiomyopathy complicating chronic parenteral nutrition.
10.Anemia: Acute anemia caused by rapid blood loss is associated with decreased cardiac output because of hypovolemic shock. In contrast, chronic anemia can be associated with symptoms of HF because of compensatory mechanisms. These include fluid retention, increased cardiac output, decreased systemic vascular resistance, and increased 2,3-diphosphoglycerate with a resultant rightward shift in the oxyhemoglobin dissociation curve. Chronic anemia (hemoglobin < 9 g/dL) may exacerbate or augment HF symptoms in patients with preexisting disease. Chronic anemia of severe proportion (hemoglobin < 7 g/dL) may result in high-output HF even in individuals with normal cardiac anatomy. Evaluation and management of the underlying cause and supportive care are advised. Thresholds for transfusion depend on the clinical context and rapidity of blood loss. Iron repletion should be considered in iron-deficient patients with IV iron. FAIR-HF and CONFIRM-HF demonstrated functional improvement with IV iron replacement. (See Section VII for current guideline recommendations regarding management of iron deficiency anemia in stage C HF.)
11.Inherited myopathies such as Becker or Duchenne muscular dystrophy and myotonic dystrophy represent a group of dystrophinopathies that can be associated with a dilated cardiomyopathy. Friedreich ataxia is most commonly associated with hypertrophic cardiomyopathy, but in rare instances can present with a dilated phenotype. Fabry disease can appear as a hypertrophic cardiomyopathy. It is an X-linked, lysosomal storage disease and will have systemic manifestations including acroparesthesias, renal dysfunction, and angiokeratomas. Mitochondrial cardiomyopathies may also present with dilated cardiomyopathy. Danon disease is an X-linked, glycogen storage disorder associated with a lysosomal associated membrane protein-2 mutation. Dilated cardiomyopathies without conduction disease may be associated with a titin (TTN) mutation. Dilated cardiomyopathies with conduction disease may be associated with Lamin A/C mutations.
12.Cardiac sarcoidosis can present with LV dysfunction with regional hypokinesis or aneurysmal dilatation. It is frequently associated with conduction abnormalities and ventricular tachyarrhythmias. The diagnosis can be supported with stereotypical findings on cardiac magnetic resonance (CMR) imaging or positron emission tomography (PET). The diagnosis is rare in the absence of extracardiac manifestations.
13.Amyloidosis can impact cardiac function secondary to deposition of insoluble proteins within the myocardial matrix. In early stages, it may be present as HFpEF but in late stages it may present as HFrEF and can have both a dilated and nondilated appearance. Cardiac amyloidosis is primarily due to either transthyretin (TTR)—senile/wild type versus mutant—or primary amyloidosis, which is secondary to a light chain dyscrasia: κ or λ (see Chapter 9).
14.Chagas disease caused by the flagellate protozoan Trypanosoma cruzi remains a common cause of HF in patients from Latin America. In the chronic symptomatic phase, patients typically present with a syndrome of ventricular dysfunction with regional wall motion abnormalities in the absence of obstructive coronary artery disease. This pattern should prompt T. cruzi titers in patients from endemic regions.
V.Signs and Symptoms
A.There is a wide spectrum of signs and symptoms in HF patients. Subjective changes in signs and symptoms are often difficult to elicit and frequently leave insufficient time lag for therapeutic interventions prior to hospitalization.
1.The most common and earliest presenting symptom is dyspnea, typically with exertion. Orthopnea is typical with more advanced disease. It is among the most sensitive (90%) and specific (90%) signs of decompensated HF. With further decompensation, paroxysmal nocturnal dyspnea and Cheyne–Stokes respiration may occur.
2.Fatigue and exercise intolerance are common complaints in patients with HF and may reflect diminished cardiac output. Seldom considered but highly prevalent symptoms include anorexia, nocturnal cough, insomnia, and depressed mood.
3.Syncope may occur in patients with underlying arrhythmia, severe cardiac dysfunction, or pulmonary arterial hypertension and requires prompt evaluation.
4.Anorexia, abdominal pain, and bloating are common in advanced right HF.
B.Physical examination of patients with significant but well-compensated systolic HF may reveal no abnormalities. Physical signs vary according to the degree of compensation, chronicity, and chamber involvement.
1.Volume overload is the hallmark of HF. Typical signs of volume overload include the following:
a.Weight gain is a sensitive indicator of congestion.
b.Pulmonary rales because of accumulation of fluid in the pulmonary interstitium and alveoli secondary to high left atrial pressure are commonly referred to as acute cardiogenic pulmonary edema. Importantly, rales may be absent in patients with chronic systolic HF who develop compensatory perivascular and lymphatic changes.
c.Jugular venous distention or elevated JVP although not directly reflecting left-sided filling pressures can track these with a reasonable sensitivity (70%) and specificity (79%). JVP should be assessed at a 45° incline with the neck fully exposed. In cases of extreme JVP elevation, the patient may need to be seated upright in order to properly visualize. Five centimeters of water should be added to the vertical distance from the sternal angle to the meniscus of the JVP to account for the distance to the midpoint of the right atrium. Compression of the right upper quadrant and a resultant positive hepatojugular reflex (defined as a sustained increase in JVP of ≥4 cm) increase the sensitivity of the JVP for detecting congestion.
d.Pedal edema by some estimates is only present in 30% of patients with decompensated HF and is somewhat nonspecific, because it may reflect venous insufficiency, nephrotic syndrome, hepatic dysfunction, or concomitant treatment with specific medications such as calcium channel blockers or thiazolidinediones.
2.Ascites and hepatomegaly may occur. Severe tricuspid regurgitation may be present in the setting of a palpable, pulsatile liver.
3.A holosystolic murmur of mitral regurgitation (MR) is often present in the setting of LV dilatation.
4.A third heart sound (S3 gallop) is best heard with the bell of the stethoscope in the left lateral position and signifies increased LV end-diastolic pressure. Often neglected are the subtle signs of peripheral hypoperfusion.
5.Pulsus alternans or a low-amplitude pulse in the absence of alternative explanations reflects severely impaired cardiac output.
6.Tachycardia and narrow pulse pressure also suggest diminished cardiac output.
7.Lethargy, pallor, mottled skin, cool extremities, and poor capillary refill are typical signs.
8.Hypotension itself may be one of the most important clinical findings in HF. Several studies have demonstrated that a systolic blood pressure <90 mm Hg is a strong predictor of morbidity and mortality.
VI.Diagnostic Evaluation
A.Laboratory work is used to diagnose potentially reversible causes, identify comorbidities, monitor and correct abnormalities before or during treatment, and assess the disease severity.
1.A comprehensive metabolic panel should be assessed on initial evaluation and then subsequently based on clinical judgment. Particular attention should be paid to the presence of hyponatremia, which portends a worse prognosis. Hypokalemia is common in the setting of ongoing diuretic therapy. Hyperkalemia can be seen in the context of overaggressive potassium repletion and ongoing treatment with renin–angiotensin–aldosterone antagonists, or K-sparing diuretics, or in diabetic patients with associated type IV renal tubular acidosis. Aside from the pragmatic considerations, many real-world registries have identified elevated blood urea nitrogen (BUN) and creatinine as powerful predictors of outcome. Renal function must also be taken into account when considering therapy. In the context of chronic, congestive right HF, liver function testing abnormalities are most consistent with cholestasis.
2.Anemia is present in up to 40% of HF patients and is associated with increased mortality and functional impairment. Although frequently because of anemia of chronic disease, a thorough diagnostic evaluation should be performed. Iron deficiency (in the absence of anemia) is also common.
3.The natriuretic peptides B-type natriuretic peptide (BNP) and N-terminal pro–B-type natriuretic peptide (NT-proBNP) are released in the setting of increased ventricular dilation or wall stress. Normal ranges (BNP < 100 pg/mL; NT-proBNP < 125 pg/mL if age < 75 years and <450 pg/mL if age ≥75 years) must be interpreted in the context of associated conditions known to alter levels. Increasing age, anemia, and worsening renal function are associated with increased levels.
a.Screening for heart failure. Although cardiac dysfunction has been associated with elevated natriuretic peptide levels, the sensitivity is relatively low in asymptomatic patients and is highly dependent on the cut-off levels chosen. In general, routine assessment of BNP is not recommended as a screening test for structural heart disease in asymptomatic patients.
b.Diagnosing heart failure. The primary use of natriuretic peptides remains the diagnosis of HF in symptomatic patients particularly when the diagnosis is unclear. The high negative predictive value (up to 90%) in this setting allows BNP testing to be useful to rule out a cardiac cause of symptoms. With the growing obesity epidemic, it is important to remember that normal natriuretic peptide levels may be present in morbidly obese patients with decompensated HF. Other noncardiac causes of elevated natriuretic peptides include sepsis, pulmonary disease, pulmonary hypertension, and critical illness.
c.Management of heart failure. Although controversial, there is emerging evidence that serial measurements of natriuretic peptides may be beneficial in guiding outpatient HF management and may result in decreased HF–related mortality versus usual care. Post-HF hospitalization assessment or predischarge natriuretic assessment can aid in additional prognostic information. Of note, BNP is a substrate for neprilysin; therefore, if a patient is on an angiotensin receptor blocker neprilysin inhibitor (ARNI), it cannot be used to follow a patient’s clinical course. However, NT-proBNP levels will not be impacted.
d.Determining prognosis of heart failure. Natriuretic peptide levels correlate with morbidity and mortality in patients with both established HF and other cardiovascular diagnoses (e.g., stable coronary artery disease, acute coronary syndromes, pulmonary hypertension, and atrial fibrillation).
4.Other biomarkers. Troponin T or I may be elevated in chronic HF and demonstrate ongoing myocyte injury. Alongside natriuretic peptides and troponins, a growing list of biomarkers assessing systemic inflammation, oxidative stress, extracellular matrix remodeling, myocardial fibrosis, and myocyte injury is commercially available or in development (e.g., soluble ST2, cystatin C, galectin-3). Whereas some of these provide useful prognostic information, it remains unclear on how to best integrate into the diagnosis and management of HF.
5.Thyroid function testing is warranted for all patients with a new diagnosis of HF.
6.Iron studies including ferritin, serum iron, and total iron binding capacity (with calculation of percent transferrin saturation) should be performed to screen for hemochromatosis and occult iron deficiency.
7.Standard laboratory screening for modifiable cardiovascular risk factors including fasting lipid panel and serum glucose should also be obtained. When clinical suspicion is heightened, consider additional screening for human immunodeficiency virus, rheumatologic processes, and amyloidosis.
B.The electrocardiogram (ECG) provides important information pertaining to the cause and management of HF and is a recommended component of the evaluation of any patient with a clinical diagnosis of HF and change in clinical status.
1.It is important to look for evidence of prior myocardial infarction, chamber enlargement and hypertrophy, conduction disease, and supraventricular or ventricular arrhythmias.
2.Specific diagnoses can be suggested in the ECG. Cardiac amyloidosis may classically present with low voltage and a pseudoinfarction pattern in the anterior leads in stark contrast to thickened walls observed on echo. Arrhythmogenic right ventricular (RV) dysplasia may present with epsilon waves or localized prolongation (>110 ms) of the QRS complex in the right precordial leads.
3.The ECG is an important means of assessing dyssynchrony. Marked first-degree atrioventricular (AV) block or very short AV delays in the presence of paced rhythms may contribute to AV dyssynchrony. The presence of QRS prolongation >120 ms (particularly left bundle branch block) suggests interventricular dyssynchrony and remains the most important predictor of response to cardiac resynchronization therapy (CRT-D).
4.Holter or event monitors are often useful in identifying occult arrhythmia, arrhythmia burden, and conduction abnormalities.
C.Examination of the chest radiograph should include an assessment of the heart size, pleura, and the condition of the pulmonary parenchyma. Determination of cardiac size is best restricted to standard posteroanterior projection, because “portable” anteroposterior projection will magnify the cardiac silhouette. The lateral projection is useful to assess for RV enlargement with associated filling of the retrosternal space and pleural effusion(s). A normal cardiac silhouette does not exclude systolic or diastolic dysfunction. The lung field abnormalities may range from mild engorgement of the perihilar vessels to bilateral pleural effusions, Kerley B lines, and frank pulmonary edema.
D.Echocardiography is perhaps the most useful diagnostic test in the evaluation of patients with HF. It can provide useful information pertaining to the etiology and prognosis of HF. As described in later sections, echocardiography also plays a key role in guiding HF therapy.
1.Etiology of heart failure. Regional wall motion abnormalities occurring in an anatomic coronary artery distribution are suggestive of ischemic cardiomyopathy. However, regional wall motion abnormalities can also be seen in the context of nonischemic dilated cardiomyopathy, stress-induced cardiomyopathy, and infiltrative cardiomyopathies (with inferobasal wall motion abnormalities classically seen in the setting of cardiac sarcoidosis). The presence and severity of valvular stenosis or insufficiency can be assessed as can the relative dysfunction of the right and left ventricles.
2.Prognosis in heart failure. The following parameters are useful in assessing the risk of HF-associated morbidity and mortality.
a.EF and LV dimensions may not correlate with HF symptoms. However exercise capacity, oxygen consumption, and EF provide valuable prognostic information. Morbidity and mortality are linked to EF and LV volumes. The American Society of Echocardiography recommends EF and LV volumes assessment by Simpson’s biplane method.
b.LV mass. Cardiac remodeling results in increased LV mass because of eccentric hypertrophy, which worsens prognosis. Eccentric hypertrophy is defined echocardiographically as an LV mass >95 g/m2 in women and >115 g/m2 in men with a regional wall thickness (2 × posterior wall thickness/LV end-diastolic dimension) of ≤0.42.
c.The myocardial performance index (Tei index) provides a useful assessment of systolic and diastolic function and is equal to the (isovolumic contraction time + the isovolumic relaxation time)/the ejection time. All dimensions are obtained via pulse wave or tissue Doppler. A Tei index of >0.77 in patients with dilated cardiomyopathy is highly predictive of cardiovascular morbidity and mortality.
d.Measures of diastolic dysfunction. Many of the measures of diastolic dysfunction detailed in Chapter 9 have powerful prognostic ability in patients with systolic HF. The presence of a restrictive filling pattern (E/A > 2, deceleration time < 115 to 150 ms) persisting despite Valsalva maneuver is a particularly ominous finding.
E.Other imaging modalities
1.Cardiac magnetic resonance imaging (Chapter 51). CMR offers unparalleled myocardial tissue characterization and allows for myocardial viability assessment. It is an increasingly useful tool in the diagnosis of specific cardiomyopathies (e.g., LV noncompaction, cardiac sarcoidosis, and amyloidosis). The distribution of late gadolinium hyperenhancement representing scar can effectively discriminate between ischemic and nonischemic causes of fibrosis. Cine magnetic resonance imaging provides accurate assessments of chamber volumes and LV and RV systolic function that can be performed in arbitrary tomographic views. Major limitations are incompatibility with implanted electronic cardiovascular devices and the potential for nephrogenic sclerosing fibrosis in patients with preexisting renal insufficiency.
2.Nuclear imaging. Single-photon emission computed tomography (SPECT) and PET imaging are primarily of use in ruling out myocardial ischemia and/or viability as well as metabolic activity. Viability assessment (i.e., discriminating between scarred and hibernating myocardium) is critical in the assessment of patients with HF and coronary artery disease and the potential for myocardial recovery with revascularization. This can be achieved with PET using concomitant flow and metabolism tracers (typically [18F]fluorodeoxyglucose) or thallium-201 versus technetium-99m SPECT redistribution imaging (see Chapter 50). There is growing evidence that PET is superior to SPECT in patients with systolic dysfunction, and when available it should be used preferentially in patients with a left ventricular ejection fraction (LVEF) <35%. Dobutamine stress echocardiography and CMR are alternative means of assessing viability. Radionuclide ventriculography using multiple-gated acquisition scanning has long served as the gold standard for precise serial measurements of the LVEF (classically in the evaluation of patients receiving cardiotoxic chemotherapeutics). Increasingly, however, it is being surpassed by CMR and three-dimensional echocardiography. A technetium pyrophosphate scan is an additional nuclear modality that can be used to assess for TTR (wild type or mutant) amyloidosis with 100% specificity and 97% sensitivity.
F.Right heart catheterization (see Chapter 60). Invasive hemodynamic monitoring is often helpful in the diagnosis and inpatient management of HF. Right heart catheterization can be combined with exercise testing or addition of inotropic or vasodilatory agents to evaluate impact on hemodynamics. Indications for right heart catheterization include short-term management of acute cardiogenic shock, evaluation of patients for cardiac transplantation or mechanical circulatory support, clarification of hemodynamics in the context-specific comorbidities (e.g., suspected RV infarction or mechanical complications of myocardial infarction), and clarification and optimization of medical therapy in patients with recurrent or refractory symptoms.
1.Cardiac output/index can be determined by thermodilution or the Fick method using estimated or measured oxygen consumption and a directly measured mixed venous oxygen saturation (MVo2).
2.Pulmonary capillary wedge pressure (PCWP) should be measured in all cases. An inability to normalize the PCWP (<16 mm Hg) with pharmacotherapy was shown in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial to confer a twofold increased risk of mortality.
3.Right atrial (RA) pressure is an important indicator of volume status and right heart function. An elevated central venous pressure has been shown to be the most important predictor of worsening renal function during hospitalizations for acute decompensated HF. RA pressure to PCWP ratio >0.63 or a right ventricular stroke work index <400 portends RV dysfunction.
G.Coronary angiography (see Chapter 64). There are many approaches to determining which patients with systolic HF warrant evaluation by coronary angiography. The Heart Failure Society of America, American College of Cardiology Foundation, and AHA recommend performing coronary angiography in patients with a high pretest probability of underlying ischemic cardiomyopathy and who are candidates for percutaneous or surgical revascularization. At a minimum, patients meeting this description should undergo some form of noninvasive stress testing. Some centers advocate for a baseline coronary angiogram in all patients with newly established systolic HF regardless of risk factors or presentation.
H.Endomyocardial biopsy (see Chapter 61) is indicated only when a specific primary myocardial disease is suspected and other causes of decompensation have been ruled out. AHA/ACC/European Society of Cardiology 2007 writing group identified 14 clinical scenarios in which there is an incremental diagnostic, prognostic (e.g., amyloidosis), or therapeutic (e.g., giant cell myocarditis) value to biopsy that can be weighed against the procedural risk.
I.Cardiopulmonary exercise testing (metabolic stress testing), although not recommended as part of the routine evaluation of patients with HF, should be considered in the context of symptoms out of proportion to clinical exam as an objective measure of disease severity, discriminating between cardiac and pulmonary etiologies of dyspnea, or assessing candidacy for advanced HF therapies: cardiac transplantation or mechanical circulatory support. The following parameters along with inappropriate blood pressure response to exercise are highly predictive of prognosis in patients with established HF.
1.Peak oxygen consumption (Vo2) is perhaps the most important parameter in objectively describing functional capacity and prognostication. Normal values based on age and sex are indexed to body weight, with a normal value being >84% predicted. Patients being considered for heart transplantation undergo risk stratification with a metabolic stress test. Patients with a peak Vo2 <14 mL/kg/min or <50% predicted are at increased risk for adverse cardiovascular events and, if the limitation is deemed to be cardiac, should be considered for transplantation. Interpretation of the peak Vo2 is highly dependent on the adequacy of effort as assessed by the respiratory exchange ratio (RER). The RER is the ratio of Vco2/Vo2 and is, at steady state, an estimate of the respiratory quotient. It signifies the conversion to anaerobic metabolism and the sudden rise in CO2 production occurring with the onset of metabolic acidosis. Failure to achieve an RER >1.05 suggests insufficient effort or premature termination of the study. Up to 50% of HF patients are incapable of achieving an adequate RER, with a modified Bruce treadmill protocol necessitating the use of alternative protocols.
2.Ventilatory anaerobic threshold is another means of assessing the adequacy of effort and represents the point at which minute ventilation (VE) increases out of proportion with Vo2 (typically occurring at 60% to 70% of peak Vo2).
3.VE/Vco2 slope is a dimensionless ratio indicating the relationship between minute ventilation and co2 production. The slope is elevated in most patients with HF and is inversely related to cardiac output at peak exercise. A slope >35 identifies higher risk individuals independently of peak Vo2.
J.Sleep study. Central and obstructive sleep apnea is common in patients with chronic HF. A formal sleep study should be considered in all patients with NYHA II–IV HF. Continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea improves oxygenation and sleep quality and reduces the apnea–hypopnea index. Adaptive sero-ventilation therapy has demonstrated harm in individuals with HFrEF and is no longer indicated for the treatment of central sleep apnea.
VII.Treatment. The effective management of HF relies on appreciating the distinction between acute and chronic therapies.
A.Acute heart failure syndromes. In the United States, AHFS continue to constitute the most common indication for hospital admission in adults over age 65 years. These hospitalizations represent an inflection point in the course and prognosis of the chronic disease, with 90-day and 1-year postdischarge mortality as high as 14% and 37%, respectively. Only 20% of AHFS represent patients with de novo HF. The majority are patients with worsening chronic HF. The initial management goals include symptom improvement, decongestion, and hemodynamic stabilization with optimization of tissue perfusion. It is important to identify and correct any precipitating factors (Table 8.3).
TABLE 8.3 Common Precipitants of Acute Decompensated Heart Failure |
Medication nonadherence |
Acute myocardial ischemia, infarction and associated complications: ventricular septal rupture, papillary muscle rupture, free wall rupture, and cardiogenic shock |
Arrhythmias (tachyarrhythmias, bradycardia) |
Pulmonary embolus |
Infections (e.g., pneumonia, urinary tract infection, bacteremia, viremia, endocarditis) |
Alcohol consumption or illicit drug use |
Uncontrolled hypertension |
Acute cardiovascular compromise: myocarditis, aortic dissection, valvular pathology |
Drugs that can acutely worsen HF symptoms (e.g., calcium channel blockers, nonsteroidal anti-inflammatory drugs, thiazolidinediones, steroids) |
β-Blocker initiation in decompensated state |
HF, heart failure.
1.Invasive hemodynamic monitoring
a.Pulmonary artery catheter. The ESCAPE trial demonstrated that routine use of pulmonary artery catheters did not result in a reduction in subsequent hospitalizations or mortality in patients with AHFS but did result in increased, anticipated adverse events. Invasive hemodynamic guided management should be restricted to scenarios outlined above or where there is need for clarification of cardiac indices and/or filling pressures in critically ill patients. A PCWP of >18 mm Hg suggests cardiogenic pulmonary edema and a cardiac index of <2.0 L/min/m2 is consistent with cardiogenic shock.
b.Arterial catheter. Continuous blood pressure monitoring with an arterial catheter can be useful in cases with marginal blood pressure and optimizes titration of IV vasodilators.
2.Maximizing oxygenation is vital. All patients with acute cardiogenic pulmonary edema should be positioned upright and receive supplemental oxygen. Noninvasive positive pressure ventilation (NIPPV) should be considered in those with ongoing increased work of breathing, respiratory acidosis, or persistent hypoxemia. The Noninvasive Ventilation in Acute Cardiogenic Pulmonary Edema trial demonstrated that NIPPV results in more rapid resolution of symptoms and metabolic derangements than CPAP ventilation or standard oxygen therapy. Although there was no evidence of a reduction in short-term mortality, this can be an invaluable tool often forestalling intubation. Patients who fail to respond to NIPPV should be promptly intubated. The use of positive end-expiratory pressure (PEEP) can be effective in improving oxygenation and decreasing cardiac afterload, but high levels of PEEP come at the cost of reduced systemic venous return and subsequently cardiac output particularly in individuals with RV dysfunction.
3.Vasodilators. In the absence of symptomatic hypotension, IV vasodilators are the first-line therapy for the management of cardiogenic pulmonary edema.
a.Nitroglycerin reduces LV filling pressures via venodilation and to a lesser extent via systemic afterload reduction. It may be given rapidly in the emergency setting (0.4 to 0.8 mg, given sublingually every 3 to 5 minutes) and by means of IV infusion in the subacute setting (starting dosage of 0.2 to 0.4 µg/kg/min), with titration every 5 minutes on the basis of symptoms or mean arterial pressure (MAP). Although there is no maximal dose, increasing beyond 300 to 400 µg/min likely yields no additional benefit and should prompt the addition of another vasodilator. Tachyphylaxis can occur with high-dose infusions. Headache is the most common side effect and its use is contraindicated in the setting of recent use of phosphodiesterase-5 (PDE-5) inhibitors.
b.Sodium nitroprusside (nipride) is a potent vasodilator with balanced venous and arteriolar effects. It requires careful hemodynamic monitoring. A starting dosage of 0.1 to 0.2 µg/kg/min is used and titrated every 5 minutes to achieve a clinical response while maintaining a MAP >65 mm Hg. Nipride is particularly useful in instances where a rapid and large reduction in afterload is desired (e.g., cardiogenic shock, acute aortic regurgitation, or acute MR). Whereas cyanide and thiocyanate toxicity are rare with short durations of therapy, nipride should be used with caution in patients with severe renal dysfunction, and long-term, high-dose infusions should be avoided. In patients with myocardial ischemia, nitroglycerin or a combination of nitroglycerin and nipride is preferred to avoid the theoretical risk of coronary steal syndrome.
c.Nesiritide is an IV vasodilator that gained popularity in the acute care setting because of its ease of use in the absence of invasive hemodynamic monitoring. Typical dosing starts with 2 mg/kg delivered by IV bolus followed by an infusion at a rate of 0.01 mg/kg/min for up to 48 hours. The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial demonstrated no effect on death or rehospitalization for HF at 30 days in patients treated with Nesiritide when compared to conventional therapy. Although providing some reassurance regarding previous safety concerns, these results have led most experts to discourage its use based on lack of efficacy.
4.Diuretics. In addition to their ability to gradually reduce intravascular volume, diuretics have an immediate vasodilatory effect, which may be responsible for their prompt symptom relief. Reductions in filling pressures may be associated with augmented forward flow because of optimization of LV and RV mechanics. Because many patients with acute cardiogenic pulmonary edema do not have total body salt and water excess, the judicious use of diuretics is recommended. Often, filling pressures normalize with the use of vasodilators alone. Patients without chronic exposure to loop diuretics usually respond to 20 to 40 mg of IV furosemide. Patients undergoing long-term furosemide therapy typically need an IV bolus dose at least equivalent to their oral dose (Diuretic Optimization Strategies Evaluation [DOSE] trial). Rather than an arbitrary therapeutic goal of net fluid balance or an estimated dry weight, frequent clinical assessments of volume status should guide therapy and define the point at which conversion to an oral maintenance regimen should occur. Nevertheless, up to 30% of patients with AHFS continue to have symptoms of congestion at the time of discharge. Important adverse effects include hypotension, hypokalemia, hypomagnesemia, and hypocalcemia. There is also extensive evidence suggesting that IV diuretics may result in at least transient neurohormonal activation, which is theoretically disadvantageous. Electrolyte repletion is best achieved with scheduled doses of potassium and magnesium supplements to prevent severe deficits. DOSE demonstrated no benefit of continuous or bolus dose IV diuretic administration and no detriment from high doses (an IV dose 2.5 times the patients’ chronic oral dose of furosemide). If a continuous diuretic infusion is opted for, it should be preceded by a bolus dose to achieve therapeutic threshold, as should any subsequent continuous dose titration. Escalating diuretic dose requirement should raise suspicion of resistance and can be addressed with the addition of sequential nephron blockade with a thiazide diuretic (hydrochlorothiazide, metolazone, or chlorothiazide) for synergistic effect. Some degree of worsening renal function must often be tolerated in order to achieve adequate decongestion. However, if progressive renal failure occurs despite persistent congestion, ultrafiltration (UF) or additional pharmacologic intervention(s) may be warranted.
5.Inotropic therapy. When signs and symptoms of decompensated HF persist despite administration of vasodilators and diuretics, IV inotropes may be considered. Their use should be restricted to patients with clear clinical or direct hemodynamic evidence of refractory elevated filling pressures and reduced cardiac indices. For patients without significant hypotension, dobutamine or milrinone can be used to augment cardiac output. Both drugs are associated with increased myocardial oxygen demand and cardiac arrhythmias and should be used with extreme caution in patients with ischemia and preexisting arrhythmias. Both drugs may cause hypotension, although this is more common with loading doses of milrinone. There is no evidence to support benefit with the use of chronic or intermittent infusion of inotropic agents, and in fact, there is extensive observational data suggesting a trend toward increased postdischarge mortality. Use is typically confined to the acute care setting as a bridge to decision making, transplant, or mechanical circulatory support or as definitive palliative therapy in patients who are not candidates for advanced therapies. In cases of severe hypotension (especially as a result of administration of vasodilators or β-blockers), temporary use of vasopressors such as dopamine or norepinephrine may be necessary. In contrast to the conventional wisdom, recent prospective data suggest that norepinephrine is not inferior to dopamine in the setting of cardiogenic shock.
a.Dobutamine acts on β-1 and to a lesser extent on β-2 and α-1 adrenergic receptors. It has a short half-life (~2 minutes). Infusions are usually started at 2.5 to 5.0 µg/kg/min. On the basis of hemodynamic response, it may be titrated by 1 to 2 µg/kg/min every 30 minutes until the desired effect or a dosage of 10 µg/kg/min is reached.
b.Milrinone is a PDE-III inhibitor that acts as a potent inodilator with a longer half-life (~ 2 to 3 hours and is renally cleared). For patients who need an immediate inotropic response, a loading dose of 50 µg/kg over 10 minutes is followed by an infusion of 0.125 to 0.75 µg/kg/min. Because it does not target β-receptors, milrinone may be more effective than dobutamine in the setting of recent or chronic β-blocker use.
6.Ultrafiltration has been used as an alternative to pharmacologic diuresis in acute decompensated HF. The UF versus intravenous diuretics for patients hospitalized for acute decompensated congestive heart failure study demonstrated that UF was safe and resulted in a reduced need for IV diuretics and inotropes. However, CARRESS-HF demonstrated a stepped pharmacologic approach to AHFS with worsening renal function was superior to UF. Currently the use of UF is reserved for patients that are refractory to IV diuretic therapy.
7.Vasopressin antagonists. The oral vasopressin receptor 2 antagonist tolvaptan was shown to be safe and results in short-term symptom improvement in patients hospitalized with acute decompensated HF. However, the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial failed to demonstrate an improvement in morbidity or mortality in patients with AHFS. Tolvaptan and the nonselective IV vasopressin receptor inhibitor conivaptan are both approved for the management of hypervolemic or euvolemic hyponatremia that can accompany decompensated HF but neither has demonstrated benefit with regards to morbidity or mortality.
8.Temporary mechanical circulatory support. The use of temporary and permanent mechanical circulatory support is described in detail in Chapter 12. Patients with refractory cardiogenic shock and cardiogenic pulmonary edema may benefit from the temporary use of intra-aortic balloon counterpulsation or an alternative temporary means of mechanical circulatory support (i.e., venoarterial extracorporeal membrane oxygenation, Impella, or TandemHeart) may facilitate bridging to stabilization or further decision making.
Transition to chronic pharmacotherapy is implemented once clinical stability is achieved. Generally, vasodilators (ACE inhibitors [ACEis], angiotensin II receptor blockers [ARBs], ARNIs, or hydralazine and isosorbide dinitrate) are reintroduced first in concert with weaning off IV vasodilators. If β-blockers were held due to cardiogenic shock, they can be cautiously reintroduced in stable, euvolemic patients.
B.Chronic medical therapies. The cornerstone of chronic medical therapy is to prolong survival and improve quality of life.
1.ACEis have been shown to reduce morbidity and mortality among patients with systolic HF. The mechanism of long-term benefit is related to attenuation of the renin–angiotensin system (RAS). In addition, ACEi improve symptoms, clinical status, and exercise capacity.
a.Use of an ACEi is first-line therapy for asymptomatic and symptomatic LV dysfunction. The dose of the ACEi should be increased to the target doses demonstrating clinical benefits in trials (Table 8.4). Although there are theoretical benefits of using “tissue” inhibitors (e.g., quinapril and ramipril), there are no data to support their preferential use. Relative contraindications include hyperkalemia (potassium > 5.5 mEq/L), renal insufficiency (creatinine > 3.0 mg/dL), and hypotension (systolic blood pressure < 90 mm Hg) and should be gauged on a case-by-case basis. It is not advisable to stop ACEis in patients with systolic HF, even when there is complete resolution of symptoms.
TABLE 8.4 Drug Dosing for Common Medical Therapies for Chronic Heart Failure |
|||
Drug |
Start (mg) |
Target (mg) |
Max (mg) |
|
ACE Inhibitors |
|||
Captopril (Capoten) |
6.25–12.5 tid |
50 tid |
100 tid |
Enalapril (Vasotec) |
2.5–5 bid |
10 bid |
20 bid |
Lisinopril (Prinivil, Zestril) |
2.5–5 qd |
20 qd |
40 qd |
Ramipril (Altace) |
1.25–2.5 bid |
5 bid |
10 bid |
Quinapril (Accupril) |
5 bid |
20 bid |
20 bid |
Fosinopril (Monopril) |
2.5 or 5 bid |
20 bid |
20 bid |
Benazepril (Lotensin)a |
2.5 or 5 bid |
20 bid |
20 bid |
Moexipril (Univasc)a |
7.5 qd |
30 qd |
30 qd |
Trandolapril (Mavik) |
1 qd |
4 qd |
4 qd |
|
Angiotensin Receptor Blockers |
|||
Candesartan (Atacand) |
16 qd |
32 qd |
32 qd |
Valsartan (Diovan) |
80 qd |
160 qd |
320 qd |
Losartan (Cozaar)a |
12.5–25 qd |
50 qd |
100 qd |
Irbesartan (Avapro)a |
150 qd |
300 qd |
300 qd |
Telmisartan (Micardis)a |
40 qd |
80 qd |
80 qd |
|
Hydralazine/Isosorbide Dinitrate |
|||
Hydralazine |
25 qid |
50–75 qid |
100 qid |
Isosorbide dinitrate |
10–20 tid |
20–80 tid |
80 tid |
Hydralazine–isosorbide dinitrate (BiDil) |
25/37.5 tid |
50/75 tid |
50/75 tid |
|
Aldosterone Antagonists |
|||
Spironolactone (Aldactone) |
12.5–25 qd |
25 qd |
50 bid |
Eplerenone (Inspra) |
25 qd |
50 qd |
100 qd |
|
Loop Diureticsc |
|||
Furosemide (Lasix) |
10 qd (IV) |
As required |
1,000 qd (IV) |
20 qd (PO) |
As required |
240 bid (PO) |
|
Bumetanide (Bumex) |
1 qd |
As required |
10 qd |
Torsemide (Demadex) |
10 qd |
As required |
200 qd |
Ethacrynic acid (Edecrin) |
50 qd |
As required |
200 bid |
|
Thiazide Diuretics |
|||
Hydrochlorothiazide (HCTZ) |
25 qd |
As required |
200 qd |
Metolazone (Zaroxolyn) |
2.5 qd |
As required |
10 qd |
Chlorthalidone |
12.5 qd |
As required |
100 qd |
Chlorothiazide (PO or IV) |
250–500 (PO) qd/bid 500–1,000 (IV) |
As required n/a |
1,000 mg n/a |
|
Potassium-Sparing Diuretics |
|||
Triamterene (Maxzide) |
50 qd |
As required |
100 bid |
Amiloride |
5 qd |
As required |
20 qd |
|
β-Blockers |
|||
Carvedilol (Coreg) |
3.125 bid |
25 bid |
50 bid |
Carvedilol phosphate (Coreg CR) |
10 qd |
40 qd |
80 qd |
Metoprolol succinate (Toprol XL) |
25 qd |
150–200 qd |
200 qd |
Bisoprolol (Zebeta)a |
1.25 qd |
8.6 qd |
10 qd |
Nebivolol (Bystolic)a,b |
1.25 qd |
10 qd |
40 qd |
|
Neprilysin Inhibitor + Angiotensin Receptor Blockers |
|||
Sacubitril/Valsartan (Entresto) |
24/26 bid |
97/103 bid |
97/103 bid |
|
If Current Inhibitor |
|||
Ivabradine (Corlanor) |
5 bid |
As required |
15 qd |
ACE, angiotensin-converting enzyme; IV, intravenous; PO, orally.
aNot yet approved by the Food and Drug Administration (FDA) for management of heart failure.
bApproved in Europe, not yet approved by the FDA for management of heart failure. SENIORS trial demonstrated all-cause mortality benefit in patients over 70 years of age.
cOral to IV conversion for furosemide is approximately 2:1. Oral to IV conversion for all other loop diuretics is 1:1.
b.After initiation, close monitoring for hyperkalemia and renal insufficiency is warranted.
(1)Hypotension is common, especially with first dose in a volume-depleted patient (e.g., after aggressive diuresis). This may require downtitration of diuretic doses and other vasodilator therapy. Because of its short half-life, captopril is usually used in the acute setting (e.g., after myocardial infarction).
(2)Renal insufficiency and hyperkalemia may occur when ACEis are given in the setting of volume depletion. It is crucial to discontinue other nephrotoxic agents (e.g., nonsteroidal anti-inflammatory agents) and ensure adequate kidney perfusion. If BUN or creatinine levels increase by <50%, ACEis can be continued safely; if they increase by >50%, the ACEi dose should be halved; if they increase by >100%, the ACEi should be held and switched to hydralazine and isosorbide dinitrate. In the case of hyperkalemia, discontinuation of potassium supplementation, K-sparing diuretic, and reducing the ACEi dose is usually effective.
c.Unique side effects of ACEis are cough and angioedema.
(1)The cough associated with ACEis is related to increased levels of bradykinin and seen in ~20% of patients. It tends to be nonproductive and involuntary, rarely resolving with altering the dose or specific agent. All attempts should be made to identify an alternative cause of cough before discontinuing ACEis.
(2)Angioedema is a rare complication of ACEis (0.4%). It involves soft tissue edema of the lips, face, tongue, and, occasionally, the oropharynx and epiglottis. Angioedema typically begins within 2 weeks of initiation of ACEi therapy, but some patients present with this complication months to years after starting therapy. Angioedema is an absolute contraindication to the use of any type of ACEi.
2.ARBs are specific receptor antagonists to the angiotensin II type 1 receptors. Although they theoretically provide more complete inhibition of the deleterious effects of angiotensin II than do ACEis, clinical trials have not demonstrated superiority in patients with HF. In general, ARBs are used and monitored in the same manner as ACEis. These drugs are reserved for patients who are ACEi intolerant, although in practice, they are used extensively. ARBs have a similar side-effect profile to ACEis (e.g., hypotension, renal insufficiency, and hyperkalemia). There appears to be a <10% incidence of cross-reactivity for ACEi-associated angioedema in patients receiving ARBs. However, consideration for the use of these agents must be weighed against the life-threatening nature of this complication. Whereas the addition of an ARB is reasonable in patients on target doses of ACEis and β-blockers with persistent symptoms, it is preferable to add an aldosterone antagonist first to get added morbidity and mortality benefit. ARBs should not be added to an ACEi in the postmyocardial infarction period. Valsartan and candesartan are the best studied ARBs in patients with HF and should be used preferentially.
3.The combination of hydralazine and isosorbide dinitrate may provide a reduction in morbidity and mortality in selected HF patients. A fixed dose combination of hydralazine and isosorbide dinitrate (BiDil) demonstrated a substantial reduction in mortality when added to African-American patients on optimal medical therapy including ACEis and β-blockers in the African-American Heart Failure Trial. This combination is also indicated in patients intolerant of ACEis or ARBs or ARNI or in patients receiving maximal RAS inhibition therapy in need of additional vasodilator therapy. Side effects of hydralazine may include reflex tachycardia and rarely drug-induced lupus erythematosus.
4.β-blockers. First-line therapy for chronic symptomatic patients with HF (NYHA class I, II, III, or stable class IV) because of their consistent mortality and morbidity benefits.
a.It is often customary to start ACEis before β-blockers. This in part reflects the fact that all major β-blocker trials demonstrated their benefit on a background of therapy with ACE inhibition. Furthermore, whereas ACEis provide immediate beneficial hemodynamic effects, β-blockers may acutely result in diminished LVEF and cardiac output, which may be poorly tolerated in decompensated patients. In some instances (e.g., postmyocardial infarction and comorbid tachyarrhythmias), β-blockers may be particularly beneficial and should be started before or concurrently with ACEis. β-Blockers should typically not be initiated or titrated in the setting of acutely decompensated HF.
b.Current ACC/AHA guidelines recommend bisoprolol, carvedilol, and metoprolol succinate for the medical treatment of chronic HF. Although atenolol and metoprolol tartrate are widely available and relatively inexpensive, there is no evidence to support their use. β-Blockers with intrinsic sympathomimetic activity (pindolol and acebutolol) should be avoided.
c.Relative contraindications to β-blocker therapy are a heart rate <60 beats/min, symptomatic hypotension, more than minimal pulmonary or systemic congestion, signs of peripheral hypoperfusion, a PR interval >0.24 seconds, second- or third-degree AV block, a history of severe reactive airway disease, and peripheral arterial disease with resting limb ischemia. It is important to note that these are relative contraindications, and particularly in the setting of reactive airway disease and peripheral arterial disease, the risks of β-blocker therapy must be weighed against their known benefits.
d.Current recommendations are to start β-blockers in those who are clinically euvolemic. The general principle is to “start low and go slow.” The initial dose is slowly uptitrated every 2 to 4 weeks over 3 to 4 months to achieve target doses, provided that the patient can tolerate side effects. It is imperative to maintain contact with the patient and adjust vasodilator or diuretic therapy during titration. It is not advisable to stop β-blockers in patients with a history of HF, even if there is complete resolution of symptoms and LV dysfunction.
e.Every effort should be made to achieve target doses, but it is clear that even low doses of these drugs provide mortality and morbidity benefit.
f.Side effects of β-blockers include the following:
(1)Dizziness and light-headedness are common and may be related to hypotension or heart block. Hypotension can be managed by staggering the timing of drug administration. In practice, carvedilol (with its nonselective, β1-blocking vasodilator effects) may have greater blood pressure lowering than selective β1-agents such as metoprolol succinate.
(2)Significant bradycardia mandates dose reduction of β-blockers and other rate-lowering agents such as digoxin and amiodarone. Advanced heart block is a contraindication to β-blockers unless a permanent pacemaker is present.
(3)Worsening HF is still an important adverse effect of β-blockers. Intensification of diuretic therapy and dose reduction or slower titration may be necessary.
5.Aldosterone receptor antagonists have long been used as weak, potassium-sparing diuretics in patients with HF. The concept of incomplete RAS blockade by ACEi or ARB led to studies demonstrating significant pleiotropic effects of aldosterone antagonism in patients with advanced HF including antifibrotic effects and reduction in sudden cardiac death. Results from the Randomized Aldactone Evaluation Study (RALES), Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), and Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms (EMPHASIS-HF) trial have demonstrated substantial mortality and morbidity benefit in stage C HF.
a.Aldosterone inhibitors are indicated in patients with HFrEF and NYHA class II–IV symptoms receiving ACEi/ARB/ARNI and β-blockers that do not have significant renal dysfunction (creatinine clearance > 30 mL/min) or hyperkalemia (potassium < 5 mEq/L). Their use is also indicated in patients with postinfarction LV dysfunction (LVEF ≤ 40%) with any HF symptoms or history of diabetes mellitus.
b.In most cases, potassium supplementation should be reduced or discontinued. A basic metabolic panel should be checked within 1 week after initiation and monitored at regular intervals.
c.The most common and life-threatening side effect of aldosterone antagonists is hyperkalemia, which is particularly problematic in patients with concomitant renal insufficiency and diabetes mellitus (type IV renal tubular acidosis). Gynecomastia and galactorrhea may occur with spironolactone.
d.Whereas clinical trials used either spironolactone (RALES) or eplerenone (EPHESUS and EMPHASIS-HF), most experts believe that aldosterone inhibitors work via class effect. Our approach is to initiate treatment with spironolactone because of its low cost and transition to eplerenone only in the setting of significant gynecomastia.
6.Diuretics are used to maintain euvolemia and to improve symptoms, but their overuse can result in volume contraction, hypotension, resistance, and renal dysfunction.
a.An effective and inexpensive initial regimen includes 20 to 120 mg of furosemide taken orally each day. If furosemide doses higher than 120 mg/d are needed, a second evening dose is typically prescribed. If this regimen fails, sequential nephron blockade with a thiazide diuretic can provide synergistic benefit.
b.More expensive loop diuretics (e.g., torsemide and bumetanide) have superior bioavailability and may be more effective in diuretic-resistant patients. Torsemide in particular may have unique benefits in the form of antifibrotic effects and minimization of the postdiuretic sodium retention that complicates the use of loop diuretics with shorter half-lives.
7.Digoxin is reasonable to use in patients with persistent HF symptoms despite appropriate, optimized guideline-directed medical therapy (GDMT) and/or in patients with atrial fibrillation to control ventricular rate.
a.Despite a fairly narrow therapeutic window, digoxin is safe and significantly reduces HF hospitalizations. A typical starting dose of 0.125 mg of digoxin daily is appropriate in patients with normal renal function.
b.Whereas the Digitalis Investigation Group trial demonstrated the best clinical outcomes in patients with a serum digoxin concentration of 0.5 to 0.8 ng/mL, routine measurement of levels is not recommended in the absence of concern for toxicity.
8.Recently approved novel drugs for the treatment of chronic systolic HF:
a.Ivabradine is an If current inhibitor within the sinus node; inhibition leads to rate reduction and subsequently increases stroke volume while preserving AV nodal conduction and contractility. Addition should be considered in HFrEF individuals, NYHA II–III receiving GDMT, including maximally tolerated dose of BB and have a heart rate >70 beats/min. The SHIFT trial demonstrated overall significant reduction in all-cause HF and cardiovascular admission in individuals with HFrEF and sinus rhythm with rate over 75 beats/min (see Table 8.4 for dosing).
b.Sacubitril/valsartan (ARNI) is first-line therapy for symptomatic HFrEF. RAS blockade can be achieved via ACE or ARB or ARNI in conjunction with additional GDMT. Sacubitril/valsartan is a combination pill that consists of a neprilysin inhibitor with angiotensin receptor blocker. Inhibition of neprilysin leads to the inhibition of natriuretic peptides and additional vasoactive peptides subsequently augmenting natriuresis and decreasing sympathetic tone, aldosterone, and cardiac fibrosis/hypertrophy. PARADIGM-HF demonstrated a 20% reduction in cardiovascular death or first HF hospitalization (see Table 8.4 for dosing). There should be a minimum 36-hour washout period between discontinuation of ACEi and administration of ARNI to avoid angioedema.
9.Other drugs and interventions of importance.
a.Statins should be used in the secondary prevention of atherosclerotic cardiovascular disease without regard to the presence of HF. There is no evidence of benefit in HF patients without coronary artery disease.
b.Aspirin clearly prevents reinfarction and other vascular events in patients with known coronary artery disease; there is growing evidence from observational and randomized studies that it may worsen outcomes in HF patients via inhibition of prostaglandin synthesis and the resultant adverse hemodynamic and renal effects. This remains a controversial subject and the decision of whether to use aspirin or not should be made on a case-by-case basis. It should likely be avoided in patients without coronary disease who have refractory HF symptoms.
10.Electrolyte supplementation is among the most important and least emphasized areas in chronic HF management. Potassium depletion is common with diuretic therapy, whereas hyperkalemia can be caused by RAS inhibitors or worsening renal insufficiency. In general, oral potassium supplementation is necessary to maintain serum potassium level in the ideal range of 4.0 to 5.0 mEq/L. Magnesium, thiamine, and calcium depletion are also common with long-standing diuretic therapy.
11.Device therapy. Chapters 55 and 56 provide detailed coverage of the indications, contraindications, and clinical issues related to implantable cardioverter defibrillators (ICD) and CRT-D.
a.Device monitoring. Currently implanted electrical cardiovascular devices including ICD and CRT-Ds have the capability to remotely monitor a variety of electrophysiologic (e.g., heart rate variability, atrial arrhythmia burden and rate, ventricular tachycardia, % biventricular pacing, and average heart rate) and physiologic (e.g., patient activity and intrathoracic impedance) parameters with prognostic value. Several implantable hemodynamic monitors (e.g., CardioMEMs) are under development for use in patients with advanced HF. How to best integrate device monitoring into a comprehensive approach to HF disease management remains to be established.
C.Chronic nonmedical therapies
1.Patient education and disease management programs remain the most effective treatment strategy for patients with systolic HF. Sodium restriction (<2,000 mg daily) and medication compliance are crucial to reducing hospitalizations. Control of blood pressure, serum glucose, and lipid levels should be emphasized. Some highly motivated patients can perform self-monitoring (i.e., daily weights and symptom assessment) and care (i.e., titration of diuretics) analogous to the chronic management of diabetes.
2.Exercise training. There is a clear body of evidence supporting the fact that exercise training improves endothelial function and functional capacity in patients with chronic HF. HF-ACTION failed to demonstrate a reduction in all-cause mortality and hospitalization; but demonstrated significant improvement in self-reported health status. A supervised cardiac rehabilitation program should be advised when available.
D.Advanced therapies. Mechanical circulatory support and orthotopic heart transplantation are therapies currently reserved for patients with ACC/AHA stage D HF refractory to other therapies. These are described in detail in Chapters 12 and 13, respectively.
VIII.PROGNOSIS. HF is associated with high rates of morbidity and mortality. In the Framingham Heart study, patients with HF had mortality rates four to eight times those of age-matched controls. A patient with NYHA class IV HF has a 1-year survival between 30% and 50%—a mortality rate comparable to that of advanced malignancies. Several risk scores have been developed to characterize the risk of HF hospitalization and mortality. The Seattle Heart Failure Model is perhaps the most widely used of these and incorporates demographic, clinical, pharmacologic, and laboratory data to provide accurate 1-, 2-, and 3-year survival estimates. Table 8.5 lists some common clinical predictors of poor survival in systolic HF.
TABLE 8.5 Common Clinical Predictors of Poor Prognosis in Systolic Heart Failure |
Increased age |
Increased New York Heart Association functional class |
Severely reduced LV ejection fraction (<25%), extensive cardiac remodeling (LVIDd > 65 mm), or reduced cardiac index (<2.5) |
Concomitant diastolic dysfunction (particularly irreversible restrictive filling, stage IV diastolic dysfunction) |
Reduced RV function |
Atrial fibrillation, elevated average heart rate, and reduced heart rate variability |
Low peak Vo2 with maximal exercise (14 mL/min/kg), low heart rate response to exercise, increased peripheral chemosensitivity (ventilatory response to hypoxia), and high VE/Vco2 |
High plasma BNP and N-terminal proBNP levels |
High levels of other cardiac and neurohormonal biomarkers including norepinephrine, renin, arginine vasopressin, aldosterone, endothelin-1, tumor necrosis factor, cardiac troponin T and I, and C-reactive protein |
Anemia |
Low systolic blood pressure |
Renal insufficiency (creatinine clearance < 60 mL/min) |
Attenuated response to diuretics and lack of hemodynamic and structural improvement (reverse remodeling) with medical therapy |
Persistent signs of congestion and fluid retention or failure to normalize filling pressures (PCWP < 16 mm Hg, CVP < 8 mm Hg) with medical therapy |
Serum sodium < 135 mg/dL |
Cardiac dyssynchrony (QRS > 130 ms, left bundle branch block) |
Depression |
Nocturnal Cheyne–Stokes respiration and obstructive sleep apnea |
BNP, B-type natriuretic peptide; CVP, central venous pressure; LV, left ventricular; LVIDd, left ventricular internal dimension at diastole; PCWP, pulmonary capillary wedge pressure; RV, right ventricular; VE, ventilation.
ACKNOWLEDGMENTS: The authors would like to thank Dr. Brian Hardaway and Michael A. Samara for their contributions to earlier editions of this chapter.
Landmark Articles
Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure (MIRACLE). N Engl J Med. 2002;346(24):1845–1853.
Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436–2448.
Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure (SCD-HeFT). N Engl J Med. 2005;352:225–237.
Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539–1549.
Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study (V-Heft). N Engl J Med. 1986;314:1547–1552.
Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–1675.
CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429–1435.
Eichhorn EJ, Domanski MJ, Krause-Steinrauf H, et al; The BEST Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344:1659–1667.
Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure (DOSE). N Engl J Med. 2011;364(9):797–805.
McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993–1004.
MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001–2007.
O’Connor CM, Whellan DJ, Lee KL, et al. Efficacy and safety of exercise training in patients with chronic heart failure (HF-ACTION). JAMA. 2009;301(14):1439–1450.
Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334:1349–1355.
Packer M, Coats ACS, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure (COPERNICUS). N Engl J Med. 2001;344:1651–1658.
Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;1349:1893–1906.
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM overall program. Lancet. 2003;362:759–766.
Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction (EPHESUS). N Engl J Med. 2003;348:1309–1321.
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure (RALES). N Engl J Med. 1999;341:709–717.
SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.
Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled study. Lancet. 2010;376:875–885.
Taylor A, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure (A-HeFT). N Engl J Med. 2004;351:2049–2057.
The CIBIS-II Investigators. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial. Lancet. 1999;353:9–13.
The Digitalis Investigation Group. The effect of digoxin on morbidity and mortality in patients with heart failure. N Engl J Med. 1997;336:525–533.
Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms (EMPHASIS). N Engl J Med. 2011;364:11–21.
Key Guidelines and Scientific Statements
Cooper LT, Baughman KL, Feldman AM, et al; AHA/ACCF/ESC Scientific Statement. The role of endomyocardial biopsy in the management of cardiovascular disease. Circulation. 2007;116:2216–2233.
Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy. Circulation. 2011;124:e783–e831.
Hershberger RE, Siegfried JD. Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol. 2011;57:1641–1649.
Lindenfeld J, Mann DL, Boehmer JP, et al. Executive summary: HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010;16:475–539.
McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J. 2012;33:1787–1847.
Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975.
Tang WH, Francis GS, Morrow DA, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: clinical utilization of cardiac biomarker testing in heart failure. Circulation. 2007;116:e99–e109.
Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the management of heart failure: a report of the ACCF/AHA task force on practice guidelines. Circulation. 2013;128:e240–e327.
Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused update on new pharmacological therapy for heart failure: update of the 2013ACCF/AHA guideline for the management of heart failure. J Am Coll Cardiol. 2016;68(13):1466–1488.
Relevant Book Chapters
Francis GS, Sonnenblick E, Tang WH. Pathophysiology of heart failure. In: Valentin F, ed. Hurst’s the Heart. 13th ed. New York, NY: McGraw-Hill; 2007:697–763.
Gheorghiade M, Filippatos GS, Felker GM. Diagnosis and management of acute heart failure syndromes. In: Libby P, Bonow RO, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: WB Saunders; 2011:583–611.
Mann DL. Management of heart failure patients with reduced ejection fraction. In: Libby P, Bonow RO, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: WB Saunders; 2011:611–641.
Mann DL. Pathophysiology of heart failure. In: Libby P, Bonow RO, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: WB Saunders; 2011:541–561.
Tang WH, Young JB. Chronic heart failure. In: Topol EJ, ed. Textbook of Cardiovascular Medicine. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:1377–1392.
Useful Web sites
HFSA Heart Failure Guidelines: http://www.hfsa.org/heart-failure-guidelines-2/
Seattle Heart Failure Model: http://depts.washington.edu/shfm/