Chapter 26. Heart Failure with Reduced Ejection Fraction

• Dyspnea on exertion and at rest, orthopnea, paroxysmal nocturnal dyspnea, and fatigue.
• Elevated jugular venous pressure, basilar rales or coarse rales throughout both lung fields with wheezing, cardiomegaly, S3 gallop, hepatomegaly, and bilateral peripheral pitting edema.
• Dilated left ventricle with a reduced ejection fraction on transthoracic echocardiography.
• Elevated left ventricular filling pressures on cardiac catheterization.

Heart failure (HF) is a complex clinical syndrome resulting from any structural or functional myocardial dysfunction that leads to an impaired ability to circulate blood at a rate sufficient to maintain the metabolic needs of internal organs and peripheral tissues. The myocardial dysfunction is often the consequence of long-standing ischemia due to coronary artery disease or loss of myocardial mass due to prior infarction, long-standing myocardial stress due to suboptimally treated hypertension or valvular disease, or direct long-term toxin exposure (alcohol abuse, illicit substance use, or chemotherapeutic agents); rarely, fulminant infections (especially viral) can lead to autoimmune myocardial damage, and in some cases, there is no apparent cause (idiopathic cardiomyopathy, usually related to inherited or spontaneous gene mutations).

The cardinal manifestations of HF are dyspnea and fatigue (which may limit exercise tolerance) and fluid retention (which may lead to pulmonary/hepatic/splanchnic congestion and peripheral edema). Both abnormalities impair the functional capacity and quality of life of affected patients, but they may not necessarily dominate the clinical picture at the same time.

The prevalence of HF in the United States is around 5.8 million patients, of which approximately 45% have reduced ejection fraction/systolic dysfunction. There are over half a million cases of HF being newly diagnosed every year, and this incidence is expected to rise to over 700,000 new cases per year by 2040, mainly due to the aging of the population, as HF incidence doubles with each successive decade above age 45 for both men and women.

At age 40, the lifetime risk for HF is as high in women as in men, and is approximately one in five. Although over 75% of HF patients have antecedent hypertension or coronary artery disease, the population attributable risk (PAR) is different in men and women; the PAR for HF associated with coronary artery disease is 39% in men and 18% in women, whereas the PAR associated with hypertension is 39% in men and 59% in women, emphasizing the crucial need for population-based strategies to prevent the development of HF.

Multiethnic epidemiologic studies showed that the highest risk for developing HF is in African Americans (highest in young women and middle-aged men), followed by Hispanics/Latinos, Caucasians, and Chinese. This higher risk likely reflects differences in the prevalence of hypertension and diabetes mellitus and in socioeconomic status between different ethnicities.

Although the survival after HF diagnosis has improved, the 5-year mortality is still close to 50%, and over a quarter million deaths every year have antecedent HF. HF is one of the leading causes of hospitalization in the United States, with over one million hospitalizations a year (a figure that has not changed over the past decade). Indeed, 85% of patients diagnosed with HF will be hospitalized within 5 years of diagnosis, and over 40% will be hospitalized at least four times. HF accounts for over 12 million office visits and 6.5 million hospital days each year in the United States, with an estimated total cost of $39 billion, making it a major contributor to total health-care expenditure and the number one health expenditure for Medicare.

When an excessive workload is imposed on the heart by increased systolic blood pressure (pressure overload, such as in chronic hypertension or aortic stenosis), increased diastolic volume (volume overload, such as in progressive dilated idiopathic cardiomyopathy or chronic aortic or mitral regurgitation), or loss of myocardium (acutely in the setting of myocardial infarction, or chronically in the setting of flow-limiting coronary artery disease), normal myocardial cells hypertrophy in order to increase the contractile force of the unaffected areas. The biochemical, electrophysiologic, and contractile changes that ensue lead to alterations in the mechanical properties of the myocardium. Eventually, the compensatory force of the normal myocardial contraction decreases as cell loss and hypertrophy continue, leading to increased ventricular volume (“cardiac remodeling”) and significant geometric ventricular alterations (ellipsoid to spherical shape). After the initial compensatory phase, the increase in ventricular volume is associated with further reductions in the ejection fraction (progressive systolic dysfunction) and with abnormalities in the peripheral circulation from activation of various neurohormonal compensatory mechanisms.

In the United States, coronary artery disease is the underlying etiology for systolic HF in more than half of the cases and a major contributor in another 15–20%. Transient ischemic events may cause prolonged systolic dysfunction that persists even after the ischemic event has resolved (myocardial stunning). The sustained reduction in the coronary blood flow leads to tissue hypoperfusion that is sufficient to maintain viability, but insufficient to maintain a normal contractility (myocardial hibernation). However, hibernation cannot be maintained indefinitely, and myocardial necrosis will ensue if coronary blood flow is not restored. Ischemia and hibernation may lead to myocyte apoptosis, which may result in progression of left ventricular systolic dysfunction characterized by a reduction in cardiac output and/or an increase in wall stress.

These functional and structural myocardial changes result in compensatory activation of neurohormonal systems, such as the renin–angiotensin–aldosterone system (RAAS), the adrenergic system, and the hypothalamic–neurohypophyseal system. The mechanisms for RAAS activation in HF include renal hypoperfusion with decreased filtered sodium reaching the macula densa and decreased stretch of the juxtaglomerular apparatus leading to increased renin release. Renin cleaves four amino acids from circulating angiotensinogen to form the biologically inactive angiotensin I. Angiotensin-converting enzyme (ACE) cleaves two amino acids from angiotensin I to form the biologically active angiotensin II, which binds to vascular angiotensin receptors causing vasoconstriction of the efferent postglomerular arterioles (promoting reabsorption of sodium, urea, and water) and to cardiac angiotensin receptors causing myocyte hypertrophy, apoptosis, and interstitial fibrosis. Increased circulating levels of angiotensin II also promote the release of aldosterone from the adrenal zona glomerulosa, resulting in sodium reabsorption and potassium excretion in the distal nephron, along with myocardial fibroblast proliferation and collagen deposition. The abnormal hypertrophy and fibrosis increase the passive stiffness of the ventricles and arterial bed, interfering with ventricular filling and reducing arterial compliance and, along with myocyte slippage and interstitial growth, result in ventricular remodeling. Finally, angiotensin II may increase the release of arginine vasopressin via a mechanism that does not rely on changes in osmolality, leading to renal free water reabsorption and dilutional hyponatremia seen with severe HF.

In patients with HF, the inhibitory input from high- pressure carotid sinus and aortic arch baroreceptors and low-pressure cardiopulmonary mechanoreceptors decreases, while nonbaroreflex peripheral chemoreceptors and muscle metaboreceptors excitatory input increases, with a net increase in sympathetic nerve traffic and blunted parasympathetic nerve traffic, and a resultant loss of heart rate variability and increased peripheral vascular resistance. As a result of the increase in sympathetic tone, there is an increase in circulating levels of norepinephrine from a combination of increased release from adrenergic nerve endings and its consequent “spillover” into the plasma, with reduced uptake of norepinephrine by adrenergic nerve endings. In patients in early stages of HF, norepinephrine increases heart rate and contractility and may support cardiac function. However, in later stages of HF, cardiac response to norepinephrine is blunted, partly because of the decreased β-receptor density seen in patients with chronic severe HF, where a shift occurs from the normal density (β1/β2 ratio of 70–80%/20–30%) to a more even distribution of 60%/40%. In addition, α-adrenergic receptors increase in the failing heart so that the end result is a more balanced distribution of myocardial α, β1, and β2 receptors. Chronic adrenergic stimulation has been shown to induce expression of proinflammatory cytokines, such as tumor necrosis factor-α, interleukin-1, and interleukin-6. Increased cytokine levels may result in the skeletal muscle myopathy characteristic of HF and cause myocardial inflammation, cell proliferation, and apoptosis, thereby worsening the HF syndrome. Tumor necrosis factor-α also activates transcription factors and enzymes involved in signal transduction, and it induces a number of genes, including the fetal gene program. Peripheral arteriolar tone is also increased in patients with HF (via α-adrenergic receptor stimulation), producing an increase in blood pressure and ventricular afterload and vasoconstriction of the renal efferent arterioles that causes significant sodium and water retention and increases production of renin, angiotensin II, and aldosterone, emphasizing the tight interplay between the adrenergic system and the RAAS. Indeed, ACE inhibition in patients with HF has been found to reduce peripheral sympathetic nerve impulse traffic and cardiac adrenergic drive, and the beneficial effects of ACE inhibitors appear to be especially prominent in patients with increased adrenergic activation. Conversely, β-blockade reduces the secretion of renin, therefore reducing the levels of angiotensin and aldosterone.

Arginine vasopressin is synthesized in the hypothalamus, and its release from the hypophysis is enhanced by osmolar stimuli as well as elevated concentrations of norepinephrine and angiotensin II. Increased release of arginine vasopressin in HF causes vasoconstriction and myocardial fibrosis (through binding to vasopressin 1 receptors) and water retention with dilutional hyponatremia (through binding to vasopressin 2 receptors).

The vasodilator peptides, such as atrial natriuretic peptide (ANP) and β-natriuretic peptide (BNP), are overexpressed in HF (as result of increased wall stress) and lead to a lowering of the right atrial, pulmonary artery, and pulmonary artery wedge pressures. In addition, systemic vascular resistance declines and cardiac output improves, circulating aldosterone and norepinephrine levels decrease, and natriuresis and glomerular filtration increase. However, in many patients with HF, the natriuretic peptides become ineffective despite high circulating levels. The profound activation of the RAAS and adrenergic system may overcome the ability of natriuretic peptides to increase sodium excretion or reduce afterload. In addition, most of the circulating natriuretic peptides in advanced HF patients are secreted as biologically inactive (“defective”) molecules. Finally, changes in renal hemodynamics and a combination of receptor downregulation and increased cyclic guanosine monophosphate phosphodiesterase activity lead to a decreased natriuretic peptide response with consequent increase in salt retention and further deterioration of renal function and increased vasoconstriction.

The development of myocardial hypertrophy, as consequence of neurohormonal activation, initially represents an important adaptive mechanism to hemodynamic stress and is characterized by structural changes at the myocyte level that are translated into alterations in chamber size and geometry. In addition to myocyte alterations, the cardiac fibroblasts and the increased production of extracellular matrix participate in the remodeling process. Increased hemodynamic stress results in changes in myocardial gene expression leading to an impairment of contractile function. In patients with HF, a marked increase in the ventricular end-diastolic pressure may be responsible for changes in the shape of the left ventricle from an ellipsoid to a more spherical configuration. These changes in ventricular geometry result in papillary muscle rearrangement and secondary mitral insufficiency. In addition, the elevated ventricular end-diastolic pressures cause subendocardial ischemia that is perpetuated by compensatory tachycardia, which shortens the diastole and decreases the coronary filling time. This is reflected at a biochemical level by increased production of lactate, adenosine triphosphate, and creatine phosphate and at a histologic level through fibrosis, lowering the threshold for malignant ventricular arrhythmias.

The myocardial fibrosis and chamber dilatation lead to electrical dyssynchrony by fibrosis of the conduction system that, in turn, results in mechanical dyssynchrony (observed in about 40% of the systolic HF patients). When mechanical dyssynchrony is present, contraction and relaxation of the lateral wall occurs earlier than that of the interventricular septum, leading to decreased stroke volume and cardiac output and eventually to secondary mitral regurgitation.

In systolic HF patients, the decreased cardiac output leads to renal hypoperfusion, and the fluid retention leads to increased venous congestion, resulting in further reduction in the renal blood flow and relative renal vasoconstriction, which further exacerbate the sodium and water retention. In addition, the elevated cytokine levels and relative resistance of the bone marrow to erythropoietin lead to anemia in many HF patients. In these patients, peripheral perfusion decreases as a result of a decreased vascular resistance, leading to neurohormonal activation with subsequent reduction in renal blood flow and kidney function, ultimately resulting in expansion of plasma volumes. The increased plasma volume results in increased cardiac work, which leads to left ventricular hypertrophy and ultimately worsens the cardiac function, which in turn worsens renal function, completing the vicious circle (cardio-renal-anemia syndrome).

The chronic elevation in the left ventricular filling pressures that occurs in the setting of left ventricular remodeling and dilatation will lead to an increase in pulmonary venous pressures and a passive increase in pulmonary artery pressures. Due to the chronic elevation in pulmonary arterial pressures (secondary pulmonary hypertension), the pulmonary vascular resistance increases, increasing the right ventricular afterload and leading to deterioration in the right ventricular function over time (right HR). This eventually leads to a decrease in both right and left ventricular stroke volume, which is associated with signs and symptoms of both congestion (dyspnea, peripheral edema, hepatomegaly, elevated jugular venous pressures) and low cardiac output (mental status changes, renal dysfunction, fatigue).

Eventually, the progressive compensatory mechanisms described earlier are overwhelmed and the patients become symptomatic and present to medical attention, often in a hospital setting. In most patients, the condition is progressive, and further deterioration occurs at a myocardial/renal/hepatic/skeletal muscle level, and patients end up having recurrent hospitalizations. There is clear evidence that each hospitalization for HF leads to further myocardial necrosis (evidence by troponin release) and renal injury, which in turn will worsen the overall prognosis and lead to progressive HF and death.

In rare circumstances, a hyperkinetic circulatory state associated with vasodilatation occurs (usually due to an increased demand on the heart from another condition, such as anemia, or thyrotoxicosis) and can trigger HF when superimposed on an underlying heart disease. Fortunately, this is often reversible by prompting treating the associated triggering condition.

One of the first principles in the clinical evaluation is to determine whether the patient is indeed presenting with HF, since the presenting signs and symptoms are often nonspecific. Despite a careful history and physical examination, additional diagnostic information may be necessary to support the diagnosis and to determine the mechanism of the symptoms, the severity of the condition, and the prognosis for the individual patient.

Symptoms & Signs

The cardinal symptoms of HF are dyspnea and fatigue that occur with exertion and/or at rest, although some patients may present with acute pulmonary edema. Dyspnea is a subjective feeling of air hunger and is the most frequent symptom in HF patients. Initially, dyspnea on exertion will be noted by a change in the extent of physical activity that causes the shortness of breath. As the HF worsens, the intensity of exertion required to produce dyspnea will decrease, and eventually the dyspnea will be present at rest. Interestingly, the severity of dyspnea decreases after right ventricular failure develops.

Paroxysmal nocturnal dyspnea occurs after the patient has been in the supine position for some time. The patient wakes up suddenly with a sensation of choking and air hunger and assumes an upright posture to relieve the symptoms. Paroxysmal nocturnal dyspnea usually precedes orthopnea, may be associated with bronchospasm and wheezing (cardiac asthma), and is caused by a mobilization of interstitial fluid from infradiaphragmatic locations during recumbency with a resultant increase in the circulating blood volume and increased pulmonary venous pressure.

Orthopnea (dyspnea occurring within a few minutes after the patient assumes a supine position) has the same cause as paroxysmal nocturnal dyspnea, but represents a more severe cardiac dysfunction. While elevating the head of the bed, sitting up, or standing can improve the symptoms, the most severely affected patients usually sleep sitting upright.

Another manifestation of pulmonary congestion is a dry or nonproductive cough (especially at night) that is usually relieved by treating the elevated left-sided filling pressures.

As with dyspnea, the mechanism of fatigue in patients with systolic HF is unclear. Although the fatigue was attributed for many years to a low cardiac output, there is mounting evidence of contribution of abnormal skeletal muscle metabolism with shifts in fiber distribution (increase in the percentage of the fast-twitch, glycolytic, easily fatigable fibers) and muscle atrophy, even in the presence of a normal cardiac output. Chronic fatigue begets further inactivity, which leads to further deconditioning and a greater extent of disability.

Other disabling symptoms in HF patients include extreme thirst (associated with activation of the arginine–vasopressin system), nocturia (due to enhanced urine formation in the recumbent position when renal vasoconstriction decreases and venous return to the heart increases), oliguria (usually associated with either increased venous congestion or markedly reduced cardiac output), cerebral symptoms—memory impairment, confusion, insomnia—(usually markers of reduced cardiac output), and ascites and abdominal fullness, accompanied by right upper quadrant pain, early satiety, and nausea (usually related to passive hepatic and splanchnic congestion).

Physical Examination

Although most patients with HF appear well nourished, those with more advanced disease (especially in the setting of chronic splanchnic congestion) frequently appear malnourished. This appearance arises from poor caloric intake (due to early satiety and nausea) and impaired absorption of fat and, occasionally, a protein-losing enteropathy, in combination with an increased metabolism due to elevated levels of norepinephrine and tumor necrosis factor-α. The combination of reduced intake and increased energy expenditure leads to a reduction of tissue mass and, in some cases, to cardiac cachexia.

Patients with systolic HF frequently show evidence of increased sympathetic activity such as diaphoresis, pallor and coldness of the limbs, peripheral cyanosis of the digits, abnormal distention of the superficial veins, and compensatory sinus tachycardia (when the cardiac output is decreased).

Cheyne-Stokes respiration (alternating phases of hyperpnea and apnea in a crescendo-decrescendo manner) can be seen in patients with systolic HF and represents an altered neurogenic control of respiration, facilitated by a combination of pulmonary congestion, prolonged circulation time from lung to the brain, and decreased sensitivity of the respiratory center to hypercapnia and hypoxia.

Pulmonary rales can be heard at the lung bases, and they are a result of the transudation of fluid into the alveoli that subsequently moves into the airways. In pulmonary edema, coarse rales and wheezes are heard all over the lung fields and may be accompanied by frothy sputum. With progressive fluid accumulation, pleural effusions (hydrothorax) occur and will increase the severity of dyspnea by further reducing pulmonary vital capacity. Dullness on percussion is the characteristic sign, and shifting dullness can be found when the patient moves from the sitting to the lateral decubitus position. Breath sounds over the area of effusion are diminished or absent. Hydrothorax usually is reabsorbed slowly as diuresis ensues, but in many cases, the pleural effusion lags behind for many days after the symptoms disappear.

Symmetric pitting edema is common in systolic HF patients and involves the dependent portions of the body with higher venous pressure: feet and ankles of ambulatory patients and the sacral area of bedridden ones. With progressive, untreated disease, the edema becomes massive and generalized (anasarca), involving the genital area, the upper extremities, and the thoracic and abdominal walls. Occasionally, in massive overload, skin breakdown and extravasation of fluid can occur. Chronic edema results in increased pigmentation, reddening, and induration of the skin of the lower extremities (stasis dermatitis).

An important part of the volume status assessment is detecting the abnormal distention of the internal jugular veins. Patients should be examined while they are lying down, with the torso and head tilted at 45 degrees. A persistent elevation of the jugular venous pressure is one of the earliest and most reliable signs of HF and is a powerful prognostic indicator of increased risk of HF hospitalizations and all-cause mortality. The inability of the right ventricle to accept transient increases in venous return (positive hepatojugular reflux) is observed during transient compression (30–60 seconds) of the upper abdomen. Passive hepatic congestion is identified by epigastric fullness, hepatomegaly and tenderness on palpation, and dullness to percussion of the right upper quadrant. As with the hydrothorax, these findings may persist after other signs of HF have disappeared because it takes longer for hepatic congestion to disappear. Occasionally, systolic pulsations of the liver may be felt in patients with severe tricuspid regurgitation.

Although rarely used, the hemodynamic response to the Valsalva maneuver is simple to perform and carries one of the best combinations of specificity (91%) and sensitivity (69%) for the detection of elevated left ventricular filling pressures. The maneuver is performed with the blood pressure cuff inflated 15 mm Hg over the systolic blood pressure. While the physician auscultates over the brachial artery, the patient is asked to perform a forced expiratory effort against a closed airway (the Valsalva maneuver). In a normal response, the Korotkoff sounds disappear during sustained maneuver and reappear after release of the maneuver. An abnormal response, in which blood pressure sounds either do not reappear after the maneuver (absent overshoot) or are maintained throughout the maneuver (square wave), is found in patients with systolic HF and elevated left ventricular filling pressures.

Cardiomegaly, with a laterally displaced and sustained point of maximal impulse, can be found on physical examination, but this is a nonspecific finding. The decrease in ventricular compliance becomes apparent by the presence of a late diastolic atrial sound (S4 gallop). A protodiastolic sound (S3 gallop), better heard in more tachycardic patients, is caused by acute deceleration of ventricular inflow after the early filling phase and is a marker of increased left ventricular filling pressures. Together with elevated jugular venous pressure, the presence of a third heart sound is a powerful predictor of outcome and is associated with an increased risk of death and hospitalization for HF. Systolic murmurs are common in HF patients and are secondary to functional mitral or tricuspid regurgitation that results from ventricular dilatation.

Pulsus alternans (a regular rhythm of alternating strong and weak pulsations) is common in patients with systolic HF and is due to an alternation in the stroke volume of the left ventricle. If persistent, it usually implies advanced HF and a chronic low output state.

It is important to emphasize that HF remains a clinical diagnosis. While the symptoms, signs, and clinical findings can, in isolation, be ascribed to other conditions, a systematic integrated approach establishes the diagnosis of HF. Several scoring systems have been used in epidemiologic and clinical studies to diagnose HF, and the Framingham Heart Study criteria have been shown to have the best sensitivity and specificity (Table 26–1). Once the HF is diagnosed, it is important to determine the clinical profile (Figure 26–1) and the severity of symptoms (New York Heart Association functional class), which will dictate the subsequent therapy.

Laboratory Testing

Patients with new-onset HF should undergo routine laboratory tests when the condition is first diagnosed. This is also recommended for patients with chronic HF and acute decompensation, when there is a change in therapeutic intervention, or in periodic monitoring for clinical stability. A basic metabolic profile can show hyponatremia (marker of advanced HF or excessive diuretic use) and signs of renal dysfunction (elevated urea and creatinine). Congestion of the liver is often associated with abnormalities of liver function tests, while hyperglycemia and abnormalities in thyroid-stimulating hormone levels can identify concomitant precipitating conditions (such as diabetes or hyper- or hypothyroidism). The recognition of anemia and iron deficiency in patients with systolic HF is important, as early treatment may reverse these abnormalities.

Determining the level of BNP or of its amino-terminal fragment (NT-proBNP) provides important diagnostic utility for diagnosing HF in the acute clinical setting. BNP levels over 100 pg/mL and NT-proBNP levels higher than 450 pg/mL in younger patients or higher than 900 pg/mL in patients older than 50 years are highly sensitive and specific for HF when the clinical diagnosis is in doubt. Although several studies have shown the incremental prognostic value of serial natriuretic peptide level determination, the efficacy of natriuretic peptide–guided therapy in systolic HF patients remains controversial.

Serum cardiac troponins (at levels that do not meet myocardial infarction criteria) are detected in over half of systolic HF patients (including in those without significant coronary artery disease) and are usually a sign of volume overload and elevated left ventricular filling pressures. Detectable serum troponin levels carry powerful prognostic information and may help in tailoring of therapy (eg, initiation and rapid titration of vasodilators and avoidance of positive intravenous inotropes in hospitalized patients).

Diagnostic Studies

Electrocardiography

An electrocardiogram should be routinely obtained and examined for evidence of underlying structural alterations (eg, left ventricular hypertrophy, prior myocardial infarctions), for rhythm abnormalities as a cause or consequence of HF decompensation (eg, atrial fibrillation/flutter, frequent ventricular ectopic beats, or sustained arrhythmias), and for the presence of conduction abnormalities (eg, left bundle branch block) that may lead to electrical dyssynchrony. The QT interval should be noted because many therapies can prolong it and provoke lethal arrhythmias. In patients who have undergone cardiac resynchronization therapy (CRT), changes in the QRS complex duration or morphology may provide information about underlying pacing or programming changes.

Chest Radiography

Careful examination of the cardiac silhouette, as well as the pulmonary vasculature, remains part of routine evaluation in all patients with systolic HF. Cardiomegaly (cardiothoracic ratio > 50%) can be found in almost all patients with chronic HF, but may be absent in those with acute HF due to acute myocarditis or myocardial infarction. In systolic HF, there is progressive vasoconstriction of pulmonary vessels in the lower lobes and redistribution of the pulmonary flow to the upper lobes. Interstitial and perivascular edema develop when the left-sided filling pressures increase above 25 mm Hg and the bronchovascular markings at the bases become prominent. Kerley lines, spindle-shaped linear opacities at the periphery of the lung bases, occur in the later stages of HF. Pleural effusions can also be seen. After lowering of the pulmonary capillary pressure, there may be a delay of 48 hours before improvement and clearing of pulmonary findings can be seen on chest radiograph.

Echocardiography

Echocardiographic evaluation is an essential diagnostic tool for assessing cardiac structure and function. It should be used early in the initial phase of the HF diagnosis in order to define the syndrome (systolic versus diastolic HF), and at any time there is a clinical change that would lead to a change in management. A careful observer will examine the right and left ventricular size/volume, wall motion abnormalities (including aneurysms), hypertrophy, left ventricular diastolic function, left-/right-sided filling pressures, stroke volume, ejection fraction, presence of intracardiac thrombus or shunt, and valvular pathology (morphology, regurgitation, stenosis). A comprehensive examination can elucidate the cardiac component of the HF symptoms and may lead to targeted treatments (eg, diuresis versus vasodilatation versus need for inotropic support).

Cardiac Magnetic Resonance Imaging (cMRI)

This newer imaging tool provides in-depth anatomic information and can provide information on the myocardial structure (scarring, fatty infiltration, or iron overload), helping in the noninvasive diagnosis of infiltrative cardiomyopathies (eg, sarcoidosis, amyloidosis), iron overload cardiomyopathies (eg, hemochromatosis), acute myocarditis, or genetic cardiomyopathies (eg, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction cardiomyopathy). In addition, in patients with coronary artery disease, it can relay information on myocardial viability that can be used to decide on percutaneous or surgical revascularization. The major limitations are the use of a magnetic field (which can interfere with cardiac implantable electrical devices that many systolic HF patients have), its relative high cost (limiting its use to major medical centers), and the claustrophobic feeling that many patients experience.

Cardiopulmonary Exercise Stress Testing (CPET)

CPET has been shown to add substantial precision in the initial evaluation of patients with HF and in their prognosis over time, especially when advanced therapies are considered. Measurements of the peak oxygen consumption (peak VO2) and the slope of the ratio of ventilation (VE) to carbon dioxide production (VCO2) (VE/VCO2) are powerful predictors of prognosis. A peak VO2 less than 14 mL/kg/min in patients intolerant of β-blockers (12 mL/kg/min on patients on β-blockers) or less than 50% predicted are considered indications for heart transplantation or left ventricular assist devices as destination therapy. Additionally, valuable information regarding chronotropic competence can be gathered from the CPET.

Cardiac Catheterization

Because coronary artery disease is the main cause of systolic HF in the United States, coronary angiography is necessary whenever the suspicion for coronary artery disease as etiologic or aggravating factor of HF is suspected. Research has clearly shown that misdiagnosis of ischemic heart disease among patients with HF is common if angiographic evaluation is not undertaken as part of the initial workup. In addition, surgical revascularization in ischemic systolic HF has been shown to improve cardiovascular outcomes.

Right heart catheterization may be important in patients who are doing poorly with severe congestion, ascites, or signs and symptoms of low cardiac output or when constrictive physiology or restrictive cardiomyopathy is suspected. Most right-sided heart catheterizations performed in patients with HF today are used to help guide therapy rather than to make a specific diagnosis.

Endomyocardial Biopsy

The role of diagnostic endomyocardial biopsy in patients with systolic HF has diminished. Although cMRI has replaced many of its uses, endomyocardial biopsy is still used in patients with suspected fulminant myocarditis, giant cell myocarditis, sarcoidosis, amyloid heart disease, or hemochromatosis. In addition, routine surveillance for rejection after cardiac transplantation still uses endomyocardial biopsies (at least for the first 6–12 months).

Genetic Testing

Clinical genetic testing in HF has become available in many commercial testing laboratories. At the present time, the best use of genetic testing remains identification of at-risk individuals for inherited cardiomyopathies that will require careful evaluation and close monitoring (eg, hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia). In addition, for specific diseases (eg, transthyretin amyloidosis, some of the idiopathic dilated cardiomyopathies), genetic tests are available for confirmatory purposes. In the future, it is possible that pharmacogenomics-guided therapy will be used to better select HF therapies most likely to benefit a specific patient.

Prevention

The burden of HF can be affected only by drastically decreasing its incidence, and as such, it is crucial to identify the primary drivers for this problem and develop/implement population-level preventive strategies. To aid in this goal, the American College of Cardiology/American Heart Association adopted a new stage-based system for the classification of HF in 2001 (Table 26–2). In this approach, stage A included patients without structural cardiac disorders or HF symptoms, but with risk factors that clearly predispose carriers toward the development of HF (eg, hypertension, coronary artery disease, diabetes). Stage B included patients without HF symptoms, but with structural cardiac abnormalities (eg, left ventricular hypertrophy, prior myocardial infarction, valvular heart disease) that if untreated could progress to symptomatic HF. Stages C and D included the symptomatic HF patients. This new classification added a useful dimension to the understanding of HF by recognizing that there are established risk factors and structural prerequisites for the development of the clinical syndrome and that therapeutic interventions performed even before the appearance of left ventricular dysfunction or symptoms can prevent the development of HF.

Because nearly 33% of adults in the United States have hypertension and due to the high PAR of hypertension in HF in both men and women, aggressive control of blood pressure is the most effective approach to reduce the incidence of HF. Primary prevention trials have shown up to a 50% reduction in the incidence of HF in patients with hypertension who are treated with thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and most β-blockers and calcium channel blockers.

The roles of coronary artery disease and myocardial infarction as major antecedents of systolic HF have been well established. Therapy with ACE inhibitors has been shown to reduce the risk of developing HF in patients with stable coronary artery disease, while therapy with ACE inhibitors, ARBs, β-blockers, and mineralocorticoid receptor blockers (MRBs) have been shown in several randomized trials to reduce the risk of progression to symptomatic HF in patients with myocardial infarction and asymptomatic left ventricular systolic dysfunction.

Diabetes mellitus has been consistently associated with a two- to fivefold increase in the risk of HF, especially in women. Although several studies have shown an 8–16% increase in the risk of hospitalizations for HF for every 1% increase in hemoglobin A1c, the optimal treatment strategy (eg, insulin versus metformin versus sulfonylureas versus thiazolidinediones) is currently unknown.

Nonpharmacologic Treatment

Dietary Measures

It is widely believed that HF management should include dietary sodium and fluid restriction, recommendations endorsed by all national and international guidelines. Most current recommendations are for 2000–3000 mg/day sodium for all HF patients and for less than 2000 mg/day with some degree of fluid restriction (1500–2000 mL/day) for HF patients with volume overload. Given the possibility that increased sodium intake leads to increased fluid retention in HF, it has been assumed that a low-sodium diet would improve outcomes in HF patients. However, the data on which these recommendations are drawn are limited, and the few clinical trials conducted to date have produced inconsistent findings. The new American Heart Association recommendations for 1500 mg/day sodium appear to be appropriate for patients with stage A and B, because of the data linking sodium intake with incidence of hypertension and HF. However, there are insufficient data to support a certain level of sodium or fluid intake in symptomatic HF patients (stages C and D).

Physical Activity and Exercise Training

For decades, exercise testing and exercise training were considered dangerous in patients with systolic HF because of concerns about exacerbating HF symptoms, potential deleterious effects on ventricular function, and the possibility of severe ventricular arrhythmias and cardiac arrest. Recent work has shown that exercise training in these patients is associated with improved response to pharmacologic vasodilators, improved endothelial function, improved skeletal muscle metabolism and performance, and attenuation of the activation of the overactive muscle ergoreflex. The large randomized trial, Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION), showed that in patients with symptomatic systolic HF exercise training was safe (no increase in arrhythmias over usual care) and was associated with a significant decrease in hospitalizations for HF and an improvement in the patients' well-being and in exercise capacity. Thus, all patients with systolic HF should be prescribed an exercise training program in addition to evidence-based pharmacologic therapy.

Treatment of Sleep-Disordered Breathing

Sleep-disordered breathing is common in systolic HF patients and is associated with adverse prognosis. Continuous positive airway pressure is the major treatment, especially if obstructive rather than central sleep apnea predominates, and its use has been associated with improvement in symptoms and ejection fraction. Adequate suppression of central sleep apnea by positive airway pressure may also be associated with improved survival. Bilevel positive airway pressure may be preferable over continuous pressure in patients who experience expiratory pressure discomfort. Adaptive (or auto) servo ventilation, which adjusts the positive airway pressure depending on the patient's airflow or tidal volume, may be useful in HF patients if continuous pressure is found ineffective.

Ultrafiltration

The mechanical removal of fluid from the vasculature is accomplished by applying hydrostatic pressure across a semipermeable membrane, resulting in isotonic plasma water separation from blood; thus, large amounts of fluid can be removed without affecting serum concentration of electrolytes and other solutes. Several small studies in HF patients have shown that ultrafiltration was associated with relief of congestive symptoms, improved exercise capacity, lower intracardiac filling pressures, and improved pulmonary function and neurohormonal levels. In recent years, ultrafiltration gained immense popularity in the treatment of hospitalized patients with HF and volume overload, and it has been increasingly used even in outpatient settings in HF patients at risk for readmission. However, in the recently published Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARESS-HF) trial, the use of a stepped diuretic algorithm was superior to a strategy of ultrafiltration for the preservation of renal function, with a similar amount of weight loss. Due to the possible side effects related to the ultrafiltration therapy, it should be reserved only for inpatients with HF and volume overload with preserved renal function who are not responding adequately to high-dose diuretic therapy.

Pharmacologic Treatment: Life-Saving Therapies

The pharmacologic treatment of symptomatic systolic HF has evolved substantially in the past 40 years, with neurohormonal antagonists becoming the mainstay of treatment due to marked improvements in morbidity and mortality.

ACE Inhibitors

Inhibition of ACE in HF results in an increase in the cardiac output, with concomitant decrease in ventricular filling pressures and pulmonary and systemic vascular resistances, without an increase in the heart rate. Over time, ACE inhibition leads to a decrease in left ventricular end-systolic and end-diastolic dimensions, a reduction in the incidence of ventricular arrhythmias, and continuous and sustained improvements in symptoms (occurring as early as 2 weeks), exercise duration, and quality of life. The most significant benefit of therapy with ACE inhibitors is the 20% increase in survival seen in all patients with systolic HF and in all patients with left ventricular systolic dysfunction after myocardial infarction, even in those without symptoms or signs of HF.

ACE inhibitors should be used in conjunction with β-blockers and MRBs as part of the “triple therapy” in order to achieve the maximal symptomatic improvement and survival benefit, and with a diuretic to maintain the sodium balance and prevent the development of fluid overload. The highest tolerated ACE inhibitor dose should be achieved, as clinical trials have shown improved HF outcomes at higher doses. Once the drug has been titrated (Table 26–3), patients can usually be maintained on long-term therapy with little difficulty. The need to decrease the ACE inhibitor dose due to hypotension and/or renal dysfunction may signal the development of end-stage HF and the need for advanced therapies (ie, ventricular assist devices, heart transplantation). Renal function and serum potassium should be assessed within 2 weeks of initiating therapy and every 3 months thereafter.

The main adverse effects of the therapy are related to the angiotensin suppression (hypotension, increase in serum creatinine and potassium) and bradykinin potentiation (cough and angioedema). The initial hypotension responds to a decrease in the dose of diuretic, liberalization of salt intake, or initiation of a lower dose of ACE inhibitor. Hypotension can be delayed and prolonged with longer acting ACE inhibitors (enalapril and lisinopril), leading to decreased systemic perfusion and compromise of renal and cerebral functions, but is shorter in duration with captopril, which rarely compromises organ perfusion. Some patients may be very sensitive to the hypotensive effects of ACE inhibitors, particularly end-stage HF patients who are dependent on the RAAS for blood pressure maintenance. In general, treatment should be reassessed if serum creatinine increases above 3 mg/dL or if serum potassium increases above 5.5 mEq/L. Patients should not be given ACE inhibitors if they are pregnant, have a history of angioedema or anuric renal failure during a previous exposure to this class, or are severely hypotensive and at risk of immediate cardiogenic shock.

ARBs

These agents block the angiotensin II receptor and inhibit the effects of angiotensin II produced not only through the classical ACE pathway, but also by the chymase pathway. Available ARBs block the angiotensin II type 1 receptors (associated with myocardial hypertrophy and remodeling) and enhance the activation of angiotensin II type 2 receptors, causing vasodilation. In addition, these effects are achieved without accumulation of bradykinin, which is considered to be responsible for some of the adverse reactions associated with the use of ACE inhibitors, such as cough or angioedema. Although the hemodynamic effects of ARBs are similar to those of ACE inhibitors, the randomized clinical trials have shown a consistent mortality benefit only in patients with systolic HF who are intolerant of ACE inhibitors. Candesartan was the only ARB that showed in clinical trials a 15% reduction in mortality when added to an ACE inhibitor. Use of ARBs in higher doses (see Table 26–3) in addition to ACE inhibitors and β-blockers is associated with symptomatic improvement and an overall modest 15% reduction in HF hospitalizations.

MRBs

Despite treatment with ACE inhibitors or ARBs, patients with HF demonstrate elevated aldosterone levels, due to alternative stimuli for aldosterone synthesis (eg, adrenocorticotropic hormone or endothelin), potassium-dependent aldosterone secretion, and reduced aldosterone clearance. Spironolactone is a renal competitive aldosterone antagonist, inhibiting its effect by competing for the aldosterone-dependent sodium–potassium exchange site in the distal tubule cells. Eplerenone is a selective MRB that prevents the binding of aldosterone and is devoid of the painful gynecomastia seen in about 10% of men taking spironolactone. Multiple clinical trials have shown that use of MRBs in addition to ACE inhibitors and β-blockers in patients with systolic HF and a variety of symptoms (New York Heart Association functional class II–IV) leads to a 15–30% decrease in mortality (including a 20% decrease in sudden cardiac death immediately after a myocardial infarction), improvement in HF symptoms, and a 30–40% decrease in hospitalizations for HF. Due to these significant benefits in a variety of systolic HF patients, MRBs and not ARBs should be the drugs of choice in the initial triple therapy with ACE inhibitors and β-blockers. The use of MRBs should be restricted to those patients with an estimated glomerular filtration rate above 30 mL/min/1.73 m2 and with serum potassium below 5 mEq/L; potassium levels should be monitored within a week of initiation and at least every 4 weeks for the first 3 months and every 3 months thereafter. Although low, the risk of hyperkalemia is real with these agents and can lead to a significant increase in morbidity and mortality.

β-Adrenergic Receptor Blockers

β-Blockers act by inhibiting the adverse effects of the sympathetic nervous system activation in patients with systolic HF. Long-term benefits of β-blockade include an increase in ejection fraction, a decrease in left ventricular volumes and in mitral regurgitation, and a reversion of the left ventricle to a more elliptical shape. Administration of β-blockers is associated with an early deterioration in cardiac function (consistent with the negative inotropic effects), followed by return to baseline values after 1 month and an increase in the ejection fraction after 3 months of treatment with further improvement for up to a year. Although the exercise capacity may not be improved by objective assessments (CPET), β-blockers, when added to ACE inhibitors, lead to marked symptomatic improvement, translated in robust 18% decreases in hospitalizations for HF and 35% improvement in survival. Only three β-blockers (bisoprolol, carvedilol, and metoprolol succinate) have been consistently shown to improve symptoms and survival in clinical trials, and therefore, only these should be used in patients with systolic HF. As in the case of ACE inhibitors, use of the highest tolerated β-blocker doses is recommended due to improvement in outcomes. In direct comparison studies, carvedilol was associated with better survival than metoprolol tartrate; in addition, the incidences of myocardial infarction, stroke, atrial fibrillation, and diabetes were lower with the use of carvedilol. In patients with reactive airway disease, bisoprolol has been shown to improve the peak expiratory flow and be better tolerated compared to the other approved β-blockers.

β-Blockers should be prescribed to all patients with asymptomatic left ventricular systolic dysfunction and stable systolic HF unless they have a contraindication. Patients should be clinically stable, receive ACE inhibitors and MRBs, and receive diuretics as needed to control the fluid retention associated with adrenergic blockade. β-Blockers should be initiated at very low doses (in euvolemic, noninotrope-dependent patients) and increased gradually, typically at 2-week intervals, to achieve the target doses from published clinical trials (Table 26–4).

Treatment with β-blockers can be associated with fatigue and weakness, which usually resolve in a few weeks. Symptomatic bradycardia is a serious adverse effect that requires a decrease in the dose or sometimes cardiac pacing. Hypotension is a side effect seen especially with nonselective blockers such as carvedilol. Usually, it occurs within the first 48 hours of initiation of therapy and subsides with repeated dosing without any change in the dose. Administration of ACE inhibitors and diuretics at a different time of day than the β-blockers can minimize the hypotension and dizziness. Administration of β-blockers is contraindicated in patients with severe bronchospasm, systolic blood pressure below 85 mm Hg, symptomatic bradycardia, or advanced heart block in the absence of a pacemaker.

Hydralazine-Nitrates Combination

Nitrates have a greater effect on venous capacitance (venodilation) than on the arterial system, while hydralazine is a direct-acting smooth muscle relaxant that seems to dilate arterioles predominantly. Long-term administration of isosorbide dinitrate has been associated with significant improvements in hemodynamic parameters, exercise capacity, and relief of symptoms in moderate-to-severe systolic HF. When used in combination with nitrates, hydralazine has shown a short-term increase in cardiac output and decrease in ventricular filling pressure. Patients who have dilated left ventricles appear to have a better hemodynamic and clinical response than do patients with lesser degrees of enlargement. The combination therapy was tested in African Americans with systolic HF in the African-American Heart Failure Trial (A-HeFT) and was associated with a significant 43% improvement in survival and a 33% decrease in HF hospitalizations, when used in addition to ACE inhibitors, β-blockers, and spironolactone. These results led to the first approval of a combination drug pill based on self-identified ethnicity. When the endothelial nitric oxide synthase (through which the combination of drugs is thought to work) was genotyped, the benefits of the therapy were evident only in those patients who were homozygous for glutamic acid in position 298 (GLU298GLU). Although 80% of African Americans have this genomic variant (as shown in A-HeFT), studies have shown that up to 40% of Caucasians have the same genotype, leading to intriguing possibilities for future pharmacogenomically targeted therapies. Unfortunately, the therapy is not easily tolerated due to side effects. Nitrates can produce headaches, while hydralazine can be associated with flushing, palpitations, nausea, vomiting, myocardial ischemia, and lupus-like syndrome.

Pharmacologic Treatment: Symptomatic Therapies

Diuretics

Diuretics provide rapid symptomatic relief of congestive symptoms by promoting excretion of sodium and water and lowering plasma volume, thus reducing congestion in the pulmonary and systemic vascular beds and improving symptoms and functional capacity. Diuretics are tightly bound to plasma proteins and are actively secreted into the proximal tubular lumen. Loop diuretics inhibit the sodium/ potassium/chloride symporter in the ascending loop of Henle; thiazide-type diuretics affect the sodium/chloride transporter in the distal convoluted tubules; whereas potassium-sparing diuretics work at sites in the collecting duct to inhibit the sodium/potassium transporter. The loop diuretics increase sodium excretion by 20–25% and enhance free water clearance. Orally dosed furosemide has variable bioavailability (10–100% in patients with HF), whereas bumetanide and torsemide are absorbed more completely, with 80% bioavailability after oral dosing. Although thiazide diuretics have bioavailability of 60–70%, their action is limited if the glomerular filtration falls below 40 mL/min/1.73m2 (with the exception of chlorothiazide and metolazone). Furosemide and thiazides are renally excreted, whereas the liver metabolizes torsemide and bumetanide. Thiazides and distal tubule diuretics have longer half-lives that allow them to be given once daily or even every other day. Because the plasma half-life of loop diuretics ranges from 1 to 4 hours, once a dose of a loop diuretic has been administered, its effect dissipates before the next dose is given. During this time, the nephron avidly reabsorbs sodium, resulting in rebound sodium retention that nullifies the prior natriuresis. In order to counteract this, the loop diuretics have to be given twice daily. Despite rapid symptomatic improvement, several retrospective analyses of systolic HF trials have linked non–potassium-sparing diuretics with an increase in mortality. Therefore, the lowest dose that achieves the desired effect should be used.

Diuretics should be used in all patients with evidence of volume overload; in an acutely decompensated state, a higher dose or combination of oral diuretics or intravenous diuretics is needed to achieve euvolemia. Using too low a diuretic dose causes fluid retention, which can diminish the response to ACE inhibitors and increase the risk of treatment with β-blockers. Use of inappropriately high doses of diuretics leads to volume contraction and increased risk of hypotension and renal insufficiency with ACE inhibitors. Diuretic resistance can be overcome by the intravenous administration of diuretics (intermittent bolus or continuous infusions have the same efficacy), the use of diuretic combinations (eg, loop and thiazide), or use of intravenous diuretics with low dose dopamine. Volume depletion (resulting in hypotension and/or renal failure), hypokalemia, hypomagnesemia, and thiamine deficiency are the most common side effects of diuretics. Diuretics may also cause metabolic alkalosis, carbohydrate intolerance, hyperuricemia, hypersensitivity reactions, and acute pancreatitis.

Digoxin

Digoxin exerts its effects by inhibition of sodium-potassium adenosine triphosphatase in the myocardium (resulting in an increase in myocardial contraction), in the vagal afferent fibers (sensitizing the cardiac baroreceptors and reducing the sympathetic outflow), and in the kidney (reducing the renal tubular reabsorption of sodium). These observations have led to the hypothesis that the beneficial effects of digoxin in HF are due to the attenuation of the activation of neurohormonal systems. Clinically, the beneficial effects in patients with systolic HF and sinus rhythm include improved HF symptoms, increased exercise time, modestly increased ejection fraction, enhanced cardiac output, and decreased HF hospitalizations. The benefits of digoxin are higher in patients with more symptomatic HF (New York Heart Association functional class IV), cardiomegaly (greater cardiothoracic ratio on chest x-ray), or an ejection fraction below 25%. However, due to its narrow therapeutic index, digoxin has a bidirectional effect with improvement in HF mortality and increase in the non-HF (presumed arrhythmic) mortality. Retrospective analyses of the Digitalis Investigation Group (DIG) trial have suggested an increased mortality with serum concentration above 1 ng/mL, especially in women. Due to these considerations, digoxin has been reserved in systolic HF patients in sinus rhythm who are still symptomatic despite triple therapy with ACE inhibitors, β-blockers, and MRBs. In patients with systolic HF and atrial fibrillation, digoxin can be used to decrease the ventricular response, usually associated with improved symptoms. Although more rare than in prior decades, digitalis intoxication may occur in patients hospitalized for HF. Common findings are nausea, vomiting, anorexia, malaise, drowsiness, headache, insomnia, altered color vision, or arrhythmia. Cardiac arrhythmias (most commonly premature ventricular beats, junctional tachycardia, paroxysmal atrial tachycardia with block, bidirectional ventricular tachycardia) can be caused by digitalis and are facilitated by hypokalemia. Digoxin toxicity is usually confirmed by the reversal of symptoms or cessation of arrhythmias after withdrawal of digoxin therapy. Severe toxicity can be reversed quickly with digoxin immune Fab.

Pharmacologic Treatment: Other Therapies

Oral Phosphodiesterase-5 Inhibitors

Due to the chronic elevation in left ventricular filling pressures, a large number of systolic HF patients will develop secondary pulmonary hypertension. While the presence of fixed pulmonary hypertension has been shown to be a poor prognostic factor in patients undergoing heart transplantation, recent studies have suggested that improvement in pulmonary artery pressures with oral phosphodiesterase-5 inhibitors (ie, sildenafil, tadalafil) may lead to improvements in symptoms in HF patients. Although this hypothesis has been recently rejected in the Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People with Diastolic Heart Failure (RELAX) study, a large randomized trial will address the question in patients with systolic HF and pulmonary hypertension. Until the results of the PDE5 Inhibition with Tadalafil Changes Outcomes in Heart Failure (PITCH-HF) trial become available, it is prudent to use these drugs in patients with systolic HF and pulmonary hypertension, only if they are compensated and have a pulmonary capillary wedge pressure close to normal.

Antiarrhythmic Agents

More than 80% of systolic HF patients have frequent and complex ventricular arrhythmias as documented by Holter monitoring, and 50% have frequent nonsustained ventricular tachycardia. In addition, 35–40% of patients have paroxysmal or persistent atrial fibrillation that can lead to HF exacerbation. Systolic HF patients frequently require some antiarrhythmic drugs in order to stabilize these arrhythmias. Due to the structural heart disease seen in HF, only some of the class III anti-arrhythmics (dofetilide and amiodarone) are safe to use. Although clinical trials have shown that amiodarone per se does not improve prognosis in systolic HF patients, they have also shown that it is a rather safe option. It can be administered acutely to control ventricular response in HF patients with atrial fibrillation, and its long-term use may restore and maintain sinus rhythm. Amiodarone may also be used to suppress symptomatic ventricular tachycardia in combination with β-blockers, especially in patients who are receiving frequent defibrillator shocks. Close monitoring for side effects is required. Dofetilide was shown to be effective in restoring sinus rhythm in patients with systolic HF and atrial fibrillation without adverse effects on overall survival. Treatment with dofetilide also decreased the overall and HF hospitalizations in the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) study. However, dofetilide dosing has to be closely titrated, based on creatinine clearance and QT interval, requiring 72-hour inpatient monitoring. Dronedarone is a benzofuran-derivative class III antiarrhythmic drug with pharmacologic properties similar to amiodarone and should not be used in patients with systolic HF due to the increased mortality risk associated with the drug.

Antithrombotic Therapy

In patients with systolic HF and sinus rhythm, antithrombotic therapy has traditionally been considered for those with very low ejection fraction. However, a multitude of clinical trials have failed to show a clear benefit of this strategy in preventing strokes in these patients. As such, the decision to use an antiplatelet or anticoagulant must be individualized, taking into account the comorbidities of the patient (eg, presence of concomitant coronary artery disease or peripheral vascular disease). All patients with systolic HF and atrial fibrillation (even paroxysmal) should be anticoagulated with warfarin or newer antithrombotic agents (apixaban, dabigatran, or rivaroxaban) in order to prevent strokes.

Statins (3-Hydroxy-3-Methyl-Glutaryl–Coenzyme A Reductase Inhibitors)

Statins are the cornerstone of primary and secondary prevention for patients with coronary artery disease or vascular disease. Paradoxically, even though 70% of systolic HF patients have coronary artery disease, the role of statins in systolic HF is only marginal. Two large randomized clinical trials testing the role of rosuvastatin in this setting failed to show a benefit on mortality. Patients with underlying coronary artery disease experienced a reduction in cardiovascular hospitalizations, presumably by averting small myocardial infarctions due to plaque destabilization. As such, statins should only be used in patients with systolic HF and clinical coronary artery disease.

Omega-3 Polyunsaturated Fatty Acids

The use of omega-3 polyunsaturated acids in systolic HF patients leads to small improvements in left ventricular ejection fraction, reduction in left ventricular end systolic volumes and functional capacity, and a small 10% decrease in cardiovascular mortality and 7% decrease in risk for cardiovascular hospitalizations. The dose used in clinical trials of 1 g (850–882 mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters in the average ratio of 1:1.2) is much smaller than the dose used to treat hypertriglyceridemia and, therefore, more likely to be tolerated by patients.

Intravenous Iron Therapy

Iron deficiency is quite frequent in patients with systolic HF, and several small studies and one large randomized trial showed improvements in symptoms, exercise capacity, and quality of life with intravenous ferric carboxymaltose. Intravenous iron therapy (there are several preparations available) is relatively safe and should be used for all patients with systolic HF who are iron deficient even in the absence of anemia (ferritin level < 100 mcg/L or 100–299 mcg/L if the transferrin saturation is < 20%).

Although anemia is common and portends poor prognosis in systolic HF, treatment with darbepoetin was not associated with improved survival or decrease in hospitalization in these patients. Moreover, patients treated with darbepoetin experience more thromboembolic events, and thus, the erythropoiesis-simulating agents should not be used or should be used very cautiously in systolic HF patients. In patients with decompensated HF and hemoglobin level < 10 g/dL, careful transfusion with packed red blood cells, while giving diuretics, has been shown to improve outcomes.

Pharmacologic Treatment: Specific Therapies in Hospitalized Patients

The majority of hospitalized patients with systolic HF are volume overloaded and may require vasodilators in order to decrease the filling pressures and improve dyspnea. For faster action, intravenous options such as sodium nitroprusside, nitroglycerin, or nesiritide are available. Due to the frequent titration needed, sodium nitroprusside and nitroglycerin can only be used in the intensive care setting. Nesiritide (recombinant BNP) is an agent with vasodilator, natriuretic, and diuretic effects that does not require titration and that can be used in telemetry units. Although proven to be safe, it has been shown to only marginally improve symptoms in patients with decompensated systolic HF, and as such, its use has been very limited.

A minority of hospitalized systolic HF patients presents with very low cardiac output (“cold” profile) and require intravenous inotropes in order to maintain perfusion and diuresis. The two most frequently used agents are dobutamine and milrinone. Dobutamine augments cardiac contractility primarily via stimulation of β-adrenergic receptors and is a modest vasodilator, whereas milrinone exerts potent inotropic and direct vasodilator effects via phosphodiesterase inhibition in the myocardium and vasculature. While these agents are fairly effective, their use is associated with further myocardial injury (evidence of troponin release even in nonischemic cardiomyopathy), and they can precipitate fatal ventricular arrhythmias. Their use is best reserved for patients in need of a bridge to mechanical circulatory support or transplant or in those patients where palliative home hospice is entertained.

Electrical Treatment

The majority of patients with systolic HF experience ventricular arrhythmias, and as many as 50% of all deaths in this population are sudden in nature. Findings from large clinical trials have clearly shown that implantable cardioverter-defibrillators (ICDs) are the most effective therapy available to prevent sudden cardiac death in these patients at risk, and ICD treatment has become standard therapy for primary and secondary prevention of sudden cardiac death in addition to optimal medical therapy in patients with left ventricular ejection fraction below 35%. Only about 10% of patients implanted with ICDs have appropriate discharges (highlighting the poor predictive value of current selection algorithms based solely on ejection fraction), with another 20% of patients experiencing inappropriate shocks (leading to an increase in mortality), and with the vast majority not using them at all. Fortunately, better discrimination algorithms for supraventricular tachycardia and the optimal use of ventricular antitachycardia pacing have markedly decreased the frequency of inappropriate shocks in these patients.

In addition, a third of systolic HF patients experience intraventricular conduction abnormalities (eg, left bundle branch block) that lead to mechanical dyssynchrony and adversely affect the cardiac performance. Several clinical trials have shown that CRT as standalone treatment or combined with ICD in patients with systolic HF and ejection fraction below 35% significantly improves the ejection fraction, decreases ventricular volumes, improves HF symptoms, improves exercise tolerance, and decreases the hospitalization rate for HF, as well as cardiovascular and all-cause mortality. These benefits are seen across the spectrum of HF patients (New York Heart Association functional class I–IV) and are more evident in patients in sinus rhythm, with a left bundle branch block pattern, QRS duration greater than 150 ms, and an ejection fraction below 35%. Proper patient selection to meet these strict criteria, together with selection of a viable (noninfarcted) lateral wall and optimal placement of the coronary sinus pacing lead can markedly decrease the frequency of CRT “nonresponders” (estimated at about 40% of the population implanted). The value of periodic CRT optimization by adjusting the atrioventricular and intraventricular timing for pacing (either via device-specific algorithms or echocardiography) is still a matter of debate, although in several studies, it has been shown to improve symptoms and ventricular remodeling parameters.

Surgical Treatment

Cardiac surgical approaches for patients with systolic HF have changed and matured over the last decade due to improved surgical techniques and as a result of several randomized clinical trials. Until recently, uncertainty still existed about the role and benefits of revascularization in patients with ischemic systolic HF. However, the Surgical Treatment of Ischemic Heart Failure (STICH) trial showed a 19% decrease in cardiovascular mortality and a 15% decrease in cardiovascular hospitalizations in patients undergoing coronary artery bypass surgery in addition to optimal medical therapy when compared to optimal medical therapy alone. Thus, patients with ischemic systolic HF should be evaluated for surgical (or possibly percutaneous) revascularization.

Many HF patients with decreased systolic function and coronary artery disease have apical aneurysms as result of prior myocardial infarctions. Based on case series, surgical aneurysm reduction was thought to be beneficial by making the left ventricular contraction more efficient; however, data from the STICH trial showed that the improvement in ventricular volume with surgical ventricular restoration did not translate into a measurable clinical benefit for the patients.

A large number of systolic HF patients develop functional mitral regurgitation as results of left ventricular enlargement. While data are more convincing for concomitant mitral valve repair at the time of coronary bypass surgery, several large case series showed that even in nonischemic patients, mitral valve repair with an undersized complete rigid annuloplasty ring and without alteration of the subvalvular apparatus can be performed safely with low operative mortality. At the present time, it is unknown if this operation will translate into reverse remodeling or improved clinical outcomes. Recently, percutaneous plication or repair of the mitral valve has become possible and may replace surgical approaches in the future.

Patients with advanced systolic HF who are not amenable to conventional pharmacologic, electrical, or surgical therapies should be considered for advanced surgical options. Although with the current advances in immunosuppression therapy, the 1-year survival after cardiac transplantation approaches 90% and 50% of patients survive more than 12 years, only about 2200 adult patients will get transplanted every year due to the lack of available organs. The strict evaluation of candidates for heart transplantation will address comorbid diseases such as pulmonary hypertension, kidney disease, diabetes, chronic obstructive lung disease, and cancers in an attempt to identify the candidates most likely to benefit long term from this therapy.

Left ventricular assist device implantation has been used as a bridge to recovery (in patients with acute myocarditis or postpartum cardiomyopathy), a bridge to transplant (for patients likely to wait extended period of time for an available organ) or destination therapy. The devices in current commercial use, ThoratecHeartMate II and HeartWare HVAD, are second- and third-generation devices that have good reliability and have transformed the field of mechanical circulatory support. While the surgical operation itself has become fairly standardized, the long-term postoperative care is complex, and the use of assisted circulation is associated with risk of complications such as gastrointestinal bleeding, right-sided HF, renal insufficiency, infection, and thromboembolic events.

Disease management programs are an important part of the care for systolic HF patients and include a broad range of health services, such as home health care, visiting nurses, and rehabilitation. The goal of these programs is to offer a combination of treatment, complication prevention, and education (about medications, diet, symptoms, etc.) in a variety of settings. Research has shown that patients enrolled in these programs receive more customized treatment and that these program may reduce the overall cost of HF care by preventing hospitalizations.

Prognostication is critical in patient management, and patients deserve careful, thoughtful, and compassionate analysis of the data and information that will guide them through the important challenges of self-care. Although many demographic and clinical variables have been shown to predict survival in epidemiologic studies and clinical trials, the clinician is faced with the almost impossible task of juggling all of these variables at the hospital bedside or in the office when seeing a patient. During day-to-day management of individuals with systolic HF, the physician should focus attention on readily available clinical information that includes symptom severity (usually New York Heart Association functional classification, distance walked in 6 minutes, or oxygen consumption on CPET), left ventricular ejection fraction, routine biochemical markers (serum sodium, creatinine, blood urea nitrogen, and uric acid levels), and select neurohormones such as BNP. Several algorithms have been developed and tested to assist in determining which patients might benefit from advanced HR options such as assist devices or cardiac transplantation. The models that are most commonly used are the Heart Failure Survival Score (using presence of ischemia, resting heart rate, left ventricular ejection fraction, presence of a QRS duration > 200 ms, mean resting blood pressure, peak oxygen uptake, and serum sodium level) and the Seattle Heart Failure Model (using 25 different demographic and clinical variables). Both models have been extensively validated and can give a fairly accurate survival estimate. When such evaluation indicates a poor prognosis, the clinician needs to have an in-depth discussion with the patient and their family, where all the options (including palliative care) should be discussed.