There are currently estimated to be 6.2 million individuals over 20 years of age in the United States with HF and 23 million individuals worldwide.³,⁴ The prevalence and incidence of HF is on the rise in the United States and other developed countries, and it is estimated that more than 750,000 new cases of HF will be diagnosed each year in the United States by 2040.⁵ A major factor contributing to this rise is the aging population. The incidence of HF doubles for each decade of life, with the lifetime likelihood of developing HF approximately 20%.⁶

HFrEF specifically is estimated to account for approximately 50% of all HF diagnoses, although, as a proportion of all HF, it is decreasing over time.¹,³ Male gender has been associated with new diagnosis of HFrEF, whereas female gender is associated with HFpEF, likely related to higher incidences of ischemic cardiomyopathy in male patients. The lifetime risk for the development of HFrEF is 10.6% in males in comparison to 5.8% for females.⁷ New diagnosis of HFrEF has also been associated with active tobacco abuse, elevated high-sensitivity troponin, and prior myocardial infarction (MI).⁸

Approximately 6% of the population has asymptomatic LV dysfunction without clinical symptoms consistent with HF. These patients have an annual risk of 10% for developing clinical HF.¹

Racial differences between the incidence and prevalence rates of HF have been observed. African American males are the highest risk group for the development of HFrEF and have a significantly higher 5-year mortality rate in comparison to Caucasian patients with HFrEF. Overall, the prevalence in African American males is 4.5% in comparison to 2.7% in Caucasian males, and similar differences have been demonstrated between African American and Caucasian females.⁹ Other studies have observed no significant difference in HFrEF prevalence rates when the populations are adjusted for prior MI, suggesting that atherosclerotic disease burden and implementation of guideline-based therapy likely is an important factor in racial disparities in HFrEF.

HF exacerbations are one of the most frequent causes for hospitalization in the United States. Every year, there are more than 1 million hospitalizations related to HF, accounting for more than 20% of hospitalizations in patients over the age of 65 years.¹ Approximately 50% of these hospitalizations involve patients with HFrEF specifically. After discharge, this patient population is at elevated risk for rehospitalization, with more than 25% of patients requiring repeat hospitalization within 1 month. Despite a growing prevalence of the disease, hospitalizations with the primary diagnosis of HF exacerbation have trended downward over the past two decades, which has been attributed to more effective therapies and increased programs focused on reduction in re-admission rates for these patients.¹⁰

HF is associated with a 5-year mortality of approximately 50% and accounts for 7% of cardiovascular (CV) deaths in the United States. The mortality rates in patients with HFrEF and HFpEF are thought to be similar, although some analyses have suggested a lower mortality rate in patients with HFpEF. In a recent meta-analysis, the annual mortality for HFrEF was
14.2% compared to 12.1% for HFpEF, irrespective of age, gender, and a number of CV risks.¹¹ However, increasingly trends point to improvements in HFrEF mortality over time, whereas mortality rates in HFpEF patients have remained stable, which is likely related to a growing number of effective therapy options for HFrEF patients. From 1993 to 2005, 30-day posthospitalization mortality improved from 12.6% to 10.8% in one study, and other studies have demonstrated similar improvements in mortality rates since 1980s.¹,¹² HF hospitalizations are one of the strongest predictors for mortality, and average median survival falls to approximately 2 years after first hospitalization for HF exacerbation.¹³ Other strong predictors for mortality include renal function, serum sodium concentration, age, and systolic blood pressure.

The economic burden of HF is significant, and total costs associated with the health care services and lost worker productivity are estimated to be more than $30 billion a year in the United States and more than $100 billion worldwide.¹ HF accounts for 2% of total health care spending in the United States. A strong contributor to these costs is HF exacerbations requiring hospitalization, with an HF hospitalization costing more than $20,000 mean and a high number of patients requiring multiple hospitalizations per year.¹⁴ Among patients with HFrEF, new pharmacologic agents as well as device therapy—such as internal cardiac defibrillators and cardiac resynchronization therapy—have improved outcomes while also contributing significantly to the rising cost of care. By 2030, it is expected that the direct health care costs associated with HF will exceed $50 billion in the United States.¹⁵

There is a wide variety of underlying etiologies associated with HFrEF. The most common etiology is ischemic cardiomyopathy, in which a combination of acute coronary events and chronic supply-demand ischemia results in declining LV systolic function. Overall, coronary artery disease accounts for approximately 40% of patients with HFrEF.¹⁶ Owing to the high prevalence of ischemic-induced HFrEF, all patients with HFrEF must undergo an ischemic evaluation and then are generally characterized as either ischemic cardiomyopathy or nonischemic cardiomyopathy.

Among patients with nonischemic cardiomyopathy, the most common identified etiologies are hypertension and valvular heart disease. However, a significant portion of patients with nonischemic cardiomyopathy are without a clearly identifiable etiology and are labeled as idiopathic or dilated cardiomyopathy. Important etiologies of nonischemic cardiomyopathy to consider include those related to increased and abnormal cardiac energetics, such as tachycardia- or stress-induced cardiomyopathy; toxin related, such as substance abuse associated or chemotherapy-related cardiomyopathy; and inflammation related, such as peripartum cardiomyopathy and myocarditis.¹⁷,¹⁸ In addition, dilated cardiomyopathy can be attributed to genetic causes in approximately 30% to 40% of cases, and in these, there may be an identifiable genetic variant in 40%.¹⁹ Other etiologies include infiltrative processes such as amyloidosis, sarcoidosis, and hemochromatosis. Congenital heart disease accounts for approximately 0.4% (Table 69.1).²⁰

As cardiac output falls and/or filling pressures rise in a patient with HFrEF, various hormonal compensatory mechanisms are activated. Initially, a fall in cardiac output and blood pressure will be detected by baroreceptors in the carotid sinus and aortic arch. In order to maintain blood pressure and end-organ perfusion, the sympathetic nerves system (SNS) is activated, resulting in the release of catecholamines primarily by the adrenal medulla but also from the myocardium itself. This is accompanied by a simultaneous reduction in parasympathetic activation. Increased levels of circulating norepinephrine effect a number of organ systems. In the myocardium, activation of β-1 receptors increases contractility and heart rate, resulting in an initial increase in cardiac output while also increasing myocardial oxygen demand. Eventually, there is downregulation of the cardiac β-adrenergic receptors. In the peripheral vasculature, stimulation of α-1 receptors results in peripheral vasoconstriction, increasing system blood pressure, and increasing LV afterload.

In the kidneys, sympathetic activation induces the production of renin via two mechanisms. Peripheral vasoconstriction results in decreased blood flow to the glomerular juxtaglomerular apparatus, which induces renin production; renin production is also triggered directly by the activation of β-1 receptors on the juxtaglomerular apparatus. Renin begins the hormonal activation of the renin-angiotensin-aldosterone
system (RAAS). Renin converts angiotensinogen, produced by the liver, to angiotensin I. Angiotensin I is converted to the active form angiotensin II by angiotensin-converting enzyme (ACE) in vascular endothelial cells, primarily in the pulmonary vascular beds. Angiotensin II results in the retention of both sodium and water via both direct and indirect mechanisms. Angiotensin II directly stimulates sodium channels and sodium pumps in the proximal tubule, the ascending loop of Henle, and in the collecting ducts. The protein also induces the release of the mineralocorticoid hormone aldosterone from the zona glomerulosa in the adrenal cortex and antidiuretic hormone (ADH) from the posterior pituitary gland. Aldosterone upregulates the expression of Na⁺/K⁺ pumps in the cells of distal tubule and collecting ducts, allowing for the increased reabsorption of sodium. Aldosterone also promotes collagen synthesis and fibrosis within the myocardium. ADH induces its effect by increasing the insertion of aquaporin-2 water channels in the collecting duct, allowing reabsorption of water.

Ultimately, the activation of the RAAS results in significant retention of sodium and water through several mechanisms, increasing blood volume and pressure. Initially, activation of these neurohormonal axes allows for short-term compensation for declining cardiac output by increasing blood volume, inducing peripheral vasoconstriction, and increasing cardiac contractility and heart rate. However, these processes increasingly become maladaptive as the disease progresses.²¹,²²

In response to increased pressures and volumes, the myocardium begins to undergo a remodeling process with changes to the LV structure and underlying histopathology. Myocyte hypertrophy develops in response to increased LV wall strain and loading. In patients with HFrEF, LV wall stress is primarily driven by volume overload, resulting in progressive dilation of the ventricle. At the cellular level, sarcomeres within the myocytes are deposited in series, allowing the individual cells to elongate in response to rising diastolic wall stress. This process is known as “eccentric hypertrophy” in contrast to concentric hypertrophy, which traditionally develops because of elevated pressures in systole. In concentric hypertrophy, additional sarcomeres are deposited in a parallel manner within the cardiac myocytes. As the LV continues to dilate and progresses from the normal ellipsoid shape of the ventricle to a spherical one in HFrEF, the geometric changes to the ventricle worsen the mechanical pumping efficiency of the heart, which correlates with a worsening prognosis. Dilatation of the ventricle and sarcomere stretch leads to increased ventricular preload.

As chamber dilation and wall thinning progress, cardiac myocytes are progressively lost via several mechanisms of cellular death, including apoptosis, autophagy, and necrosis. At this stage, neurohormonal axis activation induces a direct impact on LV remodeling by triggering cardiac myocyte death via necrosis and apoptosis. Both norepinephrine and angiotensin II at sufficient serum concentrations are capable of inducing myocyte cell death. Increased rates of cell death and the resulting inflammation within the cardiac tissue signal an
inappropriate proliferation of fibroblasts and increase deposition of extracellular matrix collagen proteins, in part due to aldosterone signaling. This slow, chronic loss of cardiac myocytes followed by myocardial fibrosis formation contributes to the continued decline in cardiac reserve and the progressive nature of the disease course.²³,²⁴

In response to increased wall strain on the atrium and ventricle, several counterregulatory mechanisms exist to induce excretion of water and sodium, lower systemic blood pressure, and slow the progression of LV remodeling. The most important hormones involved in this protective mechanism are the natriuretic peptides: the brain (or b-type) natriuretic peptide (BNP) and atrial natriuretic peptide (ANP). Although both hormones are produced and released primarily by cardiac cells, BNP derived its name from its originally isolation from brain tissue in 1988 and is the most relevant in clinical practice. ANP is released rapidly in response to acute changes in atrial pressure and has a short in vivo half-life of approximately 3 minutes. BNP is released more slowly in response to chronic changes in myocardial pressures and has a slightly longer half-life of 20 minutes in vivo. Both peptides bind to natriuretic peptide receptors, NPR-A and NPR-B, found in several tissues, including the kidneys, vascular smooth muscle, adrenal glands, and myocardium itself. Once ANP or BNP binds to the receptor, it induces the production of guanosine cyclic monophosphate (cGMP). In the kidneys, cGMP reduces sodium and water reabsorption by inhibition of Na⁺-Cl^– co-transporters in the distal convoluted tubule and inhibits activation of the RAAS by reducing renin secretion from the juxtaglomerular apparatus. RAAS activation is further inhibited by cGMP action in the adrenal cortex, thereby reducing the secretion of aldosterone. Vasodilation is induced in the vascular smooth muscle. In the myocardium itself, cGMP has a cardioprotective effect against LV remodeling by inhibition of cardiac myocyte apoptosis and inhibition of cardiac fibroblast proliferation. The natriuretic peptides are relatively quickly degraded enzymatically by neutral endopeptidase (NEP), also known as neprilysin. As HF progresses, expression of natriuretic peptides increases and assists in counterbalancing the maladaptive SNS and RAAS activations. Over time, however, the tissues develop increased resistance to natriuretic peptides by downgrading of NPR-A and NPR-B receptors, counteracting its efficiency, and accelerating disease progression.²⁵,²⁶