Overview of Heart Failure

Heart failure most commonly occurs as a result of left ventricular dysfunction (2). As a result, the Universal Classification of Heart Failure has categorized heart failure according to reduced, preserved, minimally reduced, and improved ejection fraction based on left ventricular systolic function (1). In left heart failure, cardiac output decreases and pulmonary venous pressure increases. When pulmonary capillary pressure exceeds the oncotic pressure of plasma proteins (approximately 24 mm Hg), fluid extravasates from the capillaries into the interstitial space and alveoli, reducing pulmonary compliance and increasing the work of breathing. Lymphatic drainage increases but cannot compensate for the increase in pulmonary fluid. Marked fluid accumulation in alveoli (pulmonary edema) significantly alters ventilation-perfusion (V/Q) relationships. Deoxygenated pulmonary arterial blood passes through poorly ventilated alveoli, decreasing systemic arterial oxygenation (partial pressure of arterial oxygen [PaO2]) and causing dyspnea. However, dyspnea may occur before V/Q abnormalities, probably because of elevated pulmonary venous pressure and increased work of breathing; the precise mechanism is unclear.

In severe or chronic LV failure, pleural effusions characteristically develop, further aggravating dyspnea. Minute ventilation increases; thus, partial pressure of arterial carbon dioxide (PaCO2) decreases and blood pH increases (respiratory alkalosis). Marked interstitial edema of the small airways may interfere with ventilation, elevating PaCO2—a sign of impending respiratory failure.

In HFrEF (also called systolic heart failure), global LV systolic dysfunction predominates. The LV contracts poorly and empties inadequately, leading to:

• Increased diastolic volume and pressure

• Decreased ejection fraction (≤ 40%)

Many defects in energy utilization, energy supply, electrophysiologic function, and contractile element interaction occur, with abnormalities in intracellular calcium modulation and cyclic adenosine monophosphate (cAMP) production.

Predominant systolic dysfunction is common in heart failure due to myocardial infarction, myocarditis, and dilated cardiomyopathy. Systolic dysfunction may affect primarily the LV or the right ventricle (RV); LV failure often leads to RV failure.

In HFpEF (also called diastolic heart failure), LV filling is impaired, resulting in:

• Increased LV end-diastolic pressure at rest or during exertion

• Usually, normal LV end-diastolic volume

Global contractility and hence LV ejection fraction remain normal (≥ 50%).

However, in some patients, marked restriction to LV filling can cause inappropriately low LV end-diastolic volume and thus cause low cardiac output and systemic symptoms. Elevated left atrial pressures can cause pulmonary hypertension and pulmonary congestion.

Diastolic dysfunction usually results from impaired ventricular relaxation (an active process), increased ventricular stiffness, valvular disease, or constrictive pericarditis. Acute myocardial ischemia is also a cause of diastolic dysfunction. Resistance to filling increases with age, reflecting cardiomyocyte dysfunction and cardiomyocyte loss, and increased interstitial collagen deposition; thus, diastolic dysfunction is particularly common among older adults. Diastolic dysfunction predominates in hypertrophic cardiomyopathy, other disorders with ventricular hypertrophy (eg, hypertension, significant aortic stenosis), and amyloid infiltration of the myocardium. LV filling and function may also be impaired if marked increases in RV pressure shift the interventricular septum to the left.

Diastolic dysfunction is recognized as an important cause of HF. Approximately 50% of patients with heart failure have HFpEF; the prevalence increases with age and in patients with diabetes (3). HFpEF is a complex, heterogenous, multiorgan, systemic syndrome, often with multiple concomitant pathophysiologies. Data suggest that multiple comorbidities (eg, obesity, hypertension, diabetes, chronic kidney disease) lead to systemic inflammation, widespread endothelial dysfunction, cardiac microvascular dysfunction, and, ultimately, molecular changes in the heart that cause increased myocardial fibrosis and ventricular stiffening. Thus, although HFrEF is typically associated with primary myocardial injury, HFpEF may be associated with secondary myocardial injury due to abnormalities in the periphery.

HF with mildly reduced ejection fraction (HFmrEF) is defined as an LV ejection fraction of 41 to 49%. It is unclear whether this group is a distinct population or consists of a mixture of patients with either HFpEF or HFrEF.

Patients with HF whose LV ejection fraction has improved by more than an absolute of 10% from a prior value and also measures over 40% are categorized as having HFimpEF.

Right ventricular failure most commonly occurs as a consequence of or in tandem with left ventricular failure. Isolated right heart failure is observed much less commonly. In heart failure that involves right ventricular dysfunction (see Right Heart Failure), systemic venous pressure increases, causing fluid extravasation and consequent edema, primarily in dependent tissues (feet and ankles of ambulatory patients) and abdominal viscera. The liver is most severely affected, but the stomach and intestine also become congested; fluid accumulation in the peritoneal cavity (ascites) can occur. RV failure commonly causes moderate hepatic dysfunction, with usually modest increases in conjugated and unconjugated bilirubin, prothrombin time (PT), and hepatic enzymes (particularly alkaline phosphatase and gamma-glutamyl transpeptidase [GGT]). The impaired liver breaks down less aldosterone, further contributing to fluid accumulation. Chronic venous congestion in the viscera can cause anorexia, malabsorption of nutrients and medications, protein-losing enteropathy (characterized by diarrhea and marked hypoalbuminemia), chronic gastrointestinal blood loss, and rarely ischemic bowel infarction.

When left ventricular contractility is impaired, as is the case in HRrEF, a higher preload is required to maintain cardiac output. As a result, the ventricles are remodeled over time. During remodelling, the LV becomes less ovoid and more spherical, dilates, and hypertrophies; the RV dilates and may hypertrophy. Initially compensatory, remodelling ultimately is associated with adverse outcomes because the changes eventually increase diastolic stiffness and wall tension (ie, diastolic dysfunction develops), compromising cardiac performance, especially during physical stress. Increased wall stress raises oxygen demand and accelerates apoptosis (programmed cell death) of myocardial cells. Dilation of the ventricles can also cause mitral or tricuspid valve regurgitation (due to annular dilation) with further increases in end-diastolic volumes.

With reduced cardiac output, oxygen delivery to the tissues is maintained by increasing oxygen extraction from the blood and sometimes shifting the oxyhemoglobin dissociation curve (see figure Oxyhemoglobin Dissociation Curve) to the right to favor oxygen release.

Reduced cardiac output with lower systemic blood pressure activates arterial baroreflexes, increasing sympathetic tone and decreasing parasympathetic tone. As a result, heart rate and myocardial contractility increase, arterioles in selected vascular beds constrict, venoconstriction occurs, and sodium and water are retained. These changes compensate for reduced ventricular performance and help maintain hemodynamic homeostasis in the early stages of heart failure. However, these compensatory changes increase cardiac work, preload, and afterload; reduce coronary and renal perfusion; cause fluid accumulation resulting in congestion; increase potassium excretion; and may cause cardiomyocyte necrosis and arrhythmias.

As cardiac function deteriorates, renal blood flow decreases due to low cardiac output. In addition, renal venous pressures increase, leading to renal venous congestion. These changes result in a decrease in glomerular filtration rate (GFR), and blood flow within the kidneys is redistributed. The filtration fraction and filtered sodium decrease, but tubular resorption increases, leading to sodium and water retention. Blood flow is further redistributed away from the kidneys during exercise, but renal blood flow improves during rest.

Decreased perfusion of the kidneys (and possibly decreased arterial systolic stretch secondary to declining ventricular function) activates the renin-angiotensin-aldosterone system, increasing sodium and water retention and renal and peripheral vascular tone. These effects are amplified by the intense sympathetic activation accompanying heart failure.

The renin-angiotensin-aldosterone-vasopressin (antidiuretic hormone [ADH]) system causes a cascade of potentially deleterious long-term effects. Angiotensin II worsens heart failure by causing vasoconstriction, including efferent renal vasoconstriction, and by increasing aldosterone production, which enhances sodium reabsorption in the distal nephron and also causes myocardial and vascular collagen deposition and fibrosis. Angiotensin II increases norepinephrine release, stimulates release of vasopressin, and triggers apoptosis. Angiotensin II may be involved in vascular and myocardial hypertrophy, thus contributing to the remodeling of the heart and peripheral vasculature, potentially worsening heart failure. Aldosterone can be synthesized in the heart and vasculature independently of angiotensin II (perhaps mediated by corticotropin, nitric oxide, free radicals, and other stimuli) and may have deleterious effects in these organs.

Heart failure that causes progressive renal dysfunction (including renal dysfunction caused by medications used to treat HF) contributes to worsening HF and has been termed the cardiorenal syndrome.

In conditions of stress, neurohumoral responses help increase heart function and maintain blood pressure and organ perfusion. Chronic activation of these responses is detrimental to the normal balance between myocardial-stimulating and vasoconstricting hormones and between myocardial-relaxing and vasodilating hormones.

The heart contains many neurohumoral receptors (alpha-1, beta-1, beta-2, beta-3, angiotensin II type 1 [AT1] and type 2 [AT2], muscarinic, endothelin, serotonin, adenosine, cytokine, natriuretic peptides); the roles of all of these receptors are not fully defined. In patients with heart failure, beta-1 receptors (which constitute 70% of cardiac beta receptors) are downregulated, probably in response to intense sympathetic activation. The result of downregulation is impaired myocyte contractility and increased heart rate.

Plasma norepinephrine levels are increased, largely reflecting sympathetic nerve stimulation as plasma epinephrine levels are not increased. Detrimental effects include vasoconstriction with increased preload and afterload, direct myocardial damage including apoptosis, reduced renal blood flow, and activation of other neurohumoral systems, including the renin-angiotensin-aldosterone-vasopressin system.

Vasopressin is released in response to a fall in blood pressure via various neurohormonal stimuli. Increased vasopressin decreases renal excretion of free water, possibly contributing to hyponatremia in heart failure. Vasopressin levels in patients with HF and normal blood pressure vary.

Atrial natriuretic peptide is released in response to increased atrial volume and pressure; brain (B-type) natriuretic peptide (BNP) is released from the ventricle in response to ventricular stretching. These peptides enhance renal excretion of sodium; however, in patients with HF, the effect is blunted by decreased renal perfusion pressure, receptor downregulation, and perhaps enhanced enzymatic degradation. In addition, elevated levels of natriuretic peptides exert a counter-regulatory effect on the renin-angiotensin-aldosterone system and catecholamine stimulation.

Because endothelial dysfunction occurs in HF, fewer endogenous vasodilators (eg, nitric oxide, prostaglandins) are produced, and more endogenous vasoconstrictors (eg, endothelin) are produced, thus increasing afterload.

The failing heart and other organs produce tumor necrosis factor (TNF) alpha. This cytokine increases catabolism and is possibly responsible for cardiac cachexia (loss of lean tissue ≥ 10%), which may accompany severely symptomatic HF, and for other detrimental changes. The failing heart also undergoes metabolic changes with increased free fatty acid utilization and decreased glucose utilization; these changes may become therapeutic targets.

Age-related changes in the heart and cardiovascular system lower the threshold for expression of heart failure. Interstitial collagen within the myocardium increases, the myocardium stiffens, and myocardial relaxation is prolonged. These changes lead to a significant reduction in diastolic left ventricular function, even in healthy older adults. Modest decline in systolic function also occurs with aging. An age-related decrease in myocardial and vascular responsiveness to beta-adrenergic stimulation further impairs the ability of the cardiovascular system to respond to increased work demands.

As a result of these changes, peak exercise capacity decreases significantly (approximately 8%/decade after age 30 years), and cardiac output at peak exercise decreases more modestly. This decline can be slowed by regular physical exercise. Thus, older patients are more prone than are younger ones to develop HF symptoms in response to the stress of systemic disorders or relatively modest cardiovascular insults. Stressors include infections (particularly pneumonia), hyperthyroidism, anemia, hypertension, myocardial ischemia, hypoxia, hyperthermia, renal failure, perioperative IV fluid loads, nonadherence to medication regimens or to low-salt diets, and use of certain medications (particularly nonsteroidal anti-inflammatory drugs [NSAIDs]).