cardiovascular disorders
Heart Failure (HF)
Pathophysiology of Heart Failure
In heart failure, the heart may not provide tissues with adequate blood for metabolic needs, and cardiac-related elevation of pulmonary or systemic venous pressures may result in organ congestion. This condition can result from abnormalities of systolic or diastolic function or, commonly, both. Although a primary abnormality can be a change in cardiomyocyte function, there are also changes in collagen turnover of the extracellular matrix. Cardiac structural defects (eg, congenital defects, valvular disorders), rhythm abnormalities (including persistently high heart rate), and high metabolic demands (eg, due to thyrotoxicosis) also can cause HF. In HFrEF (also called systolic HF), 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 functions, and contractile element interaction occur, with abnormalities in intracellular calcium modulation and cAMP production. Predominant systolic dysfunction is common in heat failure due to Acute Myocardial Infarction (MI) , myocarditis, and 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 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 CO (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, Overview of Cardiac Valvular Disorders , or Diastolic dysfunction has increasingly been recognized as a cause of HF. Estimates vary, but about 50% of patients with heart failure have HFpEF; the prevalence increases with age and in patients with diabetes. It is now known that HFpEF is a complex, heterogenous, multiorgan, systemic syndrome, often with multiple concomitant pathophysiologies. Current data suggest that multiple comorbidities (eg, Obesity , International societies have put forth the concept of HF with mildly reduced ejection fraction (HFmrEF), in which patients have 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. In heart failure that involves left ventricular dysfunction, CO decreases and pulmonary venous pressure increases. When pulmonary capillary pressure exceeds the oncotic pressure of plasma proteins (about 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 (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, 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 In heart failure that involves right ventricular dysfunction, 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, PT (prothrombin time), and hepatic enzymes (particularly alkaline phosphatase and gamma-glutamyl transpeptidase [GGT]). The impaired liver breaks down lessaldosterone, further contributing to fluid accumulation. Chronic venous congestion in the viscera can cause anorexia, malabsorption of nutrients and drugs, protein-losing enteropathy (characterized by diarrhea and marked hypoalbuminemia), chronic gastrointestinal blood loss, and rarely ischemic bowel infarction. In HFrEF, left ventricular systolic function is grossly impaired; therefore, a higher preload is required to maintain CO. 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 CO, oxygen delivery to the tissues is maintained by increasing oxygen extraction from the blood and sometimes shifting the oxyhemoglobin dissociation curve (see figure) to the right to favor oxygen release. Reduced CO 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 both result in a decrease in GFR (glomerular filtration rate), 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 (RAAS), 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 IIworsens 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 IIincreasesnorepinephrinerelease, stimulates release ofvasopressin, and triggers apoptosis.Angiotensin IImay be involved in vascular and myocardial hypertrophy, thus contributing to the remodeling of the heart and peripheral vasculature, potentially worsening HF. Aldosterone can be synthesized in the heart and vasculature independently ofangiotensin II(perhaps mediated bycorticotropin, 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 drugs 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, but 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 IItype 1 [AT1] and type 2 [AT2], muscarinic, endothelin, serotonin,adenosine, cytokine, natriuretic peptides); the roles of all of these receptors are not yet 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. Plasmanorepinephrinelevels are increased, largely reflecting sympathetic nerve stimulation as plasmaepinephrinelevels 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-vasopressinsystem. Vasopressinis released in response to a fall in blood pressure via various neurohormonal stimuli. Increasedvasopressindecreases renal excretion of free water, possibly contributing to hyponatremia in heart failure.Vasopressinlevels 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, but 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 people. 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 (about 8%/decade after age 30), and CO 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 drug regimens or to low-salt diets, and use of certain drugs (particularly NSAIDs [nonsteroidal anti-inflammatory drugs]). 