INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Heart failure is the pathophysiologic state in which the heart, via an abnormality of cardiac function (detectable or not), fails to pump blood at a rate commensurate with the requirements of the metabolizing tissues and/or pumps only from an abnormally elevated diastolic filling pressure.

Heart failure may be caused by myocardial failure but may also occur in the presence of near-normal cardiac function under conditions of high demand. Heart failure always causes circulatory failure, but the converse is not necessarily the case because various noncardiac conditions (eg, hypovolemic shock, septic shock) can produce circulatory failure in the presence of normal, modestly impaired, or even supranormal cardiac function.

In terms of incidence, prevalence, morbidity, and mortality, the epidemiologic magnitude of congestive heart failure (CHF) is staggering. In the United States, the estimated annual cost of heart failure is $60 billion; the estimated annual cost of inpatient care of patients with CHF is $23 billion. Approximately 1 million US hospital admissions per year are attributable to a primary diagnosis of acutely decompensated heart failure. For additional resources, please visit Heart Failure Resource Center.

Pathophysiology

Inadequate adaptation of the cardiac myocytes to increased wall stress in order to maintain adequate cardiac output following myocardial injury (whether of acute onset or over several months to years, whether a primary disturbance in myocardial contractility or an excessive hemodynamic burden placed on the ventricle, or both), is the inciting event in CHF.

Most important among these adaptations are the (1) Frank-Starling mechanism, in which an increased preload helps to sustain cardiac performance; (2) myocardial hypertrophy with or without cardiac chamber dilatation, in which the mass of contractile tissue is augmented; and (3) activation of neurohumoral systems, especially the release of norepinephrine (NE) by adrenergic cardiac nerves, which augments myocardial contractility and the activation of the renin-angiotensin-aldosterone system (RAAS) and other neurohumoral adjustments that act to maintain arterial pressure and perfusion of vital organs. In acute heart failure, the finite adaptive mechanisms that may be adequate to maintain the overall contractile performance of the heart at relatively normal levels become maladaptive when trying to sustain adequate cardiac performance.

The primary myocardial response to chronic increased wall stress includes myocyte hypertrophy and remodeling, usually of the eccentric type. The reduction of cardiac output following myocardial injury sets into motion a cascade of hemodynamic and neurohormonal derangements that provoke activation of neuroendocrine systems, most notably the above-mentioned adrenergic systems and RAAS. The release of epinephrine (E) and NE, along with the vasoactive substances endothelin-1 (ET-1) and vasopressin (V), causes vasoconstriction, which increases afterload, and, via an increase in cyclic adenosine monophosphate (cAMP), causes an increase in cytosolic calcium entry. The increased calcium entry into the myocytes augments myocardial contractility and impairs myocardial relaxation (lusitropy).

The calcium overload may also induce arrhythmias and lead to sudden death. The increase in afterload and myocardial contractility (known as inotropy) and the impairment in myocardial lusitropy lead to an increase in myocardial energy expenditure and a further decrease in cardiac output. The increase in myocardial energy expenditure leads to myocardial cell death, resulting in heart failure and further reduction in cardiac output, thus starting an accelerating cycle of further increased neurohumoral stimulation and further adverse hemodynamic and myocardial responses as described above.

In addition, the activation of the RAAS leads to salt and water retention, resulting in increased preload and further increases in myocardial energy expenditure. Increases in renin, mediated by decreased stretch of the glomerular afferent arteriole, reduced delivery of chloride to the macula densa, and increased beta1-adrenergic activity as a response to decreased cardiac output, results in an increase in angiotensin II (Ang II) levels and, in turn, aldosterone levels. This results in stimulation of release of aldosterone. Ang II, along with ET-1, is crucial in maintaining effective intravascular homeostasis mediated by vasoconstriction and aldosterone-induced salt and water retention.

Some evidence indicates that local cardiac Ang II production, with a resultant decrease in lusitropy, increase in inotropy, and increase in afterload, leads to increased myocardial energy expenditure. In this fashion, Ang II has similar actions to NE in CHF.

Ang II also mediates myocardial cellular hypertrophy and may promote progressive loss of myocardial function. The neurohumoral factors above lead to myocyte hypertrophy and interstitial fibrosis, resulting in increased myocardial volume and increased myocardial mass, as well as myocyte loss. The increase in myocardial volume results in myocyte slippage, which also results in further increases in myocardial volume and mass. These features, namely the increased myocardial volume and mass, along with myocyte loss, are the hallmark of myocardial remodeling. This remodeling process leads to early adaptive mechanisms, such as augmentation of stroke volume (Starling mechanism) and decreased wall stress (Laplace mechanism), and later, maladaptive mechanisms such as increased myocardial oxygen demand, myocardial ischemia, impaired contractility, and arrhythmogenesis.

As heart failure advances and/or becomes progressively decompensated, there is a relative decline in the counterregulatory effects of endogenous vasodilators, including nitric oxide (NO), prostaglandins (PGs), bradykinin (BK), atrial natriuretic peptide (ANP), and B-type natriuretic peptide (BNP). This occurs simultaneously with the increase in vasoconstrictor substances from the RAAS and adrenergic systems. This fosters further increases in vasoconstriction and thus preload and afterload, leading to cellular proliferation, adverse myocardial remodeling, and antinatriuresis with total body fluid excess and worsening CHF symptoms.

Both systolic and diastolic heart failure result in a decrease in stroke volume. This leads to activation of peripheral and central baroreflexes and chemoreflexes that are capable of eliciting marked increases in sympathetic nerve traffic. While there are commonalities in the neurohormonal responses to decreased stroke volume, the neurohormone-mediated events that follow have been most clearly elucidated for individuals with systolic heart failure. The ensuing elevation in plasma NE directly correlates with the degree of cardiac dysfunction and has significant prognostic implications. NE, while being directly toxic to cardiac myocytes, is also responsible for a variety of signal-transduction abnormalities, such as down-regulation of beta1-adrenergic receptors, uncoupling of beta2-adrenergic receptors, and increased activity of inhibitory G-protein. Changes in beta1-adrenergic receptors result in overexpression and promote myocardial hypertrophy.

ANP and BNP are endogenously generated peptides activated in response to atrial and ventricular volume/pressure expansion. ANP and BNP are released from the atria and ventricles, respectively, and both promote vasodilation and natriuresis. Their hemodynamic effects are mediated by decreases in ventricular filling pressures, owing to reductions in cardiac preload and afterload. BNP, in particular, produces selective afferent arteriolar vasodilation and inhibits sodium reabsorption in the proximal convoluted tubule. BNP inhibits renin and aldosterone release and, possibly, adrenergic activation as well. Both ANP and BNP are elevated in chronic heart failure. BNP, in particular, has potentially important diagnostic, therapeutic, and prognostic implications.

Other vasoactive systems that play a role in the pathogenesis of CHF include the ET receptor system, adenosine receptor system, V, and tumor necrosis factor-alpha (TNF-alpha). ET, a substance produced by the vascular endothelium, may contribute to the regulation of myocardial function, vascular tone, and peripheral resistance in CHF. Elevated levels of ET-1 closely correlate with the severity of heart failure. ET-1 is a potent vasoconstrictor and has exaggerated vasoconstrictor effects in the renal vasculature, reducing renal plasma blood flow, glomerular filtration rate (GFR), and sodium excretion. TNF-alpha has been implicated in response to various infectious and inflammatory conditions. Elevations in TNF-alpha levels have been consistently observed in CHF and seem to correlate with the degree of myocardial dysfunction. Experimental studies suggest that local production of TNF-alpha may have toxic effects on the myocardium, thus worsening myocardial systolic and diastolic function.

Thus, in individuals with systolic dysfunction, the neurohormonal responses to decreased stroke volume result in temporary improvement in systolic blood pressure and tissue perfusion. However, in all circumstances, the existing data support the notion that these neurohormonal responses accelerate the downward spiral of myocardial dysfunction in the long term.

In diastolic heart failure, the same pathophysiologic processes to decreased cardiac output that occur in systolic heart failure also occur, but they do so in response to a different set of hemodynamic and circulatory environmental factors that depress cardiac output.

In diastolic heart failure, altered relaxation of the ventricle (due to delayed calcium uptake by the myocyte sarcoplasmic reticulum and delayed calcium efflux from the myocyte) occurs in response to an increase in ventricular afterload (pressure overload). The impaired relaxation of the ventricle leads to impaired diastolic filling of the left ventricle (LV).

An increase in LV chamber stiffness occurs secondary to any one of the following 3 mechanisms or to a combination thereof: (1) a rise in filling pressure (ie, movement of the ventricle up along its pressure-volume curve to a steeper portion, as may occur in conditions such as volume overload secondary to acute valvular regurgitation or acute LV failure due to myocarditis); (2) a shift to a steeper ventricular pressure-volume curve, occurring most commonly as a result of not only increased ventricular mass and wall thickness, as observed in (a) aortic stenosis and (b) long-standing hypertension, but also in (c) infiltrative disorders such as amyloidosis, (d) endomyocardial fibrosis, and (e) myocardial ischemia; and (3) a parallel upward displacement of the diastolic pressure-volume curve, generally referred to as a decrease in ventricular distensibility, usually caused by extrinsic compression of the ventricles.

Whereas volume overload, as observed in chronic aortic and/or mitral valvular regurgitant disease, shifts the entire diastolic pressure-volume curve to the right, indicating increased chamber stiffness, pressure overload that leads to concentric LV hypertrophy (as occurs in aortic stenosis, hypertension, and hypertrophic cardiomyopathy) shifts the diastolic pressure-volume curve to the left along its volume axis so that at any diastolic volume ventricular diastolic pressure is abnormally elevated, although chamber stiffness may or may not be altered. Increases in diastolic pressure lead to increased myocardial energy expenditure, remodeling of the ventricle, increased myocardial oxygen demand, myocardial ischemia, and eventual progression of the maladaptive mechanisms of the heart that lead to decompensated heart failure.

Frequency

United States

CHF is the fastest-growing clinical cardiac disease entity in the United States, affecting 2% of the population. Nearly 1 million hospital admissions for acute decompensated CHF occur in the United States yearly, almost double the number seen 15 years ago. The rehospitalization rates during the 6 months following discharge are as much as 50%. Nearly 2% of all hospital admissions in the United States are for decompensated CHF, and heart failure is the most frequent cause of hospitalization in patients older than 65 years. The average duration of hospitalization is about 6 days. An estimated $23 billion are spent on inpatient management of CHF every year, and another $40 billion are spent in the outpatient setting on patients with compensated or mildly decompensated heart failure every year. Despite aggressive therapies, hospital admissions for CHF continue to increase, reflecting the prevalence of this malady.

International

CHF is a worldwide problem, but few accurate financial data are available. As discussed elsewhere, the most common cause of CHF in industrialized countries is ischemic cardiomyopathy. Other causes, including Chagas disease, assume a more important role in underdeveloped countries than in the United States.

Mortality/Morbidity

Despite recent advances in the management of patients with heart failure, morbidity and mortality rates remain high, with an estimated 5-year mortality rate of 50%.

• Assigning figures for inpatient mortality rates is difficult because the causes and the severity of heart failure vary considerably. The most recent estimates of inpatient mortality rates indicate that death occurs in up to 5-20% of patients.
• Hypoxemia that occurs in decompensated CHF, which may be severe, may result in myocardial ischemia or infarction.
• Respiratory failure with hypercapnic respiratory acidosis may occur in severe decompensated CHF, requiring mechanical ventilation if medical therapy is delayed or unsuccessful. Endotracheal intubation and mechanical ventilation are associated with their own risks, including aspiration (during the intubation process), mucosal trauma (more common with nasotracheal intubation than orotracheal intubation), and barotrauma.
• In patients with CHF, the risk of cardiac sudden death from ventricular tachycardia (VT) or ventricular fibrillation is considerable, and the degree of risk is correlated with the degree of decompensation and the degree of LV dysfunction. Recognition of the role of ventricular arrhythmias and advances in their treatment have resulted in decreased mortality rates in individuals with CHF.
• Progressive renal insufficiency due to decreased renal blood flow and GFR are common in patients with long-standing CHF.
• Liver dysfunction due to passive hepatic congestion is particularly common in patients with right-sided CHF with elevated right ventricular (RV) pressure that is transmitted back into the portal vein.
  • Mild jaundice, mild abnormalities in coagulation, and derangements in liver metabolism of medications, some of which are used in the treatment of heart failure, may result from this liver dysfunction.
  • Toxic levels of medications such as warfarin, theophylline, phenytoin, and digoxin can result from delayed liver metabolic clearance of these drugs in the presence of decompensated CHF, thereby leading to potentially fatal bleeding, cardiac dysrhythmias, and neurologic abnormalities.

Race

The incidence and prevalence of CHF are higher in African Americans, Hispanic persons, Native Americans, and recent immigrants from nonindustrialized nations, Russia, and the former Soviet republics.

• The higher prevalence of CHF in African Americans, Hispanic persons, and Native Americans is directly related to the higher incidence and prevalence of hypertension and diabetes. This problem is particularly exacerbated by a lack of access to health care and to substandard preventive health care of the most indigent of these and other groups; many persons within these groups are without adequate health insurance coverage.
• The higher incidence and prevalence of CHF among recent immigrants from nonindustrialized nations is largely due to a lack of prior preventive health care and to a lack of treatment or to substandard treatment for common conditions such as hypertension, diabetes, rheumatic fever, and ischemic heart disease.

Sex

Men and women have equivalent incidence and prevalence of CHF. CHF in women tends to occur later in life compared to men.

Age

The prevalence of CHF increases with age, being most common in individuals older than 65 years. In the United States, CHF is the most common reason for hospital admission in patients older than 65 years. Nonetheless, CHF can occur at any age, depending on the cause.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Breathlessness, a cardinal sign of LV failure, may manifest with progressively increasing severity as (1) exertional dyspnea, (2) orthopnea, (3) paroxysmal nocturnal dyspnea, (4) dyspnea at rest, and (5) acute pulmonary edema. The New York Heart Association (NYHA) Classification of Heart Failure (see Staging), which varies slightly from the above categorization of CHF symptoms, is widely used in practice and in clinical studies to quantify clinical assessment of CHF.

• Exertional dyspnea
• • The principal difference between exertional dyspnea in subjects who are healthy and exertional dyspnea in patients with heart failure is the degree of activity necessary to induce the symptom. As heart failure first develops, exertional dyspnea may simply appear to be an aggravation of the breathlessness that occurs in healthy persons during activity.
  • As LV failure advances, the intensity of exercise resulting in breathlessness progressively declines; however, subjective exercise capacity and objective measures of LV performance at rest in patients with heart failure are not closely correlated. Exertional dyspnea, in fact, may be absent in sedentary patients.
• Orthopnea
• • This early symptom of CHF may be defined as dyspnea that develops in the recumbent position and is relieved with elevation of the head with pillows. As in the case of exertional dyspnea, the change in the number of pillows required is important.
  • In the recumbent position, decreased pooling of blood in the lower extremities and abdomen occurs. Blood is displaced from the extrathoracic to the thoracic compartment. The failing LV, operating on the flat portion of the Starling curve, cannot accept and pump out the extra volume of blood delivered to it without dilating. As a result, pulmonary venous and capillary pressures rise further, causing interstitial pulmonary edema, reduced pulmonary compliance, increased airway resistance, and dyspnea.
  • In contrast to paroxysmal nocturnal dyspnea, orthopnea occurs rapidly, often within a minute or two of recumbency, and develops when the patient is awake. Orthopnea may occur in any condition in which the vital capacity is low. Marked ascites, whatever its etiology, is an important cause of orthopnea. In advanced LV failure, orthopnea may be so severe that the patient cannot lie down and must sleep sitting up in a chair or slumped over a table.
  • Cough, particularly during recumbency, may be an "orthopnea equivalent." This nonproductive cough may be caused by pulmonary congestion and is relieved by treatments for heart failure.
• Paroxysmal nocturnal dyspnea
• • Attacks of paroxysmal nocturnal dyspnea usually occur at night. This symptom of CHF is defined by a sudden awakening of the patient, after a couple hours of sleep, with a feeling of severe anxiety, breathlessness, and suffocation. The patient may bolt upright in bed and gasp for breath. Bronchospasm increases ventilatory difficulty and the work of breathing and is a common complicating factor of paroxysmal nocturnal dyspnea. On chest auscultation, the bronchospasm associated with a CHF exacerbation can be difficult to distinguish from an acute asthma exacerbation, although other clues from the cardiovascular examination should lead the examiner to the correct diagnosis. Both types of bronchospasm can be present in the same individual.
  • In contrast to orthopnea, which may be relieved by immediately sitting up in bed, attacks of paroxysmal nocturnal dyspnea may require 30 minutes or longer in this position for relief. Episodes of this may be so frightening that the patient may be afraid to resume sleeping, even after the symptoms have abated.
• Dyspnea at rest - Mechanisms of dyspnea in heart failure
  • Decreased pulmonary function
  • Decreased compliance
  • Increased airway resistance
  • Increased ventilatory drive
  • Hypoxemia due to increased pulmonary capillary wedge pressure (PCWP)
  • Ventilation/perfusion (V/Q) mismatching due to increased PCWP and cardiac output
  • Increased carbon dioxide production
  • Respiratory muscle dysfunction
  • Decreased respiratory muscle strength
  • Decreased endurance
  • Ischemia
• Fatigue and weakness
• • These symptoms are often accompanied by a feeling of heaviness in the limbs.
  • Fatigue and weakness are generally related to poor perfusion of the skeletal muscles in patients with a lowered cardiac output. Although generally a constant feature of advanced CHF, episodic fatigue and weakness are common in earlier stages.
• Nocturia
• • Nocturia may occur relatively early in the course of heart failure. Recumbency reduces the deficit in cardiac output in relation to oxygen demand; renal vasoconstriction diminishes and urine formation increases. This may be troublesome for the patient with heart failure because it may prevent the patient from obtaining much-needed rest.
  • Oliguria is a late finding in CHF and is found in patients with markedly reduced cardiac output from severely reduced LV function.
• Cerebral symptoms: Confusion, memory impairment, anxiety, headaches, insomnia, bad dreams or nightmares, and rarely, psychosis with disorientation, delirium, or hallucinations may occur in elderly patients with advanced heart failure, particularly in those with cerebrovascular atherosclerosis.
• Predominant right-sided heart failure
• • Ascites, congestive hepatomegaly, and anasarca due to elevated right-sided heart pressures transmitted backward into the portal vein circulation may result in increased abdominal girth and epigastric and right upper quadrant (RUQ) abdominal pain. Other gastrointestinal symptoms, owing to congestion of the hepatic and gastrointestinal venous circulation, include anorexia, bloating, nausea, and constipation. In preterminal heart failure, inadequate bowel perfusion can cause abdominal pain, distention, and bloody stools. Distinguishing right-sided CHF from hepatic failure is often clinically difficult.
  • Dyspnea, prominent in LV failure, becomes less prominent in isolated right-sided heart failure because of the absence of pulmonary congestion. On the other hand, when cardiac output becomes markedly reduced in patients with terminal right-sided heart failure (as may occur in isolated RV infarction and in the late stages of primary pulmonary hypertension and pulmonary thromboembolic disease), severe dyspnea may occur as a consequence of the reduced cardiac output, poor perfusion of respiratory muscles, hypoxemia, and metabolic acidosis.

Physical

• General appearance
  • Patients with mild heart failure appear to be in no distress after a few minutes of rest, but they may be obviously dyspneic during and immediately after moderate activity. Patients with LV failure may be dyspneic when lying flat without elevation of the head for more than a few minutes. Those with severe heart failure appear anxious and may exhibit signs of air hunger in this position.
  • Patients with recent onset of heart failure are generally well nourished, but those with chronic severe heart failure are often malnourished and sometimes even cachectic.
  • Chronic marked elevation of systemic venous pressure may produce exophthalmos and severe tricuspid regurgitation and may lead to visible pulsation of the eyes and of the neck veins.
  • Central cyanosis, icterus, and malar flush may be evident in patients with severe heart failure.
  • In mild or moderate heart failure, stroke volume is normal at rest; in severe heart failure, it is reduced, as reflected by a diminished pulse pressure and a dusky discoloration of the skin.
  • With very severe heart failure, particularly if cardiac output has declined acutely, systolic arterial pressure may be reduced. The pulse may be weak, rapid, and thready; the proportional pulse pressure (pulse pressure/systolic pressure) may be markedly reduced. The proportional pulse pressure correlates reasonably well with cardiac output. In one study, when pulse pressure was less than 25%, it usually reflected a cardiac index of less than 2.2 L/min/m².
• Evidence of increased adrenergic activity
  • Increased adrenergic activity is manifested by tachycardia, diaphoresis, pallor, peripheral cyanosis with pallor and coldness of the extremities, and obvious distention of the peripheral veins secondary to venoconstriction.
  • Diastolic arterial pressure may be slightly elevated.
• Pulmonary rales
  • Rales heard over the lung bases are characteristic of CHF of at least moderate severity. With acute pulmonary edema, rales are frequently accompanied by wheezing and expectoration of frothy, blood-tinged sputum.
  • The absence of rales, however, certainly does not exclude elevation of pulmonary capillary pressure due to LV failure.
• Systemic venous hypertension: This is manifested by jugular venous distention. Normally, jugular venous pressure declines with respiration; however, it increases in patients with heart failure, a finding known as the Kussmaul sign (also found in constrictive pericarditis).
• Hepatojugular reflux: This is found in patients with right-sided heart failure and is helpful in differentiating hepatic enlargement due to heart failure from that caused by other conditions.
• Edema
  • Although a cardinal manifestation of CHF, edema does not correlate well with the level of systemic venous pressure. In patients with chronic LV failure and low cardiac output, extracellular fluid volume may be sufficiently expanded to cause edema in the presence of only slight elevations in systemic venous pressure.
  • Usually, a substantial gain of extracellular fluid volume (ie, a minimum of 5 L in adults) must occur before peripheral edema is manifested.
  • Edema, in the absence of dyspnea or other signs of LV or RV failure, is not solely indicative of heart failure and can be observed in many other conditions, including chronic venous insufficiency, nephrotic syndrome, or other syndromes of hypoproteinemia or osmotic imbalance.
• Hepatomegaly
  • Hepatomegaly is prominent in patients with chronic right-sided heart failure, but it may occur rapidly in acute heart failure.
  • When occurring acutely, the liver is usually tender.
  • In patients with considerable tricuspid regurgitation, a prominent systolic pulsation of the liver, attributable to an enlarged right atrial V wave, is often noted. A presystolic pulsation of the liver, attributable to an enlarged right atrial A wave, can occur in tricuspid stenosis, constrictive pericarditis, restrictive cardiomyopathy involving the RV, and pulmonary hypertension (primary or secondary).
• Hydrothorax (pleural effusion)
  • Hydrothorax is most commonly observed in patients with hypertension involving both systemic and pulmonary systems. Hydrothorax is usually bilateral, although when unilateral, it is usually confined to the right side of the chest.
  • When hydrothorax develops, dyspnea usually intensifies because of further reductions in vital capacity.
• Ascites
  • This finding occurs in patients with increased pressure in the hepatic veins and in the veins draining into the peritoneum.
  • Ascites usually reflects long-standing systemic venous hypertension.
• Protodiastolic (S₃) gallop: This is the earliest cardiac physical finding in decompensated heart failure in the absence of severe mitral or tricuspid regurgitation or left-to-right shunts.
• Cardiomegaly
  • A nonspecific finding, cardiomegaly nonetheless occurs in most patients with chronic heart failure.
  • Notable exceptions include heart failure from acute myocardial infarction, constrictive pericarditis, restrictive cardiomyopathy, valve or chordae tendineae rupture, or heart failure due to tachyarrhythmias or bradyarrhythmias.
• Pulsus alternans
  • Pulsus alternans occurs most commonly in heart failure due to increased resistance to LV ejection, as occurs in hypertension, aortic stenosis, coronary atherosclerosis, and dilated cardiomyopathy.
  • It is usually associated with an S₃ gallop, signifies advanced myocardial disease, and often disappears with treatment of heart failure.
• Accentuation of P₂ heart sound, S₃ gallop, and systolic murmurs
  • This accentuation is a cardinal sign of increased pulmonary artery pressure. It disappears or improves after treatment of heart failure.
  • Mitral and tricuspid regurgitation murmurs are often present in patients with decompensated heart failure because of ventricular dilatation. These murmurs often disappear or diminish when compensation is restored. Note that correlation between the intensity of the murmur of mitral regurgitation and its significance in patients with CHF is poor. Severe mitral regurgitation may be accompanied by an unimpressively soft murmur.
  • The presence of an S₃ gallop in adults is important, pathologic, and often the most apparent finding on cardiac auscultation in patients with significant CHF.
• Cardiac cachexia
  • Cardiac cachexia is found in long-standing heart failure, particularly of the RV, because of anorexia from hepatic and intestinal congestion and sometimes because of digitalis toxicity. Occasionally, impaired intestinal absorption of fat and (rarely) protein-losing enteropathy occur.
  • Patients with heart failure may also exhibit increased total metabolism secondary to augmentation of myocardial oxygen consumption, excessive work of breathing, low-grade fever, and elevated levels of circulating TNF.
• Fever: Fever may be present in severe decompensated heart failure because of cutaneous vasoconstriction and impairment of heat loss.

Causes

From a clinical standpoint, it is useful to classify the causes of heart failure into 3 broad categories: (1) underlying causes, comprising structural abnormalities (congenital or acquired) that affect the peripheral and coronary arterial circulation, pericardium, myocardium, or cardiac valves, thus leading to the increased hemodynamic burden or myocardial or coronary insufficiency responsible for heart failure; (2) fundamental causes, comprising the biochemical and physiological mechanisms, through which either an increased hemodynamic burden or a reduction in oxygen delivery to the myocardium results in impairment of myocardial contraction; and (3) precipitating causes, including the specific causes or incidents that precipitate heart failure in most episodes of heart failure.

Note that most patients who present with significant heart failure do so because of an inability to provide adequate cardiac output in that setting. This is often a combination of the causes listed above in the setting of an abnormal myocardium. The list of causes responsible for presentation of a patient with a CHF exacerbation is very long, and it is important to search for the proximate cause in order to optimize therapeutic interventions.

Overt heart failure may be precipitated by progression of the underlying heart disease. A previously stable compensated patient may develop heart failure that is clinically apparent for the first time when the intrinsic process has advanced to a critical point, such as with further narrowing of a stenotic aortic valve or mitral valve. Alternatively, decompensation may occur as a result of failure or exhaustion of the compensatory mechanisms but without any change in the load on the heart in patients with persistent severe pressure or volume overload.

• Precipitating causes of heart failure
• • Inappropriate reduction of therapy: The most common cause of decompensation in a previously compensated patient with heart failure is inappropriate reduction in the intensity of treatment, whether dietary sodium restriction, physical activity reduction, drug regimen reduction, or, most commonly, a combination of these measures.
  • Arrhythmias
    • Tachyarrhythmias, most commonly atrial fibrillation
    • Marked bradycardia
    • Atrioventricular dissociation
    • Abnormal intraventricular conduction
  • Systemic infection or development of unrelated illness
    • Systemic infection precipitates heart failure by increasing total metabolism as a consequence of fever, discomfort, and cough, which increases the hemodynamic burden on the heart.
    • Septic shock, in particular, can precipitate heart failure by the release of endotoxin-induced factors that can depress myocardial contractility.
  • Pulmonary embolism: Patients with CHF, particularly when confined to bed, are at high risk of developing pulmonary emboli, which can increase the hemodynamic burden on the RV by further elevating RV systolic pressure, possibly causing fever, tachypnea, and tachycardia.
  • Physical, environmental, and emotional excesses: Intense, prolonged physical exertion or severe fatigue, such as may result from prolonged travel or emotional crises, or severe climate changes, either to a hot, humid environment or to a bitterly cold environment, are relatively common precipitants of cardiac decompensation.
  • Cardiac infection and inflammation
    • Myocarditis or infective endocarditis may directly impair myocardial function and exacerbate existing heart disease. The anemia, fever, and tachycardia that frequently accompany these processes are also deleterious.
    • In the case of infective endocarditis, the additional valvular damage that ensues may precipitate cardiac decompensation.
  • Excessive intake of water and/or sodium
  • Administration of cardiac depressants or drugs that cause salt retention
  • High-output states: Profound anemia, thyrotoxicosis, myxedema, Paget disease of bone, Albright syndrome, multiple myeloma, glomerulonephritis, cor pulmonale, polycythemia vera, obesity, carcinoid syndrome, pregnancy, or nutritional deficiencies (eg, thiamine deficiency, beriberi) can precipitate the clinical presentation of CHF because of increased myocardial oxygen consumption and demand beyond a critical level (ie, beyond the ability of the underlying myocardial oxygen supply to meet these demands). In particular, consider whether the patient has underlying coronary artery disease or valvular heart disease.
  • Development of a second form of heart disease
    • Patients with one form of underlying heart disease that may be well compensated can develop heart failure when a second form of heart disease ensues.
    • For example, a patient with chronic hypertension and asymptomatic LV hypertrophy may be asymptomatic until a myocardial infarction develops and precipitates heart failure.
• Underlying causes
• • Dominant systolic heart failure
    • Ischemic myocardial disease, coronary artery disease
    • Alcoholic cardiomyopathy
    • Diabetic cardiomyopathy
    • Cocaine cardiomyopathy
    • Drug-induced cardiomyopathy (eg, doxorubicin)
    • Idiopathic cardiomyopathy
    • Peripartum cardiomyopathy
    • Myocarditis
    • Preterminal valvular heart disease
    • Congenital heart disease with severe pulmonary hypertension
    • Terminal ventricular septal defect or atrial septal defect
  • Dominant diastolic heart failure
    • Hypertension
    • Severe aortic stenosis
    • Hypertrophic cardiomyopathy
    • Restrictive cardiomyopathy
    • Ischemic myocardial disease, coronary artery disease
  • Acute heart failure
    • Acute mitral or aortic regurgitation
    • Rupture of valve leaflets or supporting structures
    • Infective endocarditis with acute valve incompetence
    • Myocardial infarction
  • High-output heart failure
    • Anemia
    • Systemic arteriovenous fistulas
    • Hyperthyroidism
    • Beriberi heart disease
    • Paget disease of bone
    • Albright syndrome (fibrous dysplasia)
    • Multiple myeloma
    • Pregnancy
    • Glomerulonephritis
    • Cor pulmonale
    • Polycythemia vera
    • Carcinoid syndrome
    • Obesity
• Fundamental causes: See Pathophysiology.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

CHF should be differentiated from pulmonary edema associated with injury to the alveolar-capillary membrane caused by diverse etiologies (ie, noncardiogenic pulmonary edema, adult respiratory distress syndrome [ARDS]). Increased capillary permeability is observed in trauma, hemorrhagic shock, sepsis, respiratory infections, administration of various drugs, and ingestion of toxins such as heroin, cocaine, and toxic gases.

Several features may differentiate cardiogenic heart failure from noncardiogenic pulmonary edema. In CHF, a history of an acute cardiac event or that of progressive symptoms of heart failure is usually present. The physical examination reveals a low-flow state, S₃ gallop, elevated jugular venous distention, and crackles upon auscultation.

Patients with noncardiogenic pulmonary edema have a warm periphery, a bounding pulse, and an absence of S₃ gallop and jugular venous distention. Differentiation is often made based on PCWP measurements from invasive hemodynamic monitoring. PCWP is generally more than 18 mm Hg in CHF and is less than 18 mm Hg in noncardiogenic pulmonary edema, but superimposition of chronic pulmonary vascular disease can make this distinction more difficult to discern. With the advent of BNP level testing, reliably differentiating cardiac causes of pulmonary congestion from noncardiac causes is now possible.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC count: This study aids in the assessment of severe anemia, which may cause or aggravate heart failure. Leukocytosis may signal underlying infection. Otherwise, CBC counts are usually of little diagnostic help.
• Electrolytes
  • Serum electrolyte values are generally within reference ranges in patients with mild-to-moderate heart failure before treatment. However, in severe heart failure, prolonged, rigid sodium restriction, coupled with intensive diuretic therapy and the inability to excrete water, may lead to dilutional hyponatremia, which occurs because of a substantial expansion of extracellular fluid volume and a normal or increased level of total body sodium.
  • Potassium levels are usually within reference ranges, although the prolonged administration of diuretics may result in hypokalemia. Hyperkalemia may occur in patients with severe heart failure who show marked reductions in GFR and inadequate delivery of sodium to the distal tubular sodium-potassium exchange sites of the kidney, particularly if they are receiving potassium-sparing diuretics and/or ACE inhibitors.
• Renal function tests
  • BUN and creatinine levels can be within reference ranges in patients with mild-to-moderate heart failure and normal renal function, although elevated BUN and BUN/creatinine ratios may also be present.
  • Patients with severe heart failure, particularly those on large doses of diuretics for long periods, may have elevated BUN and creatinine levels indicative of renal insufficiency because of chronic reductions of renal blood flow from reduced cardiac output. Diuretics may aggravate renal insufficiency when these patients are overmedicated with diuretics and become volume depleted.
• Liver function tests
  • Congestive hepatomegaly and cardiac cirrhosis are often associated with impaired hepatic function, which is characterized by abnormal values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and other liver enzymes.
  • Hyperbilirubinemia, secondary to an increase in both the directly and indirectly reacting bilirubin, is common. In severe cases of acute RV or LV failure, frank jaundice may occur.
  • Acute hepatic venous congestion can result in severe jaundice, with a bilirubin level as high as 15-20 mg/dL, elevation of AST to more than 10 times the upper reference range limit, elevation of the serum alkaline phosphatase level, and prolongation of the prothrombin time. Both the clinical and the laboratory pictures may resemble viral hepatitis, but the impairment of hepatic function is rapidly resolved by successful treatment of heart failure. In patients with long-standing heart failure, albumin synthesis may be impaired, leading to hypoalbuminemia and intensifying the accumulation of fluid.
  • Fulminant hepatic failure is an uncommon, late, and sometimes terminal complication of cardiac cirrhosis.
• B-type natriuretic peptide
  • BNP is a 32-amino acid polypeptide containing a 17-amino acid ring structure common to all natriuretic peptides. Unlike ANP, whose major storage sites are in both the atria and ventricles, the major source of plasma BNP is the cardiac ventricles, suggesting that BNP may be a more sensitive and specific indicator of ventricular disorders than other natriuretic peptides. The release of BNP appears to be in direct proportion to ventricular volume expansion and pressure overload. BNP is an independent predictor of high LV end-diastolic pressure and is more useful than ANP or NE levels for assessing mortality risk in patients with CHF.
  • BNP levels rise with age. Mean BNP levels are 26.2 +/- 1.8 pg/mL in the group aged 55-64 years, 31.0 +/- 2.4 pg/mL for the group aged 65-74 years, and 63.7 +/- 6 pg/mL for the group aged 75 years and older. Additionally, women without CHF tend to have somewhat higher BNP levels than their male cohorts of the same age, with women 75 years and older having a mean BNP level of 76.5 +/- 3.5 pg/mL. Although the reason is unknown, aging women possibly have stiffer ventricles than age-matched men.
  • BNP levels correlate closely with the NYHA Classification of Heart Failure as well as the Goldman Activity Classification of Heart Failure.
  • BNP levels of more than 100 pg/mL have better than a 95% specificity and greater than a 98% sensitivity when comparing patients without CHF to all patients with CHF. Even BNP levels of more than 80 pg/mL have greater than a 93% specificity and 98% sensitivity in the diagnosis of heart failure. Furthermore, BNP levels, in several pilot studies, had a strong correlation with the severity of illness and were very reliable in differentiating CHF from pulmonary disease.
  • BNP levels also correlate highly with the change in PCWP pressure. It has been proposed that BNP levels may be a useful surrogate indicator of PCWP, although this is not common in clinical practice. BNP may help in tailoring treatment of the decompensated patient.
  • In a pilot study, BNP levels correlated highly with clinical outcomes. Patients with decreased BNP levels during their hospital stay, along with decreases in NYHA classification, had good outcomes, whereas patients whose hospital stay ended in death or readmission within 30 days of discharge had only minimal decreases of BNP levels or rising levels of BNP despite improvement or no change in their NYHA classification. In addition, the last measured BNP level was the single most reliable variable in predicting short-term outcomes in patients with CHF.

Imaging Studies

• Chest radiography
• • Chest radiographs are very helpful in distinguishing cardiogenic pulmonary edema (CPE) from other pulmonary causes of severe dyspnea.
  • Classic radiographic findings demonstrate cardiomegaly (in patients with underlying CHF) and alveolar edema with pleural effusions and bilateral infiltrates in a butterfly pattern. The other signs are loss of sharp definition of pulmonary vasculature, haziness of hilar shadows, and thickening of interlobular septa (Kerley B lines).
  • Chest radiographs in patients with abrupt onset are usually helpful but can be limited because a delay of as long as 12 hours is possible from the onset of dyspnea due to acute heart failure to the development of classic abnormal findings on x-ray films.
• Echocardiography
• • This is the easiest and least-expensive method of determining LV function, both systolic and diastolic. Echocardiography is also the easiest and least-expensive method of determining the presence of valvular heart disease, LV wall thickness, chamber sizes, presence of pericardial disease, and regional wall motion abnormalities that may suggest ischemic coronary artery disease as the cause. Echocardiography is very reliable in diagnosing the cause or causes of heart failure.
  • Transesophageal echocardiography is particularly useful in patients who are on mechanical ventilation or morbidly obese and in patients whose transthoracic echocardiogram was suboptimal in its imaging. It is an easy and safe alternative to conventional transthoracic echocardiography and provides superior imaging quality compared to conventional transthoracic echocardiography.
• Radionuclide multiple gated acquisition scan
• • Radionuclide multiple gated acquisition (MUGA) scan is a very reliable imaging technique for determining global heart function. LV ejection fraction, as determined by MUGA scanning, is often used for serial assessment of LV function because of its reliability.
  • However, this study is limited in its assessment of valvular heart disease and pericardial disease.

Other Tests

• Arterial blood gases
• • ABGs usually reveal mild hypoxemia in patients who have mild-to-moderate heart failure. ABGs are more accurate than pulse oximetry for measuring oxygen saturation. Patients with severe heart failure may have signs and symptoms ranging from severe hypoxemia, or even hypoxia, along with hypercapnia, to decreased vital capacity and poor ventilation.
  • ABGs help to assess the presence of hypercapnia, a potential early marker for impending respiratory failure. Hypoxemia and hypocapnia occur in stages 1 and 2 of pulmonary edema because of V/Q mismatch. In stage 3 of pulmonary edema, right-to-left intrapulmonary shunt develops secondary to alveolar flooding and further contributes to hypoxemia. In more severe cases, hypercapnia and respiratory acidosis are usually observed. The decision regarding intubation and use of mechanical ventilation is frequently based on the presence of hypercapnic respiratory failure with acidosis discovered on ABGs in patients with fulminant pulmonary edema.
• Pulse oximetry
• • Pulse oximetry is highly accurate at assessing the presence of hypoxemia and, therefore, the severity of heart failure.
  • Patients with mild-to-moderate heart failure show modest reductions in oxygen saturation, whereas patients with severe heart failure may have severe oxygen desaturation, even at rest.
  • Patients with mild-to-moderate heart failure may have normal oxygen saturations at rest, but they may exhibit marked reductions in oxygen saturations during physical exertion or recumbency, necessitating the use of continuous oxygen until compensation either returns oxygen saturation to normal during exertion and recumbency or on a permanent basis if oxygen desaturation during exertion and/or recumbency exist during compensated severe heart failure.
  • Pulse oximetry is useful for monitoring the patient's response to supplemental oxygen and other therapies.
• Electrocardiography
• • The presence of left atrial enlargement and LV hypertrophy is sensitive (although nonspecific) for chronic LV dysfunction.
  • ECG may suggest an acute tachyarrhythmia or bradyarrhythmia as the cause of heart failure.
  • ECG may aid in the diagnosis of acute myocardial ischemia or infarction as the cause of heart failure or may suggest the likelihood of prior myocardial infarction or presence of coronary artery disease as the cause of heart failure.
  • ECG is of limited help when an acute valvular abnormality or LV systolic dysfunction is considered to be the cause of heart failure; however, the presence of left bundle branch block (LBBB) on an ECG is a strong marker for diminished LV systolic function.

Procedures

• Right-sided heart catheterization
• • PCWP can be measured by using a pulmonary arterial catheter (Swan-Ganz catheter), and this helps differentiate cardiogenic causes of decompensated heart failure from noncardiogenic causes such as ARDS, which occurs secondary to injury to the alveolar-capillary membrane rather than to alteration in Starling forces. A PCWP exceeding 18 mm Hg in a patient not known to have chronically elevated left atrial pressure is indicative of cardiogenic decompensated heart failure. In patients with chronic pulmonary capillary hypertension, capillary wedge pressures exceeding 30 mm Hg are generally required to overcome the pumping capacity of the lymphatics and produce pulmonary edema.
  • Large V waves may sometimes be observed in the PCWP tracing with acute mitral regurgitation because large volumes of blood regurgitate into a poorly compliant left atrium. This raises pulmonary venous pressure and causes acute pulmonary edema. The pulmonary artery waveform appears falsely elevated because of the large V wave reflected from the left atrium through the compliant pulmonary vasculature. The Y descent of the waveform is quite rapid as the overdistended left atrium quickly empties. Patients with long-standing mitral regurgitation and left atrial enlargement may demonstrate much less impressive V waves even in the setting of very significant mitral regurgitation.
  • Cardiogenic shock is the result of a severe depression in myocardial function. Although many definitions for cardiogenic shock have been proposed, the following provides a useful guideline: Cardiogenic shock is present when systolic blood pressure is less than 80 mm Hg, the cardiac index is less than 1.8 L/min/m², and the PCWP is greater than 18 mm Hg. This form of shock can occur from a direct insult to the myocardium (eg, large acute myocardial infarction, severe cardiomyopathy) or from a mechanical problem that overwhelms the functional capacity of the myocardium (eg, acute severe mitral regurgitation, acute ventricular septal defect). The prognosis of patients with cardiogenic shock is poor, with in-hospital mortality rates of 50-90%.
• Left-sided heart catheterization and coronary angiography
• • Left-sided heart catheterization and coronary angiography should be undertaken when the etiology of heart failure cannot be determined by clinical or noninvasive imaging methods or when the etiology is likely to be due to acute myocardial ischemia or myocardial infarction. Coronary angiography is particularly helpful in patients with LV systolic dysfunction and known or suspected coronary artery disease in whom myocardial ischemia is thought to play a dominant role in the reduction of LV systolic function and the worsening of heart failure. As a general rule, most patients with clinically significant CHF should undergo cardiac catheterization to exclude the reversible causes listed above.
  • Specific rationales for right- and left-sided heart catheterization include the need to determine the etiologic significance and severity of mitral and/or aortic valvular disease in patients with heart failure in whom the cause-effect relationship of valvular heart disease with regard to heart failure is unclear. Furthermore, right- and left-sided heart catheterization should be performed in patients in whom constrictive pericarditis is considered a likely cause of heart failure.

Staging

• A classification of patients with heart disease based on the relation between symptoms and the amount of effort required to provoke them has been developed by the NYHA.
  • Class I: No limitations. Ordinary physical activity does not cause undue fatigue, dyspnea, or palpitations.
  • Class II: Slight limitation of physical activity. Such patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina.
  • Class III: Marked limitation of physical activity. Although patients are comfortable at rest, less-than-ordinary activity leads to fatigue, dyspnea, palpitations, or angina.
  • Class IV: Symptomatic at rest. Symptoms of CHF are present at rest; discomfort increases with any physical activity.
• The Goldman Activity Classification of Heart Failure is based on estimated metabolic cost of various activities, and classes correlate to NYHA classes.
  • Class I: Patients can perform to completion any activity up to 7 metabolic equivalents (METS).
  • Class II: Patients can perform to completion any activity up to 5 METS of activity but cannot perform to completion any activities equal to or more than 7 METS.
  • Class III: Patients can perform to completion any activity up to 2 METS of activity but cannot perform to completion any activities equal to or more than 5 METS.
  • Class IV: Patients cannot perform to completion activities equal to or more than 2 METS.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Medical therapy of heart failure focuses on 3 main goals: (1) preload reduction, (2) reduction of systemic vascular resistance (afterload reduction), and (3) inhibition of both the RAAS systems and vasoconstrictor neurohumoral factors produced by the sympathetic nervous system in patients with heart failure. The first 2 goals provide symptomatic relief. While reducing symptoms, inhibition of the RAAS and neurohumoral factors also results in significant reductions in morbidity and mortality rates.

Preload reduction results in decreased pulmonary capillary hydrostatic pressure and reduction of fluid transudation into the pulmonary interstitium and alveoli. Afterload reduction results in increased cardiac output and improved renal perfusion, which allows for diuresis in the patient with fluid overload. Inhibition of the RAAS and sympathetic nervous system results in favored vasodilation and reduction of neurohumoral vasoconstrictors, thereby increasing cardiac output and reducing blood volume and myocardial oxygen demand.

Patients with severe LV dysfunction or acute valvular disorders may present with hypotension. These patients may not tolerate medications to reduce their preload and afterload and may require inotropic support to maintain adequate blood pressure.

Patients who remain hypoxic despite supplemental oxygen or who demonstrate severe respiratory distress require mechanical ventilation, in addition to maximal medical therapy.

• Preload reduction
  • Nitroglycerin
  • Nitroglycerine (NTG) is the most effective, predictable, and rapid-acting medication available for preload reduction.
  • Multiple studies comparing NTG to furosemide or morphine sulfate have demonstrated greater efficacy and safety and a faster onset of action for NTG.
  • Use of sublingual NTG is associated with preload reduction within 5 minutes and some afterload reduction.
  • Topical NTG may be as effective as sublingual NTG in most patients with heart failure, but it should be avoided in patients with severe LV failure because of poor skin perfusion (manifesting as skin pallor or mottling) and resultant poor absorption.
  • Intravenous NTG at higher dosages provides rapid and titratable preload and afterload reduction and has been demonstrated to be an excellent single-agent therapy for patients with severe decompensated CHF.
  • Loop diuretics
  • Loop diuretics are the cornerstone of heart failure treatment and have been considered as such for many decades. Furosemide is most commonly used. Bumetanide has a higher bioavailability and may be more effective in patients with severe CHF.
  • Loop diuretics are presumed to decrease preload through 2 mechanisms: diuresis and direct pulmonary artery vasodilation and venodilation.
  • In most patients, diuresis does not occur for at least 20-90 minutes; thus, the effect is delayed.
  • In some patients with heart failure, particularly those with diastolic heart failure who are minimally fluid overloaded, continued diuretic use after resolution of acute symptoms may be associated with adverse outcomes, including electrolyte derangements and hypotension.
  • Use of medications that decrease preload (eg, NTG) and afterload (eg, ACE inhibitors), either concomitantly or before the administration of loop diuretics, can prevent potential adverse hemodynamic changes.
  • Potassium-sparing diuretics
  • Numerous studies have shown spironolactone to be as beneficial in the management of CHF as loop diuretics.
  • Some of the beneficial effects of spironolactone may be due to its neurohormonal actions.
  • Morphine sulfate
  • Morphine sulfate use in acute CHF for preload reduction has been commonplace for many years.
  • Use should be weighed against potential adverse effects (eg, nausea/vomiting, local or systemic allergic reactions, respiratory depression) that may outweigh any potential benefit, especially given the availability of much more effective medications for preload reduction (eg, NTG).
  • Any beneficial hemodynamic effect probably is due to anxiolysis, with a resulting decrease in catecholamine production and systemic vascular resistance.
• Vasodilators (combined afterload and preload reducers)
  • ACE inhibitors
  • Although initial studies focused on the efficacy of ACE inhibitors in the treatment of chronic CHF, recent studies have demonstrated excellent results for treatment of acute decompensated CHF.
  • Studies demonstrate that the use of ACE inhibitors in acute heart failure is associated with reduced admission rates to ICUs and decreased endotracheal intubation rates.
  • Hemodynamic effects of ACE inhibitors include reduced afterload, improved stroke volume and cardiac output, and reduced preload.
  • ACE inhibitors must be initiated with extreme care in individuals presenting with borderline hemodynamic parameters.
  • When administered by intravenous (enalapril 1.25 mg) or sublingual routes, hemodynamic and subjective improvements are noted within 10 minutes; improvements occur more slowly with the oral route.
  • ACE inhibitors prolong survival in heart failure. Furthermore, compared to the combination of hydralazine and long-acting nitrates, ACE inhibitors showed a trend to a greater prolongation of survival, had improved hemodynamics, and were better tolerated.
  • Ang II receptor inhibitors
  • Ang receptor inhibitors, such as losartan and candesartan, are highly recommended alternatives to ACE inhibitors in patients who cannot tolerate ACE inhibitors because of adverse effects, most notably, coughing.
  • Furthermore, these agents have gained wider use based on their low adverse effect profile and early study findings, which indicated that combined ACE inhibition and Ang II receptor inhibition is beneficial.
  • Hydralazine
  • Hydralazine was the first oral balanced (afterload and preload reduction) vasodilator and was popular before the availability of ACE inhibitors. It is a direct vasodilator, unlike ACE inhibitors or Ang receptor inhibitors, which are vasodilators through inhibition of the RAAS system.
  • When combined with long-acting nitrates, hydralazine was shown, in the Veterans Administration Heart Failure Trial (VHEFT) studies, to prolong survival in patients with CHF.
  • Hydralazine has one main advantage over ACE inhibitors in that it is safe in pregnancy. It also is not known to worsen renal function in patients with heart failure who have reduced renal function and is not associated with the risk of hyperkalemia. Additionally, hydralazine use is recommended in patients who cannot tolerate ACE inhibitors.
  • Hydralazine, as a single agent, has less reduction in myocardial oxygen demand than ACE inhibitors because of a slight increase in heart rate that usually results from its use.
  • Nitroprusside
  • Nitroprusside results in simultaneous preload and afterload reduction through direct smooth muscle relaxation, although it has a greater effect on afterload.
  • Afterload reduction is associated with increased cardiac output.
  • Potency and rapidity of onset and offset of effect make this an ideal medication for patients who are critically ill.
  • It may induce precipitous falls in blood pressure; intraarterial blood pressure monitoring often is recommended.
  • Use nitroprusside cautiously in the setting of acute myocardial infarction because of its potential to induce hypotension.
  • If nitroprusside is used, convert patients to oral or alternative intravenous vasodilator therapy as soon as possible because prolonged use is associated with thiocyanate toxicity.
  • Use in pregnancy is associated with fetal thiocyanate toxicity.
• Inotropic support
  • Digoxin (cardiac glycoside)
  • Digoxin has been a cornerstone for the treatment of heart failure for decades and is the only oral inotropic support agent currently used in clinical practice.
  • Digoxin acts by inhibiting the Na⁺/K⁺–ATPase transport pump and inhibits sodium and potassium transport across cell membranes. This increases the velocity and shortening of cardiac muscle, resulting in a shift upward and to the left of the ventricular function (Frank-Starling) curve relating stroke volume to filling volume or pressure. This occurs in healthy as well as failing myocardium and in atrial as well as ventricular muscle. The positive inotropic effect is due to an increase in the availability of cytosolic calcium during systole, thus increasing the velocity and extent of myocardial sarcomere shortening.
  • No evidence indicates that digoxin affects peripheral vascular resistance or systemic blood pressure.
  • All evidence suggests that digoxin provides, even in the short term, a moderate and metabolically efficient positive inotropic effect, an important consideration in ischemic cardiomyopathies.
  • Although the incidence and severity of digitalis intoxication is decreasing, vigilance for this important complication of therapy is essential. Drugs that interact with digoxin are numerous and include amiodarone, propafenone, quinidine, verapamil, nifedipine, diltiazem, levothyroxine, cyclosporine, flecainide, disopyramide, omeprazole, tetracycline, and erythromycin. These agents affect clearance or absorption of digoxin, thus necessitating dose alteration of digoxin in patients taking these medications. Furthermore, patients with renal insufficiency may need to have their digoxin dose adjusted downward to avoid digitalis intoxication.
  • Numerous studies confirm that digoxin does not prolong survival in patients with systolic heart failure, but it is associated with reduced hospital admissions, improved functional class, reduced symptoms of heart failure, and improved quality of life.
  • Digoxin is also an effective agent against atrial tachyarrhythmias at rest in patients with LV dysfunction, but it has limited efficacy in controlling the ventricular rate of atrial arrhythmias during exertion.
  • Dobutamine (sympathomimetic agent)
  • Dobutamine mainly serves as a beta1-receptor agonist, although it has some beta2-receptor and minimal alpha-receptor activity.
  • Intravenous dobutamine induces significant positive inotropic effects with mild chronotropic effects. It also induces mild peripheral vasodilation (decrease in afterload).
  • The combination effect of increased inotropy with decreased afterload results in a significant increase in cardiac output.
  • Combination use with intravenous NTG may be ideal for patients with myocardial infarction and decompensated heart failure and mild hypotension in order to provide simultaneous preload reduction with increased cardiac output. In the setting of acute myocardial infarction, dobutamine use could increase infarct size because of the increase in myocardial oxygen consumption that may ensue.
  • In general, avoid dobutamine in patients with moderate or severe hypotension (eg, systolic blood pressure <80 mm Hg) because of the peripheral vasodilation.
  • Dopamine (sympathomimetic agent)
  • Vascular and myocardial receptor effects are dose dependent.
  • Low dosages (0.5-3 mcg/kg/min) cause stimulation of dopaminergic receptors within the renal and splanchnic vascular beds, causing vasodilation and increased diuresis.
  • Moderate dosages (3-10 mcg/kg/min) cause stimulation of beta-receptors in the myocardium, resulting in increased cardiac contractility and heart rate.
  • High dosages (10-20 mcg/kg/min) cause stimulation of alpha-receptors, resulting in peripheral vasoconstriction (increased afterload), increased blood pressure, and no further improvement in cardiac output.
  • As with other inotropic agents, moderate and high dosages are arrhythmogenic and also result in increased myocardial oxygen demand (potential for myocardial ischemia); therefore, use dopamine only in patients with heart failure who cannot tolerate the use of dobutamine because of severe hypotension (eg, systolic blood pressure <60-80 mm Hg).
  • NE (sympathomimetic agent)
  • NE primarily stimulates alpha-receptors, resulting in significant increases in afterload (and potential myocardial ischemia) and reduced cardiac output.
  • Use of NE is generally reserved for patients with profound hypotension (eg, systolic blood pressure <60 mm Hg). Once blood pressure is restored, add other medications to maintain cardiac output.
  • Phosphodiesterase inhibitors (milrinone, amrinone)
  • Phosphodiesterase inhibitors (PDIs) increase intracellular cAMP, which results in a positive inotropic effect on the myocardium and peripheral vasodilation (decreased afterload) and a reduction in pulmonary vascular resistance (decreased preload).
  • PDIs, unlike catecholamine inotropes, are not dependent on adrenoreceptor activity; therefore, patients are less likely to develop tolerance to these medications. Tolerance to catecholamine inotropes can develop rapidly through down-regulation of the adrenoreceptors.
  • PDIs are less likely than catecholamine inotropes to cause adverse effects that are typically associated with adrenoreceptor activity (eg, increased myocardial oxygen demand, myocardial ischemia).
  • Several studies directly comparing the use of PDIs (milrinone, amrinone) to dobutamine in patients with heart failure have demonstrated that milrinone produced equal or greater improvements in stroke volume, cardiac output, PCWPs (preload), and systemic vascular resistance (afterload). They are also associated with less tachycardia and myocardial oxygen consumption. However, PDIs have been associated with a significantly greater incidence of adverse events (eg, tachyarrhythmias) than has dobutamine.
  • At present, oral PDIs have no role. Their use was associated with a 53% increase in mortality rates in patients with NYHA Class IV heart failure in the Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial, prompting an early termination of that study.
  • Unfavorable results were also evident in a smaller trial that compared oral milrinone to digoxin or placebo. Furthermore, sustained hemodynamic improvement with oral milrinone was lacking, and the incidence of adverse events, particularly cardiac arrhythmias, was greater.
• Beta-adrenergic blocking agents (metoprolol, carvedilol)
  • A large and increasing body of evidence indicates that these agents improve symptoms, exercise tolerance, cardiac hemodynamics, and LV ejection fraction and that they decrease mortality rates in patients with heart failure, particularly those with both ischemic and idiopathic cardiomyopathy.
  • A growing body of evidence suggests that long-term beta-adrenergic antagonist administration improves cardiac function, reduces myocardial ischemia, improves ventricular-arterial coupling, and decreases myocardial oxygen consumption. These agents may also reduce the incidence of sudden death due to primary ventricular arrhythmias in patients with heart failure, although this latter benefit has yet to be definitively proven.
  • Detectable improvements in ventricular function are usually not apparent for a minimum of 1-3 months, and longer-term structural changes, such as a decline in ventricular volume or mass, may take 12-18 months.
  • Beta-adrenergic antagonists with vasodilator activity, such as carvedilol and labetalol, have the added benefit of further afterload reduction because of arterial vasodilation from alpha1-receptor blockade.
• Treatment of heart failure with predominant diastolic dysfunction: The therapeutic approach to diastolic dysfunction has 2 major components. The first involves attempts to reverse the abnormal cardiac diastolic properties. The second is directed toward reducing LV filling pressure and thereby venous congestion.
  • Treatment of diastolic dysfunction
  • Pericardiectomy for constrictive pericarditis
  • Relief of ventricular systolic overload
  • ACE inhibitors and Ang receptor inhibitors slow, arrest, or even reverse myocardial fibrosis in the presence of systolic overload, thus improving diastolic dysfunction.
  • Anti-ischemic agents, such as beta-adrenergic blocking agents, calcium channel blocking agents, and nitroglycerin, are effective in immediately improving diastolic dysfunction in patients with coronary artery disease by eliminating or reducing myocardial ischemia, thus improving ventricular relaxation. Thrombolysis, mechanical revascularization (percutaneous transluminal coronary angioplasty [PTCA]), and coronary artery bypass graft surgery (CABGS), in combination with anti-ischemic agents or alone, all improve diastolic function in patients with acute and chronic myocardial ischemia by improving ventricular relaxation.
  • Calcium channel antagonists, especially verapamil, accelerate ventricular relaxation, particularly in patients with hypertensive heart disease and hypertrophic cardiomyopathy, and are useful in the treatment of diastolic dysfunction.

• Regression of ventricular hypertrophy

• Aggressive control of hypertension with beta-adrenergic blocking agents, calcium channel blocking agents, diuretics, ACE inhibitors, Ang receptor inhibitors, and central-acting antihypertensive agents (eg, methyldopa) reduces ventricular hypertrophy, thereby improving diastolic function.
• Aortic valve replacement for aortic stenosis also reduces ventricular hypertrophy and improves diastolic function.
• Relief of valvular, supravalvular, and subvalvular obstruction to ventricular outflow by operation or balloon valvuloplasty improves diastolic function by relieving ventricular pressure overload, thus regressing ventricular hypertrophy.

• Reduction of ventricular filling pressure and secondary venous congestion: These approaches are usually highly effective in patients presenting with a CHF exacerbation primarily caused by a diastolic dysfunction. Indeed, a hallmark of diastolic dysfunction is the rapid improvement in response to the therapies described below.

• Restriction of dietary sodium
• Administration of diuretics and venodilators
• Administration of NTG or long-acting nitrates
• Maintenance of normal heart rate and rhythm: Digoxin has no established place in the management of patients with predominant diastolic dysfunction and well-preserved ventricular ejection fraction, and it could potentially have an adverse effect in this group of patients.

• Newer therapies for heart failure

• Nesiritide, a recombinant BNP, is from an exciting new class of peptides that has several unique properties.
  • Nesiritide is a balanced vasodilator, slightly more venous than arterial, rapidly improves symptoms of congestion, does not increase heart rate, decreases myocardial oxygen demand, and is not proarrhythmic.
  • Nesiritide decreases aldosterone and ET-1 release through neurohumoral suppression, does not exhibit tachyphylaxis, and induces a mild diuresis and natriuresis. It significantly reduces ventricular filling pressures to a greater extent than standard care with ACE inhibitors and diuretics, even more than the combination of ACE inhibitors, diuretics, and nitroglycerin.
  • Nesiritide should be avoided in patients with systolic blood pressure of less than 80-85 mm Hg. The primary adverse event (occurring in 4% of the patients in the Veterans Administration Medical Center [VAMC] study on nesiritide) was hypotension.
  • Nesiritide has no drug interactions with any of the other treatments used in CHF, thus making it useful as an effective adjunct in patients with severe, acute decompensated CHF without cardiogenic shock.
  • Study results indicate that treatment with nesiritide could lead to a reduced length of stay in the critical care unit, decreased recurrence of decompensation, and less likelihood of rehospitalization.
• Eplerenone, a selective aldosterone-blocking agent, has been shown to reduce rates of all-cause mortality, cardiovascular mortality, and sudden cardiac death in patients with myocardial infarction and left ventricular systolic dysfunction who are in CHF and already being treated with a beta-blocker and an ACE inhibitor or Ang II blocker. Close monitoring of potassium levels and appropriate dosage adjustments or use of diuretics are necessary because a small percentage of patients taking eplerenone develop hyperkalemia.

Surgical Care

Kantrowitz initially described intraaortic balloon pumping (IABP) in 1953, but the procedure was first used clinically in 1969 in a patient with cardiogenic shock. Since the 1980s, IABP has been increasingly used in various clinical situations as a lifesaving intervention to obtain hemodynamic stabilization prior to definite therapy.

• Procedure
• • The intraaortic balloon pump is inserted percutaneously via the femoral artery using a modified Seldinger technique. The distal end of the pump is placed just distal to the aortic knob and the origin of left subclavian artery.
  • Fluoroscopy may be used for correct positioning of the balloon, and a subsequent chest radiograph should be obtained to document satisfactory balloon placement.
• Proper timing of IABP for optimal hemodynamic support
• • Proper timing of counterpulsation is necessary for maximum hemodynamic support. The timings of balloon inflation and deflation are best evaluated and adjusted at a pump frequency of 1:2.
  • Inflation of the balloon should occur in early diastole, just after aortic valve closure, and should correspond to the dicrotic notch of the aortic pressure waveform. Balloon deflation should occur in early systole, just before the aortic valve opens.
  • Proper inflation leads to an assisted peak diastolic pressure higher than the unassisted peak systolic arterial pressure. Proper deflation results in assisted aortic end-diastolic pressure approximately 10 mm Hg lower than the unassisted end-diastolic pressure.
  • Diastolic augmentation enhances perfusion of the coronary circulation and carotid arteries. The reduction in end-diastolic pressure decreases aortic impedance (afterload) and augments systole.
  • IABP reduces aortic impedance and systolic pressure, leading to a 15-25% reduction in LV wall stress. This level of afterload reduction improves LV volume, LV emptying, and myocardial oxygen consumption.
  • Diastolic aortic pressure augmentation enhances myocardial perfusion and coronary blood flow. The effects on coronary blood flow may be variable but generally range from a boost of 10-20% in ischemic territories.
  • IABP can decrease LV filling pressures by 20-25% and can improve cardiac output by 20% in patients with cardiogenic shock; therefore, IABP reduces myocardial oxygen demand significantly, although the beneficial effect of increased oxygen supply to the myocardium may also occur in some clinical situations.
• Indications for IABP
• • IABP is very effective in providing temporary support to patients in cardiogenic shock while definite therapies such as angioplasty or cardiac bypass surgery are undertaken. At most institutions,