eMedicine Specialties > Cardiology > Myocardial Disease and Cardiomyopathies

Heart Failure

Ioana Dumitru, MD, Assistant Professor, Internal Medicine, Section of Cardiology, Founder and Medical Director, Heart Failure and Cardiac Transplant Program, University of Nebraska Medical Center; Assistant Professor, Internal Medicine, Section of Cardiology, Veterans Affairs Medical Center, Omaha, Nebraska
Mathue Baker, MD, Fellow, Department of Internal Medicine, Division of Cardiology, University of Nebraska Medical Center, Omaha

Updated: Nov 24, 2009

Introduction

Background

Heart failure is a syndrome manifesting as the inability of the heart to fill with or eject blood due to any structural or functional cardiac conditions.¹  
 
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 heart failure (HF) is staggering. According to the American Heart Association, heart failure is a condition that affects nearly 5.7 million Americans of all ages and is responsible for more hospitalizations than all forms of cancer combined. It is the number 1 cause for hospitalization among Medicare patients. With improvement in survival of acute myocardial infarctions and a population that continues to age, heart failure will continue to increase in prominence as a major health problem in the United States.

For additional resources, please visit Medscape’s Heart Failure Resource Center.

Pathophysiology

Most important among these adaptations are the (1) Frank-Starling mechanism, in which an increased preload helps to sustain cardiac performance; (2) alterations in myocyte regeneration and death; (3) myocardial hypertrophy with or without cardiac chamber dilatation, in which the mass of contractile tissue is augmented; and (4) activation of neurohumoral systems, especially the release of norepinephrine by adrenergic cardiac nerves, which augments myocardial contractility and includes activation of the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), 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 is myocyte hypertrophy, death/apoptosis, and regeneration.² This process eventually leads to remodeling, usually the eccentric type. Eccentric remodeling further worsens the loading conditions on the remaining myocytes and perpetuates the deleterious cycle. The idea of lowering wall stress to slow the process of remodeling has long been exploited in treating heart failure patients.³

However, the concept of the heart as a self-renewing organ is a relatively recent development.⁴ The rate of myocyte turnover has been shown to increase during times of pathologic stress.² In heart failure, this mechanism for replacement becomes overwhelmed by an even faster increase in the rate of myocyte loss. This imbalance of hypertrophy and death over regeneration is the final common pathway at the cellular level for the progression of remodeling and heart failure. This new paradigm for myocyte biology has created an entire field of research aimed directly at augmenting myocardial regeneration.

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 and norepinephrine, along with the vasoactive substances endothelin-1 (ET-1) and vasopressin, 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/apoptosis, which results in heart failure and further reduction in cardiac output, perpetuating a 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. This results in an increase in angiotensin II (Ang II) levels and, in turn, aldosterone levels. This results in stimulation of the 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.

Research indicates that local cardiac Ang II production (which decreases lusitropy, increases inotropy, and increases afterload) leads to increased myocardial energy expenditure. Ang II has also been shown both in vitro and in vivo to increase the rate of myocyte apoptosis.⁵ In this fashion, Ang II has similar actions to norepinephrine in heart failure.

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. As a result, the cardiac architecture changes, which in turn leads to further increase in myocardial volume and mass.

In the failing heart, increased myocardial volume is characterized by larger myocytes approaching the end of their life cycle. As more myocytes drop out, an increased load is placed on the remaining myocardium and this unfavorable environment is transmitted to the progenitor cells responsible for replacing lost myocytes. Progenitor cells become progressively less effective as the underlying pathologic process worsens and myocardial failure accelerates. These features, namely the increased myocardial volume and mass, along with a net loss of myocytes, 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, 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 congestive heart failure 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 norepinephrine directly correlates with the degree of cardiac dysfunction and has significant prognostic implications. Norepinephrine, while directly toxic to cardiac myocytes, is also responsible for a variety of signal-transduction abnormalities, such as downregulation 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, therefore, 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 heart failure include the endothelin (ET) receptor system, adenosine receptor system, vasopressin, and tumor necrosis factor-alpha (TNF-alpha). Endothelin, a substance produced by the vascular endothelium, may contribute to the regulation of myocardial function, vascular tone, and peripheral resistance in heart failure. Elevated levels of endothelin-1 (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 heart failure 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 contribute to the progression of myocardial dysfunction in the long term.

In diastolic heart failure (heart failure with normal ejection fraction [HFNEF]), the same pathophysiologic processes leading 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 HFNEF, altered relaxation and increased stiffness of the ventricle (due to delayed calcium uptake by the myocyte sarcoplasmic reticulum and delayed calcium efflux from the myocyte) occur 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:

• 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)
• 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 aortic stenosis and long-standing hypertension, but also due to infiltrative disorders (such as amyloidosis), endomyocardial fibrosis, and myocardial ischemia
• 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.

Another clinically important process in the development of heart failure is the generation of arrhythmias. While life-threatening rhythms are more common in ischemic versus nonischemic cardiomyopathy, arrhythmia imparts a significant burden in all forms of heart failure. In fact, some arrhythmias even perpetuate heart failure. The most significant of all rhythms associated with heart failure are the life-threatening ventricular arrhythmias. Structural substrates for ventricular arrhythmias common in heart failure, regardless of the underlying cause include (1) ventricular dilatation, (2) myocardial hypertrophy, and (3) myocardial fibrosis. At the cellular level, myocytes may be exposed to increased stretch, wall tension, catecholamines, ischemia, and electrolyte imbalance. The combination of these factors contributes to an increased incidence of arrhythmogenic sudden cardiac death in patients with heart failure.

Frequency

United States

• Heart failure is the fastest-growing clinical cardiac disease entity in the United States, affecting 2% of the population.
• In 2006, 1.1 million patients were admitted to the hospital for acute decompensated heart failure in the United States, almost double the number seen 15 years ago. In addition, 3.4 million visits for heart failure were outpatient.
• 550,000 new cases of heart failure are diagnosed and 300,000 deaths are caused by heart failure each year.
• The rehospitalization rates⁶ during the 6 months following discharge are as much as 50%.
• Nearly 2% of all hospital admissions in the United States are for decompensated heart failure, and heart failure is the most frequent cause of hospitalization in patients older than 65 years with an annual incidence of 10 per 1,000.
• The average duration of hospitalization is about 6 days.
• In 2008, the estimated total cost of heart failure in the United States was $37.2 billion. This represents 1-2% of all healthcare expenditures.
• For updated statistics and epidemiology please see the American Heart Association and National Institutes of Health official Web sites or published summaries.⁷

International

Heart failure is a worldwide problem, but little accurate financial data are available. As discussed elsewhere, the most common cause of heart failure in industrialized countries is ischemic cardiomyopathy. Other causes, including Chagas disease and valvular cardiomyopathy, assume a more important role in underdeveloped countries than in the United States. However, as underdeveloped countries urbanize and become more affluent, the rate of heart failure increases in concordance with rates of diabetes, hypertension, a more processed diet, and a more sedentary lifestyle. This was illustrated in a population study in Soweto, South Africa. As the community transformed into a more urban and westernized city, an increase in diabetes and hypertension was met with an increased rate of heart failure.⁸

In terms of treatment, a 2006 study of European nations showed few important international differences in uptake of key therapies amongst European countries with widely differing cultures and economic status for patients with heart failure. In contrast, studies of sub-Saharan Africa, where health care resources are more limited, have shown poor outcomes in certain populations.⁹  For instance, hypertensive heart failure carries a 25% one-year mortality in some countries and HIV-associated cardiomyopathy generally progresses to death within 100 days of diagnosis in patients who are not treated with antiretroviral drugs. 

While data in developing countries is not as robust as in Western society, a few clear trends are apparent: (1) Causes tend to be largely nonischemic, (2) patients tend to present at a younger age, (3) outcomes are largely worse where health care resources are limited, and (4) isolated right heart failure tends to be more prominent with a variety of postulated causes from tuberculous pericardial disease to lung disease and pollution.

Mortality/Morbidity

In unselected samples from the community, rates of improvement in mortality have been about 20% in both short- and long-term followup between 1985 and 1995.¹⁰  This translated to a 6-month increase in survival. However, 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 heart failure, which may be severe, can result in diffuse end-organ damage including myocardial ischemia or myocardial infarction and hypoxic brain injury.
• Respiratory failure with hypercapnic respiratory acidosis may occur in severe decompensated heart failure, 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 heart failure, the risk of cardiac sudden death from ventricular tachycardia (VT) or ventricular fibrillation (VF) 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 heart failure.
• Progressive renal insufficiency is common in patients with long-standing heart failure as well as acutely decompensated heart failure. Furthermore, renal function is at least as powerful an adverse prognostic factor as most clinical variables, including ejection fraction and New York Heart Association (NYHA) function class. Although renal dysfunction predicts all-cause mortality, it is most predictive of death from progressive heart failure, which suggests that it is a manifestation of and/or exacerbating factor for left ventricular dysfunction.¹¹
• Liver dysfunction due to passive hepatic congestion is particularly common in patients with right-sided heart failure 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 heart failure, thereby leading to potentially fatal bleeding, cardiac dysrhythmias, and neurologic abnormalities.
• Patients with heart failure have high rates of depression compared with the general population; in addition, depression may confer a negative prognostic impact when present in patients with heart failure, with an increased risk of both rehospitalization and mortality. Reported prevalence rates have ranged from 11-25% for outpatients and 35-70% for inpatients. Even more so than in the general population, depression in heart failure patients goes largely untreated with published rates of around 7% of patients with heart failure who are clinically depressed receiving antidepressant medication.¹²

Race

The incidence and prevalence of heart failure are higher in African Americans, Hispanics, Native Americans, and recent immigrants from nonindustrialized nations, Russia, and the former Soviet republics.

• The higher prevalence of heart failure in African Americans, Hispanics, 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 heart failure 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 heart failure. However, many differences between men and women are observed.

• Women tend to develop heart failure later in life.
• Women are more likely to have preserved systolic function.
• Women develop depression more commonly than men.
• Women have similar, but more pronounced, signs and symptoms.
• Women survive longer with heart failure than men do.

Age

The prevalence of heart failure increases with age. The prevalence is 1-2% of the population younger than 55 years and increases dramatically to a rate of 10% of those older than 75 years. Nonetheless, heart failure can occur at any age, depending on the cause.

Clinical

History

The NYHA classification of heart failure (see Staging), which varies slightly from the above categorization of heart failure symptoms, is widely used in practice and in clinical studies to quantify clinical assessment of heart failure. Breathlessness, a cardinal symptom 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. Other cardiac symptoms of heart failure include chest pain/pressure and palpitations. Patients often manifest noncardiac symptoms of heart failure like anorexia, nausea, weight loss, bloating, fatigue, weakness, oliguria, nocturia, and cerebral symptoms of different severity ranging from anxiety to memory impairment and confusion.

• Exertional dyspnea
  • The principal difference between exertional dyspnea in patients 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 heart failure 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 Frank-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.
  • 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 the treatment of heart failure.
• Paroxysmal nocturnal dyspnea
  • Paroxysmal nocturnal dyspnea usually occurs at night and is defined as the 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 heart failure 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, 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 is the result of the following mechanisms:
  • 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
• Acute pulmonary edema is defined as the sudden increase in pulmonary capillary pressure (usually more than 25 mm Hg) as a result of acute and fulminant left ventricular failure. It is a medical emergency and has a very dramatic clinical presentation. Patient appears extremely ill, poorly perfused, restless, sweaty, with an increased work of breathing and using respiratory accessory muscles, tachypneic, tachycardic, hypoxic and coughing with frothy sputum that on occasion is blood tinged.
• Chest pain/pressure may occur as a result of either primary myocardial ischemia from coronary disease or secondary myocardial ischemia from increased filling pressure, poor cardiac output and therefore poor coronary diastolic filling, or hypotension and hypoxemia.
• Palpitations are the sensation a patient has when the heart is racing. It can be secondary to sinus tachycardia due to decompensated heart failure, or more common due to atrial or ventricular tachyarrhythmias.
• 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 heart failure, 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 heart failure 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, caused by 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 heart failure 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 heart failure 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 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). This reflects an increase in right atrial pressure and therefore right-sided heart failure.
• Hepatojugular reflux: This represents distension of the jugular vein induced by applying manual pressure over the liver. The patient's body should be positioned at a 45 º angle. This is found in patients with elevated left-sided filling pressures and reflects elevated capillary wedge pressure and left-sided heart failure.
• Edema
  • Although a cardinal manifestation of heart failure, 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 (during pulse palpation, this is the alternation of one strong and one weak beat without a change in the cycle length)
• 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 heart failure 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 heart failure.
• 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, classifying the causes of heart failure into 3 broad categories is useful: (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.

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 congestive heart failure exacerbation is very long, and searching for the proximate cause to optimize therapeutic interventions is important.

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 heart failure, 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 heart failure 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
  • Systolic heart failure
    • Coronary artery disease
    • Diabetes mellitus
    • Hypertension
    • Valvular heart disease (stenosis or regurgitant lesions)
    • Arrhythmia (supraventricular or ventricular)
    • Infections and inflammation (myocarditis)
    • Peripartum cardiomyopathy
    • Congenital heart disease
    • Drug induced (either recreational like alcohol and cocaine, or therapeutic drugs with cardiac side effects like doxorubicin)
    • Idiopathic cardiomyopathy
    • Rare conditions (endocrine abnormalities, rheumatologic disease, neuromuscular conditions)
  • Diastolic heart failure
    • Coronary artery disease
    • Diabetes mellitus
    • Hypertension
    • Valvular disease (aortic stenosis)
    • Hypertrophic cardiomyopathy
    • Restrictive cardiomyopathy (amyloidosis)
    • Constrictive pericarditis
  • Acute heart failure
    • Acute valvular (mitral or aortic) regurgitation
    • Myocardial infarction
    • Myocarditis
    • Arrhythmia
    • Drug induced (eg, cocaine, calcium channel blocker or beta-blocker overdose)
    • Sepsis
  • High-output heart failure
    • Anemia
    • Systemic arteriovenous fistulas
    • Hyperthyroidism
    • Beriberi heart disease
    • Paget disease of bone
    • Albright syndrome (fibrous dysplasia)
    • Multiple myeloma
    • Pregnancy
    • Glomerulonephritis
    • Polycythemia vera
    • Carcinoid syndrome
  • Right heart failure
    • Left ventricular failure
    • Coronary artery disease (ischemia)
    • Pulmonary hypertension
    • Pulmonary valve stenosis
    • Pulmonary embolism
    • Chronic pulmonary disease
    • Neuromuscular disease
• Fundamental causes: See Pathophysiology.

Differential Diagnoses

Other Problems to Be Considered

Heart failure 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 from noncardiogenic pulmonary edema. In heart failure, a history of an acute cardiac event or that of progressive symptoms of heart failure is usually present. The physical examination reveals 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 HF 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 from noncardiac causes of pulmonary edema is now possible.

Workup

Laboratory 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 and pressure overload. BNP is an independent predictor of high LV end-diastolic pressure and is more useful than ANP or norepinephrine levels for assessing mortality risk in patients with heart failure.
  • BNP levels are higher in older patients, women, and patients with renal dysfunction or sepsis.
  • BNP levels may be disproportionately lower in patients who are obese or have hypothyroidism or advanced end-stage heart failure (the latter due to increased fibrosis).
  • BNP levels correlate closely with the NYHA 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 heart failure to all patients with heart failure. 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 HF from pulmonary disease.
  • BNP levels are not indicated in monitoring treatment of heart failure. (Class III recommendation¹³ )
  • Measurement of BNP and N-terminal proBNP (NT-proBNP) can be useful in the evaluation of patients presenting to urgent care setting in whom the clinical diagnosis of heart failure is uncertain (Class IIa recommendation¹³ ).
  • 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 re-admission 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 heart failure.
  • Steinhart et al derived and validated a diagnostic prediction model for acute heart failure that incorporates both clinical assessment and NT-proBNP. Variables used to predict acute heart failure were age, pretest probability, and log NT-proBNP. Validation of the model in 1073 patients showed that likelihood ratios for acute heart failure with NT-proBNP were 0.11 (95% confidence interval [CI], 0.06-0.19) for cut-point values less than 300 pg/mL, increasing to 3.43 (95% CI, 2.34-5.03) for values 2700-8099 pg/mL, and 12.80 (95% CI, 5.21-31.45) for values 8100 pg/mL or higher. When the model was applied to external data, 44% of patients who had been clinically classified as having intermediate probability of acute heart failure were appropriately reclassified to either low or high probability categories with negligible (<2%) inappropriate redirection.¹⁴

Imaging Studies

• Chest radiography
  • Chest radiographs may be 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 radiographs.
  • In long standing biventricular chronic heart failure, chest radiographs may only show cardiomegaly without alveolar edema or pleural effusions due to adaptive lung mechanism with increased arterial vasoconstriction and lymphatic drainage.
• Echocardiography
  • Determines LV/RV size and function, LV wall motion abnormalities, valvular function and abnormalities, diastolic function, presence or absence of pericardial abnormalities or intracardiac masses; evaluates intracardiac filling pressures.
  • Transesophageal echocardiography is particularly useful in patients who are on mechanical ventilation or morbidly obese and in patients whose transthoracic echocardiogram is 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 reliable imaging technique for evaluation of both LV and RV function and wall motion abnormalities. LV ejection fraction, as determined by MUGA scanning, is often used for serial assessment of LV function post chemotherapy, because of its reliability.
  • However, this study is limited in its assessment of valvular heart disease and pericardial disease.
• Cardiac magnetic resonance imaging (cMRI)
  • cMRI is quickly gaining popularity as an imaging modality for heart failure.
  • Benefits of cMRI include the ability to obtain a great deal of information with one noninvasive test. cMRI provides detailed functional and morphologic information. cMRI is able to assess ischemic versus nonischemic disease, infiltrative disease, valvular and congenital disorders, hypertrophic disease, as well as determine viability.

Other Tests

• Arterial blood gas (ABG)
  • ABG usually reveals mild hypoxemia in patients who have mild-to-moderate heart failure. ABG is 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.
  • ABG helps 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 ABG in patients with fulminant pulmonary edema.
• Venous blood gas is a good indirect marker of the blood circulation time and therefore of cardiac output and cardiac performance. Patients who have advanced heart failure have low cardiac output and slower circulation time, which translates into an increased oxygen extraction by the tissue and therefore lower saturation of oxygen (<60% saturation)
• 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
  • Normal right-sided hemodynamics include right atrial pressure (RAP) of less than 7 mm Hg, right ventricular pressure (RVP) of less than 30/7 mm Hg, pulmonary pressure (PAP) of less than 30/18, pulmonary capillary wedge pressure (PCWP) of less than 18 mm Hg, cardiac index (CI) more than 2.2 L/min/m².
  • PCWP can be measured by using a pulmonary arterial catheter (Swan-Ganz catheter). 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 25 mm Hg are generally required to overcome the pumping capacity of the lymphatics and produce pulmonary edema.
  • Large V waves may be observed in the PCWP tracing in patients with significant mitral regurgitation because large volumes of blood regurgitate into a poorly compliant left atrium. This raises pulmonary venous pressure and may cause pulmonary edema.
  • 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 2.0 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%.
  • Invasive hemodynamic monitoring is indicated for patients who have respiratory distress, signs of impaired perfusion, and when intracardiac pressures cannot be determined based on clinical examination or if there is no improvement in clinical status despite maximal heart failure therapy (Class I recommendation¹³ ).
• 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.
  • 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.
• Right ventricular endomyocardial biopsy is only indicated in patients presenting with heart failure when a specific diagnosis is suspected that would influence therapy (Class IIa recommendation¹³ ).
• The six-minute walk test is a good indicator of functional status and prognosis in patients with heart failure. It evaluates distance walked, dyspnea index on a Borg scale from 0 to 10, oxygen saturation, and heart rate response to exercise. Normal values are walking more than 1500 feet. Patients who walk less than 600 feet have severe cardiac dysfunction and this translates into a worse short- and long-term prognosis.
• Cardiopulmonary stress test (maximal exercise stress testing with measurement of respiratory gas exchange) evaluates cardiac and pulmonary performance with exercise. Values of peak oxygen consumption of less than 50% of predicted or less than 14 cc/kg/min reflect poor cardiac performance and a survival of less than 50% within the next year, therefore facilitating referral for cardiac transplant or mechanical circulatory device placement.

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 2001 ACC/AHA heart failure guidelines introduced a staging classification for heart failure complementary to NYHA classification to reflect the progression of disease.
  • Stage A – Patients at risk of developing heart failure, without evidence of structural heart disease (diabetes mellitus, hypertension, coronary artery disease, OSA, obesity, metabolic syndrome, family history of cardiomyopathy, use of cardiotoxins)
  • Stage B - Patients with asymptomatic LV dysfunction (post-MI LV dysfunction, valvular cardiomyopathy, dilated cardiomyopathy); includes NYHA Class I patients
  • Stage C – Symptomatic LV dysfunction; includes NYHA Class II and III patients
  • Stage D – End-stage refractory heart failure; includes NYHA Class IV patients
• Based on cardiac output heart failure can be classified in low-output failure (most of the conditions) or high-output failure (beriberi, Paget disease, pregnancy, anemia, AV fistula, sepsis).
• Based on the ventricle affected, heart failure can be classified in LV failure, RV failure, or biventricular failure.
• Based on the LVEF, heart failure can be classified in patients with LV systolic dysfunction (LVEF <40%) and patients with preserved LVEF (LVEF >40%).
• Based on the onset of symptoms, heart failure can be acute or chronic.

Treatment

Medical Care

Diagnosis and Management of Acute Heart Failure (AHF)

Acute heart failure is rapid or gradual onset of signs and symptoms of heart failure that result in urgent, unplanned hospitalization or office or emergency department visit. This is the result of a sudden increase in filling pressures leading to systemic and pulmonary congestion, regardless of the cardiac output.

Acute heart failure accounts for more than 1 million hospitalizations per year in United States. The incidence of heart failure hospitalizations has tripled during the last 3 decades. The expenditure related to heart failure exceeds 34 billion dollars per year and it is mainly related to hospitalizations. Despite the advances in heart failure treatment, a systematic approach to acute heart failure has only recently been emphasized, as reflected in the updated ACCF/AHA heart failure guidelines from 2009.¹³

Most patients who present with acute heart failure have exacerbation of chronic heart failure with only 15-20% having acute de novo heart failure. More than 50% of patients with acute heart failure have preserved LVEF (>40%). Less than 10% of patients presenting with acute heart failure are hypotensive and require inotropic therapy. Pulmonary edema is a medical emergency and only one of the presentations of acute heart failure.

Inhospital mortality remains as high as 20% for patients who present with creatinine more than 2.75 mg/dl, SBP <115 and BUN>43 mg/dL (ADHERE registry). Post discharge mortality and rehospitalization within 3 months can reach 10-20% and 30-50% at the end of 12 months. However, 50% of the readmissions in this population will be related to a different diagnosis than heart failure.

Acute heart failure can present as fluid overload alone with or without signs of hypoperfusion, end-organ dysfunction and shock.

A systematic and expeditious approach is required, starting in the emergency room, continuing during hospitalization and extending after discharge to the outpatient setting.

Prior myocardial infarction, hypertension, diabetes mellitus, arrhythmias, valvular disease, cardiovascular accident, renal dysfunction, COPD, and anemia are among the most common etiologies for acute heart failure. Common factors that precipitate heart failure hospitalizations are noncompliance with medicine, sodium or fluid excess, acute ischemia, uncontrolled blood pressure, uncontrolled arrhythmias, drugs (NSAIDs, calcium channel blockers, thiazolidinediones, anti-TNF antibodies), pulmonary embolus, excessive alcohol or other substance abuse, infections, and endocrine abnormalities (hypo or hyperthyroidism).

A thorough history and physical examination allow the physician to determine the volume and the perfusion status and proceed with therapy. Diagnostic laboratory work-up is the same as described above and include assessment of blood counts, liver and kidney function, myocardial injury biomarkers (CK total, MB, troponin I), BNP or NT pro-BNP, chest radiograph, electrocardiogram, and echocardiogram.

Emergency department care consists of stabilizing the patients’ clinical condition; establishing the diagnosis, etiology, and precipitating factors; and initiating therapies to rapidly provide symptom relief. Use of oxygen if blood oxygen saturation is less than 90% and noninvasive positive pressure ventilation (NIPPV) provides patients with respiratory support to avoid intubation. NIPPV has shown to decrease the rate of intubation and mechanical ventilation by 50% and decrease the hospital mortality by 40%. No difference has been noted between continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BIPAP).

Use of analgesics as morphine sulfate and benzodiazepines helps with the anxiety, distress, and dyspnea. Morphine sulfate also decreases preload. If arrhythmia is present and uncontrolled ventricular response is thought to contribute to the clinical scenario of acute heart failure, then either pharmacologic rate control or emergent cardioversion with restoration of sinus rhythm is recommended. Relief of congestion is achieved using intravenous diuretics and vasodilators. If patient is hypotensive, use of either inotropic therapies and/or mechanical circulatory support (intraaortic balloon pump, extracorporeal membrane oxygenator, left ventricular assist device) in addition to continuous hemodynamic monitoring is indicated.

Hospitalization occurs on either telemetry or in an ICU setting with a small percentage on the floor or observation unit. The goal is to continue the diagnostic and therapeutic processes started in the ED. Patient’s volume and hemodynamic status is optimized using careful clinical monitoring and the heart failure medical regimen is optimized. Heart failure education, behavior modification, and exercise and diet recommendation are made. The patient must be on a stable oral regimen for at least 24 hours before discharge. To ensure compliance and understanding of a complex medical regimen, a follow-up phone call is made 3 days after discharge by a nurse with training in heart failure. Ideally, the patient should be seen in clinic 7-10 days after discharge.

2006 heart failure guidelines are as follows:¹⁵

These guidelines recommend hospitalization for acute heart failure if the following are present: 

• Severe decompensated heart failure (low blood pressure, renal dysfunction, altered mentation)
• Dyspnea at rest
• Hemodynamically significant arrhythmia
• Acute coronary syndrome

Hospitalization should be considered if the follow are present:

• Worsening congestion (weight gain >5 kg)
• Worsening signs and symptoms of systemic or pulmonary congestion, even in the absence of weight gain
• Major electrolyte abnormalities
• Associated comorbid conditions
• Repeat implantable cardioverter-defibrillator firings
• New diagnosis of heart failure with signs of active congestion

Stevenson and colleagues postulated treatment for acute heart failure based on volume and perfusion status of the patient (warm and wet, warm and dry, cold and wet, cold and dry)¹⁶

Diuretics remain the mainstay of therapy and current standard of care for acute heart failure. Intravenous administration of a loop diuretic (furosemide, bumetanide, torsemide) is preferred initially due to potential poor absorption of the oral forms in the presence of bowel edema. The dose and frequency of administration depend on the diuretic response 2-4 hours after the first dose administered. If the response is inadequate, then increasing the dose and/or increasing the frequency can help enhance diuresis. The patient is considered diuretic resistant if either (1) more than 80 mg IV bolus furosemide or more than 2 mg/kg furosemide is needed for appropriate response or (2) more than double of the diuretic dose or a second agent in the form of a thiazide diuretic is needed. Volume status, sodium, water intake and hemodynamic status for signs of poor perfusion need to be reevaluated in case of diuretic resistance.

Although initially diuretic resistance was though to be a side effect of diuretics, a meta-analysis demonstrated this phenomenon is mostly a result of advanced heart failure. Eventually, alternate strategies such as hemodialysis or ultrafiltration may be used to overcome it. Other agents, such as vasopressin antagonists and adenosine receptor blockers, can be used to assist diuretics.

Transition to oral diuretic therapy is made upon reaching near-euvolemic state. The dose of oral diuretic dose is usually equal to the IV dose. Usually 40 mg daily of furosemide is equivalent to 20 mg of torsemide and 1 mg of bumetanide. Weight, sign and symptoms, fluid balance, electrolyte levels, and renal function have to be monitored carefully on a daily basis.

• Vasodilators are recommended as first-line therapy for patients with acute heart failure in the absence of hypotension in addition to diuretic therapy for relief of symptoms. Vasodilators will decrease preload, afterload, or both.
• Nitrates are potent venodilators. They decrease preload, therefore decreasing LV filling pressure and relieving shortness of breath. They also selectively produce epicardial coronary artery vasodilatation and help with myocardial ischemia. Although nitrates can be used in different forms (sublingual, oral, transdermal, intravenous) the most common route in acute heart failure is intravenous. Their use is limited by tachyphylaxis and headache.
• Sodium nitroprusside is a potent balanced arterial and venous vasodilator resulting in a very efficient decrease of intracardiac filling pressures. It requires not only careful hemodynamic monitoring using indwelling catheters but also monitoring for cyanide toxicity, especially in the presence of renal dysfunction. It is particularly helpful for patients who present with severe pulmonary congestion in the presence of hypertension and severe mitral regurgitation. The drug should be titrated to off rather than abruptly stopped due to the rebound potential.
• Nesiritide (human BNP analog) is a vasodilator that subjectively has been demonstrated to alleviate dyspnea faster when compared with diuretics alone or in combination with low-dose nitroglycerin (VMAC trial). The drug can be initiated if systolic blood pressure is greater than 100 mm Hg at a continuous drip of 0.005 mcg/kg/min with or without an IV bolus of 2 mcg/kg. Continuous infusion can be titrated to a maximum of 0.03 mcg/kg/min, although this dose has been associated with more renal dysfunction and hypotension and the additional decongestive benefit at a higher dose is questionable. Long-term effects on mortality as well as renal function are still under investigation.
• Inotropes improve short-term symptoms and hemodynamics in patients with evidence of cardiogenic shock and end-organ dysfunction. Their use long term (REMATCH trial) or in patients not in cardiogenic shock (normotensive and without evidence of end organ perfusion) (OPTIME CHF) is not indicated and increases mortality. An adrenergic agonist (dopamine, dobutamine, epinephrine, norepinephrine), a phosphodiesterase inhibitor (milrinone, enoximone) or a calcium sensitizer (levosimendan) can be used.

• Dobutamine is a beta-receptor agonist, increases inotropy and chronotropy and decreases afterload therefore improving end-organ perfusion Doses of 5-10 mcg/kg/min are used although in the presence of a beta-blocker higher doses may be necessary. Careful hemodynamic and patient monitoring is required.
• Dopamine has beta-receptor agonist properties in doses of 3-7.5 mcg/kg/min and can be used as a positive inotrope. Initiation of it can precipitate arrhythmia due to inhibition of norepinephrine uptake. Doses of more than 7.5 mcg/kg/min will produce more peripheral vasoconstriction via alpha stimulation and can precipitate heart failure. Doses of more than 10 mcg/kg/min are used mostly for refractory hypotension in the presence of cardiogenic shock. In doses of less than 3 mcg/kg/min, it produces splanchnic vasodilation due to the stimulation of dopaminergic receptors.
• Milrinone is a phosphodiesterase inhibitor (PDEi) which increases inotropy, chronotropy and lusitropy acting via cGMP to increase the intramyocardial ATP. It is a potent vasodilator agent, both veno and arterial vasodilator, and it is used in patients with pulmonary hypertension. Milrinone can be used in presence of a beta-blocker. Milrinone is thought to create less tachycardia since it does not directly stimulate beta-receptors. Milrinone is usually initiated at 0.25 mcg/kg/min and can be titrated up to 0.75 mc/kg/min. The half-life is 2.4-6 hours and the drug needs to be adjusted for renal function. Milrinone is usually avoided in patients with severe hypotension. Milrinone should not be used routinely in patients with HF exacerbation in the absence of cardiogenic shock since it has been shown to increase mortality (OPTIME-CHF).
• Oral therapy with ACEI/ARB is usually continued. Adjustment of dose or temporary withholding may be necessary if hypotension persists and hinders diuresis or if renal function worsens.
• Beta-blockers are usually continued in the same dose or a slightly reduced dose with the exception of the situations requiring intravenous inotropic therapy where they are temporarily stopped. Usually, beta-blockers are resumed prior to discharge if patient condition allows.
• Ultrafiltration (UNLOAD trial) is now a class IIa recommendation for patients with refractory heart failure not responsive to medical therapy.

Invasive hemodynamic monitoring, although not indicated for stable patients with heart failure responding appropriately to medical therapy (ESCAPE trial showed no mortality or hospitalization benefit), is recommended in the following situations for patients with acute decompensated heart failure (Class IIa recommendation):

• Patients with uncertain fluid status, perfusion, or systemic or pulmonary vascular resistance.
• Patients with persistent symptomatic hypotension despite initial therapy.
• Patients with worsening in renal function despite initial therapy.
• Patients who require parenteral vasoactive agents.
• Patients who may be considered for advanced device therapy or transplantation.

Patients are ready for discharge when exacerbating factors have been addressed, volume status has been optimized, diuretic therapy has been successfully transitioned to oral medication with discontinuation of intravenous vasodilator and inotropic therapy for at least 24h, and oral chronic heart failure therapy has been achieved with stable clinical status. Patient and family education should be completed and extensive postdischarge instructions and follow up in 3-7 days must be arranged. Difficult and complicated patients should be referred to a disease management program.¹

HFNEF represents 50-55% of hospitalized patients. Prevalence in the population increases dramatically with age and it is more common in women than in men. Other nomenclature includes heart failure due to diastolic dysfunction or heart failure with preserved systolic function. Inhospital mortality seems to be slightly lower when compared with patients with systolic dysfunction in the ADHERE registry, despite similar hospitalization length of stay. The same registry noted the increased in-hospital mortality when patients had a BUN greater than 37 mg/dL, creatinine greater than 2 mg/dL, and SBP <125 mm Hg. Patients with HFNEF in this registry were not as likely to receive therapy with ACEI/ARB, beta-blockers, or diuretics. More than 70% of patients at discharge had lost less than 10 lb and 50% were still symptomatic. 

The most common risk factors for developing HFNEF are old age, female gender, hypertension, diabetes mellitus, coronary disease, obesity, and chronic kidney disease. 

Pathophysiology of HFNEF consists of LV concentric remodeling, impaired LV filling capacity, increased LV stiffness, impaired active relaxation with significant activation of RAAS and SNS. The Frank Starling curve in HFNEF is shifted left and upward. Minor changes in preload, afterload, or heart rate may lead to acute decompensation. 

The European Society of Cardiology proposed the following 3 conditions to establish the diagnosis of HFNEF: (1) Signs and symptoms of heart failure, (2) LVEF more than 50% (although 40-50% is still considered by most cardiologists to be HFNEF), (3) evidence of elevated LV filling pressure by either invasive hemodynamics, echo (E/E>15) or BNP/NT pro-BNP measurements (>200 pg/mL). 

Treatment is directed to alleviating symptoms and addressing the underlying condition triggering HFNEF. There is a paucity of randomized controlled studies addressing HFNEF. Control of blood pressure, volume, or other risk factors is the mainstay of the therapy. Lifestyle modification is important, including a low sodium diet, restricted fluid intake, daily weights, exercise, and weight loss. Evaluation of cardiac ischemia or sleep apnea as potential precipitating factors should also be considered.

• Careful diuretic therapy is recommended to avoid hypotension.
• ACEI/ARBs are used as indicated for patients with evidence of atherosclerotic disease, post-myocardial infarction, diabetes melitis, and hypertension. Use of candesartan in CHARM-Preserved¹⁷ , irbesartan in I-PRESERVED, or perindopril in PEP-CHF revealed no change in mortality; however, the trend was toward improved morbidity and hospitalizations. Some evidence shows LV reverse remodeling using losartan and valsartan with improvement in diastolic function and regression of LVH.
• Beta-blockers are indicated for patients with prior myocardial infarction, hypertension, and atrial fibrillation for control of ventricular rate. In the ADHERE registry, the subset of patients with HFNEF not treated with beta-blocker had a higher mortality potentially due to the higher incidence of coronary artery disease in this population. 
• Aldosterone receptor blockers are indicated in hypertension and reduce myocardial fibrosis, although no randomized controlled studies have been performed to evaluate their role in HFNEF. 
• Calcium channel blockers may improve exercise tolerance via the vasodilatory properties and nondihydropyridine calcium channel blockers are also used for ventricular rate control in patients with atrial fibrillation. Amlodipine has antianginal properties and is also indicated in hypertension. 
• Restoration of sinus rhythm should be considered if the patient remains symptomatic despite above efforts. 
• Use of digitalis or inotropes in patients with HFNEF is not indicated. 

RV failure is a clinical syndrome that impairs the ability of RV to fill with or eject blood. Clinical manifestations consist of fluid retention (peripheral edema, ascites, anasarca), low cardiac output (fatigue, exercise intolerance), and atrial or ventricular arrhythmias. 

Pathophysiology of RV failure involves pressure overload (chronic LV failure, pulmonary embolism, pulmonary hypertension, congenital heart disease where RV is the systemic ventricle), volume overload (tricuspid regurgitation, pulmonary valve insufficiency, atrial septal defect, carcinoid, rheumatic valve disease), ischemia, intrinsic myocardial disease (arrhythmogenic right ventricular dysplasia, sepsis, cardiomyopathy), pericardial disease, complex congenital heart disease. RV tolerates volume better than pressure overload. Compensatory mechanisms include RAAS, SNS, natriuretic peptides, endothelin system, and cytokines. These in turn lead to RV remodeling, altered gene expression, RV dysfunction, and eventually RV failure.

Management of RV failure includes treatment of the underlying cause; optimization of preload, afterload, and RV contractility; maintenance of sinus rhythm; and AV synchrony. Hypotension should be avoided since it can potentially lead to further RV ischemia. General measures should be applied such as sodium and fluid restriction, moderate physical activity avoiding isometric exercises, avoiding pregnancy, compliance with medications, avoiding or rapid treatment of precipitating factors such as sleep apnea, PE, sepsis, arrhythmia, ischemia, high altitude, anemia, and hypoxemia.

In patients with severe hemodynamically compromising RV failure, inotropic therapy is used with dobutamine 2-5 mcg/kg/min, dobutamine and nitric oxide, or dopamine alone. Milrinone is preferred if the patient is tachycardic or on beta-blockers.

Use of ACEI/ARB is beneficial if RV failure is secondary to LV failure; their efficacy is not known in isolated RV failure. The same recommendation applies for use of beta-blockers. The role of nesiritide in RV failure is not well defined. Use of digoxin in RV failure associated with COPD, not associated with LV dysfunction, appears not to improve exercise tolerance or RVEF.

Anticoagulation indications are standard for evidence of intracardiac thrombus, thromboembolic event, pulmonary arterial hypertension, paroxysmal or persistent atrial fibrillation/flutter, and mechanical right-sided valves.

Hypoxemia should be corrected and positive pressure should be avoided when mechanical ventilation is needed.

Atrial septostomy can be considered as a palliative measure in very symptomatic patients who failed standard therapy.

RV mechanical assist device is only indicated for RV failure secondary to LV failure or postcardiac transplantation.

Prognosis of RV failure is dependent on the etiology (better for volume overload, pulmonary stenosis, and Eisenmenger syndrome). Decreased exercise tolerance predicts poor survival.

Cardiorenal syndrome reflects advanced cardio-renal dysregulation manifested by acute heart failure, worsening renal function, and diuretic resistance. It is equally prevalent in patients with HFNEF as well as patients with heart failure and LV systolic dysfunction. Worsening renal function is one of the 3 predictors of increased mortality in hospitalized patients with heart failure regardless of the LVEF (ADHERE registry).

Cardiorenal syndrome can be classified into 5 types:

1. CR1 - Rapid worsening of cardiac function leading to acute kidney injury (HFNEF, acute heart failure, cardiogenic shock, and RV failure)
2. CR2 - Worsening renal function due to progression of chronic heart failure
3. CR3 - Abrupt and primary worsening of kidney function leading to acute cardiac dysfunction (heart failure, arrhythmia, ischemia)
4. CR4 - Chronic kidney disease leading to progressive cardiac dysfunction, LVH, diastolic dysfunction
5. CR5 - Combination of cardiac and renal dysfunction due to acute and chronic systemic conditions.

Pathophysiology for CR1 and CR2 is complex and multifactorial involving neurohormal activation (RAAS, SNS, AVP, natriuretic peptides, adenosine receptor activation), low arterial pressure, and high central venous pressure, leading to lower transglomerular perfusion pressure and decreased availability of diuretics to the proximal nephron. This results in an increased reabsorption of sodium and water and poor diuretic response; hence, diuretic resistance despite escalating doses of oral or intravenous diuretics and need for combination diuretic therapy or ultrafiltration.

A sudden increase in creatinine can be seen after initiation of diuretic therapy and is often mistaken on clinical examination as overdiuresis or intravascular depletion even in the presence of fluid overload, prompting most physicians to decrease and/or stop ACEI/ARB and/or diuretics. When diuresis or ultrafiltration is continued, an improvement in renal function, decrease in total body fluid, and increased response to diuretics as CVP is lowered is noted.

Use of low-dose dopamine to increase kidney perfusion has contradictory data with no randomized controlled studies.

Use of nesiritide, a synthetic natriuretic peptide, to increase diuresis has not been studied and should not be used unless the patient is in pulmonary edema and needs heart failure symptom relief. A meta-analysis of several trials using nesiritide suggests the potential of worsening renal function, although this has not been demonstrated in prospective trials.

The EVEREST trial showed that the vasopressin antagonist tolvaptan in acute heart failure in addition to diuretic therapy facilitates diuresis; however, it has no impact on mortality or hospitalizations.¹⁸

Currently, adenosine receptor antagonists are in trial to evaluate their role in acute heart failure.

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 facilitates diuresis in the patient with fluid overload. Inhibition of the RAAS and sympathetic nervous system produces vasodilation, thereby increasing cardiac output and decreasing myocardial oxygen demand.

Stage B includes asymptomatic patients with LV dysfunction from previous myocardial infarction, LV remodeling from left ventricular hypertrophy, and asymptomatic valvular dysfunction. In addition to heart failure education and aggressive risk factor modification, treatment with ACEI/ARB (SOLVD-prevention, SAVE, VALIANT) and/or beta-blockade (SOLVD prevention, SAVE, Capricorn) is indicated.

Evaluation for coronary revascularization either percutaneously or surgically as well as correction of valvular abnormalities may be indicated. Implantation of an internal cardiodefibrillator (ICD) for primary prevention of sudden death in patients with LVEF less than 30% more than 40 days post-myocardial infarction, is reasonable if expected survival is more than 1 year (MADIT II). There is less evidence for implantation of an ICD in patients with nonischemic cardiomyopathy, LVEF less than 30%, and no heart failure symptoms. There is no evidence for use of digoxin in these populations (DIG trial).¹⁹ Aldosterone receptor blockade with eplerenone is indicated for post–myocardial infarction LV dysfunction (EPHESUS).

Stage C includes patients with NYHA Class II and III heart failure and Stage D include patients with refractory end-stage heart failure (Class IV).

Therapeutic measures that improve symptoms and mortality and morbidity include use of ACEI/ARBs, beta-blockers, aldosterone receptor blockers, hydralazine and nitrates in combination, and cardiac resynchronization with or without an implantable cardioverter-defibrillator.

ACEIs are recommended for all patients with current or prior symptoms of heart failure and reduced LVEF unless contraindicated (SOLVD, SAVE, AIRE, TRACE, Consensus) (Class I ACCF/AHA recommendation, level of Evidence A). ACEIs block RAAS, decrease afterload, and prevent LV remodeling. They increase survival and decrease rate of heart failure hospitalization. Optimal dosing of ACEIs improves symptoms and decrease hospitalization, although it has no impact on mortality or LVEF (ATLAS). Side effects include, but are not limited to, worsening renal function, hyperkalemia, hypotension, cough, rash, change in taste, angioedema, and renal abnormalities in the fetus if administered during the first trimester of pregnancy. If cough develops, the patient can be switched to an ARB. If angioedema occurs, the ACEI should be immediately discontinued. There is a 1% chance that an ARB can also cause angioedema.

ARBs are recommended for patients with current or prior symptoms of heart failure and evidence of LV systolic dysfunction who are intolerant to ACEIs (Class I, level of Evidence A) (VAL-Heft, Charm-Alternative).²⁰ ARBs block RAAS, decrease afterload, and prevent LV remodeling. Their use increases survival and decreases hospitalization rate. ARBs are not superior to ACEIs. Pregnancy still constitutes a contraindication. Blood pressure, renal function, and potassium need to be monitored carefully.

ARBs are reasonable first-line therapy for patients with mild-to-moderate heart failure symptoms and LV dysfunction when patients are already taking them for other indications. (Class IIa, level of Evidence A). ARBs can also be used as add-on therapy for patients with refractory heart failure symptoms despite optimal heart failure therapy (Class IIb, level of Evidence B) (Charm-Added, Optimaal).²¹ Concomitant use of ACEIs, ARBs, and aldosterone receptor blockers is contraindicated due to risk of renal failure and hyperkalemia.

Use of one of the 3 beta-blockers proven to reduce mortality (bisoprolol-CIBIS II²² , carvedilol-Copernicus²³ , US carvedilol, metoprolol succinate-MERIT HF) is recommended for all stable patients with current or prior symptoms of heart failure and reduced LVEF, unless contraindicated (Class I, level of Evidence A). Beta-blockers inhibit sympathetic nervous system and decrease mortality, hospitalizations, and risk of sudden death. They improve LV function, exercise tolerance, and heart failure functional class.

Beta-blockers should not be used in patients with cardiogenic shock or requiring vasopressors. Titration should be performed carefully on an outpatient basis every 2 weeks to maximum tolerated or maximum recommended doses (bisoprolol start dose 1.25-10 mg daily, carvedilol 3.125-25 mg bid or 50 mg bid if patient’s weight exceeds 180 lb; metoprolol succinate 12.5-200 mg daily).

Aldosterone antagonists are weak diuretics that improve mortality and risk of sudden death by blocking aldosterone effects, therefore decreasing myocardial and vascular inflammation, collagen production, preventing apoptosis, decreasing RAAS and sympathetic nervous system stimulation, and acting as a membrane stabilizer preventing arrhythmia. Their use is a Class I, level of Evidence B recommendation for patients with moderately severe and severe heart failure and reduced LV systolic function (RALES) who can be carefully monitored for preserved renal function and normal potassium concentration.

Spironolactone 12.5-50 mg daily is indicated for Class III-IV patients with heart failure as add on to optimal heart failure therapy. Eplerenone 25-50 mg daily is indicated for post-myocardial infarction LV dysfunction with heart failure symptoms. Side effects of spironolactone include gynecomastia and impotence in men and breast tenderness and decreased libido in women. These hormonal side effects are not present in eplerenone. Both drugs are contraindicated if creatinine is more than 2 mg/dL in women and more than 2.5 mg/dL in men, or potassium is more than 5 mEg/dL. Follow-up renal function and potassium is recommended 7-10 days after initiation. Combined use of ACEIs or ARBs with aldosterone antagonists is contraindicated due to high risk of renal failure and hyperkalemia.

Hydralazine and nitrate combination reduces both preload and afterload. The combination is recommended to improve outcomes for patients self-described as African Americans with moderate-to-severe symptoms of heart failure on optimal medical therapy with ACEIs/ARBs, beta-blockers, and diuretics (Class I, level of Evidence B) (A-Heft trial).

The combination of hydralazine and nitrates can be added in patients with LV dysfunction who continue to have moderate-to-severe heart failure symptoms despite optimal heart failure therapy for symptom control (Class IIa, level of Evidence B).

A combination of hydralazine and nitrate can be reasonable in patients with current or prior symptoms of heart failure and LV dysfunction who cannot tolerate ACEIs or ARBs due to drug intolerance, hypotension, or renal insufficiency (Class IIb, level of Evidence C) (V-Heft).

Implantable cardioverter-defibrillators (ICDs) are a Class I, level of Evidence A recommendation for secondary prevention of sudden cardiac death in patients with current or prior heart failure symptoms and LV dysfunction who survived cardiac arrest, have evidence of ventricular fibrillation or hemodynamically unstable ventricular tachycardia (MADIT I).

ICD therapy is a Class I, level of Evidence A recommendation for primary prevention of sudden death in patients with nonischemic dilated cardiomyopathy or ischemic heart disease at least 40 days post-myocardial infarction who have an LVEF 35% or less, have NYHA Class II or III heart failure, are on optimal heart failure therapy, and have a life expectancy of more than 1 year. (SCD-Heft, MADIT II)

Patients with heart failure and low LVEF often have electrical conduction abnormalities, left bundle brunch block (LBBB) being common. Prognosis of patients with reduced LVEF and LBBB is worse than in patients without LBBB. LBBB leads to delayed activation of myocardium and therefore mechanical dyssynchrony, which clinically translates in inefficient LV contraction with increased LV end diastolic pressure, increased mitral regurgitation, and pulmonary wedge pressure, decreased cardiac output which leads to decreased exercise tolerance and progression of heart failure symptoms. Using RV and LV pacing can restore the mechanical synchrony (cardiac resynchronization) and can lead to LV reverse remodeling with decrease in cardiac pressures, mitral regurgitation and improved LVEF and exercise tolerance.

Cardiac resynchronization therapy (CRT) is indicated for patients with LVEF 35% or less, sinus rhythm, and NYHA Class III and IV symptoms who are on optimal medical therapy and have evidence of cardiac desynchrony as evident by QRS duration more than 120 msec with or without an ICD (Class I, level of Evidence A) (COMPANION, CARE-HF).²⁴ CRT with or without an ICD, maybe reasonable for patients with chronic atrial fibrillation, LVEF 35% or less, NYHA Class III and IV, QRS duration more than 120 msec on optimal medical therapy (Class IIa, level of Evidence B). CRT with or without an ICD is reasonable for patient who have frequent RV pacing, LVEF 35% or less, NYHA Class III and IV, and are on optimal heart failure therapy (Class IIa, level of Evidence C -- DAVID trial).

The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) studied the potential benefit of CRT with biventricular pacing in patients with an ejection fraction of 30% or less, a QRS duration of 130 msec or more, and New York Heart Association class I or II symptoms. Over the course of 4.5 years, 1820 patients were randomly assigned to receive CRT plus an implantable cardioverter-defibrillator (ICD) or ICD alone. CRT was associated with a significant reduction in left ventricular volumes and improvement in the ejection fraction. No significant difference occurred between the 2 groups studied in the overall risk of death.²⁵

Diuretic therapy improves symptoms by decreasing preload, afterload, and intracardiac filling pressures. Diuretics continue to be a Class I, level of Evidence C recommendation for heart failure. First-line diuretic therapy is a loop diuretic (furosemide, bumetanide, torsemide) in the lowest efficient dose either once or twice a day, although it can be used up to 3-4 times a day depending on the individual response and renal function. Response to diuretic therapy often depends on bioavailability of the drug (better on an empty stomach) and nutritional level (loop diuretics are bound to proteins for renal delivery). If the patient does not respond to the above strategy, a thiazide diuretic (hydrochlorothiazide or metolazone) can be added 30 minutes prior to the loop diuretic to enhance response. Potassium-sparing diuretics (spironolactone, eplerenone) are used usually in addition to the loop diuretics. Careful monitoring of renal function and potassium is necessary for all diuretics.

Inotropic therapy with either beta-agonists (dopamine, dobutamine) or PDEi (milrinone) is used for acute heart failure and evidence of cardiogenic shock with end-organ dysfunction (see acute heart failure for details). Long-term use of an infusion of a positive inotropic drug may be harmful and is not recommended for patients with current or prior symptoms of heart failure and reduced LVEF, except for palliation in patients with end-stage disease who cannot be stabilized with standard medical therapy (Class III, level of Evidence C).

In stage C and D patients with evidence of LV dysfunction and atrial fibrillation, treating them with a strategy of rhythm or rate control is reasonable (Class IIa, level of Evidence B) (AF-CHF).

Oxygen and morphine should be used for patients with respiratory distress due to heart failure and evidence of hypoxemia.

Drugs that can exacerbate heart failure should be avoided (NSAIDs, calcium channel blockers, most of antiarrhythmic drugs except class III) (Class I, level of Evidence B).

Use of nutritional supplements as well as hormonal therapies should be avoided in this population (Class III, level of Evidence C).

Comorbidities should be treated aggressively. Sleep apnea has an increased prevalence in heart failure and is associated with increased mortality due to further neurohormonal activation, although randomized controlled data is lacking. Anemia is also common in chronic heart failure. Whether anemia is a reflection of the severity of heart failure or contributes to worsening heart failure is not clear. Poor nutrition, ACEI, RAAS, inflammatory cytokines, hemodilution, and renal dysfunction are potential etiologies of anemia in heart failure. Anemia in heart failure is associated with increased mortality. Replacement therapy safety and efficacy is unknown, although iron supplementation seems to be beneficial and safe.

Dietary sodium restriction to 2-3 g/d is recommended. Fluid restriction to 2 L/d is recommended for patients with evidence of hyponatremia (Na <130 mEg/dL) or in patients with difficult to control fluid status despite high-dose diuretics and sodium restriction. Caloric supplementation is recommended for patients with evidence of cardiac cachexia.

Education and enrollment of family members in disease management programs is recommended for advanced heart failure patients.

Patients with refractory end-stage heart failure (stage D, NYHA Class IV) are often difficult to manage as outpatients. Therefore referral to a heart failure program with expertise in management of refractory heart failure is useful. Options of end-of-life care should be discussed with patient and family, including the option of ICD inactivation. Eligible patients should be referred for cardiac transplantation or mechanical circulatory support implantation either as a bridge to transplant or destination therapy (see Surgical Care). Although continuous infusion of inotropes maybe considered in this population for palliation of symptoms, intermittent infusion is not recommended.¹³ Education of patient and family about prognosis, functional status and survival is important for end-of-life decisions and care. Referral to palliative and hospice care to help with patient comfort and care maybe appropriate.

Surgical Care

• Coronary revascularization either percutaneously or surgically can improve LV function, heart failure symptoms, survival, and functional status.¹³ Patients with history of coronary artery disease should have comprehensive evaluation for evidence of ischemia even in the absence of symptoms to establish the amount of viable, hibernating myocardium. The increase in LVEF units can reach as much as 10% and can be achieved up to 1 year after revascularization.
• Surgical ventricular reconstruction in patients with heart failure with anteroapical myocardial infarction when coupled with surgical coronary revascularization has not shown to improve mortality, cardiac hospitalizations, or quality of life (STICH trial) (formerly called DOR procedure). Surgical ventricular reconstruction is not indicated for patients with nonischemic dilated cardiomyopathy and refractory end-stage heart failure (Class III, Level of Evidence C).
• Valvular surgery is indicated for primary valvular abnormalities leading to development of heart failure. Surgical repair/replacement of secondary valvular abnormalities related to the enlargement of the LV is not thought to be beneficial. The effectiveness of mitral valve repair or replacement for severe mitral regurgitation in refractory end-stage heart failure is not well established (Class IIb, Level of Evidence C).
• Assisted circulation in the treatment of heart failure include intraaortic balloon pump (IABP) and short- or long-term ventricular assist device (VAD), either paracorporeal or fully implantable.
  • IABP is inserted percutaneously via the femoral artery with the distal end of the pump placed just distally 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. IABP inflates in diastole, providing augmentation of coronary and carotid flow and deflates in systole, assisting decrease in afterload and LV intracardiac pressures, therefore decreasing myocardial oxygen consumption and increasing cardiac output.
    • IABP is indicated for patients with cardiogenic shock as a bridge to revascularization or VAD implantation. It can also provide stabilization of unstable angina prior to revascularization and assist with management of pulmonary edema especially in acute/severe mitral regurgitation while allowing definitive surgical correction. It also helps with pre- and postoperative management of patients with LV/RV dysfunction.
    • The absolute contraindications for IABP counterpulsation are aortic dissection, severe aortic regurgitation, presence of a large arteriovenous shunt, and severe coagulopathy.
    • The relative contraindications are severe peripheral vascular disease, recent thrombolytic therapy, and bleeding diathesis
    • IABP complications include vascular access problems at the site of cannulation, limb ischemia, mild thrombocytopenia, infection, bleeding, thromboembolic events to other organs including kidneys or intestines
  • VAD can be used short term in postcardiotomy shock patients, post-myocardial infarction cardiogenic shock patients, or patients with acute myocarditis or refractory ventricular tachyarrhythmia and in patients with decompensated chronic heart failure. Long-term support can be provided by implantable VAD—either pulsatile (Thoratec, Heartmate XVE) or axial flow device (Heartmate II). The long-term support can be used as a bridge to transplant or as destination therapy when patients are not transplant candidates. Data from the REMATCH trial supports better survival in patients with end-stage heart failure treated with LVAD rather than inotropes. Complications from VAD include bleeding, infections, thromboembolic events, mechanical failure, right heart failure, multisystem organ failure, and increased sensitization.
• Cardiac transplantation is indicated for patients with end-stage heart failure who have failed maximal medical and surgical therapy as the last option for improved survival and quality of life. Other indications for cardiac transplantation include end-stage restrictive cardiomyopathy or constrictive pericarditis, end-stage hypertrophic cardiomyopathy, refractory angina, refractory ventricular tachycardia, complex congenital heart disease, acute myocarditis unresponsive to maximal medical therapy, and failed cardiac allograft either from rejection or coronary disease. Patients eligible for cardiac transplantation have to be younger than 70 years, have no evidence of permanent end organ dysfunction, cancer, severe pulmonary hypertension, have good social support, and be compliant.

Consultations

Consultation with subspecialists depends on the underlying cause of CHF. Heart failure is now an area of subspecialization within cardiology.

• If the acute episode is attributed to an acute MI, acute cardiac ischemia, or acute dysrhythmia, consultation with a cardiologist is warranted.
• If the episode is attributed to fluid overload in patients with renal failure, consultation with a nephrologist is indicated for emergent/urgent hemodialysis.
• If heart failure results from acute valvular dysfunction, consultation with a cardiothoracic surgeon and a cardiologist for urgent valve replacement may be indicated, depending on the integrity of the valve involved.
• In patients who develop cardiogenic shock, consultation with a cardiologist is generally indicated in order to rapidly diagnose and aggressively treat with various modalities (pharmacologic and/or mechanical), to maximize cardiac performance and improve hemodynamics, and, in some cases, to place an intraaortic balloon pump to serve as a temporizing measure prior to surgery (ie, for valve replacement or coronary revascularization).

Diet

Patients admitted with heart failure or pulmonary edema should maintain a low-salt diet in order to minimize fluid overload. Monitor fluid balance closely.

Activity

• Patients with decompensated heart failure should be placed on complete bed rest until their decompensation is resolved. This is necessary to maximally reduce myocardial oxygen demand and to avoid exacerbation of the abnormal hemodynamics and symptoms of heart failure.
• Once the patient with heart failure has been stabilized, activity should be gradually and progressively increased. Emphasize the importance of cardiac rehabilitation to all patients with heart failure who require improved cardiac fitness. Encourage patients to exercise daily for at least 20-30 minutes in a low-intensity, endurance-enhancing activity such as walking, biking, or swimming. Regular exercise improves the quality of life for these patients and improves efficiency of oxygen utilization at the tissue level, thus reducing the workload of the heart in the role of oxygen delivery to end organs and muscles.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Human B-type natriuretic peptides (hBNPs)

Dilate veins and arteries. Used in the treatment of acute severe CHF.

Nesiritide (Natrecor)

Recombinant DNA form of hBNP, which dilates veins and arteries. hBNP binds to particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells. Binding to receptor causes increase in cGMP, which serves as second messenger to dilate veins and arteries. Reduces PCWP and improves dyspnea in patients with acutely decompensated CHF.

Dosing

Adult

2 mcg/kg IV bolus over 60 sec; follow by 0.01 mcg/kg/min continuous infusion; bolus volume (mL) = 0.33 X patient weight (kg); infusion flow rate of bolus (mL/h) = 0.1 X patient weight (kg)

Pediatric

Not established

Interactions

Concurrent administration with ACE inhibitors and other vasodilators may cause hypotension

Contraindications

Documented hypersensitivity; systolic blood pressure <90 mm Hg; patients suspected of having or known to have low cardiac filling pressures, severe aortic or mitral stenosis, restrictive or obstructive cardiomyopathy, constrictive pericarditis, pericardial tamponade, conditions in which cardiac output is dependent upon venous return

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not initiate at dose higher than recommended; may affect renal function in patients whose renal function may depend on activity of RAAS; may cause hypotension (administer in settings where blood pressure can be monitored closely); discontinue drug if hypotension develops; VT, nonsustained VT, headache, abdominal pain, back pain, insomnia, anxiety, angina pectoris, nausea, and vomiting may occur

Diuretics

May improve symptoms of venous congestion through elimination of retained fluid and preload reduction. Used in CHF. Help counteract the sodium and water retention caused by activation of the RAAS.

Torsemide (Demadex)

Acts from within the lumen of the thick ascending portion of the loop of Henle, where inhibits the Na/K/2Cl carrier system. Increases urinary excretion of sodium, chloride, and water, but does not significantly alter glomerular filtration rate, renal plasma flow, or acid-base balance.

Dosing

Adult

10-20 mg PO/IV qd; not to exceed 200 mg/d; titrate dose upward by approximately doubling the dose until desired diuretic effect reached; doses >200 mg/d not adequately studied

Pediatric

Not established

Interactions

Potential for salicylate toxicity in patients on high doses of salicylates and torsemide is significant (salicylates and torsemide compete for secretion by renal tubules); NSAIDs may decrease efficacy of torsemide; torsemide increases potential for lithium toxicity; simultaneous use of torsemide and cholestyramine not recommended as cholestyramine decreases absorption of oral torsemide; probenicid decreases diuretic effect of torsemide; coadministration with aminoglycosides may increase ototoxicity; enzyme inducers including phenytoin, carbamazepine, and phenobarbital may reduce efficacy of torsemide; hypotensive effects of ACE inhibitors may increase when administered concomitantly with torsemide; arrhythmias may occur in patients taking digoxin if diuretic-induced electrolyte disturbances occur

Contraindications

Documented hypersensitivity to drug or sulfonylureas; anuria; <18 y

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor for lithium toxicity in patients taking lithium; measure electrolytes, calcium, magnesium, BUN, and uric acid (frequently at first, then regularly) hyperglycemia may occur but rare; caution in hepatic failure (may precipitate hepatic coma)

Furosemide (Lasix)

Increase excretion of water by interfering with chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Bumetanide does not appear to act in the distal renal tubule. Dose must be individualized to patient. Depending on response, administer at small dose increments until desired diuresis occurs.

Dosing

Adult

20-80 mg/d PO/IV/IM; titrate up to 600 mg/d for severe edematous states; depending on response, administer at increments of 20-40 mg no sooner than 6-8 h after previous dose

Pediatric

1-2 mg/kg/dose PO; not to exceed 6 mg/kg/dose; not to administer more frequently than q6h

Interactions

Potential for salicylate toxicity in patients on high doses of salicylates and loop diuretics significant (salicylates and loop diuretics compete for secretion by renal tubules); NSAIDs may decrease efficacy of loop diuretics; loop diuretics increase potential for lithium toxicity; simultaneous use of loop diuretics and cholestyramine not recommended as cholestyramine decreases absorption of loop diuretics; probenecid decreases effect loop diuretics; coadministration with aminoglycosides may increase ototoxicity; enzyme inducers, including phenytoin, carbamazepine, and phenobarbital, may reduce efficacy of loop diuretics; hypotensive effects of ACE inhibitors may increase when administered concomitantly with loop diuretics; arrhythmias may occur in patients taking digoxin if diuretic-induced electrolyte disturbances occur

Contraindications

Documented hypersensitivity; hepatic coma, anuria, increasing anuria, and state of severe electrolyte depletion

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Torsemide is pregnancy category B; perform frequent serum electrolyte, CO₂, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter; profound diuresis with fluid and electrolyte loss may occur; caution in hepatic failure

Spironolactone (Aldactone)

For management of edema resulting from excessive aldosterone excretion. Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

Dosing

Adult

25-200 mg/d PO qd or divided bid

Pediatric

1.5-3.5 mg/kg/d PO qd or divided qid

Interactions

May decrease effect of anticoagulants; potassium and potassium-sparing diuretics may increase toxicity of spironolactone

Contraindications

Documented hypersensitivity; anuria, renal failure, hyperkalemia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal and hepatic impairment

Bumetanide (Bumex)

Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced.

Individualize dose to patient. Start at 1-2 mg IV; titrate to as high as 10 mg/d. Rarely, doses as high as 24 mg/d are used for edema but generally are not required for treatment of hyperkalemia.

One mg of bumetanide is equivalent to approximately 40 mg of furosemide.

Dosing

Adult

0.5-2 mg/dose PO 1-2 times/d; titrate dose upward until desired diuretic effect is reached; not to exceed 10 mg/d; alternatively, 0.5-1 mg/dose IV/IM; not to exceed 10 mg/d

Pediatric

Not established

Interactions

Decreases effects of indomethacin and probenecid; may increase lithium toxicity

Contraindications

Documented hypersensitivity; anuria, increasing azotemia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Profound diuresis, with fluid and electrolyte loss may occur; caution in hepatic failure

Angiotensin receptor blockers

Interfere with the binding of formed Ang II to its endogenous receptor. Used primarily when patients are intolerant of ACE inhibitors because of adverse effects but are gaining wider use as first-line vasodilator agents. Equally effective as ACE inhibitors.

Valsartan (Diovan)

Prodrug that produces direct antagonism of angiotensin II receptors. Displaces angiotensin II from AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For use in patients unable to tolerate ACE inhibitors.

Dosing

Adult

80 mg/d PO; may increase to 160 mg/d if needed

Pediatric

Not established

Interactions

May increase digoxin, lithium, and allopurinol levels; probenecid may increase valsartan levels; coadministration with diuretics, increase hypotensive effects; NSAIDs may reduce hypotensive effects of valsartan; may increase risk of hyperkalemia if taken concurrently with potassium supplements or other potassium-sparing diuretics

Contraindications

Documented hypersensitivity; severe hepatic insufficiency, biliary cirrhosis or obstruction, primary hyperaldosterism, bilateral renal artery stenosis

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in hyperkalemia, suspected bilateral renal artery stenosis or solitary kidney with unilateral RAS

Losartan (Cozaar)

Block the vasoconstrictor and aldosterone-secreting effects of Ang II. May induce more complete inhibition of RAAS than ACE inhibitors, do not affect response to BK, and are less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.

Dosing

Adult

25-100 mg PO qd/bid

Pediatric

Not established

Interactions

Ketoconazole, sulfaphenazole, and phenobarbital may decrease effects; cimetidine may increase effects of losartan and candesartan

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal impairment (serum creatinine >3.5), severe aortic stenosis, unilateral or bilateral renal artery stenosis or severe CHF; watch for serum potassium

Candesartan (Atacand)

Blocks vasoconstriction and aldosterone-secreting effects of angiotensin II. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. Use in patients unable to tolerate ACE inhibitors.

Angiotensin II receptor blockers reduce blood pressure and proteinuria, protecting renal function, and delaying onset of end-stage renal disease.

Dosing

Adult

8-16 mg/d PO initially; not to exceed 32 mg/d

Pediatric

Not established

Interactions

May increase digoxin, lithium, and allopurinol levels; probenecid may increase candesartan levels; coadministration with diuretics, increase hypotensive effects; NSAIDs may reduce hypotensive effects of candesartan; may increase risk of hyperkalemia if taken concurrently with potassium supplements or other potassium-sparing diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal impairment (serum creatinine >3.5), valvular stenosis, or severe congestive heart failure; watch for serum potassium

Vasodilators

The use of a vasodilators reduces SVR, thus allowing more forward flow and improving cardiac output. Indicated for CHF.

Nitroglycerin (Nitrostat, Deponit, Transderm-Nitro Patch)

Isosorbide dinitrate (Isordil), Isosorbide mononitrate (Imdur)--First-line therapy for patients who are not hypotensive. Provides excellent and reliable preload reduction. Higher doses provide mild afterload reduction. Has rapid onset and offset (both within minutes), allowing rapid clinical effects and rapid discontinuation of effects in adverse clinical situations.

Dosing

Adult

Nitroglycerin
Topical: Apply topically 1/2-2" q6h
Transdermal: 0.3-0.6 mg/h qd
Intravenous: 0.2-10 mcg/kg/min IV infusion; titrate by 10 mcg/min increments until desired hemodynamic effect achieved or until maximally tolerated dose reached
Spray: Single spray (0.4 mg), which is equivalent to single 1/150 sublingual; dose may be repeated q3-5min as hemodynamics permit, up to maximum of 1.2 mg
Isosorbide dinitrate: 10-80 mg PO bid/qid
Isosorbide mononitrate: 30-90 PO mg qd

Pediatric

Not established

Interactions

Sildenafil (Viagra) taken within 24 h may induce precipitous and potentially lethal decreases in blood pressure; aspirin may increase nitrate serum concentrations; marked symptomatic orthostatic hypotension may occur with coadministration of calcium channel blockers (dose adjustment of either agent may be necessary)

Contraindications

Documented sensitivity; hypotension; severe anemia; shock; postural hypotension; head trauma; closed-angle glaucoma; cerebral hemorrhage

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Extreme caution in right ventricle infarction because of importance of adequate preload in maintaining cardiac output; caution in patients with severe aortic stenosis because of needed adequate preload to maintain cardiac output

Hydralazine (Apresoline)

Decreases systemic resistance through direct vasodilation of arterioles.

Dosing

Adult

10-25 mg PO tid/qid initially; adjust dose based on individual response; typical dose range is 200-600 mg PO qd in 2-4 divided doses

Pediatric

Not established

Interactions

MAOIs and beta-blockers may increase hydralazine toxicity; pharmacologic effects of hydralazine may be decreased by indomethacin

Contraindications

Documented hypersensitivity; mitral valve rheumatic heart disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hydralazine has been implicated in myocardial infarction; caution in suspected coronary artery disease

Isosorbide dinitrate and hydralazine (BiDil)

Fixed-dose combination of isosorbide dinitrate (20 mg/tab), a vasodilator with effects on both arteries and veins, and hydralazine (37.5 mg/tab), a predominantly arterial vasodilator. Indicated for heart failure in black patients, based in part on results from the African American Heart Failure Trial. Two previous trials in the general population of patients with severe heart failure found no benefit but suggested a benefit in black patients. Compared with placebo, black patients showed a 43% reduction in mortality rate, a 39% decrease in hospitalization rate, and a decrease in symptoms from heart failure.

Dosing

Adult

1 tab PO tid; may titrate upward, not to exceed 2 tab tid

Pediatric

Not established

Interactions

Hydralazine may increase propranolol, metoprolol, and lisinopril AUC and C_max; isosorbide dinitrate may cause additive vasodilating effects with other vasodilators (eg, sildenafil [Viagra], vardenafil [Levitra]), especially when coadministered with alcohol

Contraindications

Documented hypersensitivity; allergy to organic nitrates

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause symptomatic hypotension even with small doses; careful hemodynamic monitoring required if administered in patients with acute MI
Hydralazine: May cause SLE-like symptoms, including glomerulonephritis, tachycardia, hypotension, and peripheral neuritis (pyridoxine therapy may be required)
Isosorbide dinitrate: If hypotension exists, may aggravate angina associated with hypertrophic cardiomyopathy

Nitroprusside (Nitropress)

Produces vasodilation and increases inotropic activity of the heart. At higher dosages, may exacerbate myocardial ischemia by increasing heart rate.

Dosing

Adult

Begin infusion at 0.3-0.5 mcg/kg/min IV and use increments of 0.5 mcg/kg/min; titrate to desired effect; average dose is 1-6 mcg/kg/min
Infusion rates >10 mcg/kg/min IV may lead to cyanide toxicity

Pediatric

Administer as in adults

Interactions

Effects are additive when administered with other hypotensive agents

Contraindications

Documented hypersensitivity; subaortic stenosis, decreased cerebral perfusion, arteriovenous shunt or coarctation of aorta (eg, compensatory hypertension); relatively contraindicated in atrial fibrillation or flutter with rapid ventricular rate

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in increased intracranial pressure, hepatic failure, severe renal impairment, and hypothyroidism; in renal or hepatic insufficiency, nitroprusside levels may increase and can cause cyanide toxicity; sodium nitroprusside has ability to lower blood pressure and thus should be used only in those patients with mean arterial pressures >70 mm Hg

Inotropic agents

Augment both coronary and cerebral blood flow present during the low flow states. Used in severe acute CHF with low cardiac output.

Digoxin (Lanoxin, Lanoxicaps)

Cardiac glycoside with direct inotropic effects in addition to indirect effects on cardiovascular system. Acts directly on cardiac muscle, increasing myocardial systolic contractions. Indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Dosing

Adult

0.125-0.375 mg PO qd

Pediatric

Not established

Interactions

IV calcium may produce arrhythmias in digitalized patients; medications that may increase digoxin levels include alprazolam, benzodiazepines, bepridil, captopril, cyclosporine, propafenone, propantheline, quinidine, diltiazem, aminoglycosides, oral amiodarone, anticholinergics, diphenoxylate, erythromycin, felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine, ibuprofen, indomethacin, esmolol, tetracycline, tolbutamide, and verapamil; medications that may decrease serum digoxin levels include aminoglutethimide, antihistamines, cholestyramine, neomycin, penicillamine, aminoglycosides, oral colestipol, hydantoins, hypoglycemic agents, antineoplastic treatment combinations (including carmustine, bleomycin, methotrexate, cytarabine, doxorubicin, cyclophosphamide, vincristine, procarbazine), aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid

Contraindications

Documented hypersensitivity; beriberi heart disease, idiopathic hypertrophic subaortic stenosis, constrictive pericarditis, and carotid sinus syndrome

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hypokalemia may reduce positive inotropic effect of digitalis; hypercalcemia predisposes patient to digitalis toxicity, and hypocalcemia can make digoxin ineffective until serum calcium levels are normal; magnesium replacement therapy must be instituted in patients with hypomagnesemia to prevent digitalis toxicity; patients diagnosed with incomplete AV block may progress to complete block when treated with digoxin; exercise caution in hypothyroidism, hypoxia, and acute myocarditis; adjust dose in renal impairment; highly toxic (overdoses can be fatal)

Dobutamine (Dobutrex)

Produces vasodilation and increases inotropic state. At higher dosages may cause increased heart rate, exacerbating myocardial ischemia.

Dosing

Adult

0.5 mcg/kg/min IV initially; titrate until desired therapeutic effect attained

Pediatric

Administer as in adults

Interactions

Beta-adrenergic blockers antagonize effects of dobutamine; general anesthetics may increase toxicity

Contraindications

Documented hypersensitivity; idiopathic hypertrophic subaortic stenosis and atrial fibrillation or flutter

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Following a myocardial infarction use with extreme caution; hypovolemic state should be corrected before using this drug

Dopamine (Intropin)

Naturally occurring catecholamine that acts as a precursor to norepinephrine. Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dose-dependent. Low-dose use is associated with dilation within renal and splanchnic vasculature, resulting in enhanced diuresis. Moderate doses enhance cardiac contractility and heart rate. Higher doses cause increased afterload through peripheral vasoconstriction.
Administer by continuous IV infusion. Usually used in severe heart failure. Reserved for patients with moderate hypotension (eg, systolic blood pressure 70-90 mm Hg). Typically, moderate or higher doses used.

Dosing

Adult

5 mcg/kg/min IV continuous infusion initially; titrate to blood pressure stabilization; not to exceed 20 mcg/kg/min

Pediatric

Not established

Interactions

Phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects of dopamine

Contraindications

Documented hypersensitivity; pheochromocytoma; ventricular fibrillation; obstructive hypertrophic cardiomyopathy

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor urine flow, cardiac output, pulmonary wedge pressure, and blood pressure closely during infusion; prior to infusion, correct hypovolemia with either whole blood or plasma as indicated; monitoring central venous pressure or LV filling pressure may be helpful in detecting and treating hypovolemia; 10- to 20-mcg/kg/min doses increase levels of peripheral vasoconstriction and afterload; may increase tachyarrhythmias and cause greater myocardial oxygen consumption and cardiac ischemia; alkaline solutions may inactivate dopamine if administered through same IV line

Norepinephrine (Levophed)

Naturally occurring catecholamine with potent alpha-receptor and mild beta-receptor activity. Stimulates beta1- and alpha-adrenergic receptors, resulting in increased cardiac muscle contractility, heart rate, and vasoconstriction. Increases blood pressure and afterload. Increased afterload may result in decreased cardiac output, increased myocardial oxygen demand, and cardiac ischemia. Generally reserved for use in patients with severe hypotension (eg, systolic blood pressure <70 mm Hg) or hypotension unresponsive to other medication.

Dosing

Adult

0.5-1 mcg/min IV infusion initially, titrated to effect; not to exceed 30 mcg/min

Pediatric

Not established

Interactions

Enhances pressor response of norepinephrine by blocking reflex bradycardia caused by norepinephrine

Contraindications

Documented hypersensitivity; obstructive hypertrophic cardiomyopathy; peripheral or mesenteric vascular thrombosis because ischemia may be increased and area of infarct extended

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause tachyarrhythmia (especially sinus tachycardia), increased myocardial oxygen demand, and cardiac ischemia; alkaline solutions may inactivate norepinephrine if administered through same IV line; extravasation may cause severe tissue necrosis, (administer into a large vein); if extravasation occurs, immediately infiltrate 5-10 mg of phentolamine (diluted in 10-15 mL of isotonic sodium chloride solution) to prevent necrosis; caution in occlusive vascular disease; if possible, correct blood-volume depletion before administration

Phosphodiesterase enzyme inhibitors

Inhibition of type III cAMP phosphodiesterase(s) and other mechanisms. Bipyridine-positive inotropic agents and vasodilators with little chronotropic activity. Different from both digitalis glycosides and catecholamines in mode of action. These agents are balanced vasodilators, having equal reduction in both afterload and preload, to same degree as ACE inhibitors.

Milrinone (Primacor)

Milrinone: Positive inotropic agent and vasodilator. Results in reduced afterload, reduced preload, and increased cardiac output. Several studies comparing milrinone to dobutamine have demonstrated that milrinone showed greater improvements in preload and afterload and improvements in cardiac output, without significant increases in myocardial oxygen consumption.

Dosing

Adult

50 mcg/kg IV loading dose over 10 min, followed by continuous infusion at 0.25-1.0 mcg/kg/min; titrate to maintain adequate systolic blood pressure and cardiac output

Pediatric

Not established

Interactions

Precipitates in presence of furosemide

Contraindications

Documented hypersensitivity; obstructive hypertrophic cardiomyopathy

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor fluids, electrolyte changes, and renal function during therapy; excessive diuresis may increase potassium loss and predispose digitalized patients to arrhythmias (correct hypokalemia with potassium supplementation prior to treatment); slow rates or stop infusion in patients showing excessive decreases in blood pressure; previous vigorous diuretic therapy has caused significant decreases in cardiac filling pressure; administer cautiously and monitor blood pressure, heart rate, and clinical symptomatology

Inamrinone (Inocor)

Produces vasodilation and increases inotropic state. More likely to cause tachycardia than dobutamine; may exacerbate myocardial ischemia.

Dosing

Adult

0.75 mg/kg IV bolus slowly over 2-3 min; maintenance infusion is 5.0-10 mcg/kg/min; not to exceed 10 mg/kg; adjust dose according to patient response; not to exceed 10 mg/kg

Pediatric

Administer as in adults

Interactions

Coadministration with diuretics, may result in hypovolemia and decrease in filling pressure; cardiac glycosides have additive effects on amrinone

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Discontinue therapy if symptoms of liver toxicity develop; correct hypokalemic states before giving therapy

Beta-adrenergic blockers

Inhibit chronotropic, inotropic, and vasodilatory responses to beta-adrenergic stimulation. Particularly useful in the patient with elevated blood pressure and relative tachycardia. Inhibits sympathetic nervous stimulation, particularly E and norepinephrine and blocks alpha1-adrenergic vasoconstrictor activity. Has moderate afterload reduction properties and results in slight preload reduction as well.

Carvedilol (Coreg)

Nonselective beta- and alpha1-adrenergic blocker. Does not appear to have intrinsic sympathomimetic activity. May reduce cardiac output and decrease peripheral vascular resistance.

Dosing

Adult

3.125 mg PO bid; maintain for 1-2 wk if tolerated and double dose q1-4wk to maximally tolerated dose or to maximum of 50 mg bid

Pediatric

Not established

Interactions

Rifampin, barbiturates, cholestyramine, colestipol, NSAIDs, salicylates, and penicillins may decrease effects; carvedilol may increase effects of antidiabetic agents, digoxin, and calcium channel blockers; concurrent administration with clonidine may increase blood pressure and decrease heart rate; carvedilol may decrease effect of sulfonylureas; cimetidine, fluoxetine, paroxetine, and propafenone may increase carvedilol levels

Contraindications

Documented hypersensitivity; hypotension; bradycardia; AV/SA node disease; cardiogenic shock; overt cardiac failure

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in CHF being treated with digitalis, diuretics, or ACE inhibitors (AV conduction may be slowed); discontinue if liver impairment occurs; caution in peripheral vascular disease, hyperthyroidism, and diabetes mellitus

Metoprolol XL (Toprol)

Selective beta1-adrenergic blocker at lower doses; inhibits beta2-receptors at higher doses. Does not have intrinsic sympathomimetic activity. May reduce cardiac output, but does not appear to decrease peripheral vascular resistance to any significant degree.

Dosing

Adult

100 mg PO qd; titrate to maximum dose of 400 mg/d PO in 1-2 divided doses.

Pediatric

Not established

Interactions

Rifampin, barbiturates, cholestyramine, colestipol, NSAIDs, salicylates, and penicillins may decrease effects; high doses of metoprolol XL may increase effects of antidiabetic agents, digoxin, and calcium-channel blockers because of beta2-receptor inhibition; concurrent administration with clonidine may increase blood pressure and decrease heart rate; metoprolol XL may decrease effect of sulfonylureas; cimetidine, fluoxetine, paroxetine, and propafenone may increase levels

Contraindications

Documented hypersensitivity; hypotension; bradycardia; AV/SA node disease; cardiogenic shock; overt cardiac failure

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in CHF being treated with digitalis, diuretics, or ACE inhibitors (AV conduction may be slowed); discontinue if liver impairment occurs; caution in peripheral vascular disease (at higher doses) and hyperthyroidism

Aldosterone Inhibitor

Decreases blood pressure and sodium reabsorption.

Eplerenone (Inspra)

Selectively blocks aldosterone at the mineralocorticoid receptors in epithelial (eg, kidney) and nonepithelial (eg, heart, blood vessels, and brain) tissues; thus, decreases blood pressure and sodium reabsorption. Indicated to improve survival for congestive heart failure or left ventricular dysfunction following acute MI. Compared to placebo, a significant risk reduction (15%) was observed.

Dosing

Adult

25 mg PO qd initially, titrate as tolerated up to 50 mg/d within 4 wk

Pediatric

Not established

Interactions

CYP450 3A4 substrate; potent CYP3A4 inhibitors (eg, ketoconazole) increase serum levels about 5-fold; less potent CYP3A4 inhibitors (eg, erythromycin, saquinavir, verapamil, fluconazole) increase serum levels about 2-fold; grapefruit juice increases serum levels about 25%; coadministration with potassium supplements, salt substitutes, or drugs known to increase serum potassium (eg, amiloride, spironolactone, triamterene, ACE inhibitors, angiotensin II inhibitors) increases risk of hyperkalemia

Contraindications

Documented hypersensitivity; hyperkalemia or coadministration with drugs causing increased potassium; type 2 diabetes with microalbuminuria; moderate-to-severe renal insufficiency (eg, CrCl <50 mL/min or serum creatinine >2 mg/dL in males, or >1.8 mg/dL in females)

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause hyperkalemia, headache, and dizziness; caution with hepatic insufficiency

Angiotensin-converting Enzyme (ACE) Inhibitors

Inhibit renal systemic and tissue generation of Ang II by ACE; decrease metabolism of bradykinin (BK). Their blockade of Ang II and the delayed clearance of BK by ACE blocks the direct vasoconstriction of Ang II, as well as the activation of the sympathetic nervous system, and promotes arterial and venous dilation. In addition, ACE inhibitors reduce intracavitary pressures and diminish Wass stress, thereby decreasing myocardial oxygen demand. They inhibit the release of aldosterone, thereby reducing intravascular volume and preload. Among vasodilators, the ACE inhibitors are the most balanced vasodilators, having an equal effect on reducing both afterload and preload.

Ramipril (Altace)

Prevent conversion of Ang I to Ang II (a potent vasoconstrictor), resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Dosing

Adult

2.5 mg PO bid initially; titrate up to 5 mg bid, when possible

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects of ramipril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases ramipril levels; probenecid may increase ramipril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics

Contraindications

Documented hypersensitivity; history of angioedema

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal impairment, valvular stenosis, or severe congestive heart failure

Enalapril (Vasotec)

Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.
Helps control blood pressure and proteinuria. Decreases pulmonary-to-systemic flow ratio in the catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance. Has favorable clinical effect when administered over a long period. Helps prevent potassium loss in distal tubules. Body conserves potassium; thus, less oral potassium supplementation needed.
Patients who develop a cough, angioedema, bronchospasm, or other hypersensitivity reactions after starting ACEIs should receive an angiotensin-receptor blocker.

Dosing

Adult

2.5-5 mg/d PO (increase as necessary); dosing range: 10-40 mg/d PO in 1-2 divided doses; alternatively, 1.25 mg/dose IV over 5 min q6h

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects of enalapril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases enalapril levels; probenecid may increase enalapril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal impairment, valvular stenosis, or severe congestive heart failure; IV formulation not recommended in managing neonatal hypertension because of risk of acute renal failure and oliguria

Quinapril (Accupril)

Prevent conversion of Ang I to Ang II (a potent vasoconstrictor), resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Dosing

Adult

10 mg PO qd

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects of enalapril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases enalapril levels; probenecid may increase enalapril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics

Contraindications

Documented hypersensitivity; angioedema

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal impairment (serum creatinine >3.5), valvular stenosis, or severe congestive heart failure; watch for serum potassium

Captopril (Capoten)

Lisinopril (Prinivil, Zestril); Ramipril (Altace); Fosinopril (Monopril)--Prevent conversion of Ang I to Ang II (a potent vasoconstrictor), resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Dosing

Adult

6.25-12.5 mg PO tid; not to exceed 150 mg tid

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects of ACE inhibitors; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases ACE inhibitor levels; probenecid may increase ACE inhibitor levels; hypotensive effects of ACE inhibitors may be enhanced when concurrently administered with diuretics

Contraindications

Documented hypersensitivity; renal impairment, angioedema

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in renal impairment, valvular stenosis, or severe CHF

Lisinopril (Prinivil, Zestril)

Prevent conversion of Ang I to Ang II (a potent vasoconstrictor), resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Dosing

Adult

10 mg/d PO qd or divided bid; increase by 5-10 mg/d at 1- to 2-wk intervals; not to exceed 80 mg/d

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects of lisinopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases lisinopril levels; probenecid may increase lisinopril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal impairment, valvular stenosis, or severe congestive heart failure

Follow-up

Further Inpatient Care

• After the patient has been initially stabilized and the acute episode of heart failure has been resolved, further inpatient care depends on the underlying cause of heart failure.
• Place patients with heart failure in a monitored bed to watch for acute dysrhythmias. Pay strict attention to the patient's fluid balance by closely monitoring fluid input and output. Maintain patients who are fluid-overloaded in negative fluid balance through the use of diuretics, or, if necessary in patients with renal failure, hemodialysis with ultrafiltration.
• Check cardiac enzymes to evaluate for myocardial infarction. Slight elevations in cardiac enzymes can occur with decompensated heart failure in the absence of myocardial infarction because of coronary thrombosis.
• Perform coronary angiography when heart failure is the result of an acute coronary syndrome, either unstable angina or myocardial infarction. Stress testing can also be performed later during hospitalization to evaluate for reversible ischemia in patients without acute coronary syndromes but who have prior symptoms of angina or who have a high likelihood of coronary artery disease as the cause of LV dysfunction.
• Order echocardiography at the earliest possible moment to evaluate for evidence of acute valvular dysfunction and wall motion abnormalities and to assess the patient's systolic and diastolic function. Since the long-term therapy of patients with heart failure differs significantly between those with predominantly systolic dysfunction and those with preserved LV systolic function, it is absolutely essential that all patients with heart failure have echocardiographic evaluation of cardiac function, chamber size, and valve function.
• In most patients with acute heart failure, oral vasodilator therapy, most commonly ACE inhibitors, can be used as first-line therapy to reverse the cardiac decompensation and to restore optimal cardiac function. The clinician must be extremely cautious with vasodilator therapy only in patients with severe aortic or mitral stenosis or in those with obstructive cardiomyopathy. Patients who required intravenous inotropic support should be weaned off as quickly as possible and should have their vasodilator therapy maximized quickly in order to avoid the risk of adverse cardiac events from increased myocardial oxygen consumption leading to ischemia.
• Patients in whom pulmonary edema was caused by dietary factors or medication noncompliance need strict counseling and education to help prevent recurrence.

Further Outpatient Care

• Focus further outpatient care of patients with heart failure on maximizing some or all of the medical modalities used in their treatment. Undertake further assessment of the clinical and hemodynamic effects of that therapy fairly soon after discharge and at regular intervals.
• Precise definition and aggressive treatment of all reversible causes for heart failure is absolutely essential. For instance, patients with myocardial ischemia (particularly those with reduced systolic function) should be promptly evaluated with noninvasive and/or invasive evaluations of coronary perfusion, and they should be promptly referred for revascularization if they are suitable candidates for such revascularization. Similarly, patients with severe valvular disease, assessed clinically and echocardiographically, should be promptly referred for cardiac catheterization. If a patient is a suitable candidate for valve replacement or repair, he or she should undergo prompt surgical therapy.
• Patients with nonreversible NYHA class IV heart failure who are younger than 70 years and facing the likely prospect of death within the next 6-24 months, despite maximal medical therapy, and who are not candidates for beneficial surgical therapy, should be promptly referred to a cardiac transplant center for consideration of mechanical circulatory support and cardiac transplantation.
• Screen patients with cardiomyopathy and heart failure for candidacy for cardioverter/defibrillator implantation because the risk of sudden death in these patients is considerable.

Inpatient & Outpatient Medications

See Treatment and Medications.

Transfer

Transfer of patients to a tertiary receiving hospital generally is indicated if the presenting hospital lacks adequate resources to care for such patients. Most patients with heart failure can be well managed at community hospitals. However, if the cause of heart failure is determined to require definitive surgery for stabilization, transfer is often indicated. Note the following examples:

• Patients with heart failure that develops as a result of acute valvular dysfunction requiring urgent valve replacement may require transfer to a tertiary care facility that performs open-heart surgery.
• Patients with acute myocardial infarction resulting in cardiogenic shock hypotension may require transfer for emergency PTCA or CABG. Thrombolysis may be attempted at the presenting hospital, but outcome is generally poor without angioplasty or CABG.
• Patients with severe heart failure with hemodynamic complications should be transferred from presenting hospitals that lack sufficient resources for, or experience with, managing patients with heart failure who require complex inotropic support or hemodialysis.
• Patients with NYHA class IV heart failure who are younger than 70 years and facing the likely prospect of death within the next 6-12 months, despite maximal medical therapy, and who are not candidates for coronary revascularization, should be transferred to a cardiac transplant center for consideration of cardiac transplantation if they cannot be stabilized enough to be discharged home on maximal medical therapy.

Complications

The major complications associated with heart failure are sudden cardiac death from ventricular tachyarrhythmias or bradyarrhythmias and pump failure with cardiovascular collapse. Approximately half of patients with heart failure eventually die from fatal ventricular arrhythmias. Prompt diagnosis and treatment usually prevent this complication in the acute setting. Prompt diagnosis of heart failure and prompt treatment to reduce pulmonary venous congestion, reduce afterload, and improve cardiac output is essential in preventing cardiovascular and respiratory failure.

Prognosis

• In general, the inpatient mortality rate for patients with heart failure is 5-20%, while outpatient mortality remains 20% at the end of the first year postdiagnosis and up to 50% at 5 years postdiagnosis despite marked improvement in medical and device therapy. (AHA published statistics)
• Each rehospitalization increases mortality by 20-30%.
• Cardio-pulmonary stress test can be useful in assessing survival within the next year as well as referral for either cardiac transplantation or implantation of mechanical circulatory support. If peak oxygen consumption is less than 14 mL/kg/min, or 50% of the maximum predicted survival is limited to less than 75% at the end of 1 year, the patient may benefit from alternative therapies (cardiac transplantation and/or mechanical circulatory support).
• Patients with NYHA Class IV, stage D have more than 50% mortality at 1 year.
• Heart failure associated with acute myocardial infarction is associated with an inpatient mortality rate of 20-40%; mortality approaches 80% in patients who are also hypotensive (eg, cardiogenic shock).

Patient Education

• To help prevent recurrence, counsel and educate patients in whom heart failure was caused by dietary factors or medication noncompliance with regard to the importance of proper diet and the necessity of medication compliance.
• For excellent patient education resources, visit eMedicine's Heart Center, Cholesterol Center, Diabetes Center. Also, see eMedicine's patient education articles Congestive Heart Failure, High Cholesterol, Chest Pain, Heart Rhythm Disorders, Coronary Heart Disease, and Heart Attack.

Miscellaneous

Medicolegal Pitfalls

• Failure to rapidly recognize acute heart failure and to distinguish this entity from other pulmonary diseases
• Failure to rapidly initiate medical therapy for heart failure
• Failure to rapidly diagnose and treat acute coronary syndromes that cause heart failure
• Failure to rapidly and aggressively treat cardiac arrhythmias that may cause or result from heart failure
• Failure to rapidly and aggressively treat the hypoxia and acidosis that results from acute severe heart failure with mechanical ventilation
• Failure to provide rapid and aggressive hemodynamic support and to use, when clinically indicated, invasive hemodynamic monitoring in an effective and diagnostically sound manner

Special Concerns

Consider peripartum cardiomyopathy in women presenting with symptoms suggestive of heart failure in the peripartum period.

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Keywords

heart failure, heart disease, congestive heart failure, heart failure symptoms, heart failure treatment, heart failure guidelines, myocardial failure, circulatory failure, myocardial hypertrophy, ischemic cardiomyopathy

Contributor Information and Disclosures

Author

Ioana Dumitru, MD, Assistant Professor, Internal Medicine, Section of Cardiology, Founder and Medical Director, Heart Failure and Cardiac Transplant Program, University of Nebraska Medical Center; Assistant Professor, Internal Medicine, Section of Cardiology, Veterans Affairs Medical Center, Omaha, Nebraska
Ioana Dumitru, MD is a member of the following medical societies: American College of Cardiology, Heart Failure Society of America, and International Society for Heart and Lung Transplantation
Disclosure: GSK Honoraria Speaking and teaching; Novartis Honoraria Speaking and teaching

Coauthor(s)

Mathue Baker, MD, Fellow, Department of Internal Medicine, Division of Cardiology, University of Nebraska Medical Center, Omaha
Disclosure: Nothing to disclose.

Medical Editor

George A Stouffer III, MD, Henry A Foscue Distinguished Professor of Medicine and Cardiology, Director of Interventional Cardiology, Cardiac Catheterization Laboratory, Chief of Clinical Cardiology, Division of Cardiology, University of North Carolina Medical Center
George A Stouffer III, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Physicians, American Heart Association, Phi Beta Kappa, and Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Marschall S Runge, MD, PhD, Charles and Anne Sanders Distinguished Professor of Medicine, Chairman, Department of Medicine, Vice Dean for Clinical Affairs, University of North Carolina at Chapel Hill School of Medicine
Marschall S Runge, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American College of Cardiology, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Federation for Medical Research, American Heart Association, American Physiological Society, American Society for Clinical Investigation, American Society for Investigative Pathology, Association of American Physicians, Association of Professors of Cardiology, Association of Professors of Medicine, Southern Society for Clinical Investigation, and Texas Medical Association
Disclosure: Pfizer Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; Orthoclinica Diagnostica Consulting fee Consulting

CME Editor

Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital
Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Chief Editor

David J Maron, MD, FACC, FAHA, Associate Professor of Medicine and Emergency Medicine, Vanderbilt Heart and Vascular Institute, Vanderbilt University School of Medicine
David J Maron, MD, FACC, FAHA is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, and American Heart Association
Disclosure: Cardiovascular Services of America Ownership interest Other

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Michael E Zevitz, MDto the development and writing of this article.

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