Orly Vardeny and Tien M.H. Ng
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Differentiate between the common underlying etiologies of heart failure, including ischemic, nonischemic, and idiopathic causes.
2. Describe the pathophysiology of heart failure as it relates to neurohormonal activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system (SNS).
3. Identify signs and symptoms of heart failure and classify a given patient by the New York Heart Association (NYHA) Functional Classification (FC) system and American College of Cardiology/American Heart Association (ACC/AHA) Heart Failure Staging.
4. Describe the goals of therapy for a patient with acute or chronic heart failure.
5. Develop a nonpharmacologic treatment plan which includes patient education for managing heart failure.
6. Develop a specific evidence-based pharmacologic treatment plan for a patient with acute or chronic heart failure based on disease severity and symptoms.
7. Formulate a monitoring plan for the nonpharmacologic and pharmacologic treatment of a patient with heart failure.
KEY CONCEPTS
The most common causes of heart failure are coronary artery disease (CAD), hypertension, and dilated cardiomyopathy.
Development and progression of heart failure involve activation of neurohormonal pathways, including the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS).
The clinician must identify potential reversible causes of heart failure exacerbations including prescription and nonprescription drug therapies, dietary indiscretions, and medication nonadherence.
Symptoms of left-sided heart failure include dyspnea, orthopnea, and paroxysmal nocturnal dyspnea (PND), whereas symptoms of right-sided heart failure include fluid retention, GI bloating, and fatigue.
Therapeutic goals focus on alleviating symptoms, slowing or preventing disease progression, maintaining quality of life, and improving patient survival.
Nonpharmacologic treatment involves dietary modifications such as sodium and fluid restriction, risk factor reduction including smoking cessation, timely immunizations, and supervised regular physical activity.
Diuretics are used for relief of acute symptoms of congestion and maintenance of euvolemia.
Agents with proven benefits in improving symptoms, slowing disease progression, and improving survival in chronic heart failure target neurohormonal blockade; these include angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), β-adrenergic blockers, and aldosterone antagonists.
Combination therapy with hydralazine and isosorbide dinitrate is an appropriate substitute for angiotensin II antagonism in those unable to tolerate an ACE inhibitor or ARB, or as add-on therapy in African Americans.
Treatment of acute heart failure (AHF) targets relief of congestion and optimization of cardiac output utilizing oral or IV diuretics, IV vasodilators, and, when appropriate, inotropes.
INTRODUCTION
Heart failure (HF) is defined as the inadequate ability of the heart to pump enough blood to meet the blood flow and metabolic demands of the body.1 High-output HF is characterized by an inordinate increase in the body’s metabolic demands, which outpaces an increase in cardiac output (CO) of a generally normally functioning heart. More commonly, low-output HF is a result of low CO secondary to impaired cardiac function. In this chapter, HF will refer to low-output HF.
HF is a clinical syndrome characterized by a history of specific signs and symptoms related to congestion and hypoperfusion. As HF can occur in the presence or absence of fluid overload, the term HF is preferred over the former term “congestive HF.” HF results from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.1 Many disorders such as those of the pericardium, epicardium, endocardium, or great vessels may lead to HF, but most patients develop symptoms due to impairment in left ventricular (LV) myocardial function.
The phrase “acute heart failure” (AHF) is used to signify either an acute decompensation of a patient with a history of chronic HF or a patient presenting with new-onset HF symptoms. Terms commonly associated with HF, such as cardiomyopathy and LV dysfunction, are not equivalent to HF but describe possible structural or functional reasons for the development of HF.
EPIDEMIOLOGY AND ETIOLOGY
Epidemiology
HF is a major public health concern affecting approximately 5 million people in the United States. An additional 550,000 new cases are diagnosed each year. HF manifests most commonly in adults over the age of 60.2 The growing prevalence of HF corresponds to: (a) better treatment of patients with acute myocardial infarctions (MIs) who will survive to develop HF later in life, and (b) the increasing proportion of older adults due to the aging “Baby Boomer” population. The relative incidence of HF is lower in women compared to men, but there is a greater prevalence in women overall due to their longer life expectancy. AHF accounts for 12 to 15 million office visits per year and 6.5 million hospitalizations annually.2 According to national registries, patients presenting with AHF are older (mean age 75 years) and have numerous comorbidities such as coronary artery disease (CAD), renal insufficiency, and diabetes.2
Total estimated direct and indirect costs for managing both chronic and acute HF in the United States for 2008 was approximately $34.8 billion. Medications account for approximately 10% of that cost.3 HF is the most common hospital discharge diagnosis for Medicare patients and is the most costly diagnosis in this population.
The prognosis for patients hospitalized for AHF remains poor. Average hospital length of stay is estimated to be between 4 and 6 days, a number which has remained constant over the past decade.3 The in-hospital mortality rate has been estimated at approximately 4%, but ranges from 2% to 20% depending on the report.4 In-hospital mortality increases to an average of 10.6% in patients requiring an intensive care unit admission. Readmissions are also high, with up to 30% to 60% of patients readmitted within 6 months of their initial discharge date.4 The 5-year mortality rate for chronic HF remains approximately 50%. Survival strongly correlates with severity of symptoms and functional capacity. Sudden cardiac death is the most common cause of death, occurring in approximately 40% of patients with HF.2 Although therapies targeting the upregulated neurohormonal response contributing to the pathophysiology of HF have clearly impacted morbidity and mortality, long-term survival remains low.
Etiology
HF is the eventual outcome of numerous cardiac diseases or disorders (Table 6–1).5 HF can be classified by the primary underlying etiology as ischemic or nonischemic, with 70% of HF related to ischemia. The most common causes of HF are CAD, hypertension, and dilated cardiomyopathy. CAD resulting in an acute MI and reduced ventricular function is a common presenting history. Nonischemic etiologies include hypertension, viral illness, thyroid disease, excessive alcohol use, illicit drug use, pregnancy-related heart disease, familial congenital disease, and valvular disorders such as mitral or tricuspid valve regurgitation or stenosis.
HF can also be classified based on the main component of the cardiac cycle leading to impaired ventricular function. A normal cardiac cycle is dependent on two components: systole and diastole. Expulsion of blood occurs during systole or contraction of the ventricles, while diastole relates to filling of the ventricles. Ejection fraction (EF) is the fraction of the volume present at the end of diastole that is pushed into the aorta during systole. Abnormal ventricular filling (diastolic dysfunction) and/or ventricular contraction (systolic dysfunction) can result in a similar decrease in CO and cause HF symptoms. Most HF is associated with evidence of LV systolic dysfunction (evidenced by a reduced EF) with or without a component of diastolic dysfunction, which coexists in up to two-thirds of patients. Isolated diastolic dysfunction, occurring in approximately one-third of HF patients, is diagnosed when a patient exhibits impaired ventricular filling with or without accompanying HF symptoms but normal systolic function. Long-standing hypertension is the leading cause of diastolic dysfunction. Ventricular dysfunction can also involve either the left or right chamber of the heart or both. This has implications for symptomatology, as right-sided failure manifests as systemic congestion, whereas left-sided failure results in pulmonary symptoms.
Table 6–1 Causes of Heart Failure
|
Systolic Dysfunction (Decreased Contractility) |
|
• Reduction in muscle mass (e.g., MI) |
|
• Dilated cardiomyopathies |
|
• Ventricular hypertrophy |
|
• Pressure overload (e.g., systemic or pulmonary hypertension, aortic or pulmonic valve stenosis) |
|
• Volume overload (e.g., valvular regurgitation, shunts, high-output states) |
|
Diastolic Dysfunction (Restriction in Ventricular Filling) |
|
• Increased ventricular stiffness |
|
• Ventricular hypertrophy (e.g., hypertrophic cardiomyopathy, other examples above) |
|
• Infiltrative myocardial diseases (e.g., amyloidosis, sarcoidosis, endomyocardial fibrosis) |
|
• Myocardial ischemia and infarction |
|
• Mitral or tricuspid valve stenosis |
|
• Pericardial disease (e.g., pericarditis, pericardial tamponade) |
MI, myocardial infarction.
From Parker RB, Rodgers JE, Cavallari LH. Heart failure. In: DiPiro JT, Talbert RL, Yee GC, et al. (eds.) Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:174.
PATHOPHYSIOLOGY
A basic grasp of normal cardiac function sets the stage for understanding the pathophysiologic processes leading to HF and selecting appropriate therapy for HF. CO is defined as the volume of blood ejected per unit of time (liters per minute) and is a major determinant of tissue perfusion. CO is the product of heart rate (HR) and stroke volume (SV): CO = HR × SV. The following describes how each parameter relates to CO.
HR is controlled by the autonomic nervous system, where sympathetic stimulation of β-adrenergic receptors results in an increase in HR and CO. SV is the volume of blood ejected with each systole. SV is determined by factors regulating preload, afterload, and contractility. Preload is a measure of ventricular filling pressure, or the volume of blood in the left ventricle (also known as LV end-diastolic volume). Preload is determined by venous return as well as atrial contraction. An increase in venous return to the left ventricle results in the stretch of cardiomyocyte sarcomeres (or contractile units) and a subsequent increase in the number of cross-bridges formed between actin and myosin myofilaments. This results in an increase in the force of contraction based on the Frank-Starling mechanism.6 Afterload is the resistance to ventricular ejection and is regulated by ejection impedence, wall tension, and regional wall geometry. Thus, elevated aortic and systemic pressures result in an increase in afterload and reduced SV. Contractility, also known as the inotropic state of the heart, is an intrinsic property of cardiac muscle incorporating fiber shortening and tension development. Contractility is influenced to a large degree by adrenergic nerve activity and circulating catecholamines such as epinephrine and norepinephrine.
Compensatory Mechanisms
In the setting of a sustained loss of myocardium, a number of mechanisms aid the heart when faced with an increased hemodynamic burden and reduced CO. They include the Frank-Starling mechanism, tachycardia and increased afterload, and cardiac hypertrophy and remodeling (Table 6–2).5,7
Table 6–2 Beneficial and Detrimental Effects of the Compensatory Responses in Heart Failure
Preload and the Frank-Starling Mechanism
In the setting of a sudden decrease in CO, the natural response of the body is to decrease blood flow to the periphery in order to maintain perfusion to the vital organs such as the heart and brain. Therefore, renal perfusion is compromised due to both the decreased CO, as well as shunting of blood away from peripheral tissues. This results in activation of the renin-angiotensin-aldosterone system (RAAS). The decrease in renal perfusion is sensed by the juxtaglomerular cells of the kidneys leading to the release of renin and initiation of the cascade for production of angiotensin II (AT2). AT2 stimulates the synthesis and release of aldosterone. Aldosterone in turn stimulates sodium and water retention in an attempt to increase intravascular volume, and hence preload. In a healthy heart, a large increase in CO is usually accomplished with just a small change in preload. However, in a failing heart, alterations in the contractile filaments reduce the ability of cardiomyocytes to adapt to increases in preload. Thus, an increase in preload actually impairs contractile function in the failing heart and results in a further decrease in CO.
Tachycardia and Increased Afterload
Another mechanism to maintain CO when contractility is low is to increase HR. This is achieved through sympathetic nervous system (SNS) activation and the agonist effect of norepinephrine on β-adrenergic receptors in the heart. Sympathetic activation also enhances contractility by increasing cytosolic calcium concentrations. SV is relatively fixed in HF, thus HR becomes the major determinant of CO. Although this mechanism increases CO acutely, the chronotropic and inotropic responses to sympathetic activation increase myocardial oxygen demand, worsen underlying ischemia, contribute to proarrhythmia, and further impair both systolic and diastolic function.
Activation of both the RAAS and the SNS also contribute to vasoconstriction in an attempt to redistribute blood flow from peripheral organs such as the kidneys to coronary and cerebral circulation.7However, arterial vasoconstriction leads to impaired forward ejection of blood from the heart due to an increase in afterload. This results in a decrease in CO and continued stimulation of compensatory responses, creating a vicious cycle of neurohormonal activation.
Cardiac Hypertrophy and Remodeling
Ventricular hypertrophy, an adaptive increase in ventricular muscle mass due to growth of existing myocytes, occurs in response to an increased hemodynamic burden such as volume or pressure overload.5Hypertrophy can be concentric or eccentric. Concentric hypertrophy occurs in response to pressure overload such as in long-standing hypertension or pulmonary hypertension, whereas eccentric hypertrophy occurs after an acute MI. Eccentric hypertrophy involves an increase in myocyte size in a segmental fashion, as opposed to the global hypertrophy occurring in concentric hypertrophy. Although hypertrophy helps to reduce cardiac wall stress in the short term, continued hypertrophy accelerates myocyte cell death through an overall increase in myocardial oxygen demand.
Cardiac remodeling occurs as a compensatory adaptation to a change in wall stress and is largely regulated by neurohormonal activation, with AT2 and aldosterone being key stimuli.7 The process entails changes in myocardial and extracellular matrix composition and function, which results in both structural and functional alterations to the heart. In HF, the changes in cardiac size, shape, and composition are pathologic and detrimental to heart function. In addition to myocyte size and extracellular matrix changes, heart geometry shifts from an elliptical to a less efficient spherical shape. Even after remodeling occurs, the heart can maintain CO for many years. However, heart function will continue to deteriorate until progression to clinical HF. The timeline for remodeling varies depending on the cardiac insult. For example, in the setting of an acute MI, remodeling starts within a few days.5 Chronic remodeling, however, is what progressively worsens HF and therefore is a major target of drug therapy.
Models of HF
Earlier models of HF focused on the hemodynamic consequences of volume overload from excess sodium and water retention, decreased CO secondary to impaired ventricular function, and vasoconstriction.8Congestion was a result of fluid backup due to inadequate pump function. Therefore, drug therapy was focused on relieving excess volume using diuretics, improving pump function with inotropic agents, and alleviating vasoconstriction with vasodilators. Although these agents improved HF symptoms, they did little to slow the progressive decline in cardiac function or to improve survival.
Neurohormonal Model
Development and progression of HF involves activation of neurohormonal pathways including the SNS and the RAAS. This model begins with an initial precipitating event or myocardial injury resulting in a decline in CO, followed by the compensatory mechanisms previously discussed. This includes activation of neurohormonal pathways with pathologic consequences including the RAAS, SNS, endothelin and vasopressin, and those with counterregulatory properties such as the natriuretic peptides and nitric oxide. This model currently guides our therapy for chronic HF in terms of preventing disease progression and mortality.
Angiotensin II
AT2 is a key neurohormone in the pathophysiology of HF. The vasoconstrictive effects of AT2 lead to an increase in systemic vascular resistance (SVR) and blood pressure (BP). The resulting increase in afterload contributes to an increase in myocardial oxygen demand and opposes the desired increase in SV. In the kidneys, AT2 enhances renal function acutely by raising intraglomerular pressure through constriction of the efferent arterioles.6 However, the increase in glomerular filtration pressure may be offset by a reduction in renal perfusion secondary to AT2’s influence over the release of other vasoactive neurohormones such as vasopressin and endothelin-1 (ET-1). AT2 also potentiates the release of aldosterone from the adrenal glands and norepinephrine from adrenergic nerve terminals. Additionally, AT2induces vascular hypertrophy and remodeling in both cardiac and renal cells. Clinical studies show that blocking the effects of the RAAS in HF is associated with improved cardiac function and prolonged survival. Thus, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the cornerstone of HF treatment.
Aldosterone
Aldosterone’s contribution to HF pathophysiology is also multifaceted. Renally, aldosterone causes sodium and water retention in an attempt to enhance intravascular volume and CO. This adaptive mechanism has deleterious consequences because excessive sodium and water retention worsen the already-elevated ventricular filling pressures. Aldosterone also contributes to electrolyte abnormalities seen in HF patients. Hypokalemia and hypomagnesemia contribute to the increased risk of arrhythmias. In addition, evidence supports the role of aldosterone as an etiologic factor for myocardial fibrosis and cardiac remodeling by causing increased extracellular matrix collagen deposition and cardiac fibrosis.6 Aldosterone potentially contributes to disease progression via sympathetic potentiation and ventricular remodeling. In addition, the combination of these multiple effects is likely responsible for the increased risk of sudden cardiac death attributed to aldosterone. As elevated aldosterone concentrations have been associated with a poorer prognosis in HF, its blockade has become an important therapeutic target for improvement of long-term prognosis.
Norepinephrine
Norepinephrine is a classic marker for SNS activation. It plays an adaptive role in the failing heart by stimulating HR and myocardial contractility to augment CO and by producing vasoconstriction to maintain organ perfusion. However, excess levels are directly cardiotoxic. In addition, sympathetic activation increases the risk for arrhythmias, ischemia, and myocyte cell death through increased myocardial workload and accelerated apoptosis (i.e., programmed cell death). Ventricular hypertrophy and remodeling are also influenced by norepinephrine.8
Plasma norepinephrine concentrations are elevated proportionally to HF severity, with the highest levels correlating to the poorest prognosis. Several mechanisms relate to diminished responsiveness to catecholamines (e.g., norepinephrine) as cardiac function declines.6 Adrenergic receptor desensitization and downregulation (decreased postreceptor responses and signaling and decreased receptor number) occur under sustained sympathetic stimulation. The desensitization contributes to further release of norepinephrine.5 β-Adrenergic blocking agents, although intrinsically negatively inotropic, have become an essential therapy for chronic HF. β-Adrenergic blockers negate deleterious effects of norepinephrine, and therefore decrease HF disease progression.
Endothelin
ET-1, one of the most potent physiologic vasoconstrictors, is an important contributor to HF pathophysiology.9 ET-1 binds to two G-protein-coupled receptors, endothelin-A (ET-A) and endothelin-B (ET-B). ET-A receptors mediate vasoconstriction and are prevalent in vascular smooth muscle and cardiac cells. ET-B receptors are expressed on the endothelium and in vascular smooth muscle, and receptor stimulation mediates vasodilation. Levels of ET-1 correlate with HF functional class and mortality.
Arginine Vasopressin
Higher vasopressin concentrations are linked to dilutional hyponatremia and a poor prognosis in HF. Vasopressin exerts its effects through vasopressin type 1a (V1a) and vasopressin type 2 (V2) receptors.5,7V1a stimulation leads to vasoconstriction, while actions on the V2 receptor cause free water retention through aquaporin channels in the collecting duct. Vasopressin increases preload, afterload, and myocardial oxygen demand in the failing heart.
Counterregulatory Hormones (Natriuretic Peptides, Bradykinin, and Nitric Oxide)
Atrial natriuretic peptide (ANP) and B-type (formerly brain) natriuretic peptide (BNP) are endogenous neurohormones that regulate sodium and water balance. Natriuretic peptides decrease sodium reabsorption in the collecting duct of the kidney.10 Natriuretic peptides also cause vasodilation through the cyclic guanosine monophosphate (cGMP) pathway. ANP is synthesized and stored in the atria, while BNP is produced mainly in the ventricles. Release of ANP and BNP is stimulated by increased cardiac chamber wall stretch, usually indicative of volume load. Higher concentrations of natriuretic peptides correlate with a more severe HF functional class and prognosis. BNP is sensitive to volume status; thus, the plasma concentration can be used as a diagnostic marker in HF.10
Bradykinin is part of the kallikrein-kinin system, which shares a link to the RAAS through ACE. Bradykinin is a vasodilatory peptide that is released in response to a variety of stimuli, including neurohormonal and inflammatory mediators known to be activated in HF.9 As a consequence, bradykinin levels are elevated in HF patients and thought to partially antagonize the vasoconstrictive peptides.
Nitric oxide, a vasodilatory hormone released by the endothelium, is found in higher concentrations in HF patients and provides two main benefits in HF: vasodilation and neurohormonal antagonism of ET.9Nitric oxide production is affected by the enzyme inducible nitric oxide synthetase (iNOS), which is upregulated in the setting of HF, likely due to increased levels of AT2, norepinephrine, and multiple cytokines. In HF, the physiologic response to nitric oxide appears to be blunted, which contributes to the imbalance between vasoconstriction and vasodilation.
Cardiorenal Model
There is growing evidence of a link between renal disease and HF.8 Renal insufficiency is present in one-third of HF patients and is associated with a worse prognosis. In hospitalized HF patients, the presence of renal insufficiency is associated with longer lengths of stay, increased in-hospital morbidity and mortality, and detrimental neurohormonal alterations. Conversely, renal dysfunction is a common complication of HF or results from its treatment. Renal failure is also a common cause for HF decompensation.
Proinflammatory Cytokines
Inflammatory cytokines have been implicated in the pathophysiology of HF.9 Several proinflammatory (e.g., tumor necrosis factor-α [TNF-α], interleukin-1, interleukin-6, and interferon-γ) and anti-inflammatory cytokines (e.g., interleukin-10) are overexpressed in the failing heart. The most is known about TNF-α, a pleiotrophic cytokine that acts as a negative inotrope, stimulates cardiac cell apoptosis, uncouples β-adrenergic receptors from adenylyl cyclase, and is related to cardiac cachexia. The exact role of cytokines and inflammation in HF pathophysiology continues to be studied.
Precipitating and Exacerbating Factors in HF
HF patients exist in one of two clinical states. When a patient’s volume status and symptoms are stable, their HF condition is said to be “compensated.” In situations of volume overload or other worsening symptoms, the patient is considered “decompensated.” Acute decompensation can be precipitated by numerous etiologies that can be grouped into cardiac, metabolic, or patient-related causes (Table 6–3).5
The clinician must identify potential pharmacologic and dietary reversible causes of HF exacerbations including prescription and nonprescription drug therapies, dietary indiscretions, and medication nonadherence. Nonadherence with dietary restrictions or chronic HF medications deserves special attention, as it is the most common cause of acute decompensation and can be prevented. As such, an accurate history regarding diet, food choices, and the patient’s knowledge regarding sodium and fluid intake (including alcohol) is valuable in assessing dietary indiscretion. Nonadherence with medical recommendations such as laboratory and other follow-up appointments can also be indicative of nonadherence with diet or medications.
Table 6–3 Exacerbating or Precipitating Factors in HF
Patient Encounter, Part 1
BE is a 62-year-old female with a history of known CAD and type 2 diabetes mellitus who presents for a belated follow-up clinic visit (her last visit was 2 years ago). She states that she used to be able to walk over one-half mile (0.8 km) and two flights of stairs before experiencing chest pain and becoming short of breath. Since her last visit, she has had increasing symptoms and has now progressed to shortness of breath (SOB) with walking only half a block and doing chores around the house. She also notes her ankles are always swollen and her shoes no longer fit, therefore she only wears slippers. Additionally, her appetite is decreased, and she often feels bloated. She also feels full after eating only a few bites of each meal.
What information is suggestive of a diagnosis of HF?
What additional information do you need to know before creating a treatment plan for BE?
CLINICAL PRESENTATION AND DIAGNOSIS OF CHRONIC HF
In low-output HF, symptoms are generally related to either congestion behind the failing ventricle(s), hypoperfusion (decreased tissue blood supply), or both. Congestion is the most common symptom in HF, followed by symptoms related to decreased perfusion to peripheral tissues including decreased renal output, mental confusion, and cold extremities. Activation of the compensatory mechanisms occurs in an effort to increase CO and preserve blood flow to vital organs. However, the increase in preload and afterload in the setting of a failing ventricle leads to elevated filling pressures and further impairment of cardiac function, which manifests as systemic and/or pulmonary congestion. It is important to remember that congestion develops behind the failing ventricle, caused by the inability of that ventricle to eject the blood that it receives from the atria and venous return. As such, signs and symptoms may be classified as left sided or right sided. 
Symptoms of left-sided HF include dyspnea, orthopnea, and paroxysmal nocturnal dyspnea (PND), whereas symptoms of right-sided HF include fluid retention, GI bloating, and fatigue. Although most patients initially have left ventricular failure (LVF; pulmonary congestion), the ventricles share a septal wall, and because LVF increases the workload of the right ventricle, both ventricles eventually fail and contribute to the HF syndrome. Because of the complex nature of this syndrome, it has become exceedingly more difficult to attribute a specific sign or symptom as caused by either right ventricular failure (RVF; systemic congestion) or LVF. Therefore, the numerous signs and symptoms associated with this disorder are collectively attributed to HF rather than to dysfunction of a specific ventricle.
Clinical Presentation and Diagnosis of Chronic HF
General
Patient presentation may range from asymptomatic to cardiogenic shock.
Symptoms
• Dyspnea, particularly on exertion
• Orthopnea
• SOB
• PND
• Exercise intolerance
• Tachypnea
• Cough
• Fatigue
• Nocturia and/or polyuria
• Hemoptysis
• Abdominal pain
• Anorexia
• Nausea
• Bloating
• Ascites
• Mental status changes
• Weakness
• Lethargy
Signs
• Pulmonary rales
• Pulmonary edema
• S3 gallop
• Pleural effusion
• Cheyne-Stokes respiration
• Tachycardia
• Cardiomegaly
• Peripheral edema (e.g., pedal edema, which is swelling of feet and ankles)
• Jugular venous distention (JVD)
• Hepatojugular reflux (HJR)
• Hepatomegaly
• Cyanosis of the digits
• Pallor or cool extremities
Laboratory Tests
• BNP greater than 100 pg/mL (greater than 100 ng/L or 28.9 pmol/L) or N-terminal proBNP (NT-proBNP) greater than 300 pg/mL (greater than 300 ng/L or greater than 35.4 pmol/L)
• ECG: May be normal or could show numerous abnormalities including acute ST-T wave changes from myocardial ischemia, atrial fibrillation, bradycardia, and LV hypertrophy
• Serum creatinine: May be increased owing to hypoperfusion; pre-existing renal dysfunction can contribute to volume overload
• CBC: Useful to determine if HF is due to reduced oxygencarrying capacity
• CXR: Useful for detection of cardiac enlargement, pulmonary edema, and pleural effusions
• Echocardiogram: Used to assess LV size, valve function, pericardial effusion, wall motion abnormalities, and EF
BNP, B-type natriuretic peptide; CBC, complete blood cell count; CXR, chest x-ray; EF, ejection fraction; LV, left ventricular.
General Signs and Symptoms
Hypoperfusion of skeletal muscles leads to fatigue, weakness, and exercise intolerance. Decreased perfusion of the CNS is related to confusion, hallucinations, insomnia, and lethargy. Peripheral vasoconstriction due to SNS activity causes pallor, cool extremities, and cyanosis of the digits. Tachycardia is also common in these patients and may reflect increased SNS activity. Patients will often exhibit polyuria and nocturia. Polyuria is a result of increased release of natriuretic peptides caused by volume overload. Nocturia occurs due to increased renal perfusion as a consequence of reduced SNS renal vasoconstrictive effects at night. In chronic severe HF, unintentional weight loss can occur which leads to a syndrome of cardiac cachexia. Cardiac cachexia can be defined as a nonedematous weight loss greater than 6% of the previous normal weight over a period of at least 6 months. HF prognosis worsens considerably once cardiac cachexia has been diagnosed, regardless of HF severity. This results from several factors including loss of appetite, malabsorption due to GI edema, elevated metabolic rate, and elevated levels of norepinephrine and pro-inflammatory cytokines. Absorption of fats is especially affected, leading to deficiencies of fat soluble vitamins.
Patients can experience a variety of symptoms related to buildup of fluid in the lungs. Dyspnea, or shortness of breath (SOB), can result from pulmonary congestion or systemic hypoperfusion due to LVF. Exertional dyspnea occurs when patients describe breathlessness induced by physical activity or a lower level of activity than previously known to cause breathlessness. Patients often state that activities such as stair climbing, carrying groceries, or walking a particular distance cause SOB. Severity of HF is inversely proportional to the amount of activity required to produce dyspnea. In severe HF, dyspnea will be present even at rest.
Orthopnea is dyspnea that is positional. Orthopnea is present if a patient is unable to breathe while lying flat on a bed (i.e., in the recumbent position). It manifests within minutes of a patient lying down and is relieved immediately when the patient sits upright. Patients can relieve orthopnea by elevating their head and shoulders with pillows. The practitioner should inquire as to the number of pillows needed to prevent dyspnea as a marker of worsening HF. PND occurs when patients awaken suddenly with a feeling of breathlessness and suffocation. PND is caused by increased venous return and mobilization of interstitial fluid from the extremities leading to alveolar edema, and usually occurs within 1 to 4 hours of sleep. In contrast to orthopnea, PND is not relieved immediately by sitting upright and often takes up to 30 minutes for symptoms to subside.
Pulmonary congestion may also cause a nonproductive cough that occurs at night or with exertion. Cheyne-Stokes respiration, or periodic breathing, is also common in advanced HF. It is usually associated with low-output states and may be perceived by the patient as either severe dyspnea or transient cessation of breathing. In cases of pulmonary edema, the most severe form of pulmonary congestion, patients may produce a pink, frothy sputum and experience extreme breathlessness and anxiety due to feelings of suffocation and drowning. If not treated aggressively, patients can become cyanotic and acidotic. Severe pulmonary edema can progress to respiratory failure, necessitating mechanical ventilation.
Systemic venous congestion results mainly from RVF. A clinically validated assessment of the jugular venous pressure (JVP) is performed by examining the right internal jugular vein for distention or elevation of the pulsation while reclining at a 45-degree angle. A JVP of more than 4 cm above the sternal angle is indicative of elevated right atrial pressure. JVP may be normal at rest, but if application of pressure to the abdomen can elicit a sustained elevation of JVP, this is defined as hepatojugular reflux (HJR). A positive finding of HJR indicates hepatic congestion and results from displacement of volume from the abdomen into the jugular vein because the right atrium is unable to accept this additional blood. Hepatic congestion can cause abnormalities in liver function, which can be evident in liver function tests and/or clotting times. Development of hepatomegaly occurs infrequently and is caused by long-term systemic venous congestion. Intestinal or abdominal congestion can also be present, but usually doesn’t lead to characteristic signs unless overt ascites is evident. In advanced RVF, evidence of pulmonary hypertension may be present (e.g., right ventricular heave).
The most recognized finding of systemic congestion is peripheral edema. It usually occurs in dependent areas of the body, such as the ankles (pedal edema) for ambulatory patients, or the sacral region for bedridden patients. Weight gain often precedes signs of overt peripheral edema. Therefore, it is crucial for patients to weigh themselves daily even in the absence of symptoms to assess fluid status.
Patients may complain of swelling of their feet and ankles, which can extend up to their calves or thighs. Abdominal congestion may cause a bloated feeling, abdominal pain, early satiety, nausea, anorexia, and constipation. Often patients may have difficulty fitting into their shoes or pants due to edema.
Patient History
A thorough history is crucial to identify cardiac and noncardiac disorders or behaviors that may lead to or accelerate the development of HF. Past medical history, family history, and social history are important for identifying comorbid illnesses that are risk factors for the development of HF or underlying etiologic factors. A complete medication history (including prescription and nonprescription drugs, herbal therapy, and vitamin supplements) should be obtained each time a patient is seen to evaluate adherence, to assess appropriateness of therapy, to eliminate drugs that may be harmful in HF (Table 6–4), and to determine additional monitoring requirements. For newly diagnosed HF, previous use of chemotherapeutic agents as well as current or past use of alcohol and illicit drugs should be assessed. In addition, for patients with a known history of HF, questions related to symptomatology and exercise tolerance are essential for assessing any changes in clinical status that may warrant further evaluation or adjustment of the medication regimen.
HF Classification
There are two common systems for categorizing patients with HF. The New York Heart Association (NYHA) Functional Class (FC) system is based on the patient’s activity level and exercise tolerance. It divides patients into one of four classes, with FC I patients exhibiting no symptoms or limitations of daily activities, and FC IV patients who are symptomatic at rest (Table 6–5). The NYHA FC system reflects a subjective assessment by a health care provider and can change frequently over short periods of time. FC correlates poorly with EF; however, EF is one of the strongest predictors of prognosis. In general, anticipated survival declines in conjunction with a decline in functional ability.
Table 6–4 Drugs That May Precipitate or Exacerbate HF
|
Agents Causing Negative Inotropic Effect |
|
Cardiotoxic Agents |
|
Agents Causing Sodium and Water Retention |
COX-2, cyclooxygenase-2; NSAIDs, nonsteroidal anti-inflammatory drugs.
From Parker RB, Rodgers JE, Cavallari JH. Heart failure. In: DiPiro JT, Talbert RL, Yee GC, et al. (eds.) Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:180.
Table 6–5 NYHA Functional Classification and ACC/AHA Staging
The American College of Cardiology/American Heart Association (ACC/AHA) has proposed another system based on the development and progression of the disease. Instead of classifications, patients are placed into stages A through D (Table 6–5).11 Because the staging system is related to development and progression of HF, it also proposes management strategies for each stage including risk factor modification. The staging system is meant to complement the NYHA FC system; however, patients can move between NYHA FCs as symptoms improve with treatment, whereas HF staging does not allow for patients to move to a lower stage (e.g., patients cannot be categorized as stage C and move to stage B after treatment). Currently, patients are categorized based on both systems. NYHA FC and ACC/AHA staging are useful from a clinician’s perspective, allowing for a longitudinal assessment of a patient’s risk and progress, requirements for nonpharmacologic interventions, response to medications, and overall prognosis.
Patient Encounter, Part 2
BE’s medical history, physical exam, and diagnostic test results.
PMH: Type 2 diabetes mellitus for 15 years; coronary artery disease for 10 years (MIs in 1999 and 2002); tobacco use; history of back surgery in 2001
Allergies: NKDA
Meds: Diltiazem CD 240 mg once daily; nitroglycerin 0.4 mg sublingual (SL) as needed (last use yesterday after showering); glipizide 10 mg twice daily for diabetes; ibuprofen 600 mg twice daily for arthritis pain; vitamin B12 once daily; multivitamin daily; aspirin 325 mg once daily
FH: Significant for early heart disease in father (MI at age 53)
SH: Disabled from a previous accident; married, has six children, and runs her own business; she does not drink alcohol and smokes one to two packs of cigarettes per day
PE:
BP 126/70 mm Hg, P 60 bpm and regular, RR 16/min, ht 5’8” (173 cm), wt 114 kg (251 lb), BMI 38.2 kg/m2
Lungs: Clear to auscultation with a prolonged expiratory phase; rales are present bilaterally
CV: RRR with normal S1 and S2; there is an S3 and a soft S4 present; there is a 2/6 systolic ejection murmur heard best at the left lower sternal border; point of maximal impulse is within normal limits at the midclavicular line; there is no JVD
Abd: Soft, nontender, and bowel sounds are present; 2+ pitting edema of extremities extending to below the knees is observed
CXR: Bilateral pleural effusions and cardiomegaly
Echo: EF 35%
Laboratory Values
Hct: 41.1%
WBC: 5.3 × 103mm3 (5.3 × 109L)
Sodium: 132 mEq/L (132 mmol/L)
Potassium: 3.2 mEq/L (3.2 mmol/L)
Bicarb: 30 mEq/L (30 mmol/L)
Chloride: 90 mEq/L (90 mmol/L)
Magnesium: 1.5 mEq/L (0.8 mmol/L)
Fasting blood sugar: 120 mg/dL (6.7 mmol/L)
Uric acid: 8 mg/dL (476 μmol/L)
Blood urea nitrogen (BUN): 40 mg/dL (14 mmol/L)
SCr: 0.8 mg/dL (71 μmol/L)
Alk phos: 120 IU/L (2 piKat/L)
Aspartate aminotransferase: 100 IU/L (1.7 μKat/L)
What other laboratory or other diagnostic tests are required for assessment of BE’s condition?
How would you classify BE’s NYHA FC and ACC/AHA HF stage?
Identify exacerbating or precipitating factors that may worsen BE’s HF.
What are your treatment goals for BE?
TREATMENT OF CHRONIC HF
Desired Therapeutic Outcomes
There is no cure for HF. 
The general management goals for chronic HF include preventing the onset of clinical symptoms or reducing symptoms, preventing or reducing hospitalizations, slowing progression of the disease, improving quality of life, and prolonging survival. The ACC/AHA staging system described earlier provides a guide for application of these goals based on the clinical progression of HF for a given patient. The goals are additive as one moves from stage A to stage D.1,11 For stage A, risk factor management is the primary goal. Stage B includes the addition of pharmacologic therapies known to slow the progression of the disease in an attempt to prevent the onset of clinical symptoms. Stage C involves the use of additional therapies aimed at controlling symptoms and decreasing morbidity. Finally, in stage D, the goals shift toward quality of life related issues. Only with aggressive management throughout all the stages of the disease will the ultimate goal of improving survival be realized. The attainment of these goals is based on designing a therapeutic approach that encompasses strategies aimed at control and treatment of contributing disorders, nonpharmacologic interventions, and optimal use of pharmacologic therapies.12,13
Control and Treatment of Contributing Disorders
All causes of HF must be investigated to determine the etiology of cardiac dysfunction in a given patient. Because the most common etiology of HF in the United States is ischemic heart disease, assessment for cardiac ischemia, which may include stress testing, echocardiography, and/or coronary angiography is warranted in the majority of patients with a history suggestive of underlying CAD. Revascularization of those with significant CAD may help restore some cardiac function in patients with reversible ischemic defects. Aggressive control of hypertension, diabetes, and obesity is also essential because each of these conditions can cause further cardiac damage. Surgical repair of valvular disease or congenital malformations may be warranted if detected. Because clinical HF is partly dependent on metabolic processes, correction of imbalances such as thyroid disease, anemia, and nutritional deficiencies is required. Other more rare causes such as autoimmune disorders or acquired illnesses may have specific treatments. Identifying and discontinuing medications that can exacerbate HF is also an important intervention, as is eliminating alcohol for those with alcohol-related cardiomyopathy.
Nonpharmacologic Interventions
It is imperative that patients recognize the role of selfmanagement in HF. 
Nonpharmacologic treatment involves dietary modifications such as sodium and fluid restriction, risk factor reduction including smoking cessation, timely immunizations, and supervised regular physical activity. Patient education regarding monitoring symptoms, dietary and medication adherence, exercise and physical fitness, risk factor reduction, and immunizations are important for prevention of AHF exacerbations.
Patients should be encouraged to become involved in their own care through several avenues, the first of which is self-monitoring. Home monitoring should include daily assessment of weight and exercise tolerance. Daily weights should be done first thing in the morning upon arising and before any food intake to maintain consistency. Patients should record their weight daily in a journal and bring this log to each clinic or office visit. Changes in weight can indicate fluid retention and congestion prior to onset of peripheral or pulmonary symptoms. Individuals who have an increase of 0.9 to 1.4 kg (2-3 lb) in a single day or 2.3 kg (5 lb) over 5 days should alert their HF care provider. Some patients may be educated about self-adjusting diuretic doses based on daily weights. In addition to weight changes, a marked decline in exercise tolerance should also be reported to the HF care provider.
Nonadherence is an important issue as it relates to acute exacerbations of HF. Ensuring an understanding of the importance of each medication used to treat HF, proper administration, and potential adverse effects may improve adherence. Stressing the rationale for each medication is important, especially for NYHA FC I or ACC/AHA stage B patients who are asymptomatic, yet started on drugs that may worsen symptoms initially. A clinician’s involvement in emphasizing medication adherence, offering adherence suggestions such as optimal timing of medications or use of weekly pill containers, and providing intensive follow-up care has been shown to reduce AHF hospitalizations.
Dietary modifications in HF consist of initiation of an AHA step II diet as part of cardiac risk factor reduction, I sodium restriction, and sometimes fluid restriction. As sodium and water retention is a compensatory mechanism that contributes to volume overload in HF, salt and fluid restriction is often necessary to help avoid or minimize congestion. The normal American diet includes 3 to 6 g of sodium per day. Most patients with HF should limit salt intake to a maximum of 2 g/day. Patients should be educated to avoid cooking with salt and to limit intake of foods with high salt content, such as fried or processed food (lunchmeats, soups, cheeses, salted snack foods, canned food, and some ethnic food). Salt restriction can be challenging for many patients. The clinician should counsel to restrict salt slowly over time. Drastic dietary changes may lead to nonadherence due to an unpalatable diet. Substituting spices to flavor food is a useful recommendation. Salt substitutes should be used judiciously, as many contain significant amounts of potassium, which can increase the risk of hyperkalemia. Fluid restriction may not be necessary in many patients. When applicable, fluid intake is generally limited from all sources to less than 2 L/day.
Exercise, while discouraged when the patient is acutely decompensated to ease cardiac workload, is recommended when patients are stable. The heart is a muscle that requires activity to prevent atrophy. In addition, exercise improves peripheral muscle conditioning and efficiency, which may contribute to better exercise tolerance despite the low CO state. Regular, low-intensity aerobic exercise that includes walking, swimming, or riding a bike is encouraged, while heavy weight training is discouraged. The prescribed exercise regimen needs to be tailored to the individual’s functional ability, and thus it is suggested that patients participate in cardiac rehabilitation programs, at least initially. It is important that patients not overexert themselves to fatigue or exertional dyspnea.
Modification of classic risk factors, such as tobacco and alcohol consumption, is important to minimize the potential for further aggravation of heart function. Data from observational studies suggest that patients with HF who smoke have a mortality rate 40% higher than those who do not consume tobacco products.1 All HF patients who smoke should be counseled on the importance of tobacco cessation and offered a referral to a cessation program. Patients with an alcoholic cardiomyopathy should abstain from alcohol. Whether all patients with other forms of HF should abstain from any alcohol intake remains controversial. Proponents of moderation of alcohol base their rationale on the potential cardio-protective effects. However, opponents to any alcohol intake point out that alcohol is cardiotoxic and should be avoided.
In general, it is suggested that patients remain up to date on standard immunizations. Patients with HF should be counseled to receive yearly influenza vaccinations. Additionally, a pneumococcal vaccine is recommended.
Pharmacologic Treatment
In addition to determining therapeutic goals, the ACC/AHA staging system delineates specific therapy options based on disease progression.1,11 For patients in stage A, every effort is made to minimize the impact of diseases that can injure the heart. Antihypertensive and lipid-lowering therapies should be utilized when appropriate to decrease the risk for stroke, MI, and HF. ACE inhibitors should be considered in high-risk vascular disease patients. For stage B patients, the goal is to prevent or slow disease progression by interfering with neurohormonal pathways that lead to cardiac damage and mediate pathologic remodeling. The goal is to prevent the onset of HF symptoms. The backbone of therapy in these patients includes ACE inhibitors or ARBs and β-blockers. In stage C patients with symptomatic LV systolic dysfunction (EF less than 40%), the goals focus on alleviating fluid retention, minimizing disability, slowing disease progression, and reducing long-term risk for hospitalizations and death. Treatment entails a strategy that combines diuretics to control intravascular fluid balance with neurohormonal antagonists to minimize the effects of the RAAS and SNS. Additional neurohormonal blockade with aldosterone antagonists or other therapies such as digoxin are often added as cardiac function continues to decline. Patients with advanced stage D disease are offered more modest goals, such as improvement in quality of life. Enhancing quality of life is often achieved at the expense of expected survival. Treatment options include mechanical support, transplantation, and continuous use of IV vasoactive therapies, in addition to maintaining an optimal regimen of chronic oral medications (Fig. 6–1).
Diuretics
Diuretics have been the mainstay for HF symptom management for many years. 
Diuretics are used for relief of acute symptoms of congestion and maintenance of euvolemia. These agents interfere with sodium retention by increasing urinary sodium and free water excretion. No prospective data exist on the effects of diuretics on patient outcomes.14 Therefore, the primary rationale for the use of diuretic therapy is to maintain euvolemia in symptomatic or stages C and D HF. Diuretic therapy is recommended for all patients with clinical evidence of fluid overload retention.15,16 In more mild HF, diuretics may be used on an as-needed basis. However, once the development of edema is persistent, regularly scheduled doses will be required.
Two types of diuretics are used for volume management in HF: thiazides and loop diuretics. Thiazide diuretics such as hydrochlorothiazide, chlorthalidone, and metolazone block sodium and chloride reabsorption in the distal convoluted tubule. Thiazides are weaker than loop diuretics in terms of effecting an increase in urine output and therefore are not utilized frequently as monotherapy in HF. They are optimally suited for patients with hypertension who have mild congestion. Additionally, the action of thiazides is limited in patients with renal insufficiency (creatinine clearance [CrCl] less than 30 mL/min) due to reduced secretion into their site of action. An exception is metolazone, which retains its potent action in patients with renal dysfunction. Metolazone is often used in combination with loop diuretics when patients exhibit diuretic resistance, defined as edema unresponsive to loop diuretics alone.
Loop diuretics are the most widely used diuretics in HF. These agents, including furosemide, bumetanide, and torsemide, exert their action at the thick ascending loop of Henle. Loop diuretics are not filtered through the glomerulus, but instead undergo active transport into the tubular lumen via the organic acid pathway. As a result, drugs that compete for this active transport (e.g., probenecid and organic byproducts of uremia) can lower efficacy of loop diuretics. Loop diuretics increase sodium and water excretion, and induce a prostaglandin-mediated increase in renal blood flow which contributes to their natriuretic effect. Unlike thiazides, they retain their diuretic ability in patients with poor renal function. The various loop diuretics are equally effective when used at equipotent doses, although there are intrinsic differences in pharmacokinetics and pharmacodynamics (Table 6–6).5 The choice of which loop diuretic to use and the route of administration depends on clinical factors, such as presence of intestinal edema and rapidity of desired effect. Oral diuretic efficacy may vary based on differing bioavailability, which is almost complete for torsemide and bumetanide, but averages only 50% for furosemide. Therefore, oral torsemide can be considered an alternative to the IV route of administration for patients who do not respond to oral furosemide in the setting of profound edema. The onset of effect is slightly delayed after oral administration but occurs within a few minutes with IV dosing. Consequently, bioequivalent doses of IV furosemide are half the oral dose, whereas bumetanide and torsemide IV doses are generally equivalent to the oral doses.
FIGURE 6–1. Treatment algorithm for chronic HF. Table 6–5 describes staging of heart failure. (ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; EF, ejection fraction; HF, heart failure; LV, left ventricular; MI, myocardial infarction; SOB, shortness of breath.)
Table 6–6 Loop Diuretics Used in HF
In patients with evidence of mild to moderate volume overload, diuretics should be initiated at a low dose and titrated to achieve a weight loss of up to 0.91 kg/day (2 lb/day). Patients with severe volume overload should be managed in an inpatient setting. Once diuretic therapy is initiated, dosage adjustments are based on symptomatic improvement and daily body weight. As body weight changes are a sensitive marker of fluid retention or loss, patients should continue to weigh themselves daily. Once a patient reaches a euvolemic state, diuretics may be cautiously tapered and then withdrawn in appropriate patients. In stable, educated, and adherent patients, another option is self-adjusted diuretic dosing. Based on daily body weight, patients may temporarily increase their diuretic regimen in order to reduce the incidence of overt edema. This also avoids overuse of diuretics and possible complications of overdiuresis such as hypotension, fatigue, and renal impairment.
The maximal response to diuretics is reduced in HF, creating a “ceiling dose” above which there is limited added benefit. This diuretic resistance is due to a compensatory increase in sodium reabsorption in the distal tubules, which decreases the effect of blocking sodium reabsorption in the loop of Henle.17 In addition, there is a simultaneous increase in the reabsorption of sodium from the proximal tubule, allowing less to reach the site of action for loop diuretics. Apart from increasing diuretic doses, strategies to improve diuretic efficacy include increasing the frequency of dosing to two or three times daily, utilizing a continuous infusion of a loop diuretic, and/or combining a loop diuretic with a thiazide diuretic.17,18 The latter strategy theoretically prevents sodium and water reabsorption at both the loop of Henle and the compensating distal convoluted tubule. Metolazone is used most often for this purpose, as it retains its activity in settings of a low CrCl. Metolazone can be dosed daily or as little as once weekly. This combination is usually maintained until the patient reaches his or her baseline weight. The clinician must use metolazone cautiously, as its potent activity predisposes a patient to metabolic abnormalities as outlined below.
Diuretics cause numerous adverse effects and metabolic abnormalities, with severity linked to diuretic potency. A particularly worrisome adverse effect in the setting of HF is hypokalemia. Low serum potassium can predispose patients to arrhythmias and sudden death. Hypomagnesemia often occurs concomitantly with diuretic-induced hypokalemia, and therefore both should be assessed and replaced in patients needing correction of hypokalemia. Magnesium is an essential cofactor for movement of potassium intracellularly to restore body stores. Patients taking diuretics are also at risk for renal insufficiency due to overdiuresis and reflex activation of the renin-angiotensin system. The potential reduction in renal blood flow and glomerular pressure is amplified by concomitant use of ACE inhibitors or ARBs.
Neurohormonal Blocking Agents
Agents with proven benefits in improving symptoms, slowing disease progression, and improving survival in chronic HF target neurohormonal blockade. These include ACE inhibitors, ARBs, β-adrenergic blockers, and aldosterone antagonists.
ACE Inhibitors
ACE inhibitors are the cornerstone of treatment for HF. ACE inhibitors decrease neurohormonal activation by blocking the conversion of angiotensin I (AT1) to AT2, a potent mediator of vasoconstriction and cardiac remodeling. The breakdown of bradykinin is also reduced. Bradykinin enhances the release of vasodilatory prostaglandins and histamines. These effects result in arterial and venous dilatation, and a decrease in myocardial workload through reduction of both preload and afterload. ACE inhibitors demonstrate favorable effects on cardiac hemodynamics, such as long-term increases in cardiac index (CI), stroke work index, and SV index, as well as significant reductions in LV filling pressure, SVR, mean arterial pressure, and HR.
There is extensive clinical experience with ACE inhibitors in systolic HF. Numerous clinical studies show ACE inhibitor therapy is associated with improvements in clinical symptoms, exercise tolerance, NYHA functional class, LV size and function, and quality of life as compared with placebo.18–21 ACE inhibitors significantly reduce hospitalization rates and mortality regardless of underlying disease severity or etiology. ACE inhibitors are also effective in preventing HF development in high-risk patients. Studies in acute MI patients show a reduction in new-onset HF and death with ACE inhibitors whether they are initiated early (within 36 hours) or started later. In addition, ACE inhibition decreases the risk of HF hospitalization and death in patients with asymptomatic LV dysfunction. The exact mechanisms for decreased HF progression and mortality are postulated to involve both the hemo dynamic improvement and the inhibition of AT2’s growth promoting and remodeling effects. All patients with documented LV systolic dysfunction, regardless of existing HF symptoms, should receive ACE inhibitors unless a contraindication or intolerance is present.
There is no evidence to suggest that one ACE inhibitor is preferred over another. ACE inhibitors should be initiated using low doses and titrated up to target doses over several weeks depending on tolerability (adverse effects and BP). The ACC/AHA 2005 guidelines advocate using the doses that were proven to decrease mortality in clinical trials as the target doses (Table 6–7).1 If the target dose cannot be attained in a given patient, the highest tolerated dose should be used chronically. Although there is incremental benefit with higher doses of ACE inhibitors, it is accepted that lower doses provide substantial if not the majority of the effect.22 Because ACE inhibitors are only one component of a mortality-reducing treatment plan in HF, targeting a high ACE inhibitor dose should not interfere with starting a β-blocker or aldosterone antagonist by accentuating the hypotensive effects. Higher ACE inhibitor dosing may also limit tolerability of a regimen that also includes β-blockers and aldosterone antagonists.
Table 6–7 Dosing and Monitoring for Neurohormonal Blocking Agents
Despite their clear benefits, ACE inhibitors are still underutilized in HF. One reason is undue concern or confusion regarding absolute versus relative contraindications for their use. Absolute contraindications include a history of angioedema, bilateral renal artery stenosis, and pregnancy. Relative contraindications include unilateral renal artery stenosis, renal insufficiency, hypotension, hyperkalemia, and cough. Relative contraindications provide a warning that close monitoring is required, but they do not necessarily preclude their use.
Clinicians are especially concerned about the use of ACE inhibitors in patients with renal insufficiency. It is important to recognize that ACE inhibitors can potentially contribute to preservation or decline in renal function depending on the clinical scenario. Through preferential efferent arteriole vasodilation, ACE inhibitors can reduce intraglomerular pressure. Reduced glomerular pressures are renoprotective chronically; however, in situations of reduced or fixed renal blood flow, this leads to a reduction in filtration. In general, ACE inhibitors can be used in patients with serum creatinine less than 2.5 to 3 mg/dL (221-265 μmol/L). In HF, their addition can result in improved renal function through an increase in CO and renal perfusion. Although a small increase in serum creatinine (less than 0.5 mg/dL [44 μmol/L]) is possible with the addition of an ACE inhibitor, it is usually transient or becomes the patient’s new serum creatinine baseline level. However, ACE inhibition can also worsen renal function as glomerular filtration is maintained in the setting of reduced CO through AT2’s constriction of the efferent arteriole. Patients most dependent on AT2 for maintenance of glomerular filtration pressure, and hence most susceptible to ACE inhibitor worsening of renal function, include those with hyponatremia, severely depressed LV function, or dehydration. The most common reason for creatinine elevation in a patient without a history of renal dysfunction is overdiuresis. Therefore, clinicians should consider decreasing or holding diuretic doses if an elevation in serum creatinine occurs concomitantly with a rise in blood urea nitrogen.
Hypotension occurs commonly at the initiation of therapy or with dosage increases but may happen any time during therapy. Hypotension can manifest as dizziness, lightheadedness, presyncope, or syncope. The risk of hypotension due to possible volume depletion increases when ACE inhibitors are initiated or used concomitantly in patients on high diuretic doses. Therefore, in euvolemic patients, diuretic doses may often be decreased or withheld during ACE inhibitor dose titration. Initiating at a low dose and titrating slowly can also minimize hypotension. It may be advisable to initiate therapy with a short-acting ACE inhibitor, such as captopril, and subsequently switch to a longer-acting agent, such as lisinopril or enalapril, once the patient is stabilized.
Hyperkalemia results from reduced AT2-stimulated aldosterone release. The risk of hyperkalemia with ACE inhibitors is also increased in HF due to a propensity for impaired renal function and additive effects with aldosterone antagonists. The ACE inhibitor dose may need to be decreased or held if serum potassium increases above 5 mEq/L (5 mmol/L). Persistent hyperkalemia in the setting of renal insufficiency may preclude the use of an ACE inhibitor.
Cough is commonly seen with ACE inhibitors (5-15%) and may be related to accumulation of tissue bradykinins.5 It can be challenging to distinguish an ACE inhibitor-induced cough from cough caused by pulmonary congestion. A productive or wet cough usually signifies congestion, whereas a dry, hacking cough is more indicative of a drugrelated etiology. If a cough is determined to be ACE inhibitor-induced, its severity should be evaluated before deciding on a course of action. If the cough is truly bothersome, a trial with a different ACE inhibitor or switching to an ARB is warranted.
ARBs
ARBs selectively antagonize the effects of AT2 directly at the AT1-receptor. AT1-receptor stimulation is associated with vasoconstriction, release of aldosterone, and cellular growth promoting effects, while AT2 stimulation causes vasodilation. By selectively blocking AT1 but leaving AT2 unaffected, ARBs block the detrimental AT1 effects on cardiac function while allowing AT2-mediated vasodilation and inhibition of ventricular remodeling. ARBs are considered an equally effective replacement for ACE inhibitors in patients who are intolerant or have a contraindication to an ACE inhibitor.
It was hoped that the more complete blockade of AT2’s AT1 effects would confer greater long-term efficacy with ARBs compared to ACE inhibitors. However, prospective, randomized trials suggest that the clinical efficacy of ARBs is similar to that of ACE inhibitors for reduction of hospitalizations for HF, sudden cardiac death, and all-cause mortality.23–25 Despite poorer suppression of AT2, comparable efficacy of ACE inhibitors may be due to the additional effects on the kallikrein-kinin system. Although ARBs produce hemodynamic and neurohormonal effects similar to those of ACE inhibitors, they are considered second-line therapy due to the overwhelming clinical trial experience with ACE inhibitors.
Because the mechanism for long-term benefit appears different for ACE inhibitors and ARBs, the combination has been studied for additive benefits. One study evaluated the addition of the ARB candesartan versus placebo in HF patients with systolic dysfunction intolerant to an ACE inhibitor, systolic dysfunction currently on ACE inhibitor therapy, or patients with preserved systolic function.25 Candesartan reduced the combined incidence of cardiovascular death and hospitalization for HF in all three groups; the greatest benefit was noted in those not on an ACE inhibitor. Candesartan significantly decreased mortality compared to placebo when all three groups were combined. Based on this study, the addition of an ARB to ACE inhibitor therapy can be considered in patients with evidence of disease progression despite optimal ACE inhibitor therapy.1 This study also demonstrates the importance of having some form of AT2 antagonism as part of a treatment regimen.
ARBs show similar tolerability to ACE inhibitors with regard to hypotension and hyperkalemia, but they have markedly less incidence of cough as ARBs do not cause an accumulation of bradykinin. ARBs can be considered in patients with ACE inhibitor-induced angioedema, but they should be initiated cautiously, as cross-reactivity has been reported. Many of the other considerations for the use of ARBs are similar to those of ACE inhibitors, including the need for monitoring renal function, BP, and potassium. Contraindications are similar to those of ACE inhibitors. In patients truly intolerant or contraindicated to ACE inhibitors or ARBs, the combination of hydralazine and isosorbide dinitrate should be considered.
Hydralazine and Isosorbide Dinitrate
Complementary hemodynamic actions originally led to the combination of nitrates with hydralazine. Nitrates reduce preload by causing primarily venous vasodilation through activating guanylate cyclase and a subsequent increase in cGMP in vascular smooth muscle. Hydralazine reduces afterload through direct arterial smooth muscle relaxation via an unknown mechanism. More recently, nitric oxide has been implicated in modulating numerous pathophysiologic processes in the failing heart, including inflammation, cardiac remodeling, and oxidative damage. Supplementation of nitric oxide via administration of nitrates has also been proposed as a mechanism for benefit from this combination therapy. The beneficial effect of an external nitric oxide source may be more apparent in the African American population, which appears to be predisposed to having an imbalance in nitric oxide production. In addition, hydralazine may reduce the development of nitrate tolerance when nitrates are given chronically.
The combination of hydralazine and isosorbide dinitrate was the first therapy shown to improve long-term survival in patients with systolic HF, but has largely been supplanted by AT2 antagonist therapy (ACE inhibitors and ARBs).26,27 Therefore, until recently, this combination therapy was reserved for patients intolerant to ACE inhibitors or ARBs secondary to renal impairment, angioedema, or hyperkalemia. New insight into the pathophysiologic role of nitric oxide has reinvigorated research into this combination therapy.
The nitrate-hydralazine combination was first shown to improve survival compared to placebo.26 Subsequently, the combination of isosorbide dinitrate 40 mg and hydralazine 75 mg, both given four times daily, was compared to the ACE inhibitor enalapril.27 Enalapril produced a 28% greater decrease in mortality. Therefore, the combination is considered a third-line vasodilatory option for patients truly intolerant of ACE inhibitors and ARBs.
More recently, the value of adding the combination of isosorbide dinitrate 40 mg and hydralazine 75 mg three times daily to therapy including ACE inhibitors, β-blockers, digoxin, and diuretics was shown in a prospective, randomized trial in African American patients.28 
Combination therapy with hydralazine and isosorbide dinitrate is an appropriate substitute for AT’ antagonism in those unable to tolerate an ACE inhibitor or ARB or as add-on therapy in African Americans. The ACC/AHA HF guidelines now recommend considering the addition of isosorbide dinitrate and hydralazine in African Americans already on ACE inhibitors or ARBs.1 Combination therapy with isosorbide dinitrate and hydralazine should be initiated and titrated as are other neurohormonal agents such as ACE inhibitors and β-blockers. Low doses are used to initiate therapy with subsequent titration of the dose toward target doses based on tolerability. Adverse effects such as hypotension and headache cause frequent discontinuations in patients taking this combination, and full doses often cannot be tolerated. Patients should be monitored for headache, hypotension, and tachycardia. Hydralazine is also associated with a dose-dependent risk for lupus.
The frequent dosing of isosorbide dinitrate (e.g., three of four times daily) is not conducive to patient adherence; therefore, a once-daily isosorbide mononitrate is commonly substituted for isosorbide dinitrate to simplify the dosing regimen. A nitrate-free interval is still required when using nitrates for HF.
β-Adrenergic Antagonists
β-Adrenergic antagonists, or β-blockers, competitively block the influence of the SNS at β-adrenergic receptors. As recently as 15 years ago, β-adrenergic blockers were thought to be detrimental in HF due to their negative inotropic actions, which could potentially worsen symptoms and cause acute decompensations. Since then, the benefits of inhibiting the SNS have been recognized as far outweighing the acute negative inotropic effects. Chronic β-blockade reduces ventricular mass, improves ventricular shape, and reduces LV end-systolic and diastolic volumes.6,8 β-Blockers also exhibit antiarrhythmic effects, slow or reverse catecholamine-induced ventricular remodeling, decrease myocyte death from catecholamine-induced necrosis or apoptosis, and prevent myocardial fetal gene expression. Consequently, β-blockers improve EF, reduce all-cause and HF-related hospitalizations, and decrease all-cause mortality in patients with systolic HF.29–33
The ACC/AHA recommends that β-blockers be initiated in all patients with NYHA FC I to IV or ACC/AHA stages B through D HF if clinically stable.1 To date, only three β-blockers have been shown to reduce mortality in systolic HF, including the selective β-antagonists bisoprolol and metoprolol succinate, and the nonselective β1-, β2-, and α-antagonist carvedilol.29–33 The positive findings of β-blockers are not a class effect, as bucindolol did not exhibit a beneficial effect on mortality when studied for HF, and there is limited information with propranolol and atenolol.
Although metoprolol and carvedilol are the most commonly used β-antagonists in HF, it is unknown whether one agent should be considered first-line. To compare their relative effects on patient outcomes, one study compared immediate-release metoprolol tartrate to carvedilol in 3,000 patients with mild to severe HF.33 Carvedilol lowered all-cause mortality significantly more than metoprolol tartrate. However, there are questions about the validity of using immediate-release metoprolol tartrate as the comparison agent, and the low average dose of metoprolol tartrate achieved in the study.
The key to utilizing β-blockers in systolic HF is initiation with low doses and slow titration to target doses over weeks to months. It is important that the β-blocker be initiated when a patient is clinically stable and euvolemic. Volume overload at the time of β-blocker initiation increases the risk for worsening symptoms. β-Blockade should begin with the lowest possible dose (Table 6–7), after which the dose may be doubled every 2 to 4 weeks depending on patient tolerability. β-Blockers may cause an acute decrease in left ventricular ejection fraction (LVEF) and short-term worsening of HF symptoms upon initiation and at each dosage titration. After each dose titration, if the patient experiences symptomatic hypotension, bradycardia, orthostasis, or worsening symptoms, further increases in dose should be withheld until the patient stabilizes. After stabilization, attempts to increase the dose should be reinstituted. If mild congestion ensues as a result of the β-blocker, an increase in diuretic dose may be warranted. If moderate or severe symptoms of congestion occur, a reduction in β-blocker dose should be considered along with an increase in diuretic dose. Dose titration should continue until target clinical trial doses are achieved (Table 6–7) or until limited by repeated hemodynamic or symptomatic intolerance. Patient education regarding the possibility of acutely worsening symptoms but improved long-term function and survival is essential to ensure adherence.
Apart from possible clinical differences between the β-blockers approved for HF, selection of a β-blocker may also be affected by pharmacologic differences. Carvedilol exhibits a more pronounced BP lowering effect and thus causes more frequent dizziness and hypotension as a consequence of its β1-and α1-receptor blocking activities. Therefore, in patients predisposed to symptomatic hypotension, such as those with advanced LV dysfunction (LVEF less than 20%) who normally exhibit low systolic BPs, metoprolol succinate may be the more desirable first-line β-blocker. In patients with uncontrolled hypertension, carvedilol may provide additional antihypertensive efficacy.
β-Blockers may be used by those with reactive airway disease or peripheral vascular disease, but should be used with considerable caution or avoided if patients display active respiratory symptoms. Care must also be used in interpreting SOB in these patients, as the etiology could be either cardiac or pulmonary. A selective β1-blocker such as metoprolol is a reasonable option for patients with reactive airway disease. The risk versus benefit of using any β1-blocker in peripheral vascular disease must be weighed based on the severity of the peripheral disease.
Both metoprolol and carvedilol are metabolized by the liver through cytochrome P-450 (CYP450) 2D6 and undergo extensive first-pass metabolism. β-Blockers should not be used in patients with severe hepatic failure. Bisoprolol is not as commonly used since it is not FDA-approved for this use.
Aldosterone Antagonists
Currently, the aldosterone antagonists available are spironolactone and eplerenone. Both agents are inhibitors of aldosterone that produce weak diuretic effects while sparing potassium concentrations. Eplerenone is selective for the mineralocorticoid receptor and hence does not exhibit the endocrine adverse-effect profile commonly seen with spironolactone. The initial rationale for specifically targeting aldosterone for treatment of HF was based on the knowledge that ACE inhibitors do not suppress the chronic production and release of aldosterone. Aldosterone is a key pathologic neurohormone that exerts multiple detrimental effects in HF. Similar to norepinephrine and AT2, aldosterone levels are increased in HF and have been shown to correlate with disease severity and patient outcomes.
Each agent (spironolactone and eplerenone) has been studied in a defined population of patients with HF. One study established efficacy with low-dose spironolactone in NYHA FC III and IV HF patients in reducing HF hospitalizations, improving functional class, reducing sudden cardiac death, and improving all-cause mortality.34 Another study investigated the use of eplerenone in patients within 14 days of MI and LVEF less than 40%.35Eplerenone was found to decrease mortality as well as cardiovascular death and related hospitalization, mainly due to reducing occurrence of sudden cardiac death. Based on these two studies, the ACC/AHA guidelines recommend that the addition of spironolactone be considered in NYHA FC III and IV (ACC/AHA stages C and D) patients, and eplerenone in directly post-MI patients with evidence of LV dysfunction.1
The major risk related to aldosterone antagonists is hyperkalemia. Therefore, the decision for use of these agents should balance the benefit of decreasing death and hospitalization from HF and the potential risks of life-threatening hyperkalemia. Before and within 1 week of initiating therapy, two parameters must be assessed: serum potassium and CrCl (or serum creatinine). Aldosterone antagonists should not be initiated in patients with potassium concentrations greater than 5.5 mEq/L (5.5 mmol/L). Likewise, these agents should not be given when CrCl is less than 30 mL/min or serum creatinine is greater than 2.5 mg/dL (221 μmol/L).
In patients without contraindications, spironolactone is initiated at a dose of 12.5 to 25 mg daily, or occasionally on alternate days for patients with baseline renal insufficiency. Eplerenone is used at a dose of 25 mg daily, with the option to titrate up to 50 mg daily. Doses should be halved or switched to alternate-day dosing if CrCl falls below 50 mL/min. Potassium supplementation is often decreased or stopped after aldosterone antagonists are initiated, and patients should be counseled to avoid high-potassium foods. At any time after initiation of therapy, if potassium concentrations exceed 5.5 mEq/L (5.5 mmol/L), the dose of the aldosterone antagonist should be reduced or discontinued. In addition, worsening renal function dictates consideration for stopping the aldosterone antagonist. Other adverse effects observed mainly with spironolactone include gynecomastia for men and breast tenderness and menstrual irregularities for women. Gynecomastia leads to discontinuation in up to 10% of patients on spironolactone. Eplerenone is a CYP3A4 substrate and should not be used concomitantly with strong inhibitors of 3A4.
Digoxin
Digoxin has been used for several decades in the treatment of HF. Traditionally, it was considered useful for its positive inotropic effects, but more recently its benefits are thought to be related to neurohormonal modulation. Digoxin exerts positive inotropic effects through binding to sodium-and potassium-activated adenosine triphosphate (ATP) pumps, leading to increased intracellular sodium concentrations and subsequently more available intracellular calcium during systole. The mechanism of digoxin’s neurohormonal blocking effect is less well understood, but may be related to restoration of baroreceptor sensitivity and reduced central sympathetic outflow.5
The exact role of digoxin in therapy remains controversial largely due to disagreement on the risk versus benefit of routinely using this drug in patients with systolic HF. Digoxin was shown to decrease HF-related hospitalizations but did not decrease HF progression or improve survival.36 Moreover, digoxin was associated with an increased risk for concentration related toxicity and numerous adverse effects. Post hoc study analyses demonstrated a clear relationship between digoxin plasma concentration and outcomes. Concentrations below 1.2 ng/mL (1.5 nmol/L) were associated with no apparent adverse effect on survival, whereas higher concentrations increased the relative risk of mortality.37,38 Current recommendations are for the addition of digoxin for patients who remain symptomatic despite an optimal HF regimen consisting of an ACE inhibitor or ARB, β-blocker, and diuretic. In patients with concomitant atrial fibrillation, digoxin may be added to slow ventricular rate regardless of HF symptomology.
Digoxin is initiated at a dose of 0.125 to 0.25 mg daily depending on age, renal function, weight, and risk for toxicity. The lower dose should be used if the patient satisfies any of the following criteria: over 65 years of age, CrCl less than 60 mL/min, or ideal body weight less than 70 kg (154 lb). The 0.125 mg daily dose is adequate in the majority of patients. Doses are halved or switched to alternate-day dosing in patients with moderate to severe renal failure. The desired concentration range for digoxin is 0.5 to 1.2 ng/mL (0.64-1.5 nmol/L), preferably with concentrations at or less than 0.8 ng/mL (1 nmol/L). Routine monitoring of serum drug concentrations is not required but recommended in those with changes in renal function, suspected toxicity, or after addition or subtraction of an interacting drug.
Digoxin toxicity may manifest as nonspecific findings such as fatigue or weakness, and other CNS effects such as confusion, delirium, and psychosis. GI manifestations include nausea, vomiting, or anorexia, and visual disturbances may occur such as halos, photophobia, and color perception problems (red-green or yellow-green vision). Cardiac findings include numerous types of arrhythmias related to enhanced automaticity, slowed or accelerated conduction, or delayed after depolarizations. These include ventricular tachycardia and fibrillation, atrioventricular nodal block, and sinus bradycardia. Risk of digoxin toxicity, in particular the cardiac manifestations, are increased with electrolyte disturbances such as hypokalemia, hypercalcemia, and hypomagnesemia. To reduce the proarrhythmic risk of digoxin, serum potassium and magnesium should be monitored closely and supplemented when appropriate to ensure adequate concentrations (potassium greater than 4.0 mEq/L [4.0 mmol/L] and magnesium greater than 2.0 mEq/L [1 mmol/L]). In patients with life-threatening toxicity due to cardiac or other findings, administration of digoxin-specific Fab antibody fragments usually reverses adverse effects within an hour in most cases.
Calcium Channel Blockers
Treatment with nondihydropyridine calcium channel blockers (diltiazem and verapamil) may worsen HF and increase the risk of death in patients with advanced LV systolic dysfunction due to their negative inotropic effects. Conversely, dihydropyridine calcium channel blockers, although negative inotropes in vitro, do not appear to decrease contractility in vivo. Amlodipine and felodipine are the two most extensively studied dihydropyridine calcium channel blockers for systolic HF.39,40 These two agents have not been shown to affect patient survival, either positively or negatively. As such, they are not routinely recommended as part of a standard HF regimen; however, amlodipine and felodipine can safely be used in HF patients to treat uncontrolled hypertension or angina once all other appropriate drugs are maximized.
Antiplatelets and Anticoagulation
Patients with HF are at an increased risk of thromboembolic events secondary to a combination of hypercoagulability, relative stasis of blood, and endothelial dysfunction. However, the role of antiplatelets and anticoagulants remains debatable due to a lack of prospective clinical trials.
Aspirin is generally used in HF patients with an underlying ischemic etiology, a history of ischemic heart disease, or other compelling indications such as history of embolic stroke. Routine use in nonischemic cardiomyopathy patients is currently discouraged because of a lack of data supporting any long-term benefit, as well as the potential negative drug-drug interaction with ACE inhibitors and ARBs. If aspirin is indicated, the preference is to use a low dose (81 mg daily).41
Current consensus recommendations support the use of warfarin in patients with reduced LV systolic dysfunction and a compelling indication such as atrial fibrillation or prosthetic heart valves.42 In addition, warfarin is empirically used in patients with echocardiographic evidence of a mural thrombus or severely depressed (LVEF less than 20%) LV function.43 However, there are limited data supporting the use of empiric warfarin based on echocardiographic findings. Patients with HF often have difficulty maintaining a therapeutic International Normalized Ratio (INR) due to fluctuating volume status and varying drug absorption. Therefore, the benefit of using warfarin should be evaluated in the context of the risk for bleeding.
Complementary and Alternative Medicine
Complementary and alternative medicines (CAM) are treatment strategies not commonly used in Western medicine. Natural health products (NHP) are one component of CAM and are considered nutrition supplements by the FDA. Some patients with HF use NHP for heart problems, weight loss, anxiety, and arthritis. Fish oils, n-3 polyunsaturated fatty acids, or omega-3 fatty acids were recently studied for HF and found to mildly decrease cardiovascular admissions and mortality without significant adverse effects. Fish oils are more commonly used for treatment of hypertriglyceridemia. Their mechanism in HF is incompletely understood, but postulated to involve decreased membrane excitability (thus reducing arrhythmias), decreased inflammation and platelet aggregation, and favorable changes in autonomic tone. Hawthorn is another NHP studied in HF, shown to increase exercise capacity and reduce HF symptoms. Its benefits are thought to be due to flavonoids, which increase force of contraction and CO. The ACC/AHA guidelines do not currently advocate the use of fish oils and hawthorn for HF. It is important to counsel patients to remain on their other HF medications if they decide to initiate a NHP, and to let their health care providers know when starting a new supplement.
HF With Preserved LVEF
It is now recognized that a significant number of patients exhibiting HF symptoms have normal systolic function or preserved LVEF (40-60%). It is believed that the primary defect in these patients is impaired ventricular relaxation and filling, commonly referred to as diastolic dysfunction or diastolic HF. HF with preserved EF is more prevalent in older women and is closely associated with hypertension or diabetes, and to a lesser extent, CAD and atrial fibrillation.44 Morbidity in HF patients with preserved EF is comparable to those with depressed EF, as both are characterized by frequent, repeated hospitalizations.44 However, HT with preserved TT is associated with better survival. The diagnosis is based on findings of typical signs and symptoms of HT, in conjunction with echocardiographic evidence of normal LV systolic function and no valvular disease.
Patient Encounter, Part 3
Based on the information presented and your problem-based assessment, create a care plan for BE’s HF. Your plan should include:
Nonpharmacologic treatment options.
Acute and chronic treatment plans to address BE’s symptoms and prevent disease deterioration.
Monitoring plan for acute and chronic treatments.
Unlike systolic HF, few prospective trials have evaluated the safety and efficacy of various cardiac medications in patients with diastolic HF or preserved EF. The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) study demonstrated that angiotensin receptor blockade with candesartan resulted in beneficial effects on HF morbidity in patients with preserved LVEF similar to those seen in depressed LV function.25
In the absence of more landmark clinical studies, the current treatment approach for diastolic dysfunction or preserved LVEF is: (a) correction or control of underlying etiologies (including optimal treatment of hypertension and CAD and maintenance of normal sinus rhythm); (b) reduction of cardiac filling pressures at rest and during exertion; and (c) increased diastolic filling time. Diuretics are frequently used to control congestion. Recent studies failed to show significant reductions in mortality or hospitalizations with use of ARBs. β-Blockers and calcium channel blockers can theoretically improve ventricular relaxation through negative inotropic and chronotropic effects. Unlike in systolic HF, nondihydropyridine calcium channel blockers (diltiazem and verapamil) may be especially useful in improving diastolic function by limiting the availability of calcium that mediates contractility. A recent study did not find favorable effects with digoxin in patients with mild to moderate diastolic HF. Therefore, the role of digoxin for symptom management and HR control in these patients is not well established.
Special Populations and Patients With Concomitant Disorders
Ethnic and Genetic Considerations
HF is more prevalent and associated with a worse prognosis in African Americans compared to the general population.1 Unfortunately, deficiencies in disease prevention, detection, and access to treatment are well documented in minority populations. African Americans and other races are under-represented in clinical trials, compromising the extrapolation of results from these studies to ethnic subpopulations. The influence of race on efficacy and safety of medications used in HF treatment has received additional attention with the advent of pharmacogenomics (the influence of genetics on drug response). The application of race and genetics to pharmacotherapeutic decision making for HF is in the early stages. However, these concepts are being applied to the use of hydralazine and isosorbide dinitrate in African American patients.28 It is anticipated that further investigation will lead to better insight relating to the clinical applicability of genetic variations to drug responses.
Peripartum Cardiomyopathy and Pregnancy
Peripartum cardiomyopathy (PPCM) is currently defined as clinical and echocardiographic evidence for new-onset HF occurring during pregnancy and up to 6 months after delivery, with other etiologies excluded. Although PPCM is not well understood, it manifests in pregnant women of all ages, but the risk is elevated in women older than 30 years of age.45 The true incidence of idiopathic PPCM is debatable, with reported rates for peripartum HF at 1 case per 100 to 4,000 deliveries.46 The leading hypothesis for PPCM pathogenesis is myocarditis caused by a viral infection or an abnormal immune response to pregnancy. HF may persist after delivery but can be reversible (with partial or full recovery of cardiac function) in many cases.45
The clinical presentation of peripartum HF is indistinguishable from that of other types of HF. Initial treatment is also similar, with the exception of ACE inhibitors and ARBs being contraindicated during the antepartum period. Treatment includes reducing preload by sodium restriction and diuretics, afterload reduction with vasodilators, and sometimes inotropic support with digoxin. Hydralazine is utilized frequently in pregnancy and is classified as FDA pregnancy category C. Labetalol is used for acute parenteral control of BP, but long-term β-blocker use corresponds with low birth-weight infants. Management of the cardiomyopathy after delivery includes use of ACE inhibitors and β-blockers, although these treatment guidelines have been extrapolated from studies in patients with idiopathic dilated cardiomyopathy rather than specific trials in PPCM. Patients with PPCM also have a high rate of thromboembolism. Treatment options during pregnancy are limited to unfractionated heparin and low-molecular-weight heparin as warfarin is contraindicated. After delivery, anticoagulation is recommended in patients with LVEF less than 20%.46
OUTCOME EVALUATION OF CHRONIC HF
• The evaluation of therapy is influenced by the ability of treatment to successfully reduce symptoms, improve quality of life, decrease frequency of hospitalizations for AHF, reduce disease progression, and prolong survival (Fig. 6–1).
• The major outcome parameters focus on: (a) volume status; (b) exercise tolerance; (c) overall symptoms/quality of life; (d) adverse drug reactions; and (e) disease progression and cardiac function. Assess quality of life by evaluating patients’ ability to continue their activities of daily living.
• Assess symptoms of HF such as dyspnea on exertion, orthopnea, weight gain, and edema, and abdominal manifestations such as nausea, bloating, and loss of appetite.
• If diuretic therapy is warranted, monitor for therapeutic response by assessing weight loss and improvement of fluid retention, as well as exercise tolerance and presence of fatigue.
• Once therapy for preventing disease progression is initiated, monitoring for symptomatic improvement continues.
• It is important to keep in mind that patients’ symptoms of HF can worsen with β-blockers, and it may take weeks or months before patients notice improvement.
• Monitor BP to evaluate for hypotension caused by drug therapy.
• To assess for prevention of disease progression, practitioners may utilize serial echocardiograms every 6 months to assess cardiac function and evaluate the effects of drug therapy.
• Occasional exercise testing is conducted in order to ascertain disease prognosis or suitability for heart transplant. Even though these tests can demonstrate improvement in heart function and therefore slowed disease progression, patient symptoms may not improve.
ACUTE AND ADVANCED HF
Clinical Presentation and Diagnosis of AHF
Patients with AHF present with symptoms of worsening fluid retention or decreasing exercise tolerance and fatigue (typically worsening of symptoms presented in the chronic HF clinical presentation text box). These symptoms reflect congestion behind the failing ventricle and/or hypoperfusion. Patients can be categorized into hemodynamic subsets based on assessment of physical signs and symptoms of congestion and/or hypoperfusion.47 Patients can be described as “wet” or “dry” depending on volume status, as well as “warm” or “cool” based on adequacy of tissue perfusion. “Wet” refers to patients with volume/fluid overload (e.g., edema and jugular venous distention [JVD]), whereas “dry” refers to euvolemic patients. “Warm” refers to patients with adequate CO to perfuse peripheral tissues (and hence the skin will be warm to touch), whereas “cool” refers to patients with evidence of hypoperfusion (skin cool to touch with diminished pulses). Additionally, invasive hemodynamic monitoring can be used to provide objective data for assessing volume status (pulmonary capillary wedge pressure [PCWP]) and perfusion (CO). A CI below 2.2 L/min/m2 is consistent with hypoperfusion and reduced contractility, and a PCWP above 18 mm Hg correlates with congestion and an elevated preload. The four possible hemodynamic subsets a patient may fall into are “warm and dry,” “warm and wet,” “cool and dry,” or “cool and wet.”
Clinical Presentation and Diagnosis of AHF
Subset I (Warm and Dry)
• CI greater than 2.2 L/min/m2, pulmonary capillary wedge pressure (PCWP) less than 18 mm Hg
• Patients considered well compensated and perfused, without evidence of congestion
• No immediate interventions necessary except optimizing oral medications and monitoring
Subset II (Warm and Wet)
• CI greater than 2.2 L/min/m2, PCWP greater than 18 mm Hg
• Patients adequately perfused and display signs and symptoms of congestion
• Main goal is to reduce preload (PCWP) carefully with loop diuretics and vasodilators
Subset III (Cool and Dry)
• CI less than 2.2 L/min/m2, PCWP less than 18 mm Hg
• Patients are inadequately perfused and not congested
• Hypoperfusion leads to increased mortality, elevating death rates fourfold compared to those who are adequately perfused
• Treatment focuses on increasing CO with positive inotropic agents and/or replacing intravascular fluids
• Fluid replacement must be performed cautiously, as patients can rapidly become congested
Subset IV (Cool and Wet)
• CI less than 2.2 L/min/m2, PCWP greater than 18 mm Hg
• Patients are inadequately perfused and congested
• Classified as the most complicated clinical presentation of AHF with the worst prognosis
• Most challenging to treat; therapy targets alleviating signs and symptoms of congestion by increasing CI as well as reducing PCWP, while maintaining adequate mean arterial pressure
• Treatment involves a delicate balance among diuretics, vasodilators, and inotropic agents
• Use of vasopressors is sometimes necessary to maintain BP
Clinical Assessment and Diagnosis
Precipitating Factors
It is important for the clinician to identify the cause(s) of AHF in order to maximize treatment efficacy and reduce future disease exacerbations. Cardiovascular, metabolic, and lifestyle factors can all precipitate AHF. The most common precipitating factors for acute decompensation and how they contribute pathophysiologically are listed in Table 6–3.
Laboratory Assessment
Routine laboratory testing of patients with AHF includes electrolytes and blood glucose, as well as serum creatinine and blood urea nitrogen to assess renal function. CBC count is measured to determine if anemia or infection is present. Creatine kinase and/or troponin concentrations are used to diagnose ischemia, and hepatic transaminases are measured to assess hepatic congestion. Thyroid function tests are measured to assess hyperthyroidism or hypothyroidism as causes of AHF. A urinalysis is obtained in patients with an unknown history of renal disease to rule out nephrotic syndrome. Lastly, a toxicology screen is obtained in patients in whom use of illicit drugs is suspected.
Assays measuring BNP and its degradation product NTproBNP are being used with greater frequency in clinical practice.10 BNP is synthesized, stored, and released from the ventricles in response to increased ventricular filling pressures. Hence, plasma levels of BNP can be used as a marker for volume overload. The most widely accepted indication for BNP measurement is as an adjunctive aid for diagnosing a cardiac etiology for dyspnea.10
The current values for ruling out a cardiac etiology for dyspnea are a BNP less than 100 pg/mL (100 ng/L or 28.9 pmol/L) or an NT-proBNP less than 300 pg/mL (300 ng/L or 35.4 pmol/L). BNP measurements require cautious interpretation, as numerous conditions can also elevate BNP concentrations. These include older age, renal dysfunction, pulmonary embolism, and chronic pulmonary disease. Nesiritide, a recombinant BNP drug, has an identical structure to native BNP and will interfere with the commercial BNP assay, resulting in a falsely elevated level. Therefore, blood for BNP determination should be obtained 2 hours after the end of a nesiritide infusion, or alternatively the NT-proBNP assay should be utilized.
Other diagnostic tests should also be obtained in order to help determine precipitating factors (chest radiograph) and to evaluate cardiac function (ECG).
Invasive hemodynamic monitoring in patients with HF entails placement of a right heart or pulmonary artery catheter (PAC). The catheter is inserted percutaneously through a central vein and advanced through the right side of the heart to the pulmonary artery. Inflation of a balloon proximal to the end port allows the catheter to “wedge,” yielding the PCWP, which estimates pressures in the left ventricle during diastole. Additionally, CO can be estimated and SVR calculated (Table 6–8).
There are no universally accepted guidelines dictating when invasive monitoring in HF is required. The use of a PAC remains an essential component of management and monitoring of patients in cardiogenic shock; however, the use of inotropic agents does not mandate invasive monitoring. Invasive hemodynamic monitoring is most commonly used to aid in the assessment of hemodynamics when there is disagreement between signs and symptoms and clinical response. In addition, invasive monitoring is helpful in guiding ongoing therapy for AHF. Invasive monitoring offers the advantage of immediate hemodynamic assessment of an intervention, allowing for prompt adjustments. Risks with PACs include infection, bleeding, thrombosis, catheter malfunction, and ventricular ectopy.
Table 6–8 Hemodynamic Monitoring: Normal Values
Treatment of AHF
Desired Therapeutic Outcomes
The goals of therapy for AHF are to: (a) correct the underlying precipitating factor(s); (b) relieve the patient’s symptoms; (c) improve hemodynamics; (d) optimize a chronic oral medication regimen; and (e) educate the patient, reinforcing adherence to lifestyle modifications and the drug regimen. The ultimate goal for a patient hospitalized for AHF is the return to a compensated HF state and discharge to the outpatient setting on oral medications. Only through aggressive management to achieve all of these goals will a patient’s prognosis be improved and future hospitalizations for acute decompensations prevented.
Removal or control of precipitating factors is essential for an optimal response to pharmacologic therapy. Relief of symptoms should occur rapidly to minimize length of hospitalization. Although a rapid discharge from the hospital is desirable, a patient should not be discharged before ensuring that he or she is in a euvolemic, or nearly euvolemic, state with a body weight and functional capacity similar to before the acute decompensation. Oral agents such as β-blockers, ACE inhibitors or ARBs, and aldosterone antagonists should be initiated as soon as possible during the hospitalization. These chronic oral medications not only improve mortality and prevent readmissions, acutely they also contribute to improvement in hemodynamics. Patient education prior to discharge from the hospital is recommended to assist in minimizing adverse effects and nonadherence. Dissemination of written information, in addition to verbal information, is helpful for patient comprehension and retention. This can include therapy goals, lifestyle modifications, drug regimen, dosage information, and relevant adverse effects, as well as symptom and diary cards.
Pharmacologic Approaches to Treatment
Treatment of AHF targets relief of congestion and optimization of CO utilizing oral or IV diuretics, IV vasodilators, and when appropriate inotropes based on presenting hemodynamics. Current treatment strategies in AHF target improving hemodynamics while preserving organ function. A specific treatment approach is formulated depending on the patient’s symptoms (congestion versus hypoperfusion) and hemodynamic indices (CI and PCWP).48,49 If the patient primarily exhibits signs and symptoms of congestion, treatment entails use of diuretics as first-line agents to decrease PCWP. Additionally, IV vasodilators are added to provide rapid relief of congestion and additional reductions in PCWP. By reducing congestion in the heart, cardiac contractile function may improve, which results in an increase in SV and CO, and hence perfusion to vital organs. For patients primarily displaying symptoms of hypoperfusion, treatment relies on use of agents that increase cardiac contractility, known as positive inotropes. Some patients display both symptoms of congestion as well as hypoperfusion, and thus require use of combination therapies. One of the current challenges to the treatment of AHF is achieving hemodynamic improvement without adversely affecting organ function. In the case of inotropes, the increased contractility occurs at the expense of an increase in cardiac workload and proarrhythmia. In addition, high-dose diuretic therapy is associated with worsened renal function and possibly neurohormonal activation.
Diuretics
Loop diuretics, including furosemide, bumetanide, and torsemide, are the diuretics of choice in the management of AHF. Furosemide is the most commonly used agent. Diuretics decrease preload by functional venodilation within 5 to 15 minutes of administration and subsequently by an increase in sodium and water excretion. This provides rapid improvement in symptoms of pulmonary congestion. Diuretics reduce PCWP but do not increase CI as do positive inotropes and arterial vasodilators. Patients who have significant volume overload often have impaired absorption of oral loop diuretics because of intestinal edema or altered transit time. Therefore, doses are usually administered via IV boluses or continuous IV infusions, given either at the same dose as the home oral dose for those taking diuretics regularly or at lower doses for diuretic-naïve patients (Table 6–9). Higher doses may be required for patients with renal insufficiency due to decreased drug delivery to the site of action in the loop of Henle.
There is a paucity of clinical trial evidence comparing the benefit of diuretics to other therapies for symptom relief or long-term outcomes. Additionally, excessive preload reduction can lead to a decrease in CO resulting in reflex increase in sympathetic activation, renin release, and the expected consequences of vasoconstriction, tachycardia, and increased myocardial oxygen demand. Careful use of diuretics is recommended to avoid overdiuresis. Monitoring of serum electrolytes such as potassium, sodium, and magnesium is done frequently to identify and correct imbalances. Monitor serum creatinine and blood urea nitrogen daily at a minimum to assess volume depletion and renal function.
Occasionally, patients with HF do not respond to a diuretic, defined as failure to achieve a weight reduction of at least 0.5 kg (1.1 lb; or negative net fluid balance of at least 500 mL) after several increasing bolus doses.17
Several strategies are employed to overcome diuretic resistance. These include using larger oral doses, converting to IV dosing, or increasing the frequency of administration. Small studies using low-dose continuous infusions of furosemide and torsemide have shown an increase in urine output compared to intermittent bolus dosing.50 Continuous infusions may provide a theoretical advantage of continuous presence of high drug levels within the tubular lumen, causing a sustained natriuresis. Most regimens include a bolus dose followed by a maintenance infusion (Table 6–9).51 Another useful strategy is to combine two diuretics with different sites of action within the nephron. The most common combination is the use of a loop diuretic with a thiazide diuretic such as metolazone. Combining diuretics should be used with caution due to an increased risk for cardiovascular collapse due to rapid intravascular volume depletion. Strict monitoring of electrolytes, vital signs, and fluid balance is warranted.
Table 6–9 IV Diuretics Used to Treat HF-Related Fluid Retention
Finally, poor CO may contribute to diuretic resistance. In these patients, it may become necessary to add vasodilators or inotropes to enhance perfusion to the kidneys. Care must be taken, as vasodilators can decrease renal blood flow despite increasing CO through dilation of central and peripheral vascular beds.
Vasodilators
IV vasodilators cause a rapid decrease in arterial tone, resulting in a decrease in SVR and a subsequent increase in SV and CO. Additionally, vasodilators reduce ventricular filling pressures (PCWP) within 24 to 48 hours, reduce myocardial oxygen consumption, and decrease ventricular workload. Vasodilators are commonly used in patients presenting with AHF accompanied by moderate to severe congestion. This class includes nitroglycerin, nitroprusside, and nesiritide. Hemodynamic effects and dosages for these agents are included in Tables 6-10 and 6-11, respectively. Although vasodilators are generally safe and effective, identification of the proper patient for use is important to minimize the risk of significant hypotension. In addition, vasodilators are contraindicated in patients whose cardiac filling (and hence CO) depends on venous return or intravascular volume, as well as patients who present with shock.
Nitroglycerin
Nitroglycerin acts as a source of nitric oxide, which induces smooth muscle relaxation in venous and arterial vascular beds. Nitroglycerin is primarily a venous vasodilator at lower doses, but exerts potent arterial vasodilatory effects at higher doses. Thus, at lower doses, nitroglycerin causes decreases in preload (or filling pressures) and improved coronary blood flow. At higher doses (greater than 100 mcg/min), additional reduction in preload is achieved, along with a decrease in afterload and subsequent increase in SV and CO. IV nitroglycerin is primarily used as a preload reducer for patients exhibiting pulmonary congestion or in combination with inotropes for congested patients with severely reduced CO.52
Table 6–10 Usual Hemodynamic Effects of Commonly Used IV Agents for Treatment of Acute or Severe HF
Table 6–11 Usual Doses and Monitoring of Commonly Used Hemodynamic Medications
Continuous infusions of nitroglycerin should be initiated at a dose of 5 to 10 mcg/min and increased every 5 to 10 minutes until symptomatic or hemodynamic improvement. Effective doses range from 35 to 200 mcg/min. The most common adverse events reported are headache, dose-related hypotension, and tachycardia. A limitation to nitroglycerin’s use is the development of tachyphylaxis, or tolerance to its effects, which can be evident within 12 hours after initiation of continuous infusion and necessitate additional titrations to higher doses.
Nitroprusside
Nitroprusside, like nitroglycerin, causes the formation of nitric oxide and vascular smooth muscle relaxation. In contrast to nitroglycerin, nitroprusside is both a venous and arterial vasodilator regardless of dosage. Nitroprusside causes a pronounced decrease in PCWP, SVR, and BP, with a modest increase in CO. Nitroprusside has been studied to a limited extent in AHF and no studies have evaluated its effects on mortality.48 Nitroprusside is initiated at 0.1 to 0.25 mcg/kg/min, followed by dose adjustments in 0.1 to 0.2 mcg/kg/min increments if necessary to achieve desired effect. Because of its rapid onset of action and metabolism, nitroprusside is administered as a continuous infusion that is easy to titrate and provides predictable hemodynamic effects. Nitroprusside requires strict monitoring of BP and HR. Nitroprusside’s use is limited in AHF due to recommended hemodynamic monitoring with an arterial line and mandatory intensive care unit admission at many institutions. Abrupt withdrawal of therapy should be avoided, as rebound neurohormonal activation may occur. Therefore, the dose should be tapered slowly. Nitroprusside has the potential to cause cyanide and thiocyanate toxicity, especially in patients with hepatic and renal insufficiency, respectively. Toxicity is most common with use longer than 3 days and with higher doses. Nitroprusside should be avoided in patients with active ischemia, because its powerful afterload-reducing effects within the myocardium can “steal” coronary blood flow from myocardial segments that are supplied by epicardial vessels with high-grade lesions.
Nesiritide
BNP is an endogenous neurohormone that is synthesized and released from the ventricles in response to chamber wall stretch or increased filling pressures. Recombinant BNP, or nesiritide, is the newest compound developed for AHF. Nesiritide binds to guanylate cyclase receptors in vascular smooth muscle and endothelial cells, causing an increase in cGMP concentrations leading to vasodilation (venous and arterial) and natriuresis. Nesiritide also antagonizes the effects of the RAAS and ET. Nesiritide reduces PCWP, right atrial pressure, and SVR. Consequently, it also increases SV and CO without affecting HR. Continuous infusions result in sustained effects for 24 hours without tachyphylaxis, although experience with its use beyond 72 hours is limited.
Nesiritide has been shown to improve symptoms of dyspnea and fatigue. In a randomized clinical trial,53 nesiritide was found to significantly decrease PCWP more than nitroglycerin and placebo over 3 hours. Nesiritide improved patients’ self-reported dyspnea scores compared to placebo at 3 hours, but there was no difference compared to nitroglycerin. There are no prospective mortality studies with nesiritide in AHF.
Currently, nesiritide is indicated for patients with AHF exhibiting dyspnea at rest or with minimal activity. The recommended dose regimen is a bolus of 2 mcg/kg, followed by a continuous infusion for up to 24 hours of 0.01 mcg/kg/min. Because nesiritide’s effects are predictable and sustained at the recommended dosage, titration of the infusion rate (maximum of 0.03 mcg/kg/min) is not commonly required nor is invasive hemodynamic monitoring. Nesiritide should be avoided in patients with systolic BP less than 90 mm Hg. Although nesiritide’s place in AHF therapy is not firmly defined, it is used as one of the first-line agents (in combination with diuretics) for many patients presenting in moderate to severe decompensation, mainly due to its proven benefits and unique mechanism of action. One potential disadvantage compared to other vasodilators is its longer half-life. If hypotension occurs, the effect can be prolonged (2 hours). There are also concerns relating to elevations in serum creatinine observed with nesiritide; however, whether this effect is clinically relevant remains unanswered.
Inotropic Agents
Currently available positive inotropic agents act via increasing intracellular cyclic adenosine monophosphate (cAMP) concentrations through different mechanisms. β-Agonists activate adenylate cyclase through stimulation of β-adrenergic receptors, which subsequently catalyzes the conversion of ATP to cAMP. In contrast, phosphodiesterase inhibitors reduce degradation of cAMP. The resulting elevation in cAMP levels leads to enhanced phospholipase activity, which then increases the rate and extent of calcium influx during systole, thereby enhancing contractility. Additionally, during diastole, cAMP promotes uptake of calcium by the sarcoplasmic reticulum which improves cardiac relaxation. The inotropes approved for use in AHF are discussed in the following sections. Inotropes have been associated with increased risk for arrhythmias and higher mortality rates, and therefore require careful monitoring.
Dobutamine Dobutamine has historically been the inotrope of choice for AHF. As a synthetic catecholamine, it acts as an agonist mainly on β1-and β-receptors and minimally on α1-receptors. The resulting hemodynamic effects are due to both receptor-and reflex-mediated activities. These effects include increased contractility and HR through β -(and β2-) receptors and vasodilation through a relatively greater effect on β2-than α1-receptors. Dobutamine can increase, decrease, or cause little change in mean arterial pressure depending on whether the resulting increase in CO is enough to offset the modest vasodilation. Although dobutamine displays a half-life of approximately 2 minutes, its positive hemodynamic effects can be observed for several days to months after administration. The use of dobutamine is supported by several small studies documenting improved hemodynamics, but large-scale clinical trials in AHF are lacking.54
Dobutamine is initiated at a dose of 2.5 to 5 mcg/kg/min, which can be gradually titrated to 20 mcg/kg/min based on clinical response. There are several practical considerations to dobutamine therapy in AHF. First, owing to its vasodilatory potential, monotherapy with dobutamine is reserved for patients with systolic BPs greater than 90 mm Hg. However, it is commonly used in combination with vasopressors in patients with lower systolic BPs. Second, due to downregulation of β1-receptors or uncoupling of β2-receptors from adenylate cyclase with prolonged exposure to dobutamine, attenuation of hemodynamic effects has been reported to occur as early as 48 hours after initiation of a continuous infusion, although tachyphylaxis is more evident with use spanning longer than 72 hours. Full sensitivity to dobutamine’s effects can be restored 7 to 10 days after the drug is withdrawn. Third, many patients with AHF will be taking β-blockers on a chronic basis. Because of β-blockers’ high affinity for β-receptors, the effectiveness of β-agonists such as dobutamine will be reduced. In patients on β-blocker therapy, it is recommended that consideration be given to the use of phosphodiesterase inhibitors such as milrinone, which are not dependent on β-receptors for effect.55,56 Although commonly practiced, use of high doses of dobutamine to overcome the β-blockade should be discouraged, as this negates any of the protective benefits of the β-blocker.
Dopamine
Dopamine is most commonly reserved for patients with low systolic BPs and those approaching cardiogenic shock. It may also be used in low doses (less than 3 mcg/kg/min) to improve renal function in a patient with inadequate urine output despite high filling pressures and volume overload, although this indication is controversial.
Dopamine exerts its effects through direct stimulation of adrenergic receptors, as well as release of norepinephrine from adrenergic nerve terminals. Dopamine produces hemodynamic effects that differ based on dosing. At lower doses, dopamine stimulates dopamine type 1 (D1) receptors and thus increases renal perfusion. Positive inotropic effects are more pronounced at doses of 3 to 10 mcg/kg/min. CI is increased due to increased SV and HR. At doses higher than 10 mcg/kg/min, chronotropic and α1-mediated vasoconstriction effects are evident. This causes an increase in mean arterial pressure due to higher CI and SVR. The ultimate effect on cardiac hemodynamics will depend largely on the dosage prescribed and must be individually tailored to the patient’s clinical status. Dopamine is generally associated with an increase in CO and BP, with a concomitant increase in PCWP. Dopamine increases myocardial oxygen demand and may decrease coronary blood flow through vasoconstriction and increased wall tension. As with other inotropes, dopamine is associated with a risk for arrhythmias.
Phosphodiesterase Inhibitors
Milrinone and inamrinone work by inhibiting phosphodiesterase III, the enzyme responsible for the breakdown of cAMP. The increase in cAMP levels leads to increased intracellular calcium concentrations and enhanced contractile force generation. Milrinone has replaced inamrinone as the phosphodiesterase inhibitor of choice due to the higher frequency of throm-bocytopenia seen with inamrinone.
Milrinone has both positive inotropic and vasodilating properties and as such is referred to as an “inodilator.” Its vasodilating activities are especially prominent on venous capacitance vessels and pulmonary vascular beds, although a reduction in arterial tone is also noted. IV administration results in an increase in SV and CO, and usually only minor changes in HR. Milrinone also lowers PCWP through venodilation. Routine use of milrinone during acute decompensations in NYHA FC II to IV HF is not recommended, and milrinone use remains limited to patients who require inotropic support.57
Dosing recommendations for milrinone include a loading dose of 50 mcg/kg, followed by an infusion beginning at 0.5 mcg/kg/min (range 0.23 mcg/kg/min for patients with renal failure up to 0.75 mcg/kg/min). A loading dose is not necessary if immediate hemodynamic effects are not required or if patients have low systolic BPs (less than 90 mm Hg). Decreases in BP during an infusion may necessitate dose reductions as well. Lower doses are also used in patients with renal insufficiency.
Milrinone is a good option for patients requiring an inotrope who are also chronically receiving β-blockers, as the inotropic effects are achieved independent of β-adrenergic receptors. However, milrinone exhibits a long distribution and elimination half-life compared to β-agonists, thus requiring a loading dose when an immediate response is desired. Potential adverse effects include hypotension, arrhythmias, and less commonly, thrombocytopenia. Milrinone should not be used in patients in whom vasodilation is contraindicated.
Mechanical, Surgical, and Device Therapies
Implantable Cardioverter Defibrillators
Implantable cardioverter defibrillators (ICDs) are the most effective modality for primary and secondary prevention of sudden cardiac death in patients with LV dysfunction. Studies universally demonstrate greater efficacy compared to antiarrhythmic therapy and a significant reduction in mortality compared to placebo.58–60 Recent studies have expanded the eligible patient populations beyond classic indications, such as prior MI and nonsustained ventricular tachycardia or nonsuppressible ventricular tachycardia during an electrophysiologic study. A clear advantage of implanting ICDs in all symptomatic patients with LVEF less than 35% regardless of etiology or other cardiac parameters has been demonstrated.60 Because ICD implantation and follow-up is associated with a significant economic burden, the cost effectiveness of widespread ICD use continues to be debated. Defining subgroups that would derive the greatest benefit and determining the optimal ICD configuration will aid in improving the potential costs compared to benefits.
Cardiac Resynchronization Therapy
Dyssynchronous contraction, as a reflection of intra-and interventricular conduction delays between chambers of the heart, is common in advanced HF patients. Dyssynchrony contributes to diminished cardiac function and unfavorable myocardial energetics through altered filling times, valvular dysfunction, and wall motion defects. Cardiac resynchronization therapy (CRT) with biventricular pacing devices improves cardiac function, quality of life, and mortality in patients with NYHA FC III or IV HF, evidence of intraventricular conduction delay (QRS greater than 120 msec), depressed LV function (LVBF less than 35%), and on an optimal pharmacologic regimen. A recent study also showed that the addition of an ICD to CRT with biventricular pacing further reduced hospitalizations and mortality.61
Intra-aortic Balloon Counterpulsation
Intra-aortic balloon counterpulsation (IABC) or intra-aortic balloon pumps (IABPs) are one of the most widely used mechanical circulatory assistance devices for patients with cardiac failure who do not respond to standard therapies. An IABP is placed percutaneously into the femoral artery and advanced to the high descending thoracic aorta. Once in position, the balloon is programmed to inflate during diastole and deflate during systole. Two main beneficial mechanisms are: (a) inflation during diastole increases aortic pressure and perfusion of the coronary arteries, and (b) deflation just prior to the aortic valve opening reduces arterial impedence (afterload). As such, IABC increases myocardial oxygen supply and decreases oxygen demand. This device has many indications including cardiogenic shock, high-risk unstable angina in conjunction with percutaneous interventions, pre-operative stabilization of high-risk patients prior to surgery, and patients who cannot be weaned from cardiopulmonary bypass. Possible complications include infection, bleeding, thrombosis, limb ischemia, and device malfunction. The device is typically useful for short-term therapy due to the invasiveness of the device, the need for limb immobilization, and the requirement for anticoagulation.
Patient Encounter, Part 4
After 6 months, BE returns to clinic complaining of extreme SOB with any activity, including dressing and showering, as well as at rest. She sleeps sitting up due to severe orthopnea, is unable to eat without nausea, and states she has gained 10 kg (22 lb) from her baseline weight. She also states that she does not feel her furosemide therapy is working. She is admitted to the cardiology unit.
SH: BE admits to resuming smoking after quitting for 2 months; additionally, she has been eating out in restaurants more often in the past 2 weeks.
Meds: Lisinopril 10 mg once daily; furosemide 80 mg twice daily; glipizide 10 mg twice daily for diabetes; metformin 1,000 mg twice daily for diabetes; nitroglycerin 0.4 mg sublingual (SL) as needed; multivitamin daily; Aspirin 325 mg daily
VS: BP 146/94 mm Hg, pulse 102 bpm and regular, RR 22/min, temperature 37°C (98.6°F), Wt 123 kg (271 lb), BMI 41.2
Lungs: There are rales present bilaterally
CV: RRR with normal S1 and S2; there is an S3 and an S4; a 4/6 systolic ejection murmur is present and heard best at the left lower sternal border; point of maximal impulse is displaced laterally; jugular veins are distended, JVP is 11 cm above sternal angle; a positive HJR is observed
Abd: Hard, tender, and bowel sounds are absent; 3+ pitting edema of extremities is observed
CXR: Bilateral pleural effusions and cardiomegaly
Echo: EF 20%
Labs: BNP 740 pg/mL (740 ng/L or 214 pmol/L), K 4.2 mEq/L (4.2 mmol/L), BUN 64 mg/dL (23 mmol/L), SCr 2.4 mg/dL (212 mmol/L), Mg 1.8 mEq/L (0.9 mmol/L)
A pulmonary catheter is placed, revealing the following: PCWP 37 mm Hg; CI 2.2 L/min/m2
What NYHA FC, ACC/AHA stage, and hemodynamic subset is BE currently in?
What are your initial treatment goals?
What pharmacologic agents are appropriate to use at this time?
Identify a monitoring plan to assess for efficacy and toxicity of the recommended drug therapy.
Once BE’s symptoms are improved, how would you optimize her oral medication therapy for HF?
Ventricular Assist Device
The ventricular assist device (VAD) is a surgically implanted pump that reduces or replaces the work of the right, left, or both ventricles. VADs are currently indicated for short-term support in patients refractory to pharmacologic therapies, as long-term bridge therapy (a temporary transition treatment) in patients awaiting cardiac transplant, or in some instances, as the destination therapy (treatment for patients in lieu of cardiac transplant for those who are not appropriate candidates for transplantation).1 The most common complications are infection and thromboembolism. Other adverse effects include bleeding, air embolism, device failure, and multiorgan failure.
Surgical Therapy
Heart transplantation represents the final option for refractory, end-stage HF patients who have exhausted medical and device therapies. Heart transplantation is not a cure, but should be considered a trade between a life-threatening syndrome and the risks associated with the operation and long-term immunosuppression. Assessment of appropriate candidates includes comorbid illnesses, psychosocial behavior, available financial and social support, and patient willingness to adhere to lifelong therapy and close medical follow-up.1 Overall, the transplant recipient’s quality of life may be improved, but not all patients receive this benefit. Posttransplant survival continues to improve due to advances in immunosuppression, treatment and prevention of infection, and optimal management of patient comorbidities.
Investigational Therapies
Clinical trials are currently investigating new agents for the treatment of AHF. These compounds offer unique mechanisms of action by targeting different neurohormonal receptors (vasopressin, ET, ANP, and adenosine) or through completely novel pharmacologic profiles (myosin ATPase agonists). Some agents or drug classes being studied include tolvaptan, a V2-selective vasopressin antagonist; various ET-A selective and nonselective antagonists; and an adenosine-1 receptor agonist.
OUTCOME EVALUATION OF AHF
• Focus on: (a) acute improvement of symptoms and hemodynamics due to IV therapies; (b) criteria for a safe discharge from the hospital; and (c) optimization of oral therapy.
Patient Care and Monitoring
1. Assess the severity and duration of the patient’s symptoms including limitations in activity. Rule out potential exacerbating factors.
2. Obtain a thorough history of prescription, nonprescription, and herbal medication use. Is the patient taking any medications that can exacerbate HF?
3. Review available diagnostic information from the chest radiograph, ECG, and echocardiogram.
4. Review the patient’s lifestyle habits including salt and alcohol intake, tobacco product use, and exercise routine.
5. If unknown, investigate the patient’s underlying etiology of HF. Verify that comorbidities that lead to or worsen HF are optimally managed with appropriate drug therapy.
6. Educate the patient on lifestyle modifications such as salt restriction (maximum 2 g/day), fluid restriction if appropriate, limitation of alcohol, tobacco cessation, participation in a cardiac rehabilitation and exercise program, and proper immunizations such as the pneumococcal vaccine and yearly influenza vaccine.
7. Develop a treatment plan to alleviate symptoms and maintain euvolemia with diuretics. Daily weights to assess fluid retention are recommended.
8. Develop a medication regimen to slow the progression of HF with the use of neurohormonal blockers such as vasodilators (ACE inhibitors, ARBs, or hydralazine/isosorbide dinitrate), β-blockers, and aldosterone antagonists. Utilize digoxin if the patient remains symptomatic despite optimization of the above therapies.
• Is the patient at goal or maximally tolerated doses of vasodilator and β-blocker therapy?
• Are aldosterone antagonists utilized in appropriate patients with proper electrolyte and renal function monitoring?
9. Stress the importance of adherence to the therapeutic regimen and lifestyle changes for maintenance of a compensated state and slowing of disease progression.
10. Evaluate the patient for presence of adverse drug reactions, drug allergies, and drug interactions.
11. Provide patient education with regard to disease state and drug therapy, and reinforce self-monitoring for symptoms of HF that necessitate follow-up with a health care practitioner.
• Initially, monitor patients for rapid relief of symptoms related to the chief complaint on admission. This includes improvement of dyspnea, oxygenation, fatigue, JVD, and other markers of congestion or distress.
• Monitor for adequate perfusion of vital organs through assessment of mental status, CrCl, liver function tests, and a stable HR between 50 and 100 bpm. Additionally, adequate skin and muscle blood perfusion and normal pH is desirable.
• Monitor changes in hemodynamic variables if available. CI should increase, with a goal to maintain it above 2.2 L/min/m2. PCWP should decrease in volume overloaded patients to a goal of less than 18 mm Hg.
• Closely monitor BPs and renal function while decreasing preload with diuretics and vasodilators.
• Ensure patients are euvolemic or nearly euvolemic prior to discharge.
• Because oral therapies can both improve symptoms and prolong survival, optimizing outpatient HF management is a priority when preparing a patient for hospital discharge. Ensure that the patient’s regimen includes a vasodilator, β-blocker, a diuretic at an adequate dose to maintain euvolemia, and digoxin or aldosterone antagonist if indicated.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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