++
The abnormalities of myocardial structure and function that characterize CHF are often irreversible. These changes narrow the end-diastolic volume range that is compatible with normal cardiac function. Although CHF is predominately a chronic disease, subtle changes to an individual's hemodynamic status (e.g., increased circulating volume from high dietary sodium intake, increased systemic blood pressure from medication nonadherence) often provoke an acute clinical decompensation.
++
Not surprisingly, therefore, CHF therapy has for many years utilized diuretics to control volume overload and subsequent worsening in LV function. Other proven pharmacotherapies target ventricular wall stress, the renin–angiotensin–aldosterone axis, and the sympathetic nervous system to decrease pathologic ventricular remodeling, attenuate disease progression, and improve survival in selected patients with severe CHF and low LV ejection fraction. Figure 28–1 provides an overview of the sites of action for major drug classes commonly used in clinical practice. Note that these therapies largely improve cardiac hemodynamics and function through preload reduction, afterload reduction, and enhancement of inotropy (i.e., myocardial contractility). In addition, pharmacotherapeutics that target peripheral and coronary vascular function are receiving increased attention as potential participants in the comprehensive management of CHF patients.
++
++
Diuretics remain central in the pharmacologic management of congestive symptoms in patients with CHF. The pharmacologic properties of these agents are presented in detail in Chapter 25. Their importance (and frequency of use) in CHF management reflects the deleterious downstream effects of volume expansion on increased LV end-diastolic volume, an intermediate step in the development of elevated right-heart pressure, pulmonary venous congestion, and peripheral edema (Hillege et al., 2000).
++
Diuretics reduce extracellular fluid volume and ventricular filling pressure (or "preload"). Because CHF patients often operate on a "plateau" phase of the Frank-Starling curve (Figure 28–2), incremental preload reduction occurs under these conditions without a reduction in cardiac output. Sustained natriuresis and/or a rapid decline in intravascular volume, however, may "push" one's profile leftward on the Frank-Starling curve, resulting in an unwanted decrease in cardiac output. In this way, excessive diuresis is counterproductive secondary to reciprocal neurohormonal overactivation from volume depletion (McCurley et al., 2004). For this reason, it is preferable to avoid diuretics in patients with asymptomatic LV dysfunction and to only administer the minimal dose required to maintain euvolemia in those patients symptomatic from hypervolemia. Despite the efficacy of loop or thiazide diuretics in controlling congestive symptoms and improving exercise capacity, their use is not associated with a reduction in CHF mortality.
++
++
Dietary Sodium Restriction. All patients with clinically significant LV dysfunction, regardless of symptom status, should be advised to limit dietary sodium intake to 2-3 g/day. More stringent salt restriction is seldom necessary and may be counterproductive, as it can lead to hyponatremia, hypokalemia, and hypochloremic metabolic alkalosis when combined with loop diuretic administration.
++
Loop Diuretics. Of the loop diuretics currently available, furosemide (lasix, others), bumetanide (bumex, others), and torsemide (demadex, others) are widely used in the treatment of CHF. Due to the increased risk of ototoxicity, ethacrynic acid (edecrin) is recommended only for patients with sulfonamides allergies or who are intolerant to alternative options.
++
Loop diuretics inhibit a specific ion transport protein, the Na+-K+-2Cl– symporter on the apical membrane of renal epithelial cells in the ascending limb of the loop of Henle to increase Na+ and fluid delivery to distal nephron segments (see Chapter 25). These drugs also enhance K+ secretion, particularly in the presence of elevated aldosterone levels, as is typical in CHF.
+
The bioavailability of orally administered furosemide ranges from 40-70%. High drug concentrations often are required to initiate diuresis in patients with worsening symptoms or in those with impaired gastrointestinal absorption, as may occur in severely hypervolemic patients with CHF-induced gut edema (Gottlieb, 2004). In contrast, the oral bioavailabilities of bumetanide and torsemide are >80%, and as a result, these agents are more consistently absorbed but are financially more costly.
Furosemide and bumetanide are short-acting drugs, and rebound Na+ retention that occurs with sub-steady state drug levels make ≥2/day dosing an acceptable treatment strategy when using these agents, provided adequate monitoring of daily body weight and blood electrolyte level monitoring is possible.
++
Thiazide Diuretics. Monotherapy with thiazide diuretics (diuril, hydrodiuril, others) has a limited role in CHF. However, combination therapy with loop diuretics is often effective in those refractory to loop diuretics alone. Thiazide diuretics act on the Na+Cl− cotransporter in the distal convoluted tubule (see Chapter 25) and are associated with a greater degree K+ wasting per fluid volume reduction when compared to loop diuretics (Gottlieb, 2004).
++
K+-Sparing Diuretics. K+-sparing diuretics (see Chapter 25) inhibit apical membrane Na+-conductance channels in renal epithelial cells (e.g., amiloride, triamterene) or are mineralocorticoid (e.g., aldosterone) receptor antagonists (e.g., canrenone [not commercially available in the U.S.], spironolactone, and eplerenone). Collectively, these agents are weak diuretics, but have historically been used to achieve volume reduction with limited K+ and Mg2+ wasting. The beneficial role of aldosterone receptor blockers on survival in CHF is discussed later.
++
Diuretics in Clinical Practice. The majority of CHF patients will require chronic administration of a loop diuretic to maintain euvolemia. In patients with clinically evident fluid retention, furosemide typically is started at a dose of 40 mg once or twice daily, and the dosage is increased until an adequate diuresis is achieved. A larger initial dose may be necessary in patients with advanced CHF and azotemia. Serum electrolytes and renal function are monitored frequently in these patients or in those for whom a rapid diuresis is necessary. If present, hypokalemia from therapy may be corrected by oral or intravenous K+ supplementation or by the addition of a K+-sparing diuretic. When appropriate, diuretics are decreased to the minimum effective concentration for maintaining euvolemia.
++
Diuretics in the Decompensated Patient. In patients with decompensated CHF warranting hospital admission, repetitive intravenously administered boluses or a constant infusion titrated to achieve a desired response may be needed to provide expeditious (and reliable) diuresis (Dormans et al., 1996). One advantage to intravenous infusion is that sustained natriuresis is achieved as a consequence of consistently elevated drug levels within the lumen of the renal tubules. In addition, the risk of ototoxicity is reduced by continuous infusion when compared to repetitive, intermittent intravenous dosing (Lahav et al., 1992).
+
A typical continuous furosemide infusion is initiated with a 40-mg bolus injection followed by a constant rate of 10 mg/h, with uptitration as necessary. If renal perfusion is reduced, drug efficacy may be enhanced by co-administration of drugs that increase cardiac output (e.g., dobutamine).
++
Diuretic Resistance. As mentioned earlier, a compensatory increase in renal tubular Na+ reabsorption may prevent effective diuresis when dosed daily; as a result, reduction of diuretic dosing intervals may be warranted. In advanced CHF, invasive assessment of intracardiac filling pressures and cardiac output may be required to distinguish between low intravascular volume from aggressive diuresis versus low cardiac output states, although both states are aligned with lower diuretic delivery and drug efficacy. Furthermore, edema, decreased bowel-wall motility, and reduced splanchnic blood flow impair absorption and may delay or attenuate peak diuretic effect.
++
Atherosclerotic renal artery disease is associated with reduced renal perfusion pressures to levels below that necessary for adequate drug delivery. In patients with reduced renal arterial perfusion pressure (e.g., renal artery stenosis or low cardiac output), AngII-mediated efferent glomerular arteriole tone is important for preservation of normal glomerular filtration pressure. Angiotensin-converting enzyme (ACE) inhibitors or AT1 receptor antagonists in combination with loop diuretics may, therefore, be met with a decline in creatinine clearance that is associated with low diuretic delivery and decreased drug efficacy (Ellison, 1999). Other common causes of diuretic resistance are listed in Table 28–1.
++
+
Metabolic Consequences of Diuretic Therapy. The side effects of diuretics are discussed in Chapter 25. With regard to diuretic use in CHF, the most important adverse sequelae of diuretics are electrolyte abnormalities, including hyponatremia, hypokalemia, and hypochloremic metabolic alkalosis. The clinical importance (or even existence) of significant Mg2+ deficiency with chronic diuretic use is controversial (Bigger, 1994).
++
Adenosine A1 Receptor Antagonists. Adenosine A1 receptor antagonists may provide a renal protective therapeutic strategy for enhanced volume loss in decompensated CHF. Adenosine is secreted from the macula densa in the renal arteriole in response to diuretic-induced increases in Na+ and Cl− tubular flow concentrations. This results in increased Na+ resorption, a volume-loss counterregulatory mechanism (see Chapter 26). Na+ reabsorption, in addition to adenosine-induced renal arteriole vasoconstriction, appears responsible (in part) for the development of complications common to the use of diuretics in decompensated CHF patients, particularly prerenal azotemia. The role of adenosine in the macula densa and juxtaglomerular (granular) cells (see Figure 26–2) suggests other effects of A1 antagonists on the renin-angiotensin system.
+
As an example of the use of A1 antagonists, the administration of KW-3902 (rolofylline) (30 mg) to patients with decompensated CHF already treated with loop diuretics is associated with increased volume reduction, improved renal function, and lower diuretic dosing, as compared to placebo (Givertz et al., 2007). Favorable effects on urine output and renal function also have been observed in similar patients with the A1 receptor antagonist BG9179 (naxifylline) (Gottlieb et al., 2002). A large clinical trial failed to show significant benefits of rolofylline in patients with CHF, and clinical development of the drug was stopped in 2009. No A1 antagonists are currently marketed in the U.S.
+++
Aldosterone Antagonistsand Clinical Outcome
++
LV systolic dysfunction deceases renal blood flow and results in overactivation of the renin–angiotensin– aldosterone axis and may increase circulating plasma aldosterone levels in CHF to 20-fold above normal (Figure 28–3). The pathophysiologic effects of hyperaldosteronemia are diverse (Table 28–2) and extend beyond Na+ and fluid retention; importantly, however, the precise mechanism by which aldosterone receptor blockade improves outcome in CHF remains unresolved (Weber, 2004).
++
++
+
In the Randomized Aldactone Evaluation Study, CHF patients with low LV ejection fraction receiving spironolactone (25 mg/day) had a significant (~30%) reduction in mortality (from progressive heart failure or sudden cardiac death) and fewer CHF-related hospitalizations compared with the placebo group (Pitt et al., 1999). Treatment was well tolerated overall; most notably, however, 10% of men reported gynecomastia and 2% of all patients developed severe hyperkalemia (>6.0 mEq/L) on spironolactone (Pitt et al., 1999). Data from this and other clinical studies (Pitt et al., 2003) suggest that despite maximum ACE inhibition, clinically important aldosterone levels are still achieved in CHF. This may account for the beneficial effects observed in these trials where aldosterone-receptor antagonists were used in combination with ACE inhibitor therapy. Combination therapy in those with renal impairment, however, increases the probability of drug-induced hyperkalemia.
The role of aldosterone antagonists in patients with asymptomatic LV dysfunction or in those with minimal CHF-associated symptoms has not been established.
++
The rationale for oral vasodilator drugs in the pharmacotherapy of CHF derives from experience with parenterally administered phentolamine and nitroprusside in patients with advanced disease and elevated systemic vascular resistance (Cohn and Franciosa, 1977). Although numerous vasodilators have since been developed that improve CHF symptoms, only the hydralazine–isosorbide dinitrate combination, ACE inhibitors, and AT1 receptor blockers (ARBs) demonstrably improve survival. The therapeutic use of vasodilators in the treatment of hypertension and myocardial ischemia is considered in detail in Chapter 27. This chapter will focus on the uses for some of these same vasodilator drugs in the treatment of CHF. Table 28–3 summarizes properties of vasodilators commonly used to treat CHF.
++
++
Nitrovasodilators. Nitrovasodilators are nitric oxide (NO) donors that activate soluble guanylate cyclase in vascular smooth muscle cells, leading to vasodilation. The mechanism underlying the variable response profiles to nitrovasodilators in different vascular beds remains controversial; e.g., nitroglycerin preferentially induces epicardial coronary artery vasodilation. Furthermore, the mechanisms by which nitrovasodilators are converted to their active forms in vivo depend on the particular agent. Unlike nitroprusside, which is converted to NO• by cellular reducing agents such as glutathione, nitroglycerin and other organic nitrates undergo a more complex enzymatic biotransformation to NO• or bioactive S-nitrosothiols. The activities of specific enzyme(s) and cofactor(s) required for this biotransformation appear to differ by target organ and even by different vasculature beds within a particular organ (Münzel et al., 2005).
++
Organic Nitrates. As discussed in Chapter 27, organic nitrates are available in a number of formulations that include rapid-acting nitroglycerin tablets or spray for sublingual administration, short-acting oral agents such as isosorbide dinitrate (isordil, others), long-acting oral agents such as isosorbide mononitrate (ismo, others), topical preparations such as nitroglycerin ointment and transdermal patches, and intravenous nitroglycerin. These preparations are relatively safe and effective; specifically, their principal action in CHF is reducing LV filling pressure. This occurs, in part, by augmentation of peripheral venous capacitance that results in preload reduction. Additional effects of organic nitrates include pulmonary and systemic vascular resistance reduction, particularly at higher doses, and epicardial coronary artery vasodilation for which systolic and diastolic ventricular function is enhanced by increased coronary blood flow. Collectively, these beneficial physiologic effects translate into improved exercise capacity and CHF-symptom reduction. However, these drugs do not substantially influence systemic vascular resistance, and pharmacologic tolerance greatly limits their utility over time. For these reasons and others, organic nitrates are not commonly used alone; rather, a number of trials have shown that when used together, selected organic nitrates increase the clinical effectiveness of other vasodilators, such as hydralazine, resulting in a sustained improvement in hemodynamics.
++
Nitrate tolerance. Nitrate tolerance may limit the long-term effectiveness of these drugs in the treatment of CHF. Blood nitrate levels may be permitted to fall to negligible levels for at least 6-8 hours each day (see Chapter 27). The timing of nitrate withdrawal symptoms, if present, may be useful, however, for developing an appropriate drug-dosing schedule. Patients with recurrent orthopnea or paroxysmal nocturnal dyspnea, e.g., might benefit from nighttime nitrate use. Likewise, co-treatment with hydralazine (e.g., isosorbide dinitrate and hydralazine [BIDIL]) may decrease nitrate tolerance by an antioxidant effect that attenuates superoxide formation, thereby increasing the bioavailable NO levels (Münzel et al., 1996).
+++
Parenteral Vasodilators
++
Sodium Nitroprusside. Sodium nitroprusside (nitropress, others) is a direct NO donor and potent vasodilator that is effective in reducing both ventricular filling pressure and systemic vascular resistance. The downstream beneficial physiologic effects of afterload reduction in CHF are outlined in Figure 28–4. Onset to activation of sodium nitroprusside is rapid (2-5 minutes), and the drug is quickly metabolized to NO, properties that afford easy titration to achieve the desired hemodynamic effect.
++
++
Nitroprusside is particularly effective in treating critically ill patients with CHF who have elevated systemic vascular resistance or mechanical complications that follow acute MI (e.g., mitral regurgitation or ventricular septal defect-induced left-to-right shunts). As with other vasodilators, the most common adverse side effect of nitroprusside is hypotension. In general, nitroprusside initiation in patients with severe CHF results in increased cardiac output and a parallel increase in renal blood flow, improving both glomerular filtration and diuretic effectiveness. However, excessive reduction of systemic arterial pressure may limit or prevent an increase in renal blood flow in patients with more severe LV contractile dysfunction.
+
Cyanide produced during the biotransformation of nitroprusside is rapidly metabolized by the liver to thiocyanate, which is then renally excreted. Thiocyanate and/or cyanide toxicity is uncommon but may occur in the setting of hepatic or renal failure, or following prolonged periods of high-dose drug infusion (see Chapter 27 for details). Typical symptoms include unexplained abdominal pain, mental status changes, convulsions, and lactic acidosis. Methemoglobinemia is another unusual complication and is due to the oxidation of hemoglobin by NO•.
++
Intravenous Nitroglycerin. Intravenous nitroglycerin, like nitroprusside, is a vasoactive NO donor that is commonly used in the intensive care unit setting. Unlike nitroprusside, nitroglycerin is relatively selective for venous capacitance vessels, particularly at low infusion rates. In CHF, intravenous nitroglycerin is most commonly used in the treatment of LV dysfunction due to an acute myocardial ischemia. Parenteral nitroglycerin also is used in the treatment of nonischemic cardiomyopathy when expeditious LV filling pressure reduction is desired. At higher infusion rates, this drug also may decrease systemic arterial resistance, although this effect is less predictable. Nitroglycerin therapy may be limited by headache and nitrate tolerance; tolerance may be partially offset by increasing the dosage. Administration requires the use of an infusion pump capable of controlling the rate of administration.
++
Hydralazine. Hydralazine is a direct vasodilator that has long been in clinical use, yet its precise mechanism of action is poorly understood. The effects of this agent are not mediated through recognized neurohumoral systems, and its mechanism of action at the cellular level in vascular smooth muscle is uncertain. Lack of mechanistic understanding not with standing, hydralazine is an effective antihypertensive drug (see Chapter 27), particularly when combined with agents that blunt compensatory increases in sympathetic tone and salt and water retention. In CHF, hydralazine reduces right and left ventricular afterload by reducing pulmonary and systemic vascular resistance. This results in an augmentation of forward stroke volume and a reduction in ventricular wall stress in systole. Hydralazine also appears to have moderate "direct" positive inotropic activity in cardiac muscle independent of its afterload-reducing effects. Hydralazine is effective in reducing renal vascular resistance and in increasing renal blood flow to a greater degree than are most other vasodilators, with the exception of ACE inhibitors. For this reason, hydralazine often is used in CHF patients with renal dysfunction intolerant of ACE-inhibitor therapy.
+
The landmark Veterans Administration Cooperative Vasodilator-Heart Failure Trial I (V-HeFT I) demonstrated that combination therapy with isosorbide dinitrate and hydralazine (a pill containing these two compounds in combination is marketed as BiDil) reduces CHF mortality in patients with systolic dysfunction (Cohn et al., 1986). In V-HeFT I, the mortality benefit was agent specific: the α1 receptor antagonist prazosin offered no advantage over placebo when compared with isosorbide plus hydralazine.
Hydralazine provides additional hemodynamic improvement for patients with advanced CHF (with or without nitrates) already treated with conventional doses of an ACE inhibitor, digoxin, and diuretics (Cohn, 1994). The hypothesis that hydralazine-mediated antioxidant effects benefit CHF patients at elevated risk for vascular endothelial dysfunction is supported by the African-American Heart Failure Trial, in which isosorbide dinitrate-hydralazine substantially decreased all-cause mortality in self-described black patients, a group associated with impaired vascular endothelial function and diminished bioavailable levels of NO when compared to white counterparts (Taylor et al., 2007).
There are several important considerations for hydralazine use. First, ACE inhibitors appear to be superior to hydralazine for mortality reduction in severe CHF. Second, side effects requiring dose adjustment of hydralazine withdrawal are common. In V-HeFT I, e.g., only 55% of patients were taking full doses of both hydralazine and isosorbide dinitrate after 6 months. The lupus-like side effects associated with hydralazine are relatively uncommon and may be more likely to occur in selected patients with the "slow-acetylator" phenotype (see Chapter 27). Finally, hydralazine is a medication taken three or four times daily, and adherence may be difficult for CHF patients, who are often prescribed multiple medications concurrently.
The oral bioavailability and pharmacokinetics of hydralazine are not altered significantly in CHF, unless severe hepatic congestion or hypoperfusion is present. Intravenous hydralazine is available but provides little practical advantage over oral formulations except for urgent use in pregnant patients. In these individuals, hydralazine is often used owing to contraindications that exist for use of most other vasodilators in pregnancy. Hydralazine is typically started at a dose of 10-25 mg three or four times per day and uptitrated to a maximum of 100 mg three or four times daily, as tolerated. At total daily doses >200 mg, hydralazine is associated with an increased risk of lupus-like effects.
+++
Targeting Neurohormonal Regulation: The Renin–Angiotensin–Aldosterone Axis and Vasopressin Antagonists
++
Renin–Angiotensin–Aldosterone Axis Antagonists. The renin–angiotensin–aldosterone axis plays a central role in the pathophysiology of CHF (Figure 28–3). AngII is a potent arterial vasoconstrictor and an important mediator of Na+ and water retention through its effects on glomerular filtration pressure and aldosterone secretion. AngII also modulates neural and adrenal medulla catecholamine release, is arrhythmogenic, promotes vascular hyperplasia and myocardial hypertrophy, and induces myocyte death. Consequently, reduction of the effects of AngII constitutes a cornerstone of CHF management (Weber, 2004).
+
ACE inhibitors suppress AngII (and aldosterone) production, decrease sympathetic nervous system activity, and potentiate the effects of diuretics in CHF. However, AngII levels frequently return to baseline values following chronic treatment with ACE inhibitors (see Chapter 26), due in part to AngII production via ACE-independent enzymes. The sustained clinical effectiveness of ACE inhibitors despite this AngII "escape" suggests that alternate mechanisms contribute to the clinical benefits of ACE inhibitors in CHF. ACE is identical to kininase II, which degrades bradykinin and other kinins that stimulate production of NO, cyclic GMP, and vasoactive eicosanoids. These oppose AngII-induced vascular smooth muscle cell and cardiac fibroblasts proliferation and inhibit unfavorable extracellular matrix deposition.
++
ACE inhibitors are preferential arterial vasodilators. ACE-inhibitor–mediated decreases in LV afterload result in increased stroke volume and cardiac output; ultimately, the magnitude of these effects is associated with the observed change in mean arterial pressure. Heart rate typically is unchanged with treatment, often despite decreases in systemic arterial pressure, a response that probably is a consequence of decreased sympathetic nervous system activity from ACE inhibition.
++
Most clinical actions of AngII, including its deleterious effects in CHF, are mediated through the AT1 angiotensin receptor, whereas AT2 receptor activation appears to counterbalance the downstream biologic effects of AT1 receptor stimulation. Owing to enhanced target specificity, AT1 receptor antagonists more efficiently block the effects of AngII than do ACE inhibitors. In addition, the elevated level of circulating AngII that occurs secondary to AT1 receptor blockade results in a relative increase in AT2 receptor activation. Unlike ACE inhibitors, AT1 blockers do not influence bradykinin metabolism (see the next section).
++
Angiotensin-Converting Enzyme Inhibitors. The first orally administered ACE inhibitor, captopril (capoten, others), was introduced in 1977. Since then, six additional ACE inhibitors—enalapril (vasotec, others), ramipril (altace, others), lisinopril (prinivil, zestril, others), quinapril (accupril, others), trandolapril (mavik, others) and fosinopril (monopril, others) have been FDA- approved for the treatment of CHF. Data from numerous clinical trials involving well over 100,000 patients support ACE inhibition in the management of CHF of any severity, including those with asymptomatic LV dysfunction.
+
ACE-inhibitor therapy typically is initiated at a low dose (e.g., 6.25 mg of captopril, 5 mg of lisinopril) to avoid iatrogenic hypotension, particularly in the setting of volume contraction. Hypotension following drug administration usually can be reversed by intravascular volume expansion, but, of course, this may be counterproductive in symptomatic CHF patients. Therefore, it is reasonable to consider initiation of these drugs while congestive symptoms are present. ACE-inhibitor doses customarily are increased over several days in hospitalized patients or over weeks in ambulatory patients, with careful observation of blood pressure, serum electrolytes, and serum creatinine levels.
If possible, drug doses are targeted in practice to match those affording maximum clinical benefit in controlled trials: captopril, 50 mg three times daily (Pfeffer et al., 1992); enalapril, 10 mg twice daily (SOLVD Investigators, 1992; Cohn et al., 1991); lisinopril, 10 mg once daily (GISSI-3, 1994); and ramipril, 5 mg twice daily (AIRE Study Investigators, 1993). If an adequate clinical response is not achieved at these doses, further increases, as tolerated, may be effective (Packer et al., 1999).
In CHF patients with decreased renal blood flow, ACE inhibitors, unlike nitrosovasodilators, impair autoregulation of glomerular perfusion pressure, reflecting their selective effect on efferent (over afferent) arteriolar tone (Kittleson et al., 2003). In the event of acute renal failure or a decrease in the glomerular filtration rate by >20%, ACE-inhibitor dosing should be reduced or the drug discontinued. Rarely, renal function impairment following drug initiation is indicative of bilateral renal artery stenosis.
++
ACE-Inhibitor Side Effects. Elevated bradykinin levels from ACE inhibition are associated with angioedema, a potentially life-threatening drug side effect. If this occurs, immediate and permanent cessation of all ACE inhibitors is indicated. Angioedema may occur at any time over the course of ACE inhibitor therapy. A characteristic, dry cough from the same mechanism is common; in this case, substitution of an AT1 receptor antagonist for the ACE inhibitor often is curative. A small rise in serum K+ levels is common with ACE-inhibitor use. This increase may be substantial, however, in patients with renal impairment or in diabetic patients with type IV renal tubular acidosis. Mild hyperkalemia is best managed by institution of a low-potassium diet but may require drug dose adjustment. The inability to implement ACE inhibitors as a consequence of cardiorenal side effects (e.g., excessive hypotension, progressive renal insufficiency, hyperkalemia) is itself a poor prognostic indicator in the CHF patient (Kittleson et al., 2003).
++
ACE Inhibitors and Survival in CHF. A number of randomized, placebo-controlled clinical trials have demonstrated that ACE inhibitors improve survival in patients with CHF due to systolic dysfunction, independent of etiology. For example, ACE inhibitors prevent mortality and the development of clinically significant LV dysfunction after acute MI (Pfeffer et al., 1992; Konstam et al., 1992; St. John Sutton et al., 1994). This occurs through attenuation or prevention of increased LV end-diastolic and end-systolic volumes, and the decline in LV ejection fraction that is central to the natural history of AMI. ACE inhibitors appear to confer these benefits by preventing postinfarction-associated adverse ventricular remodeling.
+
The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS Trial Study Group 1987) demonstrated a 40% mortality reduction after 6 months of enalapril therapy in severe CHF, while others have shown that enalapril also improves survival in patients with mild-to-moderate CHF (SOLVD Investigators, 1992). Furthermore, across the spectrum of CHF severity, when compared with other vasodilators, ACE inhibitors appear superior in reducing mortality (Fonarow et al., 1992). In asymptomatic patients with LV dysfunction, ACE inhibitors slow the development of symptomatic CHF.
++
AT1Receptor Antagonists. Activation of the AT1 receptor mediates most of the deleterious effects of AngII that are described earlier. AT1-receptor antagonism, in turn, largely obviates AngII "escape" and substantially decreases the probability of developing bradykinin-mediated side effects associated with ACE inhibition. Importantly, however, although rare, angioedema has been reported with AT1-receptor antagonist use. Therefore, caution is still warranted when prescribing these agents to patients with a history of ACE-inhibitor–associated angioedema.
+
AT1 receptor blockers (ARBs) are effective antihypertensives, and their influence on mortality in acute or chronic CHF from systolic dysfunction after acute MI is akin to that of ACE-inhibitor therapy (Konstam et al., 2005; Dickstein et al., 2002; White et al., 2005). Owing to their favorable side-effect profile, ARBs are an excellent alternative in CHF patients intolerant of ACE inhibitors (Pitt et al., 1997; Doggrell, 2005). Interestingly, age >75 years may increase the probability of developing clinically significant hypotension, renal dysfunction, and hyperkalemia (White et al., 2005).
The role of combination ACE-inhibitor and ARB therapy in the treatment of CHF remains unresolved. Although preliminary studies suggested that combined therapy with candesartan and enalapril, e.g., favorably affected cardiovascular hemodynamics, LV remodeling, and neurohormonal profile compared to therapy with either agent alone (McKelvie et al., 1999), subsequent trials have been unable to demonstrate an incremental mortality benefit from combination therapy despite a significant reduction in CHF-associated hospitalizations (McMurray et al., 2003).
Based on the hypothesis that ARB efficacy is at least in part a consequence of reduced circulating aldosterone levels, combined treatment with aldosterone receptor inhibition has been explored. Combination therapy is associated with a significant increase in LV ejection fraction and quality of life scores in patients with CHF from systolic dysfunction treated for 1 year with candesartan (8 mg daily) and spironolactone (25 mg daily) compared to those treated with candesartan alone (Chan et al., 2007). Others have corroborated the beneficial effects of combined therapy on LV remodeling, 6-minute walk distance, and functional capacity (Kum et al., 2008). The beneficial effects of dual therapy are provocative but must be weighed against the increased likelihood for inducing hyperkalemia, hypotension, and elevated elective treatment withdrawal rates reported in some trials. Data regarding mortality benefit attendant to combination therapy are not available at present.
In CHF from impaired diastolic relaxation (i.e., preserved LV ejection fraction), the role of AT1 receptor antagonists is unresolved. These drugs do not appear to improve mortality or echocardiographic indices of diastolic relaxation but are associated with fewer CHF hospitalizations (Yusuf et al., 2003; Solomon et al., 2007; Massie et al., 2008). Some have suggested that ARB-induced improvement in arteriolar flow reserve may be protective in patients with diastolic CHF, although this hypothesis remains speculative at present (Kamezaki et al., 2007).
++
Direct Renin Inhibitors. There is accumulating scientific and clinical evidence to suggest that maximal pharmacologic ACE inhibition alone is insufficient for optimal attenuation of AngII-induced cardiovascular dysfunction in patients with CHF. Several molecular mechanisms have been ascribed to explain this hypothesis (Abassi et al., 2009), including:
++
the presence of ACE-independent pathways that facilitate AngI conversion to AngII
the activation of ACE homologues (e.g., ACE2) that are insensitive to conventional ACE-I therapy
the suppression of the negative feedback effect exerted by AngI on renin secretion in the kidney
++
For these reasons, inhibition of renin has pharmacotherapeutic objectives for enhanced suppression of AngII synthesis in CHF.
++
Renin-mediated conversion of angiotensinogen to AngI is the first and rate-limiting step in the biochemical cascade that generates AngII and aldosterone (see Figures 26–1 and 28–3). The first generation of orally administered direct renin inhibitors was studied in the 1980s and was designed for the treatment of hypertension, but the broader use of these agents was hampered by the drugs' suboptimal efficacy, reflecting, at least in part, their limited bioavailability (Staessen et al., 2006). Aliskiren (tekturna, rasilez) is the first orally administered direct renin inhibitor to obtain FDA approval for use in clinical practice. The pharmocokinetic advantages of aliskiren over earlier direct renin inhibitor prototypes include an increased bioavailability (2.7%) and a long plasma t1/2 (~23 hour). Pilot clinical trials in humans established that aliskiren induces a concentration-dependent decrease in plasma renin activity and AngI and AngII levels that was associated with a decrease in systemic blood pressure without significant reflex tachycardia. The pharmacology of aliskiren is presented in more detail in Chapter 26.
+
The effect of aliskiren on blood pressure is the most thoroughly evaluated cardiovascular treatment endpoint. Several small studies have concluded that aliskiren is superior to placebo or to an ARB for monotherapy of mild-to-moderate hypertension (Sanoski, 2009). Aliskiren also appears to exert beneficial effects on myocardial remodeling by decreasing LV mass in hypertensive patients, suggesting that, similar to observations in ACE inhibitor or ARB therapy, direct renin inhibition may attenuate hypertension-induced end-organ damage (Solomon et al., 2009). Collectively, these observations provide evidence that aliskiren-mediated reductions in plasma renin activity and circulating levels of AngII may have salutary effects on the cardiovascular system in hypertension, thus opening the door for investigation of this therapy in patients with CHF.
The safety profile of aliskiren in CHF was established recently by the Aliskiren Observation of Heart Failure Treatment (aloft) trial (McMurray et al., 2008). Aliskiren (150 mg/day) add-on therapy to a β receptor antagonist and an ACE inhibitor or ARB was not associated with a significant increase in hypotension or hyperkalemia in a study cohort that mainly included symptomatic CHF patients with a low LV ejection fraction (~30%). Results from this trial also demonstrated that compared with placebo, aliskiren significantly decreased plasma N-terminal-proBNP levels, a clinically useful neurohumoral biomarker of active CHF. These findings affirm that inhibition of renin activity is an important potential target for improving symptoms and functional capacity in CHF. However, aliskiren has not yet been studied in sufficiently powered randomized-controlled clinical trials designed to analyze the efficacy of this drug in treatment of CHF.
++
Vasopressin Receptor Antagonists. Neurohumoral dysregulation in CHF extends beyond the renin– angiotensin–aldosterone axis to include abnormal arginine vasopressin (AVP) secretion, resulting in the perturbation of fluid balance, among various additional pathophysiogic effects. In response to 1) serum hypertonicity-induced activation of anterior pituitary osmoreceptors and 2) a perceived drop in blood pressure detected by baroreceptors in the carotid artery, aortic arch, and left atrium, AVP is secreted into the systemic circulation (Arai et al., 2007). The physiology and pharmacology of vasopressin are presented in Chapter 25.
++
The active form of AVP is a 9–amino acid peptide that interacts with three receptor subtypes: V1a, V1b, and V2 (see Chapter 25). The AVP-V2 receptor interaction on the basolateral membrane of the renal collecting ducts stimulates de novo synthesis of aquaporin-2 water channels that mediate free water reabsorption, thereby impairing diuresis and, ultimately, correcting plasma hypertonicity. Additional cell signaling pathways important in the pathophysiology of CHF include vasoconstriction, cell hypertrophy, and increased platelet aggregation mediated by activation of V1a receptors in vascular smooth muscle cells and cardiac myocytes. In addition, AngII-mediated activation of centrally located AT1 receptors is associated with increased AVP levels in CHF and may represent one mechanism by which the use of AT1-receptor antagonists are effective in the clinical management of these patients.
+
LV systolic dysfunction can be associated with hypervasopressinemia. Numerous observational and case-controlled studies have reported AVP levels nearly 2-fold above normal in CHF patients (Finley et al., 2008). The mechanisms to account for dysregulated AVP synthesis in CHF may involve impaired atrial stretch receptor sensitivity, normally a counterregulatory mechanism for AVP secretion, and increased adrenergic tone (Bristow et al., 2005). These probably do not fully explain the relationship between CHF and AVP levels; e.g., elevated levels of AVP have been observed in asymptomatic patients with significantly decreased LV function, calling into question the attributable role of sympathetically mediated adrenergic tone as a cause of hypervasopressinemia (Francis et al., 1990).
In addition, there is evidence to suggest that CHF is a disease of abnormal responsiveness to vasopressin rather than one of excessive vasopressin production alone. For example, vasopressin infusion in CHF patients decreases cardiac output and stroke volume and causes an exaggerated increase in systemic vascular resistance and pulmonary capillary wedge pressure (Finley et al., 2008). In turn, V2 antagonists attenuate the adverse pathophysiologic effects of hypervasopressinemia by decreasing capillary wedge pressure, right atrial pressure, and pulmonary artery systolic blood pressure (Udelson et al., 2008). These agents also restore and maintain normal serum sodium levels in decompensated CHF patients, but their long-term use has not yet been convincingly linked to a decrease in CHF-associated symptoms or mortality (Gheorghiade et al., 2004).
Generally, trials designed to measure the effect of vasopressin-receptor antagonists have used agents selective for the V2 receptor, although some drugs with both V2 and V1a receptor affinity also have been studied. Tolvaptan (samsca), which preferentially binds the V2 receptor over the V1a receptor (receptor affinity ~29:1), is perhaps the most widely tested vasopressin receptor antagonist in patients with CHF and also is approved for hyponatremia. Due to the risk of overly rapid correction of hyponatremia causing osmotic demyelination, tolvaptan should be started only in a hospital setting where Na+ levels can be monitored closely and possible drug interactions mediated by CYP and P-gp can be considered (black box warning). Conivaptan, used mainly for the treatment of hyponatremia rather than for CHF per se, differs from tolvaptan in that it may be intravenously administered, demonstrates high affinity for both V2- and V1a-vasopressin receptors, and has a t1/2 that is nearly twice as long.
In the randomized, placebo-controlled EVEREST trial, the effect of tolvaptan (30 mg/day) in addition to standard therapy on immediate symptom improvement was assessed in patients administered the drug <48 hours into hospitalization for CHF (Gheorghiade et al., 2007). Data from this study substantiated that from the others, indicating that AVP antagonists decrease body weight, self-reported dypsnea, and physician-assessed peripheral edema, rales, and fatigue after a short course of therapy (<7 days). Long-term outcomes (survival, hospitalizations) were not significantly different from placebo. The identification of a CHF subgroup that stands to benefit most from AVP antagonists, in addition to the preferred agent and therapy duration, are questions of ongoing clinical investigation.
+++
β Adrenergic Receptor Antagonists
++
Sympathetic nervous system activation in CHF supports circulatory function by enhancing contractility (inotropy), augmenting ventricular relaxation and filling (lusitropy), and increasing heart rate (chronotropy). For many years, pharmacologic approaches to CHF treatment targeted drugs with sympathomimetic properties. This reflected the viewpoint that CHF is fundamentally a disorder of impaired stroke volume and cardiac output. For example, CHF symptom relief from short-term dobutamine and dopamine use in patients with ventricular dysfunction led to the belief that long-term sympathomimetic use would further improve clinical outcome. Under this model, the use of β receptor antagonists was believed to be counterproductive; however, the reverse appears to be the case. Long-term sympathomimetic use is associated with increased CHF mortality rates, whereas a survival benefit is associated with chronic administration of β receptor antagonists. Initially, clinical investigation of β receptor antagonists in the treatment of CHF encountered skepticism, but reports beginning in the early 1990s demonstrated that β antagonists (e.g., metoprolol) improve symptoms, exercise tolerance, and are measures of LV function over several months in idiopathic dilated cardiomyopathy patients with CHF (Waagstein et al., 1993; Gottlieb et al., 1998; Swedberg, 1993; Bristow, 2000). Serial echocardiographic measurements in CHF patients indicate that a decrease in systolic function occurs immediately after initiation of a β antagonist treatment, but this recovers and improves beyond baseline over the ensuing 2-4 months (Hall et al., 1995). This trend may be due to attenuation or prevention of the β receptor–mediated adverse effects of catecholamines on the myocardium (Eichhorn and Bristow, 1996).
++
Mechanism of Action. The mechanisms by which β receptor antagonists influence outcome in CHF patients are not fully delineated. By preventing myocardial ischemia without significantly influencing serum electrolytes, β receptor antagonists probably influence mortality, in part, by decreasing the frequency of unstable tachyarrhythmias to which CHF patients are particularly prone. In addition, these agents may influence survival by favorably affecting LV geometry, specifically by decreasing LV chamber size and increasing LV ejection fraction. Through inhibition of sustained sympathetic nervous system activation, these agents prevent or delay progression of myocardial contractile dysfunction by inhibiting maladaptive proliferative cell signaling in the myocardium, reducing catecholamine-induced cardiomyocyte toxicity, and decreasing myocyte apoptosis (Communal et al., 1998; Bisognano et al., 2000). β Receptor antagonists may also induce positive LV remodeling by decreasing oxidative stress in the myocardium (Sawyer and Colucci, 2000).
++
Metoprolol. Metoprolol (lopressor, toprol xl, others) is a β1-selective receptor antagonist. The short-acting form of this drug has a drug elimination t1/2 of ~6 hours, and therefore appropriate dosing is three to four times daily. Conversely, the extended-release formulation is sufficiently dosed once daily.
+
A number of clinical trials have demonstrated the beneficial effects of β-antagonist therapy in CHF. In the Metoprolol Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF Study Group 1999), patients with low LV ejection fraction and severe CHF receiving metoprolol succinate (target dose, 200 mg/day) received a 34% all-cause mortality benefit, an effect attributable to reductions in sudden death and death from worsening CHF. Despite the high target drug dose, the majority of patients achieved this therapeutic goal.
++
Carvedilol. Carvedilol (coreg, others) is a nonselective β receptor antagonist and α1-selective antagonist that is FDA approved for the management of mild-to-severe CHF.
+
The U.S. Carvedilol Trial randomized patients with symptomatic but compensated CHF (New York Heart Association [NYHA] classes II to IV) and low LV ejection fraction to receive carvedilol or placebo (Packer et al., 1996). Carvedilol (25 mg twice daily) was associated with a 65% reduction in all-cause mortality that was independent of age, sex, CHF etiology, or LV ejection fraction. The mortality benefit and improvement in LV ejection fraction was carvedilol concentration dependent (Bristow et al., 1996). Exercise capacity (e.g., 6-minute walk test) did not improve with carvedilol, however, but therapy did appear to slow the progression of CHF in a subgroup of patients with good exercise capacity and mild symptoms at baseline (Colucci et al., 1996).
In the Carvedilol Post Infarct Survival Control in LV Dysfunction Trial (Dargie, 2001), patients with recent MI (3-21 days prior to enrollment) and impaired LV systolic function were randomized to carvedilol (25 mg twice daily) or placebo. Patients with symptomatic CHF and those with asymptomatic LV dysfunction were included. Although there was no difference in the primary endpoint of all-cause mortality, carvedilol therapy was associated with a significant reduction in the combined endpoint of all-cause mortality and nonfatal MI. At the opposite end of the spectrum, patients with symptomatic CHF at rest or with minimal exertion and impaired LV systolic function were randomized to carvedilol versus placebo in the Carvedilol Prospective Randomized Cumulative Survival Study (Packer et al., 2002b). Consistent with previous trials, there was a 35% decrease in all-cause mortality. Although the patients included in the trial had established CHF, it merits emphasis that the placebo group mortality at 1 year was ~18%, a finding suggestive that the patient cohort was not representative of patients with advanced CHF.
+++
Clinical Use of β Adrenergic Receptor Antagonists in Heart Failure
++
Data from more than 15,000 patients with mild-to-moderate chronic CHF enrolled in various clinical trials have established that β receptor antagonists improve disease-associated symptoms, hospitalization, and mortality. Accordingly, β antagonists are recommended for use in patients with an LV ejection fraction <35% and NYHA class II or III symptoms in conjunction with an ACE inhibitor or AT1 receptor antagonist, and diuretics as required to palliate symptoms. Interpretation of these and other clinical guidelines should, however, consider the following areas of uncertainty.
++
The role of β receptor antagonists in severe CHF or under circumstances of an acute clinical decompensation is not yet clear. Likewise, the utility of β blockade in patients with asymptomatic LV dysfunction has not been systematically evaluated. The marked heterogeneous pharmacologic characteristics (e.g., receptor selectivity, pharmacokinetics) of specific agents within this general drug class, as discussed in Chapter 12, play a key role in predicting the overall efficacy of a particular β receptor antagonist.
++
β receptor antagonist therapy is customarily initiated at very low doses, generally less than one-tenth of the final target dose, and titrated cautiously upward. Even when initiated properly, a tendency to retain fluid exists that may require diuretic dose adjustment. Insufficient evidence exists to support the unrestricted administration of β receptor antagonists in patients with severe (NYHA class IIIB and IV), new-onset, or acutely decompensated CHF.
++
The English botanist, chemist, and physician Sir William Withering is credited with the first published observation in 1785 that digitalis purpurea, a derivative of the purple foxglove flower, could be used for the treatment of "cardiac dropsy," or congestive heart failure. The benefits of cardiac glycosides in CHF have been extensively studied (Eichhorn and Gheorghiade, 2002) and are generally attributed to:
++
Inhibition of the plasma membrane Na+, K+-ATPase in myocytes
A positive inotropic effect on the failing myocardium
Suppression of rapid ventricular rate response in CHF-associated atrial fibrillation
Regulation of downstream deleterious effects of sympathetic nervous system overactivation
++
Mechanism of the Positive Inotropic Effect. With each cardiac myocyte depolarization, Na+ and Ca2+ ions shift into the intracellular space (Figure 28–5). Ca2+ that enters the cell via the L-type Ca2+ channel during depolarization triggers the release of stored intracellular Ca2+ from the sarcoplasmic reticulum via the ryanodine receptor (RyR). This Ca2+-induced Ca2+ release increases the level of cytosolic Ca2+ available for interaction with myocyte contractile proteins, ultimately increasing myocardial contraction force. During myocyte repolarization and relaxation, cellular Ca2+ is re-sequestered by the sarcoplasmic reticular Ca2+-ATPase and is removed from the cell by the Na+Ca2+ exchanger and, to a much lesser extent, by the sarcolemmal Ca2+-ATPase.
++
++
Cardiac glycosides bind and inhibit the phosphorylated (α subunit of the sarcolemmal Na+,K+-ATPase and thereby decreasing Na+ extrusion and increasing cytosolic [Na+]. This decreases the transmembrane Na+ gradient that drives Na+−Ca2+ exchange during myocyte repolarization. As a consequence, less Ca2+ is removed from the cell and more Ca2+ is accumulated in the sarcoplasmic reticulum (SR) by SERCA2. This increase in releasable Ca2+ (from the SR) is the mechanism by which cardiac glycosides enhance myocardial contractility. Elevated extracellular K+ levels (i.e., hyperkalemia) cause dephosphorylation of the ATPase α subunit, altering the site of action of the most commonly used cardiac glycoside, digoxin, and thereby reducing the drug's binding and effect.
+
Electrophysiologic Actions. At therapeutic serum or plasma concentrations (i.e., 1-2 ng/mL), digoxin decreases automaticity and increases the maximal diastolic resting membrane potential in atrial and atrioventricular (AV) nodal tissues. This occurs via increases in vagal tone and sympathetic nervous system activity inhibition. In addition, digoxin prolongs the effective refractory period and decreases conduction velocity in AV nodal tissue. Collectively, these may contribute to sinus bradycardia, sinus arrest, prolongation of AV conduction, or high-grade AV block. At higher concentrations, cardiac glycosides may increase sympathetic nervous system activity that influences cardiac tissue automaticity, change associated with the genesis of atrial and ventricular arrhythmias. Increased intracellular Ca2+ loading and sympathetic tone increases the spontaneous (phase 4) rate of diastolic depolarization as well as promoting delayed afterdepolarization; together, these decrease the threshold for generation of a propagated action potential and predisposes to malignant ventricular arrhythmias (see Chapter 29).
Regulation of Sympathetic Nervous System Activity. Sympathetic nervous system overactivation in CHF occurs, in part, from aberrant arterial baroreflex responses to low cardiac output. Specifically, a decline in baroreflex response to blood pressure results in a decline in baroreflex-mediated tonic suppression of CNS-directed sympathetic activity. This cascade contributes to the sustained elevation in plasma NE, renin, and vasopressin (Ferguson et al., 1989). Cardiac glycosides favorably influence carotid baroreflex responsiveness to changes in carotid sinus pressure (Wang et al., 1990). In patients with moderate-to-advanced CHF, cardiac glycoside infusion increases forearm blood flow and cardiac index and decreased heart rate. There is clinical evidence to suggest that digoxin decreases centrally mediated sympathetic nervous system tone, although the mechanism to explain this is unresolved (Ferguson et al., 1989).
++
Pharmacokinetics. The elimination t1/2 for digoxin is 36-48 hours in patients with normal or near-normal renal function, permitting once-daily dosing. Near steady-state blood levels are achieved ~7 days after initiation of maintenance therapy. Digoxin is excreted by the kidney, and increases in cardiac output or renal blood flow from vasodilator therapy or sympathomimetic agents may increase renal digoxin clearance, necessitating adjustment of daily maintenance doses. The volume of distribution and drug clearance rate are both decreased in elderly patients.
+
Despite renal clearance, digoxin is not removed effectively by hemodialysis due to the drug's large (4-7 L/kg) volume of distribution. The principal tissue reservoir is skeletal muscle and not adipose tissue, and thus dosing should be based on estimated lean body mass. Most digoxin tablets average 70-80% oral bioavailability; however, ~10% of the general population harbors the enteric bacterium Eubacterium lentum, which inactivates digoxin and thus may account for drug tolerance that is observed in some patients. Liquid-filled capsules of digoxin (lanoxicaps) have a higher bioavailability than do tablets (lanoxin); thus, the drug requires dosage adjustment if a patient is switched from one delivery form to the other. Digoxin is available for intravenous administration, and maintenance doses can be given intravenously when oral dosing is inappropriate. Digoxin administered intramuscularly is erratically absorbed, causes local discomfort, and usually is unnecessary. A number of clinical conditions may alter the pharmacokinetics of digoxin or patient susceptibility to the toxic manifestations of this drug. For example, chronic renal failure decreases the volume of distribution of digoxin and therefore requires a decrease in maintenance dosage of the drug. In addition, drug interactions that may influence circulating serum digoxin levels include several commonly used cardiovascular medications such as verapamil, amiodarone, propafenone, and spironolactone. The rapid administration of Ca2+ increases the risk of inducing malignant arrhythmias in patients already treated with digoxin. Electrolyte disturbances, especially hypokalemia, acid–base imbalances, and one's form of underlying heart disease also may alter a patient's susceptibility to digoxin side effects.
Maximal increase in LV contractility becomes apparent at serum digoxin levels ~1.4 ng/mL (1.8 nmol) (Kelly and Smith, 1992). The neurohormonal benefits of digoxin, however, may occur between 0.5-1 ng/mL. In turn, higher serum concentrations are not associated with incrementally increased clinical benefit. Moreover, there are data to suggest that the risk of death is greater with increasing serum concentrations, even at values within the traditional therapeutic range, and therefore many advocate maintaining digoxin levels <1 ng/mL.
++
Clinical Use of Digoxin in Heart Failure. Data from contemporary clinical trials have re-characterized the utility of cardiac glycosides, once first-line agents, in CHF, especially in patients with normal sinus rhythm (as opposed to atrial fibrillation).
+
Digoxin discontinuation in clinically stable patients with mild-to-moderate CHF from LV systolic dysfunction worsened symptoms and decreased maximal treadmill exercise (Uretsky et al., 1993; Packer et al., 1993). However, eventhough digoxin may decrease CHF-associated hospitalizations in patients with severe forms of the disease, drug use does not reduce all-cause mortality. Overall, digoxin use usually is limited to CHF patients with LV systolic dysfunction in atrial fibrillation or to patients in sinus rhythm who remain symptomatic despite maximal therapy with ACE inhibitors and β adrenergic receptor antagonists. The latter agents are viewed as first-line therapies because of their proven mortality benefit.
++
Digoxin Toxicity. The incidence and severity of digoxin toxicity have declined substantially in the past 2 decades as a consequence of alternative drugs available for the treatment of supraventricular arrhythmias in CHF, increased understanding of digoxin pharmacokinetics, improved serum digoxin level monitoring, and identification of important interactions between digoxin and other commonly co-administered drugs. Nevertheless, the recognition of digoxin toxicity remains an important consideration in the differential diagnosis of arrhythmias, and neurologic or gastrointestinal symptoms in patients receiving cardiac glycosides. An antidote, digoxin immune Fab (digibind, digifab), is available to treat toxicity.
+
Among the more common electrophysiologic manifestations of digoxin toxicity are ectopic beats originating from the AV junction or ventricle, first-degree AV block, abnormally slow ventricular rate response to atrial fibrillation, or an accelerated AV junctional pacemaker. When present, only dosage adjustment and appropriate monitoring are usually necessary. Sinus bradycardia, sinoatrial arrest or exit block, and second- or third-degree AV conduction delay requiring atropine or temporary ventricular pacing are uncommon. Unless in the setting of high-degree AV block, potassium administration should be considered for patients with evidence of increased AV junctional or ventricular automaticity even if serum K+ levels are in the normal range. Lidocaine or phenytoin, which have minimal effects on AV conduction, may be used for the treatment of digoxin-induced ventricular arrhythmias that threaten hemodynamic compromise (see Chapter 29). Electrical cardioversion carries an increased risk of inducing severe rhythm disturbances in patients with overt digitalis toxicity and should be used with particular caution. Note, too, that inhibition of the Na+,K+-ATPase activity of skeletal muscle can cause hyperkalemia. An effective antidote for life-threatening digoxin (or digitoxin) toxicity is available in the form of anti-digoxin immunotherapy. Purified Fab fragments from ovine anti-digoxin antisera (digibind) are usually dosed by the estimated total dose of digoxin ingested in order to achieve a fully neutralizing effect. For a more comprehensive review of the treatment of digitalis toxicity, see Kelly and Smith (1992).
+++
β Adrenergic and Dopaminergic Agonists
++
In the setting of severely decompensated CHF from reduced cardiac output, the principal focus of initial therapy is to increase myocardial contractility. Dopamine and dobutamine are positive inotropic agents most often used to accomplish this. These drugs provide short-term circulatory support in advanced CHF via stimulation of cardiac myocyte dopamine (D1) and β adrenergic receptors that stimulate the Gs-adenylyl cyclase-cyclic AMP–PKA pathway. The catalytic subunit of PKA phosphorylates a number of substrates that enhance Ca+2-dependent myocardial contraction and accelerate relaxation (Figure 28–5). Isoproterenol, epinephrine, and norepinephrine are useful in certain circumstances but have little role in routine CHF management. Indeed, inotropic agents that elevate cardiac cell cyclic AMP are consistently associated with increased risks of hospitalization and death, particularly in patients with NYHA class IV. At the cellular level, enhanced cyclic AMP levels have been associated with apoptosis (Brunton, 2005; Yan et al., 2007). The basic pharmacology of adrenergic agonists is discussed in Chapter 12.
++
Dopamine. Dopamine is an endogenous catecholamine with only limited utility in the treatment of most patients with cardiogenic circulatory failure. The pharmacologic and hemodynamic effects of dopamine are concentration dependent. Low doses (≤2 μg/kg lean body mass/min) induces cyclic AMP–dependent vascular smooth muscle vasodilation. In addition, activation of D2 receptors on sympathetic nerves in the peripheral circulation at these concentrations also inhibits NE release and reduces α adrenergic stimulation of vascular smooth muscle, particularly in splanchnic and renal arterial beds. Therefore, low-dose dopamine infusion often is used to increase renal blood flow and thereby maintain an adequate glomerular filtration rate in hospitalized CHF patients with impaired renal function refractory to diuretics. Dopamine also exhibits a pro-diuretic effect directly on renal tubular epithelial cells that contributes to volume reduction.
++
At intermediate infusion rates (2-5 μg/kg/min), dopamine directly stimulates cardiac α receptors and vascular sympathetic neurons that enhance myocardial contractility and neural NE release. At higher infusion rates (5-15 μg/kg/min), α adrenergic receptor stimulation–mediated peripheral arterial and venous constriction occurs. This may be desirable in patients with critically reduced arterial pressure or in those with circulatory failure from severe vasodilation (e.g., sepsis, anaphylaxis). However, high-dose dopamine infusion has little role in the treatment of patients with primary cardiac contractile dysfunction; in this setting, increased vasoconstriction will lead to increased afterload and worsening of LV performance. Tachycardia, which is more pronounced with dopamine than with dobutamine, may actually provoke ischemia (and ischemia-induced malignant arrhythmias) in patients with coronary artery disease.
++
Dobutamine. Dobutamine is the β agonist of choice for the management of CHF patients with systolic dysfunction. In the formulation available for clinical use, dobutamine is a racemic mixture that stimulates both β1 and β2 receptor subtypes. In addition, the (−) enantiomer is an agonist for α adrenergic receptors, whereas the (+) enantiomer is a weak, partial agonist. At infusion rates that result in a positive inotropic effect in humans, the β1 adrenergic effect in the myocardium predominates. In the vasculature, the α adrenergic agonist effect of the (−) enantiomer appears to be offset by the (+) enantiomer and vasodilating effects of β2 receptor stimulation. Thus, the principal hemodynamic effect of dobutamine is an increase in stroke volume from positive inotropy, although β2 receptor activation may cause a decrease in systemic vascular resistance and, therefore, mean arterial pressure. Despite increases in cardiac output, there is relatively little chronotropic effect.
++
Continuous dobutamine infusions are typically initiated at 2-3 μg/kg/min without a loading dose and uptitrated until the desired hemodynamic response is achieved. Pharmacologic tolerance may limit infusion efficacy beyond 4 days, and, therefore, addition or substitution with a class III PDE inhibitor may be necessary to maintain adequate circulatory support. The major side effects of dobutamine are tachycardia and supraventricular or ventricular arrhythmias, which may require a reduction in dosage. Recent β receptor antagonist use is a common cause of blunted clinical responsiveness to dobutamine.
++
Phosphodiesterase Inhibitors. The cyclic AMP–PDE inhibitors decrease cellular cyclic AMP degradation, resulting in elevated levels of cyclic AMP in cardiac and smooth muscle myocytes. The physiologic effects of this are positive myocardial inotropism and dilation of resistance and capacitance vessels. Collectively, therefore, PDE inhibition improves cardiac output through ionotropy and by decreasing preload and afterload (thus giving rise to the term inodilator). The clinical application of early-generation PDE inhibitors (e.g., theophylline, caffeine) is limited by low cardiovascular specificity and an unfavorable side-effect profile, whereas inamrinone, milrinone, and other more recently developed PDE inhibitors are preferred.
+
Inamrinone and Milrinone. Parenteral formulations of inamrinone (previously named amrinone) and milrinone are approved for short-term circulation support in advanced CHF. Both drugs are bipyridine derivatives and are selective PDE3 inhibitors, the cyclic GMP–inhibited cyclic AMP–PDE. These drugs directly stimulate myocardial contractility and accelerate myocardial relaxation. In addition, they cause balanced arterial and venous dilation with a consequent fall in systemic and pulmonary vascular resistances and left and right-heart filling pressure. As a result of its effect on LV contractility, the increase in cardiac output from milrinone is superior to that from nitroprusside, despite comparable reductions in systemic vascular resistance. Conversely, the arterial and venodilatory effects of milrinone are greater than those of dobutamine at concentrations that produce similar increases in cardiac output.
Parenteral administration of inamrinone and milrinone in patients with CHF from systolic dysfunction should be initiated with a loading dose followed by continuous infusion. For inamrinone, a 0.75-mg/kg bolus injection administered over 2-3 minutes is typically followed by a 2-20-μg/kg/min infusion. The loading dose of milrinone is ordinarily 50 μg/kg, and the continuous infusion rate ranges from 0.25-1 μg/kg/min. The elimination half-lives of inamrinone and milrinone in normal individuals are 2-3 hours and 0.5-1 hour, respectively, but are nearly doubled in patients with severe CHF. Clinically significant thrombocytopenia occurs in ~10% of those receiving inamrinone but is rare with milrinone. Because of enhanced selectivity for PDE3, short t1/2, and favorable side-effect profile, milrinone is the agent of choice among currently available PDE inhibitors for short-term, parenteral inotropic support. However, vasodilation-mediated reductions in mean arterial pressure are one practical barrier to milrinone administration in patients with marginal systemic arterial blood pressure from low cardiac output.
Sildenafil. In contrast to inamrinone and milrinone, sildenafil (revatio) inhibits PDE5, which is the most common PDE isoform in lung tissue. This characteristic of PDE5 likely accounts for the enhanced pulmonary artery specificity observed with sildenafil use. In fact, until recently, the primary clinical application of sildenafil in CHF has mainly been limited to those with isolated right ventricular systolic failure from pulmonary artery hypertension. However, recently published reports suggest that sildenafil favorably influences exercise capacity and right-heart hemodynamics in patients with pulmonary hypertension from LV systolic dysfunction as well (Lewis et al., 2007). Preclinical experimental models also have raised the possibility that PDE5 inhibition is directly cardioprotective via attenuation of adrenergic stimulation-induced myocardial contraction and by suppressing pressure-overload mediated myocardial hypertrophy and attendant ventricular dysfunction (Kass et al., 2007). The pharmacology of PDE5 inhibitors is presented in Chapter 27.
+++
Chronic Positive Inotropic Therapy
++
Several orally administered agents with combined inotropic and vasodilator properties are available for clinical use. Although improvements in CHF symptoms, functional status, and hemodynamic profile have been reported, the effect of long-term therapy on mortality is disappointing. In fact, the dopaminergic agonist ibopamine; PDE inhibitors milrinone, inamrinone, and vesnarinone; and pimobendan are associated with increased mortality (Hampton et al., 1997; Packer et al., 1991; Cohn et al., 1998). At present, digoxin remains the only oral inotropic agent available for CHF patient use.
+
Continuous or intermittent outpatient therapy with intravenous dobutamine or milrinone, administered by a portable or home-based infusion pump through a central venous catheter, is available for end-stage CHF patients with symptoms refractory to optimized medical therapy.
+++
Diastolic Heart Failure
++
Data from population studies suggest that up to 40% of CHF patients have preserved LV systolic function. The pathogenesis of diastolic CHF includes structural and functional abnormalities of the ventricle(s) that are associated with impaired ventricular relaxation and LV distensibility. These abnormalities are reflected in the LV pressure–volume relationship during diastole, which is shifted upward and to the left relative to normal subjects (Figure 28–6). Consonant with the definition of CHF outlined earlier in this chapter, the diagnosis of diastolic CHF is made when the LV is unable to maintain adequate cardiac output without filling at an abnormally elevated end-diastolic filling pressure.
++
++
In patients with primary diastolic dysfunction, the myocardial abnormality that accounts for abnormal filling is intrinsic to the myocardium; e.g., by infiltrative disorders including cardiac amyloidosis, hemochromatosis, sarcoidosis, and rarer conditions such as endomyocardial fibrosis and Fabry's disease. Although not a disease of myocardium infiltration, clinically evident CHF may occur despite intact LV systolic function in familial hypertrophic cardiomyopathy.
++
Secondary diastolic dysfunction occurs as a consequence of excessive preload (e.g., renal failure), excessive afterload (e.g., systemic hypertension), or changes in LV geometry that occur in response to chronically abnormal loading conditions. Diastolic CHF also is observed in patients with long-standing epicardial coronary artery or pericardial disease. The prevalence of secondary diastolic dysfunction is higher in women and with advanced age. Reported annual mortality rates for diastolic CHF are 5-8%, although this range likely represents an underestimation (Jones et al., 2004).
++
Patients with diastolic CHF are typically dependent on preload to maintain adequate cardiac output. Although hypervolemic patients generally benefit from careful intravascular volume reduction, this should be accomplished gradually and treatment goals reassessed frequently. Maintaining synchronous atrial contraction (or at least ventricular rate response control) helps to maintain adequate LV filling during the latter phase of diastole and is therefore a paramount goal in the management of CHF from diastolic dysfunction. Evaluation and treatment of predisposing conditions to impaired diastolic function, such as myocardial ischemia and poorly controlled systemic hypertension, are fundamental to the overall pharmacotherapeutic strategy of this complex form of CHF.
+++
Future Therapies: Targeting Vascular Dysfunction in Congestive Heart Failure from Systolic Dysfunction
++
Vascular dysfunction is an established component of the CHF syndrome and has evolved into a novel pharmacotherapeutic target for the clinical management of patients with this disease (Varin et al., 2000) (Figure 28–7). Contemporary scientific observations suggest that the blood vessel is a dynamic structure integral to normal myocardial function. This represents a paradigm shift away from the traditional perspective that blood vessels are conduit "tubes" necessary only for blood transport. Elevated levels of oxidant, nitrosative, and other forms of inflammatory stress observed in patients with CHF may impair vascular reactivity by disruption of normal vasodilatory cell signaling pathways (Erwin et al., 2005; Doehner et al., 2001). The precise mechanism by which impaired vascular reactivity is aligned with the progressive natural history of CHF is unresolved; when present, however, vascular dysfunction is associated with decreased exercise tolerance and a poorer clinical outcome. For example, hyperaldosteronism due to overactivation of the renin–angiotensin–aldosterone axis in the setting of LV dysfunction adversely affects both endothelium-dependent and endothelium-independent vascular reactivity (Leopold et al., 2007, Maron et al., 2009) enfothelium XO-I zenthine oxidase inhibitor vascular reactivity. This process is in part mediated by increased levels of reactive oxygen species, decreased endogenous levels of antioxidant enzymes, and decreased levels of bioavailable NO (Leopold et al., 2007; Farquharson and Struthers, 2000). As discussed previously, the undesirable effects of hyperaldosteronism on vascular dysfunction are attenuated clinically by aldosterone receptor blockade, resulting in significantly decreased CHF-associated morbidity and mortality (Pitt et al., 1999).
++
++
Xanthine Oxidase and Vascular Dysfunction. Xanthine oxidase (XO) is necessary for normal purine metabolism and catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid in a reaction that generates superoxide. Elevated levels of uric acid are associated with clinically evident CHF (Hare et al., 2008). For example, epidemiologic data support a positive, graded association between impaired exercise capacity and circulating uric acid levels (Doehner et al., 2001). Although the myocardium is rich in XO, vascular endothelial cells also contain high concentrations of XO, an observation that ultimately lead to the hypothesis that increased XO-generated superoxide impairs vascular reactivity in CHF patients (Hare et al., 2008).
+
Early studies suggested allopurinol (300 mg/day), an XO inhibitor, effectively decreases generation of free oxygen radicals and improves peripheral arterial vasodilation and blood flow in hyperuricemic patients with mild-to-moderate CHF from systolic dysfunction (Doehner et al., 2002). Interestingly, probenecid, which decreases circulating urate levels by enhancing its elimination rather than by inhibiting XO activity, has not been shown to influence vascular reactivity. In patients with advanced CHF, allopurinol-induced serum uric acid level reduction (over 24 weeks) is associated with functional class improvement, but only in those with baseline serum uric acid levels >9.5 mg/dL. Overall, randomized, placebo-controlled clinical trials examining the long-term efficacy of allopurinol therapy in CHF are sparse, and active investigation in this area continues.
++
Statins and Vascular Dysfunction. HMG-CoA (3-hydroxy-3-methyl-glutaryl–coenzyme A) reductase catalyzes the formation of L-mevalonic acid, a key biochemical precursor in the cholesterol synthesis pathway (Goldstein and Brown, 1990). Current evidence suggests a role of crosstalk between mevalonate metabolism and cell signaling pathways involved in inflammation and oxidant stress. In this way, HMG-CoA reductase inhibitors, or "statins", may exert beneficial cardiovascular effects beyond their original intent of low-density lipoprotein reduction; specifically, statins are associated with positive LV remodeling, increased arteriolar blood flow, and decreased circulating platelet aggregation (Liao et al., 2005).
++
Intermediate byproducts of mevalonate metabolism (i.e., isopenylated proteins that upregulate activation of Rho, RAS, and other G proteins) are linked to impaired vascular function by increasing levels of oxidant stress and decreasing bioavailable NO levels (Hernandez-Perera et al., 1998). Statins inhibit these intermediary pathways and appear to restore endothelium-dependent (Feron et al., 2001) and endothelium-independent vascular function (Drexler et al., 1993). The pharmacology of the statins and other cholesterol-lowering agents is presented in Chapter 31.
+
A large number of population studies have demonstrated a favorable effect of statin therapy on outcome in CHF. For example, one retrospective analysis of ischemic- and non-ischemic cardiomyopathy patients with CHF reported a significant reduction in mortality in those treated with a statin for 1 year compared to case-matched patients treated only with standard medical therapy (Horwich et al., 2004). Others have suggested that statins delay CHF in at-risk patients with ischemic heart disease (Kjekshus et al., 1997). Unfortunately, there is a paucity of sufficiently powered prospective, randomized, placebo-controlled clinical trials demonstrating a favorable effect of statin therapy on outcome in patients with CHF. Overall, the evidence in support of statin use in CHF (of either ischemic or non-ischemic etiologies) is primarily based on observational clinical data. The clinical indications for statin therapy in CHF, preferred drug isoform, and optimal drug concentration, for example, remain undefined.
++
Direct Activators of Soluble Guanylyl Cyclase. Soluble guanylyl cyclase (sGC) is an enzyme that catalyzes the conversion of guanosine triphosphate to cyclic GMP, a second messenger necessary for normal vascular smooth muscle cell relaxation (Koesling, 1999). Under physiologic conditions, NO is the primary biologically active stimulator of sGC. Elevated levels of oxidant stress deactivate sGC through various molecular mechanisms. For example, aldosterone levels comparable to those observed in patients with decompensated CHF are associated with increased oxidant stress that converts sGC to an NO-insensitive state (Maron et al., 2009), thereby disrupting vasodilatory signaling necessary for normal vascular function.
++
Organic nitrates, which promote sGC activation by increasing bioavailable NO levels, are subject to pharmacologic tolerance that complicates long-term drug use, dosing, and administration frequency (see the organic nitrates section in Chapter 27). Although the precise mechanism to explain this phenomenon is unknown, it is likely mediated in part by elevated levels of oxidant stress that convert sGC to an NO-insensitive state. BAY compounds (e.g., BAY 58-2667 [cinaciguat]) activate sGC by an NO-independent mechanism, thereby promoting normal sGC function despite conditions of oxidant stress (Stasch et al., 2006). Data from preclinical CHF studies in animals have validated these beneficial molecular effects. In healthy humans, BAY compound administration has not been associated with severe side effects, but hypotension and headache have been reported. Likewise in humans, circulating plasma drug concentrations are decreased to clinically insignificant levels ≤30 minutes after infusion termination (Frey et al., 2008).
+
The utility of BAY 58-2667 in the clinical management of patients with CHF is a topic of ongoing investigation, although early published reports suggest potential for the use of this novel drug class. In a group of patients with acutely decompensated CHF, BAY 58-2667 responders demonstrated a significant decrease in pulmonary capillary wedge pressure, mean right atrial pressure, mean pulmonary artery pressure, pulmonary vascular resistance, and systemic vascular resistance. Cardiac output was significantly increased as well (Lapp et al., 2009). The potential mainstream application of BAY 58-2667 (and other similar compounds) is currently under evaluation in larger clinical trials. Nevertheless, these preliminary observations are encouraging and may expose sustained sGC activity despite enzyme insensitivity to NO• as a promising therapeutic target for CHF patients.