Congestive heart failure (CHF) is responsible for more than half a million deaths annually in the U.S., carries a 1-year mortality rate of more than 50% in patients with advanced forms of the condition. Substantive advances in CHF pharmacotherapy have altered clinical practice by shifting the paradigm of its management from exclusively symptom palliation to modification of disease progression and prolonged survival.
DEFINING CONGESTIVE HEART FAILURE. The onset and progression of clinically evident CHF from left ventricular (LV) systolic dysfunction follows a pathophysiologic sequence in response to an initial insult to myocardial dysfunction. A reduction in forward cardiac output leads to expanded activation of the sympathetic nervous system and the renin–angiotensin–aldosterone axis that, together, maintain perfusion of vital organs by increasing LV preload, stimulating myocardial contractility, and increasing arterial tone. Acutely, these mechanisms sustain cardiac output by allowing the heart to operate at elevated end-diastolic volumes, while peripheral vasoconstriction promotes regional redistribution of the cardiac output to the CNS, coronary, and renal vascular beds.
Unfortunately, these compensatory mechanisms over time propagate disease progression. Intravascular volume expansion increases diastolic and systolic wall stress that disrupts myocardial energetics and causes pathologic LV hypertrophy. By increasing LV afterload, peripheral arterial vasoconstriction also adversely affects diastolic ventricular wall stress, thereby increasing myocardial O2 demand. Finally, neurohumoral effectors such as NE and AngII are associated with myocyte apoptosis, abnormal myocyte gene expression, and pathologic changes in the extracellular matrix that increase LV stiffness.
Clinically, the term CHF describes a final common pathway for the expression of myocardial dysfunction. While some emphasize the clinical distinction between systolic versus diastolic heart failure, many patients demonstrate dysfunction in both contractile performance and ventricular relaxation/filling. Indeed, these physiologic processes are interrelated; for example, the rate and duration of LV diastolic filling are directly influenced by impairment in systolic contractile performance. The following definitions are useful for establishing a conceptual framework to describe this clinical syndrome:
Congestive heart failure is the pathophysiologic state in which the heart is unable to pump blood at a rate commensurate with the requirements of metabolizing tissues, or can do so only from an elevated filling pressure.
Heart failure is a complex of symptoms—fatigue, shortness of breath, and congestion—that are related to the inadequate perfusion of tissue during exertion and often to the retention of fluid. Its primary cause is an impairment of the heart’s ability to fill or empty the left ventricle properly.
One may consider CHF as a condition in which failure of the heart to provide adequate forward output at normal end-diastolic filling pressures results in a clinical syndrome of decreased exercise tolerance with pulmonary and systemic venous congestion. Numerous cardiovascular comorbidities are associated with CHF, including coronary artery disease, MI, and sudden cardiac death.
PHARMACOLOGIC TREATMENT OF HEART FAILURE
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 used 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 to improve cardiac hemodynamics and function through preload reduction, afterload reduction, and enhancement of inotropy (i.e., myocardial contractility).
Figure 28–1 Pathophysiologic mechanisms of heart failure and major sites of drug action. Congestive heart failure is accompanied by compensatory neurohormonal responses, including activation of the sympathetic nervous and renin–angiotensin–aldosterone axis. Increased ventricular afterload, due to systemic vasoconstriction and chamber dilation, causes depression in systolic function. In addition, increased afterload and the direct effects of angiotensin and norepinephrine on the ventricular myocardium cause pathologic remodeling characterized by progressive chamber dilation and loss of contractile function. Key congestive heart failure medications and their targets of action are presented. ACE, angiotensin-converting enzyme; AT1 receptor, type 1 angiotensin receptor.
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. Thus, 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.
Figure 28–2 Hemodynamic responses to pharmacologic interventions in heart failure. The relationships between diastolic filling pressure (preload) and stroke volume (ventricular performance) are illustrated for a normal heart (green line; the Frank-Starling relationship) and for a patient with heart failure due to predominant systolic dysfunction (red line). Note that positive inotropic agents (I), such as cardiac glycosides or dobutamine, move patients to a higher ventricular function curve (lower dashed line), resulting in greater cardiac work for a given level of ventricular filling pressure. Vasodilators (V), such as angiotensin-converting enzyme (ACE) inhibitors or nitroprusside, also move patients to improved ventricular function curves while reducing cardiac filling pressures. Diuretics (D) improve symptoms of congestive heart failure by moving patients to lower cardiac filling pressures along the same ventricular function curve.
Dietary Na+ 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.
Loop Diuretics. 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. 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– co-transporter 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.
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 been used to achieve volume reduction with limited K+ and Mg2+ wasting.
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. If present, hypokalemia from therapy may be corrected by oral or intravenous K+ supplementation or by the addition of a K+-sparing diuretic.
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 diuresis. 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 coadministration of drugs that increase cardiac output (e.g., dobutamine).
Diuretic Resistance. (Table 28–1). 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. Other factors can contribute to diuretic resistance (see Table 28–1).
Causes of Diuretic Resistance in Heart Failure
Metabolic Consequences of Diuretic Therapy. With regard to diuretic use in CHF, the most important adverse sequelae of diuretics are electrolyte abnormalities, including hyponatremia, hypokalemia, and hypochloremic metabolic alkalosis.
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 suggests other effects of A1 antagonists on the renin-angiotensin system (see Figure 26–3). Administration of A1 antagonists KW-3902 (ROLOFYLLINE) or BG9179 (NAXIFYLLINE), to patients with decompensated CHF already treated with loop diuretics, has been associated with increased volume reduction, improved renal function, and lower diuretic dosing, however, a 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 ANTAGONISTS AND CLINICAL OUTCOME
LV systolic dysfunction decreases 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. The pathophysiologic effects of hyperaldosteronemia are diverse (Table 28–2) and extend beyond Na+ and fluid retention; however, the precise mechanism by which aldosterone receptor blockade improves outcome in CHF remains unresolved.
Potential Roles of Aldosterone in the Pathophysiology of Heart Failure
Aldosterone-receptor antagonists in combination with ACE inhibitor therapy have provided beneficial effects in clinical trials. In CHF patients with low LV ejection fraction, spironolactone (25 mg/day) decreased mortality by ~30% (from progressive heart failure or sudden cardiac death), and patients had fewer CHF-related hospitalizations compared with the placebo group. Treatment was well tolerated; however, 10% of men reported gynecomastia and 2% of all patients developed severe hyperkalemia (>6.0 mEq/L).
Although numerous vasodilators have 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 focuses on the uses for some of these same vasodilator drugs in the treatment of CHF, mainly through their capacity to reduce preload and afterload (Table 28–3).
Vasodilator Drugs Used to Treat Heart Failure
NITROVASODILATORS. Nitrovasodilators are nitric oxide (NO) donors that activate soluble guanylate cyclase in vascular smooth muscle cells, leading to vasodilation. 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.
Organic Nitrates. 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. The principal action of these preparations 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, and coronary artery vasodilation for which systolic and diastolic ventricular function is enhanced by increased coronary blood flow. These beneficial physiologic effects translate into improved exercise capacity and CHF-symptom reduction. However, these drugs do not substantially influence systemic vascular resistance, andpharmacologic tolerance limits their utility over time. Organic nitrates are commonly used with other vasodilators (e.g., hydralazine) to increase the clinical effectiveness.
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 h each day(see Chapter 27). Patients with recurrent orthopnea or paroxysmal nocturnal dyspnea, e.g., might benefit from nighttime nitrate use. Likewise, co-treatment with hydralazine may decrease nitrate tolerance by an antioxidant effect that attenuates superoxide formation, thereby increasing the bioavailable NO levels.
Sodium Nitroprusside. Sodium nitroprusside (NITRO-PRESS, others) is a direct NO donor and potent vasodilator that is effective in reducing both ventricular filling pressure and systemic vascular resistance (Figure 28–3). Onset to action is rapid (2-5 min) as the drug is quickly metabolized to NO. Nitroprusside is 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). It increases cardiac output and renal blood flow, improving both glomerular filtration and diuretic effectiveness. The most common adverse side effect of nitroprusside is hypotension. Excessive reduction of systemic arterial pressure may limit or prevent an increase in renal blood flow in patients with more severe LV contractile dysfunction.
Figure 28–3 Relationship between ventricular outflow resistance and stroke volume in patients with systolic ventricular dysfunction. An increase in ventricular outflow resistance, a principal determinant of afterload, has little effect on stroke volume in normal hearts, as illustrated by the relatively flat curve. In contrast, in patients with systolic ventricular dysfunction, an increase in outflow resistance often is accompanied by a sharp decline in stroke volume. With more severe ventricular dysfunction, this curve becomes steeper. Because of this relationship, a reduction in systemic vascular resistance (1 component of outflow resistance) in response to an arterial vasodilator may markedly increase stroke volume in patients with severe myocardial dysfunction. The resultant increase in stroke volume may be sufficient to offset the decrease in systemic vascular resistance, thereby preventing a fall in systemic arterial pressure. (Adapted from Cohn and Franciosa, 1977.)
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 is a vasoactive NO donor that is 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. Nitroglycerin therapy may be limited by headache and nitrate tolerance; tolerance may be partially offset by increasing the dosage.
Hydralazine. Hydralazine is a direct vasodilator whose mechanism of action is poorly understood. 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 LV 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. Hydralazine often is used in CHF patients with renal dysfunction intolerant of ACE-inhibitor therapy. Combination therapy with isosorbide dinitrate and hydralazine reduces CHF mortality in patients with systolic dysfunction. 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.
The oral bioavailability and pharmacokinetics of hydralazine are not altered significantly in CHF, unless severe hepatic congestion or hypoperfusion is present. Hydralazine is typically started at a dose of 10-25 mg 3 or 4 times per day and uptitrated to a maximum of 100 mg 3 or 4 times daily, as tolerated. At total daily doses >200 mg, hydralazine is associated with an increased risk of lupus-like effects.
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. 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 3 or 4 times daily, and adherence may be difficult for CHF patients, who are prescribed multiple medications concurrently.
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 28–4).
Figure 28–4 The renin–angiotensin–aldosterone axis. Renin, excreted in response to β adrenergic stimulation of the juxtaglomerular (j-g) or granular cells of the kidney, cleaves plasma angiotensinogen to produce angiotensin I. Angiotensin-converting enzyme (ACE) catalyzes the conversion of angiotensin I to angiotensin II (AngII). Most of the known biologic effects of AngII are mediated by the type 1 angiotensin (AT1) receptor. In general, the AT2 receptor appears to counteract the effects of AngII that are mediated by activation of the AT1 pathway. AngII also may be formed through ACE-independent pathways. These pathways, and possibly incomplete inhibition of tissue ACE, may account for persistence of AngII in patients treated with ACE inhibitors. ACE inhibition decreases bradykinin degradation, thus enhancing its levels and biologic effects, including the production of NO and PGI2. Bradykinin may mediate some of the biological effects of ACE inhibitors.
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.
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. 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. 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 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 ACE inhibitors captopril, enalapril, ramipril, lisinopril, quinapril, trandolapril, and fosinopril (see Chapter 26) are FDA-approved for the treatment of CHF. Data from numerous clinical trials 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. ACE-inhibitor doses customarily are increased over several days in hospitalized patients or over weeks in ambulatory patients, with monitoring of blood pressure, serum electrolytes, and creatinine levels. In CHF patients with decreased renal blood flow, ACE inhibitors impair autoregulation of glomerular perfusion pressure, reflecting their selective effect on efferent (over afferent) arteriolar tone. 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.
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. 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 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 or dose adjustment.
ACE Inhibitors and Survival in CHF. When compared with other vasodilators, ACE inhibitors appear superior in reducing mortality in CHF. ACE inhibitors improve survival in patients with CHF due to systolic dysfunction. ACE inhibitors also prevent the development of clinically significant LV dysfunction after acute MI. ACE inhibitors appear to confer these benefits by preventing postinfarction-associated adverse ventricular remodeling. In asymptomatic patients with LV dysfunction, ACE inhibitors slow the development of symptomatic CHF.
AT1 RECEPTOR ANTAGONISTS. AT1 receptor antagonism obviates AngII “escape” and decreases the probability of developing bradykinin-mediated side effects associated with ACE inhibition. Although rare, angioedema has been reported with AT1 receptor antagonist use. 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. Owing to their favorable side-effect profile, ARBs are an excellent alternative in CHF patients intolerant of ACE inhibitors. In the elderly, there is an increased probability of developing clinically significant hypotension, renal dysfunction, and hyperkalemia.
The role of combination ACE-inhibitor and ARB therapy in the treatment of CHF remains unresolved. Based on the hypothesis that ARB efficacy is at least in part a consequence of reduced circulating aldosterone levels, combined. Combined ARB treatment with aldosterone receptor inhibition has also 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. Data regarding mortality benefit attendant to combination therapy are not available at present.
DIRECT RENIN INHIBITORS. Maximal pharmacologic ACE inhibition alone may be insufficient for optimal attenuation of AngII-induced cardiovascular dysfunction in patients with CHF. Several molecular mechanisms may contribute:
• ACE-independent pathways that facilitate AngI → AngII conversion
• Suppression of the negative feedback exerted by AngII on renin secretion in the kidney
Thus, inhibition of renin to further suppress AngII synthesis in CHF has gained popularity. 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 28–4).
Aliskiren (TEKTURNA, RASILEZ) is the first orally administered direct renin inhibitor to obtain FDA approval for use in clinical practice. The pharmacokinetic advantages of aliskiren over earlier direct renin inhibitor prototypes include an increased bioavailability (2.7%) and a long plasma t1/2 (~23 h). Aliskiren induces a concentration-dependent decrease in plasma renin activity and AngI and AngII levels that are associated with a decrease in systemic blood pressure without significant reflex tachycardia (see Chapter 26).
Aliskiren is as effective as an ARB for monotherapy of mild-to-moderate hypertension. Aliskiren also appears to exert beneficial effects on myocardial remodeling by decreasing LV mass in hypertensive patients, suggesting that direct renin inhibition may attenuate hypertension-induced end-organ damage. 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. Combining aliskiren (150 mg/day) with a β receptor antagonist and an ACE inhibitor or ARB did not produce a significant increase in hypotension or hyperkalemia in a cohort that mainly included symptomatic CHF patients with a low LV ejection fraction (~30%). Results from this trial also demonstrated that 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.
VASOPRESSIN RECEPTOR ANTAGONISTS. Neurohumoral dysregulation in CHF includes abnormal arginine vasopressin (AVP) secretion, resulting in the perturbation of fluid balance. AVP is secreted into the systemic circulation 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 (see Chapter 25).
The active form of AVP is a 9–amino acid peptide that interacts with 3 receptor subtypes: V1a, V1b, and V2. 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 1 mechanism by which the use of AT1-receptor antagonists are effective in the clinical management of these patients.
AVP levels are nearly 2-fold above normal in CHF patients. This dysregulation of AVP synthesis in CHF may involve impaired atrial stretch receptor sensitivity, normally a counterregulatory mechanism for AVP secretion, and increased adrenergic tone. However, elevated levels of AVP have been observed in asymptomatic patients with significantly decreased LV function. CHF may have a component ofabnormal responsiveness to vasopressin rather than one of excessive vasopressin production alone. 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. 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. 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.
Tolvaptan (SAMSCA), which preferentially binds the V2 receptor over the V1a receptor (receptor selectivity ~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, has high affinity for both V2 and V1a receptors, and has a t1/2 nearly twice as long.
β ADRENERGIC RECEPTOR ANTAGONISTS
Long-term sympathomimetic use is associated with increased CHF mortality rates, whereas a survival benefit is associated with chronic administration of β receptor antagonists. 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. 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.
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. β Receptor antagonists may also induce positive LV remodeling by decreasing oxidative stress in the myocardium.
Metoprolol. Metoprolol (LOPRESSOR, TOPROL XL, others) is a β1-selective receptor antagonist. The short-acting form of this drug has a t1/2 of ~6 h. 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.
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. In clinical trials, 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. Exercise capacity (e.g., 6-min walk test) did not improve with carvedilol, but therapy did appear to slow the progression of CHF in a subgroup of patients with good exercise capacity and mild symptoms at baseline.
CLINICAL USE OF β ADRENERGIC RECEPTOR ANTAGONISTS IN CHF
Data from patients with mild-to-moderate chronic CHF establish 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.
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 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 upward.
The benefits of cardiac glycosides in CHF 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 cardiac myocyte depolarization (Figure 28–5), Ca2+ enters the cell via the L-type Ca2+ channel and triggers the release of stored 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 by the sarcolemmal Ca2+-ATPase.
Figure 28–5 Sarcolemmal exchange of Na+ and Ca2+ during cell depolarization and repolarization. Na+ and Ca2+ enter the cardiac myocyte via the Na+ channel and the L-type Ca2+ channel during each cycle of membrane depolarization, triggering the release, through the ryanodine receptor (RyR), of larger amounts of Ca2+ from internal stores in the sarcoplasmic reticulum (SR). The resulting increase in intracellular Ca2+ interacts with troponin C and activates interactions between actin and myosin that result in sarcomere shortening. The electrochemical gradient for Na+ across the sarcolemma is maintained by active transport of Na+ out of the cell by the sarcolemmal Na+, K+-ATPase. The bulk of cytosolic Ca2+ is pumped back into the SR by a Ca2+-ATPase, SERCA2. The remainder is removed from the cell by either a sarcolemmal Ca2+-ATPase or a high-capacity Na+-Ca2+ exchanger, NCX. NCX exchanges 3 Na+ for a Ca2+, using the electrochemical potential of Na+ to drive Ca2+ extrusion. The direction of Na+-Ca2+ exchange may reverse briefly during depolarization, when the electrical gradient across the sarcolemma is transiently reversed. β adrenergic agonists and PDE inhibitors, by increasing intracellular cyclic AMP levels, activate PKA, which phosphorylates phospholamban (PL), the α subunit of the L-type Ca2+ channel, and regulatory components of the RyR, as well as TnI, the inhibitory subunit of troponin (not shown). As a result, the probabilities of opening of the L-type Ca2+ channel and the RyR2 Ca2+ channel are doubled; SERCA2 is uninhibited and accumulates Ca2+ into the SR faster, more avidly, and to a higher concentration; and relaxation occurs at slightly higher [Ca2+]i due to slightly reduced sensitivity of the troponin complex to Ca2+. The net effect of these phosphorylations is a positive inotropic effect: a faster rate of tension development to a higher level of tension, followed by a faster rate of relaxation. indicates site of cardiac glycoside binding. See the text for the mechanism of positive inotropic effect of cardiac glycosides.
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 effect.
Electrophysiologic Actions. At therapeutic 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 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 after depolarization; 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. Cardiac glycosides favorably influence carotid baroreflex responsiveness to changes in carotid sinus pressure. In patients with moderate-to-advanced CHF, cardiac glycoside infusion increases forearm blood flow and cardiac index and decreased heart rate. Digoxin also decreases centrally mediated sympathetic nervous system tone, although the mechanism to explain this is unresolved.
Pharmacokinetics. The elimination t1/2 for digoxin is 36-48 h permitting once-daily dosing. 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. 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 dosing should be based on estimated lean body mass. Liquid-filled capsules of digoxin (LANOXICAPS) have a higher bioavailability than do tablets (LANOXIN). Digoxin is available for intravenous administration.
Chronic renal failure decreases the volume of distribution of digoxin and therefore requires a decrease in maintenance dosage of the drug. 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). Higher serum concentrations are not associated with incrementally increased clinical benefit. The risk of death is greater with increasing serum concentrations and it is recommended to maintain digoxin levels <1 ng/mL.
Clinical Use of Digoxin in Heart Failure. 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 and increased understanding of digoxin pharmacokinetics. 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. 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. Inhibition of the Na+, K+-ATPase activity of skeletal muscle can cause hyperkalemia. An effective antidote for digoxin toxicity is 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.
β ADRENERGIC AND DOPAMINERGIC AGONISTS
In 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 stimulate cardiac myocyte dopamine (D1) and β adrenergic receptors that stimulate the Gs-adenylyl cyclase-cyclic AMP–PKA pathway. PDE inhibitors slow degradation of cyclic AMP, thereby raising the steady-state level of cyclic AMP in cells. The catalytic subunit of PKA phosphorylates a number of substrates that enhance Ca2+-dependent myocardial contraction and accelerate relaxation (see Figure 28–5). Isoproterenol, Epi, and NE 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. At the cellular level, enhanced cyclic AMP levels have been associated with apoptosis (see Chapter 12).
Dopamine (DA). The pharmacologic and hemodynamic effects of DA are concentration dependent. Low doses (≤2 μg/kg lean body mass/min) induces cyclic AMP–dependent vascular smooth muscle vasodilation. 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. Low-dose DA 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. DA 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 β 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), but has little role in the treatment of patients with primary cardiac contractile dysfunction. Tachycardia, which is more pronounced with DA than with dobutamine, may provoke ischemia in patients with coronary artery disease.
Dobutamine. Dobutamine is the β agonist of choice for the management of CHF patients with systolic dysfunction. For clinical use, dobutamine is available as 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 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.
The cyclic AMP–PDE inhibitors decrease cellular cyclic AMP degradation, resulting in elevated levels of cyclic AMP. The physiologic effects are positive myocardial inotropism and dilation of resistance and capacitance vessels. Collectively, PDE inhibition improves cardiac output through inotropy and by decreasing preload and afterload (thus giving rise to the term inodilator).
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 selective inhibitors of PDE3, the cyclic GMP–inhibited cyclic AMP PDE. By elevating cellular cyclic AMP levels, these drugs 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. Conversely, the arterial and venodilatory effects of milrinone are greater than those of dobutamine at concentrations that produce similar increases in cardiac output.
For inamrinone, a 0.75-mg/kg bolus injection administered over 2-3 min 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 h and 0.5-1 h, respectively, but are nearly doubled in patients with severe CHF. Clinically significant thrombocytopenia occurs in b10% 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.
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. The pharmacology of PDE5 inhibitors is presented in Chapter 27.
CHRONIC POSITIVE INOTROPIC THERAPY
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. At present, digoxin remains the only oral inotropic agent available for CHF patient use.
DIASTOLIC HEART FAILURE
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). Diastolic CHF is diagnosed when the LV is unable to maintain adequate cardiac output without filling at an abnormally elevated end-diastolic filling pressure.
Figure 28–6 Pressure–volume relationships in normal heart and heart with diastolic dysfunction. Normal P-V loop (green) based on normal end-diastolic pressure–volume relationship (EDPVR). P-V loop with diastolic dysfunction is shown in red. ESPVR, end-systolic pressure–volume relationship.
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 disease. Although not a disease of myocardium infiltration, 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%, likely represents an underestimation.
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 must be accomplished gradually with frequent reassessment of treatment goals. 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. 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.
TARGETING VASCULAR DYSFUNCTION IN CHF
Vascular dysfunction is an established component of the CHF syndrome associated with poorer clinical outcome and has evolved into a novel pharmacotherapeutic target (Figure 28–7). Elevated levels of oxidant, nitrosative, and other forms of inflammatory stress observed in patients with CHF may impair vascular reactivity by disruption of cell signaling pathways that lead to vasodilation.
Figure 28–7 Preserving normal vascular reactivity is a target of evolving priority in the treatment of patients with chronic CHF. Increased levels of reactive oxygen species (ROS, e.g., superoxide [O2–] and hydrogen peroxide [H2O2]) that are generated in endothelial cells (EC) and vascular smooth muscle cells (VSMC) impair key signaling pathways necessary for normal vascular function. For example, excessive aldosterone can cause a reduction in antioxidant enzyme activity in EC, such as glucose-6-phosphate dehydrogenase (G6PD), resulting in increased ROS formation. Likewise, increased xanthine oxidase (XO) activity, AT1 receptor activation, and upregulation of signaling pathways associated with cholesterol metabolism favor ROS formation. In EC, elevated levels of ROS impair vascular reactivity, in part, by decreasing endothelial nitric oxide synthase (eNOS) activity and increasing peroxynitrite (ONOO–) formation (which will decrease bioavailable NO). In VSMC, oxidant stress decreases NO levels and impairs sensitivity of soluble guanylyl cyclase (sGC) to NO, reducing cyclic GMP-dependent VSMC relaxation. Mineralocorticoid (MR)-receptor antagonists, XO inhibitors (XO-I), HMG-CoA–reductase inhibitors (statin), AT1 receptor blockers (ARBs), and angiotensin-converting enzyme inhibitors (ACE-I) block various cellular reactions associated with elevated levels of ROS and impaired vascular reactivity. The BAY compounds (e.g., BAY 58-2667; figure inset), are a novel group of direct sGC activators that increase enzyme activity despite oxidant stress-induced sGC modifications that convert the enzyme to an NO-insensitive state.
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. Epidemiologic data support a positive, graded association between impaired exercise capacity and circulating uric acid levels. The myocardium and vascular endothelial cells contain high concentrations of XO. This lead to the hypothesis that increased XO-generated superoxide impairs vascular reactivity in CHF patients.
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. 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.
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. Current evidence suggests a role of crosstalk between mevalonate metabolism and cell signaling pathways involved in inflammation and oxidant stress. Intermediate by-products 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. Statins inhibit these intermediary pathways and appear to restore endothelium-dependent and endothelium-independent vascular function. A large number of population studies have demonstrated a favorable effect of statin therapy on outcome in CHF.
Direct Activators of Soluble Guanylyl Cyclase. Soluble guanylyl cyclase (sGC) is an enzyme that catalyzes the conversion of GTP to cyclic GMP, a second messenger necessary for normal vascular smooth muscle cell relaxation. Under physiologic conditions, NO is the primary biologically active stimulator of sGC. Elevated levels of oxidant stress deactivate sGC through various molecular mechanisms. 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 (seeChapter 27). 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. In healthy humans, BAY compound administration has not been associated with severe side effects, but hypotension and headaches have been reported. The utility of BAY 58-2667 in the clinical management of patients with CHF is a topic of ongoing investigation.
PROGESSION OF DISEASE AND THERAPY IN CHF
CHF is a chronic and usually progressive illness. Therapy also needs to be progressive in response to the disease:
Stage 1. Patient at risk but asymptomatic:
• Identify and reduce risk factors, educate patient and family
• Manage measurable risk factors; treat hypertension, diabetes, dyslipidemias
Stage 2. With structural remodeling but few symptoms:
• Reduce effects of AngII (ACEI or AT1 blocker); add β1 blocker as appropriate
Stage 3. Structural disease, symptoms of failure:
• Add ACEI or AT1 blocker and β1 blocker
• Reduce dietary Na+ intake; add diuretics, digoxin
• Treat bundle-branch block (resynchronize), if needed
• Revascularize, replace mitral valve, as appropriate
• Add aldosterone antagonist
Stage 4. Symptoms refractory to treatment:
• Use inotropic agents
• Employ surgical interventions (ventricular assist device; heart transplant)
A few new treatments are advancing through clinical trials. The hormone relaxin, which acts via four GPCRs, has a complex physiology but appears to be useful in heart failure. In the near future, we may have treatments that correct some of the molecular contributors of heart failure, such as a SERCA2 transgene that enhances uptake, storage, and release of Ca2+ in cardiac myocytes (see Figure 28–5).