INTRODUCTION OF THE AFTERLOAD REDUCTION CONCEPT
It has long been recognized that impedance to left ventricular (LV) outflow (afterload or increased wall stress during systole) is a critical determinant of cardiac performance.1–4 This is especially true of patients with impaired LV systolic performance, such as that occurs in systolic heart failure (Fig. 1).5 Ultimately, the failing heart's ability to respond to increased impedance is diminished. We now know that specific drugs lower aortic impedance, thus, restoring myocardial systolic function to some extent.
Fig. 1: The relationship between various degrees of left ventricular dysfunction and afterload stress.
The factors that makeup impedance and impair LV ejection of blood in patients with heart failure are multiple, complex, and highly interactive. They include:
- Peripheral arteriolar vasoconstriction: This is due to heightened neurohormonal activity including augmentation of the sympathetic nervous system, and intense activation of the renin-angiotensin-aldosterone system (RAAS). There is also release of vasopressin and endothelin, potent peripheral vasoconstrictors.
- Increased LV wall stress during cardiac myocyte shortening—a concept known as “afterload”. Afterload is a term that emerged years ago from the study of isolated muscles. It is a laboratory but not a bedside measurement.
- Diminished distensibility of the large vessels such as the aorta and its major branches.
- Reduction in small vessel caliber and compliance.
- Increased blood viscosity and inertia.
Each of these forces can act collectively to impair LV outflow tract flow or cardiac output during contraction and may improve to some extent with vasodilator therapy.
Heightened resistance or impedance to LV ejection is often referred to as “afterload”, but the term afterload originates from isolated muscle studies done in the mid-1970s and is not, strictly speaking, appropriately applied to the clinical setting. Afterload is defined as ventricular wall stress during myocyte shortening, and cannot be easily measured in the intact circulation. It is a product of LV cavity size (LaPlace relationship) and systolic arterial pressure and is inversely related to wall thickness or hypertrophy. In clinical practice, systemic vascular resistance (SVR) is a surrogate for afterload that is frequently calculated from right heart catheterization data [SVR = (mean arterial pressure – CVP) × 80/cardiac output], but this calculation is largely an estimate of small peripheral vessel resistance. SVR is, therefore, only a part of the total impedance that affects LV ejection (Table 1). The failing ventricles (both left and right) are exquisitely sensitive to afterload conditions, and it is a logical extension of this concept that drugs that reduce aortic impedance will improve cardiac systolic performance, independent of any effect on myocardial contractility.
Vasodilator Drugs and Low Blood Pressure
Patients with moderate-to-severe heart failure often have low blood pressure that is asymptomatic. Low brachial systolic pressure is sometimes perceived by physicians as a contraindication to the use of arteriolar dilator drugs such as nitrates, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or carvedilol. However, vasodilator drugs can maintain systolic blood pressure by increasing stroke volume in patients with impaired systolic function. Observations from large clinical trials have challenged the belief that vasodilators are deleterious in patients with low systolic blood pressure.6–8 Generally speaking, vasodilator drugs should be continued in patients with systolic heart failure and asymptomatic low systolic blood pressure in the range of 80–110 mmHg is not necessarily a contraindication to vasodilator therapy. Severe, symptomatic hypotension can sometimes occur in a volume-depleted patient in response to the first dose of an ACE inhibitor. For example, this might occur following a robust diuresis. Such brisk falls in blood pressure can be treated by leg elevation. Clinicians recognize that symptomatic hypotension is a well described adverse event that can occur when ACE inhibitors or ARBs are used in the context of hypovolemia and an activated RAAS. Symptomatic reduction in systolic blood pressure in response to vasodilators in a euvolemic or volume overloaded patient with severe LV dysfunction is another matter. Such patients are said to be truly intolerant of vasodilators, and symptomatic hypotension in response to drug therapy is a very powerful sign of poor prognosis. Low blood pressure without symptoms is far more common and is usually tolerated by patients using vasodilator drugs.
To avoid symptomatic hypotension when using vasodilator drugs to treat heart failure, it is best to begin with the lowest tolerable dose, and then gradually titrate the drugs over several weeks. This requires great patience and frequent contact with the patient. However, the goal is to prevent adverse effects, such as dizziness, light-headedness, syncope, extreme fatigue, and re-admission to the hospital for generalized malaise. It is now a common practice to have highly trained nurses with expertise in heart failure manage such patients soon after hospital discharge (1 week or sooner at our medical center) to carefully proceed with medication titration in a highly monitored setting. In addition to monitoring patient response, serum electrolytes and renal function are frequently assessed. Frequent follow-up soon after hospital discharge with measurement of electrolytes and careful physical examination seems to be an important element in reducing re-hospitalization.
Arterial versus Venous Effects of Vasodilator Drugs in Patients with Systolic Heart Failure
The hemodynamic effects of vasodilator drugs are dependent on the relative effects of the drug on resistance and capacitance vessels. Arterial vasodilators such as hydralazine or amlodipine reduce aortic impedance and thereby increase the velocity of shortening during LV ejection. LV end-systolic volume is thus reduced, and LV ejection fraction increases. With hydralazine, LV end-diastolic volume (i.e., preload) is not acutely altered, so the stroke volume response can be markedly increased.9 When venodilator drugs such as nitrates are employed in patients with systolic heart failure, blood volume may acutely redistribute into the large capacitance veins, and LV end-diastolic volume or preload is reduced. The reduced LV end-diastolic volume can limit the increase in stroke volume to some extent.10 With balanced arteriolar-venous vasodilator drugs, such as sodium nitroprusside, a combination of decreased venous pressure (decongestion) and decreased aortic impedance is achieved, which results in improved stroke volume. In patients with severe regurgitant lesions such as mitral or aortic regurgitation, vasodilator drugs also reduce the regurgitant fraction and increase forward cardiac output, thus adding to their beneficial effects. It should be so noted that there are no adequately powered randomized controlled trials with the use of vasodilators in valvular heart disease that support their use to improve long-term outcomes.
The reflex tachycardia observed in normal subjects in response to arterial vasodilators is not seen in patients with advanced systolic heart failure.11 This is likely due to a reduction in cardiac norepinephrine spillover rate in the setting of heart failure with unloading of the baroreceptors and low pressure mechanoreceptors in response to systemic vasodilation.12 In fact, the magnitude of the blunted neurohumoral response to nitroprusside infusion in patients with systolic heart failure (i.e., lack of reflex tachycardia) may be a marker of the severity and prognosis of heart failure.11
In general, the beneficial response to vasodilator drug therapy is most pronounced in patients with systolic heart failure and a dilated LV. Patients with normal LV cavity size may be more sensitive to changes in preload reduction, and hypotension can occur in response to reduced afterload if the heart is small or there is a relatively reduced preload.
Fig. 2: Nitroglycerin (NTG) alone is associated with the development of early tolerance, whereas the combination of NTG and hydralazine (HYD) 75 mg four times per day is associated with less NTG tolerance. (*: Statistically significant changes).
Its mechanism of action is still not completely understood, but it appears to be a direct and potent arteriolar dilator that relaxes the smooth muscles of small resistance vessels. It has essentially no venodilating effects. Hydralazine primarily dilates the renal and peripheral resistant arterioles, and has little effect on coronary or liver blood flow. It may also have antioxidant effects, and can prevent tolerance to nitrates (Fig. 2).
Hydralazine is well-known to cause reflex tachycardia when used in patients without heart failure. For example, in patients with systemic hypertension large doses can produce a reflex tachycardia, edema and may rarely worsen angina. Reflex tachycardia and excess salt and water retention in response to hydralazine is not typically observed in patients with more advanced systolic heart failure because of a blunted baroreceptor response.
Hydralazine can be given orally, where it is rapidly absorbed from the gastrointestinal tract. However, the actual bioavailability is highly variable, and depends on the rate of acetylation by the liver, a genetically determined trait. In the United States, about half of people are fast acetylators and half are slow acetylators. Acetylation activity is not routinely measured in patients. A lupus-like syndrome from hydralazine is more likely to occur in slow acetylators, and this typically wanes when hydralazine is stopped. Fast acetylators may require higher doses of hydralazine. Chronic hydralazine use can cause vitamin B6 deficiency.
The hemodynamic response to chronic oral hydralazine therapy in patients with systolic heart failure is usually characterized by no change in heart rate, a fall in SVR, and about a 50% increase in cardiac output.13 Most commonly, blood pressure does not change much with hydralazine. Patients with chronic mitral or aortic regurgitation demonstrate a reduction in the regurgitant jet by echo and auscultation, and forward stroke volume is markedly increased. There is no long-term improvement in exercise capacity despite a modest, persistent improvement in ejection fraction. The combination of hydralazine and isosorbide dinitrate ushered in the vasodilator era for the treatment of heart failure in the 1980s (Fig. 3).
Even today we do not know entirely how to properly dose hydralazine for individual patients with advanced heart failure. Because of the high success rate of other vasodilator drugs, such as ACE inhibitors and ARBs, hydralazine has been relegated to second-tier therapy. The one important exception is the safety and efficacy of hydralazine and isosorbide dinitrate in the African-American Heart Failure Trial (A-HeFT) (Fig. 4).14 In this trial, the fixed combination of hydralazine and isosorbide dinitrate (BiDil®) added to standard therapy markedly improved survival and other outcomes among self-identified black patients with systolic heart failure. One rationale for the trial was that isosorbide dinitrate might augment nitric oxide production, and therefore improve endothelial function. Hydralazine may also work as an antioxidant and can reduce nitrate tolerance.15 The results of the A-HeFT trial have not been robustly translated into clinical practice for a number of reasons.
Fig. 3: Mortality curves of patients with heart failure randomized to placebo, prazosin or isosorbide dinitrate/hydralazine in the first Vasodilator Heart Failure Trial (V-HeFT 1); p= 0.046 on the generalized Wilcoxon test, which gives more weight to the treatment differences in the early part of the mortality curves.
Fig. 4: Mortality curves of African-American patients randomized to placebo or isosorbide dinitrate/hydralazine in addition to standard therapy for heart failure in the African-American Heart Failure Trial (A-HeFT).14
The combination of hydralazine and isosorbide dinitrate today is generally considered as an add-on therapy, superimposed on more conventional therapy, when patients are demonstrating signs and symptoms of worsening heart failure.
Typically, hydralazine is prescribed along with isosorbide dinitrate to improve cardiac output and reduce pulmonary capillary wedge pressure. The initial hydralazine dose used in A-HeFT was 37.5 mg three times per day and gradually increased to 75 mg three times per day. Isosorbide dinitrate was slowly titrated to a dose of 80 mg three times per day. Doses of hydralazine as high as 1,200 mg/day have been used to treat systolic heart failure, but onset of the lupus syndrome is seen in 15–20% of patients receiving more than 400 mg/day. Fluid retention is also more common when higher doses of hydralazine are used. There is likely a survival advantage associated with long-term hydralazine therapy when taken with isosorbide dinitrate to treat systolic heart failure.
Amlodipine is a dihydropyridine L-type calcium channel blocking agent that is widely used to treat hypertension and angina. It is a long-acting, potent, arteriolar dilating drug that is well-tolerated. The typical starting dose is 2.5 or 5 mg/day and the target dose for many patients with hypertension is 10 mg/day. Calcium channel drugs are vasodilators and have anti-ischemic effects, so it is logical that they would be investigated in patients with systolic heart failure. The most promising calcium channel blocker to emerge from these studies as potential heart failure therapy was amlodipine. A minor drawback to amlodipine is the frequent development of pedal edema with the higher dose, but this is assumed to be due to benign vasodilation in the small arterioles and venules in the ankles, and not due to heart failure per se. Other non-dihydropyridine calcium channel blockers such as verapamil and diltiazem have negative inotropic properties, may cause cardiac electrical conduction problems, and are not very powerful vasodilators. They have never played a primary role in the treatment of heart failure.
The effect of amlodipine on outcomes in patients with chronic systolic heart failure was evaluated in two PRAISE (Prospective Randomized Amlodipine Survival Evaluation) studies.16,17 The earlier of the two studies demonstrated that all-cause mortality might be lower in a subset of patients with nonischemic dilated cardiomyopathy treated with amlodipine, though overall, the trial was neutral. The PRAISE II trial was then focused solely in patients with nonischemic dilated cardiomyopathy. In PRAISE II, an overall neutral effect of amlodipine was once again observed. It seems clear that amlodipine is safe to use in patients with systolic heart failure when needed to control hypertension or angina. However, amlodipine is not effective as a life-saving therapy for the treatment of systolic heart failure, despite its powerful vasodilating properties. The observations suggest that vasodilation alone is not enough to provide a mortality benefit. Several other potent vasodilators have failed to improve mortality in patients with heart failure, including prazosin, flosequinan, nesiritide, and synthetic prostacyclin (epoprostenol) or Flolan. Presumably, it is not simple “vasodilation” that provides for the survival benefit, but there should be some neurohumoral modulation property or some other mechanisms beyond simple reduction in afterload.
Nitrates have been widely used to treat angina by physicians for well over 100 years. It is only in the past 25 years that they have been used to treat systolic heart failure. Their favorable effects on angina, systolic heart failure, mitral regurgitation and coronary spasm are now well known. The mechanism of action of nitrates is complex, but these molecules appear to undergo a metabolic biotransformation in vascular smooth muscle, which leads to the formation of nitric oxide or a related S-nitrosothiol. These breakdown products of nitrates stimulate the enzyme guanylate cyclase, leading to the formulation of cyclic guanosine monophosphate (cGMP). cGMP in turn reduces calcium influx, which leads to venous and arterial vasodilation.18 It is also likely that the vascular endothelium responds to nitrates with the synthesis and release of prostacyclin,19 thus improving endothelial function. Nitrates primarily cause venodilation, which typically increases venous capacitance and reduces preload, thus lowering end-diastolic volume, reducing cardiac wall tension and diminishing pulmonary capillary wedge pressure.
Fig. 5: The data indicate that tolerance can develop to intravenous nitroglycerin (NTG) over 24 hours. There is a brisk initial response to IV NTG manifested by a fall in pulmonary capillary wedge pressure (PCWP) during titration; but during 24 hours of infusion, PCWP increases back toward control in both the NTG and the placebo arms of the study.
Dyspnea is relieved. Larger doses lead to arteriolar dilation, further reducing afterload and improving forward flow. LV cavity size diminishes, reducing mitral regurgitation.20 It is not surprising that oral nitrate therapy has emerged as an important treatment for systolic heart failure. Nitrates are among the few vasodilators that are able to increase exercise tolerance in patients with systolic heart failure.21,22 However, nitrate tolerance occurs in many patients (Fig. 5), thus casting suspicion on long-term efficiency. This can be offset to some extent by concomitant use of hydralazine.15
RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM BLOCKERS
Angiotensin Converting Enzyme Inhibitors
Angiotensin converting enzyme (ACE) inhibitors were introduced into clinical practice in the 1980s for the treatment of hypertension and heart failure.
Figs 6A and B: In the CONSENSUS Trial, the difference between treatments is even more striking, as the patients likely had more advanced heart failure. Kaplan-Meier survival curves (A) from The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).28
This class of drug therapy has revolutionized the treatment for these two conditions, and has been demonstrated to improve survival in patients with systolic heart failure (Figs 6A and B). The success of ACE inhibitors for the treatment of heart failure was predicated on the observation that the RAAS is activated in chronic systolic heart failure,23 and this activation contributes importantly to heightened afterload and to the LV remodeling process.
Angiotensinogen is produced in the liver and is converted in the blood by renin to form a small peptide, angiotensin I (Fig. 7). Angiotensin I is then further cleaved to form angiotensin II, a very small peptide, but potent arteriole constrictor. Angiotensin II subserves a host of other biological activities primarily through the angiotensin II receptor, including promotion of volume retention, activation of and sensitization to the sympathetic nervous system, thirst, regulation of salt and water balance, modulation of potassium balance, cardiac myocyte and vascular smooth muscle growth, to name but a few. Its actions are central to the development of acute and chronic systolic heart failure.
Early, overly simplistic thinking was that systolic heart failure was essentially a vasoconstricted state caused by excessive sympathetic nervous system activity and heightened levels of other vasoconstrictor neurohormones, including angiotensin II, arginine vasopressin, (AVP) and endothelin. When it became apparent that ACE inhibitors could block the production of angiotensin II, ACE inhibitors became an attractive candidate for the treatment of patients with hypertension and systolic heart failure. ACE inhibitors would be expected to reduce afterload, and in turn would increase cardiac output and forward flow. Although the initial clinical studies indeed supported this hypothesis,24 it soon became clear that ACE inhibitors were doing much more than reducing afterload. Long-term clinical improvement was accompanied by reduced LV remodeling and improved patient survival when applied to postmyocardial infarction patients,25 very similar to the seminal animal work of Pfeffer and colleagues.26 ACE inhibitors were no longer thought of as simple arteriolar dilators, but were neurohormone modulators that could very favorably alter the natural history of systolic heart failure and improve survival by inhibiting the progression of LV remodeling (Fig. 8).
We now recognize that neurohormonal activation plays a key role in the initiation and progression of heart failure. The RAAS is central to this neurohormonal cascade, as patients with systolic heart failure and high renin levels seemingly derive the most acute benefit from blocking the RAAS.27 It is now well established that ACE inhibitors slow the progression of heart failure and improve survival in patients with a reduced ejection fraction and congestive heart failure.28
Fig. 8: Heart failure is a complex clinical syndrome characterized by extensive neuroendocrine activation. The release of neurohormones appears to be in response to reduced cardiac function and a perceived reduction in effective circulatory volume. It is as if neuroendocrine activity is attempting to protect the blood pressure and maintain circulatory homeostasis. Although this may be adaptive early on, chronic neuroendocrine activation leads to peripheral vasoconstriction, left ventricular remodeling and worsening left ventricular performance, and thus becomes an attractive therapeutic target. Drugs designed to block the exuberant neuroendocrine response, such as ACE inhibitors, have now become the cornerstone of treatment for heart failure.
Much of this improvement is believed to be due to “reverse remodeling”. Even patients with a reduced ejection fraction, but few or no heart failure symptoms, derive clinical benefit from ACE inhibitor therapy.29 The development of symptomatic heart failure is delayed in these patients. The activation of neurohormones (renin, norepinephrine and AVP) appears to occur early in the natural history of the syndrome, before symptoms occur.30 This observation suggested that early introduction of neurohormonal blocking drugs before symptoms ensue may slow the progression of systolic heart failure or even delay its onset of signs and symptoms.29 Indeed, today neurohumoral modulating drugs are recommended for patients who demonstrate impaired LV systolic function even in the absence of symptoms. Many investigators observed that the RAAS was markedly activated during decompensated heart failure, but returns to normal once the patient clinically stabilizes, even though severe LV dysfunction may persist.31 The concept that blocking the RAAS improves patients with systolic heart failure became widely recognized in the 1990s.
In the 1980s, a number of hypotheses and concepts emerged that challenged the long-standing notion that systolic heart failure was fundamentally a mechanical problem. Katz introduced the idea that heart failure may be a disorder of abnormal gene expressional growth response to injury,32 and many others believed that the myocardial remodeling was at least in part due to activation of neurohormonal systems,33 which were well known to also be cardiac growth factors when studied in vitro.34 Alteration of loading conditions due to increased LV chamber size and increased wall stress also undoubtedly led to progressive LV remodeling.34 Both mechanical and neurohormonal signals regulated the remodeling process, as did altered gene expression. It became clear that the all-important LV remodeling process was largely structural and not functional.35 Additional data emerged indicating that excessive angiotensin II caused cardiac myocyte necrosis under experimental conditions.36 Eventually a coherent story emerged suggesting that systolic heart failure was at least in part driven by excessive neurohormonal activation,37,38 setting up a vicious cycle of worsening heart failure and death (Fig. 8). These neurohormonal systems are likely adaptive in an evolutionary sense,39 and are not simple biomarkers or epiphenomena. They are known to directly contribute to LV remodeling40–42 and subsequent patient mortality.43 The strong notion emerged that pharmacological inhibition of the RAAS (and the sympathetic nervous system) might reduce the progression of LV remodeling,44–47 and, therefore, such drugs should improve patient survival.28
The ACE inhibitors were the first class of drugs to really test the neurohumoral hypothesis (Figs 6A and B). Needless to say, they have now become a standard of care for patients with hypertension, systolic heart failure, acute myocardial infarction and advanced cardiovascular disease. The ACE inhibitor class of drugs reduces afterload, presumably by inhibiting angiotensin II arteriolar constriction reducing sympathetic tone. There is also venodilation with a fall in pulmonary capillary wedge pressure, presumably due to reduction in sympathetic activity to veins and desensitization of venous capacitance vessels to norepinephrine. Angiotensin II does not directly dilate veins, so there is no direct effect of ACE inhibitors on venous capacitance vessels. There is modest improvement in cardiac index with ACE inhibitors, and heart rate may slightly slow. As previously mentioned, if the patient is acutely hyper-reninemic as a consequence of vigorous diuresis, there can be a substantial and prolonged fall in blood pressure with even small doses of ACE inhibition. This is why many physicians prefer to use short-acting ACE inhibitors such as captopril in hospitalized patients with acute systolic heart failure, as patients are less likely to develop prolonged symptomatic hypotension. If symptomatic hypotension ensues, the patient should lie down and the feet should be elevated until these symptoms resolve and the blood pressure improves. Usually a sense of improved well-being is established with the use of ACE inhibitors despite chronically low arterial pressures. Rarely, dysgeusia or loss of taste occurs, sometimes requiring withdrawal of the drug. Rash is uncommon with the smaller doses of ACE inhibitors used today. A dry, non-productive cough occurs in some patients receiving ACE inhibitors, and the drug is discontinued in 5–10% of patients for this reason. The mechanism of the cough is not entirely clear, but is believed to be due to the effects of bradykinin on sensory neurons in the proximal airways.
There is now a long list of ACE inhibitors to choose from (Table 2). They have somewhat dissimilar pharmacodynamics, pharmacokinetics, and rates of elimination. In general, it is best to start with small doses of an ACE inhibitor that has been tested in a large clinical trial and slowly titrates up over days to weeks to a target dose established as safe and effective by use in large clinical trials. It is expected that many patients with advanced systolic heart failure will have about a 20% increase in serum creatinine with ACE inhibitor use. This is usually not reason to discontinue or lower the dose of the ACE inhibitor. However, this class of drug is contraindicated in patients with cardiogenic shock or acute renal failure, and can cause renal insufficiency when used in patients with renal artery stenosis. Occasionally, hyperkalemia can occur requiring alteration of dose or temporary/permanent discontinuation of the ACE inhibitor. Careful, regular follow-up with monitoring of electrolytes, BUN (blood urea nitrogen) and serum creatinine is important in the care of these patients when making decisions about altering the dose of ACE inhibitors. Renal function and serum electrolytes should be checked at about one week following initiation of ACE inhibitor therapy.
Angiotensin Receptor Blockers
Angiotensin receptors of the AT1 subtype bind angiotensin II with a high structural specificity but limited binding capacity.48 The remarkable success of ACE inhibitors in the treatment of hypertension, arterial disease, myocardial hypertrophy, heart failure and diabetic renal disease encouraged the exploration of alternative drugs to block the RAAS. It was eventually recognized that ACE inhibitors blocked only one of several pathways that normally increase angiotensin II activity, and that angiotensin II could “escape” from chronic ACE inhibition. ARBs do not demonstrate this “escape” phenomenon. ARBs do not cause cough. They can be used safely in patients who develop angioedema during treatment with an ACE inhibitor. Increased levels of angiotensin II peptides seen with the use of ARBs do not appear to have unexpected off-target effects despite activating AT2 receptors.
First-dose hypotension is not typically seen when ARBs are given to diuretic-treated patients, as often occurs with ACE inhibitors. This is probably because ARBs have a much slower onset of action. Orthostatic hypotension is rare. Rebound hypertension upon withdrawal of ARBs does not appear to be a problem. As with ACE inhibitors, acute renal failure may occur with ARBs if administered to patients with renal artery stenosis or cardiogenic shock. The incidence of renal dysfunction and hyperkalemia is comparable with ARBs and ACE inhibitors.49 It is now reasonably clear that ACE inhibitors and ARBs should not be used together, as the likelihood of hyperkalemia, hypotension and worsening renal function is greater.50
Many randomized controlled trials of ARBs have been performed in patients with chronic systolic heart failure,51,52 in patients with acute myocardial infarction complicated by heart failure or LV dysfunction,53 and in patients at high-risk for vascular events.54 Several important points have emerged from these large trials:
- ARBs and ACE inhibitors appear to have very similar efficacy in these patient groups
- If the patient does not tolerate an ACE inhibitor, an ARB is a suitable substitution
- Although generally more expensive, ARBs are better tolerated than ACE inhibitors
- The combination of an ACE inhibitor and an ARB (dual RAAS blocking effect) is not more effective and is associated with more hypotension, worsening renal function, and hyperkalemia55
- Despite earlier favorable reports, ARBs do not appear to prevent recurrent atrial fibrillation.56
The dose of ARBs has generally been determined by pharmaceutical generated data and subsequent verification of these doses in large clinical trials (Table 2). Extensive experience with RAAS blockers over the years has led to changes in dose recommendations. For example, the Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) trial demonstrated that losartan 150 mg daily reduced the rate of death or admission for heart failure to a greater extent than a dose of 50 mg/day.57
Similar to ACE inhibitors, we now have data to suggest that inhibition of the RAAS with ARBs also results in favorable structural and functional changes. Treatment with the ACE inhibitor captopril, the ARB valsartan, or the combination of captopril plus valsartan resulted in similar changes in cardiac volume, ejection fraction and infarct segment length in patients 20 months following acute myocardial infarction.58 These observations suggest that ARBs are similar to ACE inhibitors with regard to their anti-remodeling properties. Neither ACE inhibitors nor ARBs improve outcomes in patients with heart failure with preserved ejection fraction.59
MINERALOCORTICOID (ALDOSTERONE) RECEPTOR BLOCKERS
Aldosterone and Systolic Heart Failure
Aldosterone was structurally identified more than 50 years ago, and was soon after designated a mineralocorticoid due to its salt retaining properties. It also promotes loss of potassium from the kidney, gastrointestinal tract, sweat and salivary glands. It has long been known to play a pathophysiologic role in cardiovascular disease, including congestive heart failure (Fig. 9).60,61 In addition to its mineralocorticoid properties, which can cause hypokalemia and hypomagnesemia, aldosterone contributes in many ways to the development of heart failure. It likely causes vascular and cardiac remodeling, endothelial dysfunction, inhibits norepinephrine reuptake, and causes baroreceptor dysfunction (Fig. 9). It expands intravascular and extravascular volume. Inhibition of aldosterone is believed to be favorable due to:
- Reduced collagen deposition and possibly anti-remodeling effects
- Blood pressure reduction
- Prevention of hypokalemia and associated arrhythmias
- Modulation of nitric oxide synthesis.
Fig. 9: Aldosterone is a mineralocorticoid that has a central role in a host of biological activities. Many of these activities can be excessive due to dysregulation of aldosterone activity, thus contributing to cardiovascular disease.
The major mineralocorticoid in heart failure is cortisol and not aldosterone. Serum aldosterone levels are not consistently elevated in patients with heart failure in the absence of diuretics. Accordingly, it is not aldosterone blockade per se, but mineralocorticoid receptor blockade that is important. Spironolactone and eplerenone are thus mineralocorticoid receptor blockers more than simply aldosterone receptor blockers.
ACE inhibitors were originally believed to chronically suppress angiotensin II in patients with heart failure, a major determinant of aldosterone production by the adrenal glands. This notion probably led to some initial loss of interest in aldosterone receptor inhibitors for the treatment of systolic heart failure. We now know that ACE inhibitors do not suppress angiotensin II long-term, and that there is an aldosterone escape phenomenon. Three landmark studies, the Randomized Aldosterone Evaluation Study (RALES) (Fig. 10),62 the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) (Fig. 11)63 and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)64 have remarkably increased the role of aldosterone mineralocorticoid antagonists for the everyday treatment of systolic heart failure. Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms in the EMPHASIS-HF trial.
Fig. 10: Survival curves of patients with advanced heart failure randomly allocated to spironolactone or placebo. Most patients were not receiving β-adrenergic blockers. There was a 30% reduction in mortality in patients randomized to spironolactone compared to patients in the placebo group. From the Randomized Aldactone Evaluation Study (RALES).62
Fig. 11: Kaplan-Meier estimates of the rate of death from any cause in the EPHESUS trial.63
This finding is particularly important as it expands the use of mineralocorticoid antagonists for the New York Heart Association (NYHA) functional class II patients. Spironolactone62 and eplerenone63 are now widely used to treat chronic systolic heart failure and postmyocardial infarction heart failure. Despite their greater use today, in the USA it was estimated that less than one-third of eligible patients hospitalized for heart failure received appropriate, guideline-recommended aldosterone antagonist therapy.65 Some of the reluctance to use aldosterone blockers in patients with systolic heart failure may be justified because of the advanced age of patients, the frequency of chronic renal insufficiency, other common comorbidities such as diabetes mellitus, and the serious threat of hyperkalemia.66 However, when used according to protocol, hyperkalemia is seemingly not such a major problem. Careful follow-up of patients and frequent measurement of renal function and serum potassium are necessary to ensure safety when using aldosterone receptor blocking drugs.
The RAAS is likely an ancient (~400–600 million years) system that evolved in such a way as to allow them to adapt to salt and volume depletion, as might have occurred during transition from the sea to land eons ago. The notion is that regulation of salt and water retention is adaptive, perhaps by protecting intravascular volume, blood pressure and perfusion to vital organs. We now know that chronic stimulation of the RAAS in patients with heart failure can be maladaptive, and that pharmacologically blocking the RAAS can improve patient survival. Blockade of aldosterone membrane receptors is a widely accepted form of therapy for systolic heart failure. The RALES and EPHESUS studies provide strong evidence that aldosterone mineralocorticoid receptor blockade is effective therapy for patients with heart failure across all degrees of severity. Postmyocardial infarction heart failure is also improved by mineralocorticoid receptor blockers.63 The role of nuclear aldosterone receptors is less clear, but given the complex array of regulatory properties that angiotensin II and aldosterone demonstrate, including inflammation, collagen synthesis, cytokine production, regulation of nitric oxide and cell adhesion molecules, one has to suspect that the activation of nuclear aldosterone receptors with resultant regulation of selective gene expression is also responsible for many of the biological activities of aldosterone, some of which are seen in systolic heart failure.
Spironolactone and Eplerenone in Chronic Heart Failure
The mechanism of action of spironolactone is complex, as aldosterone mineralocorticoid modulates many features of the heart failure syndrome. Although spironolactone is still used as an antihypertensive agent, it is not considered to be a “vasodilator” in the usual sense. Patients taking spironolactone need to be frequently and carefully monitored (patients in RALES were seen monthly for the first 12 weeks), as hyperkalemia and azotemia can occur with spironolactone,65 particularly if non-steroidal anti-inflammatory drugs are used concomitantly. Diabetes mellitus, chronic kidney disease, volume depletion, advanced age and use of other potassium sparing agents and non-steroidal anti-inflammatory drugs are all risk factors for the development of hyperkalemia when using RAAS blocking drugs.61 With careful monitoring, however, serious hyperkalemia is uncommon.62
Because of the central importance of aldosterone in the pathophysiology of heart failure, it is not surprising that the aldosterone receptor blocker spironolactone has emerged as an important therapy. Spironolactone is an old drug that was primarily used in large doses to treat ascites, edema and refractory hypertension. Excessive mineralocorticoid, common in patients with heart failure, promotes sodium retention, loss of magnesium and potassium, sympathetic nervous system activation, parasympathetic nervous system inhibition, myocardial and vascular fibrosis, baroreceptor dysfunction, and impaired arterial compliance.67
The definitive RALES was published in 199962 and clearly demonstrated that spironolactone (25–50 mg/day) added to standard therapy (β-blockers were not yet in widespread use) was safe and reduced mortality by 30% (Fig. 7). Death from progressive heart failure and sudden death were both reduced by spironolactone. The patients who participated in RALES were primarily NYHA class III (70%) and IV (30%).
Eplerenone, a newer, more selective aldosterone mineralocorticoid receptor blocker, causes less gynecomastia and breast tenderness than spironolactone. It is more mineralocorticoid specific than spironolactone. EPHESUS63 was conducted in patients who experienced a recent acute myocardial infarction with an ejection fraction of 40% or less who had heart failure, or had a history of diabetes mellitus. The patients in EPHESUS were randomly allocated to eplerenone or placebo in addition to standard therapy for acute myocardial infarction. In EPHESUS, eplerenone (average dose 42.6 mg/day) reduced all-cause mortality by 15%, cardiovascular mortality by 17%, and significantly lowered the need for subsequent hospitalization (Fig. 11). Sudden cardiac death was also reduced. As with RALES, serious hyperkalemia was unusual.
The EMPHASIS-HF trial suggests that eplerenone is effective in patients with systolic heart failure and NYHA functional class II symptoms. In EMPHASIS-HF hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol/L occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P <0.001). Today, aldosterone mineralocorticoid antagonists are widely used to treat advanced heart failure and selected patients with acute myocardial infarction. However, less than one-third of eligible patients hospitalized for heart failure are receiving guideline-recommended aldosterone receptor blocking drugs.64 This is perhaps due in part to the need for more frequent and careful follow-up, and the fear of hyperkalemia. There is a perception by some physicians that this class of drugs poses more risk than other RAAS blockers. Nevertheless, aldosterone receptor blockers are effective and safe when properly prescribed and monitored, and their indications are seemingly expanding. There appears to be considerably less reverse remodeling in patients with mild-to-moderate heart failure and LV systolic dysfunction randomly assigned to eplerenone, even though there is a reduction in collagen turnover and a reduction in brain natriuretic peptide (BNP) factor.68 Despite these surprising neutral effects on reverse remodeling, the results of EMPHASIS-HF trial suggest that patients with mild-to-moderate systolic heart failure still derive a favorable effect on morbidity and mortality from eplerenone.
Recently, the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial has been completed and published.69 This was a study aimed at patients with heart failure with a preserved ejection fraction rather than heart failure with a reduced ejection fraction. Overall, there was no improvement in cardiovascular mortality. However, spironolactone was associated with a significant (P = 0.04) reduction in hospitalization (17%). It is unclear how physicians will adopt the results of TOPCAT.
A new therapy for hypertension and heart failure has been developed by Novartis. LCZ696 is a novel molecule that includes both valsartan and a neprilysin inhibitor. The valsartan moiety of the molecule suppresses the renin-angiotensin system (RAS) while the neprilysin inhibitor reduces the degradation of brain natriuretic peptide (BNP), thereby increasing circulating BNP in plasma (Fig. 12). LCZ696 is taken twice per day. In a recent large clinical trial, 8436 patients with a reduced ejection fraction and NYHA class II to IV symptoms were randomly allocated to LCZ696 at 200 mg twice daily or enalapril at 10 mg twice daily. A favorable effect on survival was observed with LCZ696 relative to enalapril.70 It is possible that this new form of therapy may emerge as a prominent form of treatment for patients with heart failure and reduced ejection fraction.
PHOSPHODIESTERASE TYPE 5 INHIBITORS
Sildenafil and Tadalafil
Phosphodiesterases are enzymes that hydrolyze the cyclic nucleotides—cGMP and cyclic adenosine monophosphate. At least eleven families of phosphodiesterase isoenzymes have been identified. Phosphodiesterase 5 (PDE 5) degrades cGMP via hydrolysis, thus influencing cGMP's ability to modulate smooth muscle tone,71 particularly in the venous system of the penile corpus cavernosum and in the pulmonary vasculature. The discovery of sildenafil, a highly selective inhibitor of PDE 5, was initially aimed to be a novel treatment for coronary artery disease. The initial clinical studies in the early 1990s were not promising for this target, but the off-target effect of enhancement of penile erections did not escape the notice of investigators. The use of PDE 5 inhibitors was then redirected toward erectile dysfunction and more recently pulmonary hypertension.
Nitric oxide activates soluble guanylate cyclase, stimulating the production of cGMP. PDE 5 normally hydrolyzes cGMP. Sildenafil inhibits PDE 5, leading to increased cGMP and vasodilation in response to nitric oxide. For years it was known that PDE 5 was not present in normal cardiac myocytes, and the heart itself was not considered an appropriate target. This was challenged by Kass and colleagues72 who demonstrated that inhibiting PDE 5 in hypertrophied RVs induces a positive inotropic response.73 In fact, PDE 5 is markedly upregulated in hypertrophied ventricles, and PDE 5 inhibition may lead to regression of RV hypertrophy.73 PDE 5 has long been known to be highly expressed in lung vasculature, and so it is not surprising that sildenafil is beneficial for the treatment of patients with pulmonary hypertension. As of this writing, it is still not clear if normal cardiac myocytes express PDE 5, but hypertrophied and/or failing myocytes do express it, and PDE 5 inhibition can be clinically helpful in patients with pulmonary hypertension and some element of right ventricular hypertrophy or failing right ventricle.
Sildenafil and tadalafil are both PDE 5 inhibitors that are indicated for use in patients with pulmonary arterial hypertension who have mild to moderately severe symptoms.74 Preliminary data on sildenafil suggest that its use may also be safe and beneficial in patients with disproportionate pulmonary hypertension and LV dysfunction.75,76 Sildenafil citrate is prescribed in doses of 20 mg TID and tadalafil is much longer acting and is prescribed in doses of 40 mg/day to control pulmonary hypertension. Hypotension can occur with PDE 5 inhibitors, especially when they are used with nitrates. Visual disturbances and priapism have also been observed with this class of drugs. There is no specific antidote for PDE 5 induced hypotension. Sildenafil and tadalafil are not approved for use in patients with heart failure, but they are being investigated. A small case series (3 patients) has recently implied that a combination of sildenafil and nitrates can be used in patients with heart failure and pulmonary hypertension,77 though clearly more robust clinical trials are needed. Experimental data indicate that PDE 5 levels are increased in severely failing hearts78 and that sildenafil reduces myocardial remodeling.79 Recent data also suggest that PDE 5 is regulated in the LV by oxidative stress.80 Clearly this story is still unfolding and we have much to learn. Nevertheless, drugs such as sildenafil and tadalafil that selectively restore right ventricular contractility, limit right ventricular hypertrophy and reduce pulmonary artery remodeling are intriguing as potential therapy for right heart failure due to disproportionately increased pulmonary artery pressure. Perhaps PDE 5 inhibitors will also favorably affect left-sided systolic heart failure, particularly if there is associated pulmonary hypertension. More studies are needed, and use of these drugs for the treatment of heart failure remains investigational for now.
Accordingly, the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial was designed to test the hypothesis that, compared with placebo, therapy with the PDE-5 inhibitor sildenafil would improve exercise capacity in heart failure with preserved ejection fraction (HFpEF) after 24 weeks of therapy, assessed by the change in peak oxygen consumption.81 Among these patients with HFpEF, sildenafil did not significantly improve exercise capacity or clinical status relative to placebo. Nevertheless, many experts believe that there still may be a role for phosphodiesterase-5 inhibitors in selected patients with HFpEF and disproportionate pulmonary hypertension.
Sodium nitroprusside can be dramatic in reversing the deleterious hemodynamics of acute systolic heart failure. Those who have had experienced using the drug in this setting are often astonished how quickly the drug lowers pulmonary capillary wedge pressure (PCWP) and improves cardiac output, leading to prompt and often striking clinic improvement. The drug is usually started as doses of 10 μg/min, and gradually titrated up to no more than 400 μg/min, as needed to control hemodynamic abnormalities and symptoms. Some clinicians give nitroprusside according to body weight, with the typical dose starting at 10–20 μg/kg/min. Our extensive experience with nitroprusside suggests that with low dose infusion rates (<3 μg/kg/min) used for less than 72 hours, toxicity is almost never observed.82 The systolic blood pressure should not be allowed to be less than 90 mmHg or to a level that includes hypotensive symptoms. Invasive monitoring with a pulmonary artery catheter and an arterial catheter can be useful if the patient has marginal blood pressure. Persistent or severe hypotension will nearly always dissipate as soon as nitroprusside is stopped.
Metabolism and Toxicity of Nitroprusside
Nitroprusside has been used to treat severe heart failure for many years,83 though the Food and Drug Administration (FDA) has approved it only for severe hypertension and for certain neurosurgical procedures. It must be used carefully by experienced nurses and clinicians. Thiocyanate toxicity can rarely occur, and thiocyanate levels should be monitored, particularly if the patient has received a high dose for a prolonged period of time. Measurement of thiocyanate is a simple, inexpensive colorimetric test, normal levels being less than 10 mg/mL. Metabolic acidosis, anuria, and a prolonged high dose of nitroprusside (>400 μg/min) can predispose to thiocyanate toxicity, prompting measurement of thiocyanate levels. The thiocyanate ion is also readily removed by hemodialysis. When thiocyanate toxicity does occur, the patient may present with confusion, hyperreflexia and convulsions. Occasionally, mild hypoxemia occurs from nitroprusside due to ventilation-perfusion mismatch, but it is usually of little clinical consequence, as cardiac output rises and the delivery of oxygen to tissues increases. Coronary “steal” can occur when nitroprusside is used in the setting of acute myocardial infarction, and it should not be used routinely in this setting.84,85 If intravenous vasodilator therapy is used for patients with acute myocardial infarction and severe heart failure, intravenous nitroglycerin may be preferred. Nevertheless, nitroprusside has been used successfully in this setting when given in the subacute phase.84 If nitroprusside is used to treat severe heart failure related to acute myocardial infarction, it should be given later, perhaps 12 hours after admission to the hospital.85
Nitroprusside and Severe Heart Failure
Nitroprusside quickly improves hemodynamics and symptoms in patients with severe heart failure.86 Even patients with hypotension and shock may improve with nitroprusside,87 as blood pressure may stabilize or even improve with large increases in cardiac output. Patients with severe mitral regurgitations or aortic regurgitation may also demonstrate dramatic clinical improvement with nitroprusside. Patients with severe aortic stenosis and worsening heart failure can be improved with nitroprusside used prior to aortic value replacement,88 provided they are not hypotensive. It can also be used to stabilize acute heart failure in patients who demonstrate a ruptured interventricular septum following acute myocardial infarction. Recent observational data indicate that in patients hospitalized with advanced, low-output heart failure, those stabilized in the hospital with nitroprusside may have a more favorable long-term clinical outcome.89
Similar to nitroprusside, intravenous nitroglycerin has an immediate onset and offset of action. The infusion rate is usually initiated at 10–20 μg/min with gradual titration to 200–400 μg/min as needed to control symptoms and improve hemodynamic parameters. It is not approved by the FDA for the treatment of heart failure, but has been widely used for this indication over the past 20 years. Intravenous nitroglycerin is endothelium dependent, and unlike nitroprusside, it has more effect on the venous circulation than on the arterial circulation. However, higher doses of intravenous nitroglycerin have arteriolar dilating properties and may decrease afterload. Therefore, cardiac output may increase and blood pressure can be maintained. PCWP is reduced. Mitral regurgitation improves. There are few data available on the effects of intravenous nitroglycerin on coronary circulation in patients with heart failure. Coronary blood flow appears to improve. This suggests that both the epicardial conductance vessels and the coronary arteriolar resistance vessels are favorably influenced by intravenous nitroglycerin.
Limitations of Intravenous Nitroglycerin in the Treatment of Patients with Heart Failure
Intravenous nitroglycerin causes headaches in about 20% of patients, and when severe, may require cessation of the infusion. Hypotension (10%), nausea and bradycardia occasionally occur. Some patients are relatively resistant to intravenous nitroglycerin and seemingly require very large doses to afford a hemodynamic effect. The reason for this is not particularly clear, but very large doses in excess of 500 μg/min are best avoided. Nitrate tolerance is said to occur when there is a robust initial hemodynamic response, but by 1–2 hours the dose of intravenous nitroglycerin must be increased to establish a continued hemodynamic response. About one-half of patients develop nitrate tolerance, and it cannot be predicted by baseline hemodynamic values (Fig. 5). The mechanism of resistance to intravenous nitroglycerin is not clear, but it is possibly prevented by concomitant use of oral hydralazine (Fig. 2).
Nesiritide is pure, human BNP synthesized using recombinant DNA techniques. It has the same 32-amino acid sequence as endogenous BNP released from the heart where it is synthesized and stored. When infused intravenously into the circulation of patients with heart failure, the mean terminal elimination half-life of nesiritide is about 18 minutes. Plasma BNP levels increase about three to six-fold with a nesiritide infusion. Human BNP is eliminated from the circulation through complex, multiple mechanisms. Most of the BNP is cleared by c-receptors on cell surfaces, but some is cleared by neutral endopeptidases in renal tubular and vascular cells, and a smaller amount is cleared by renal filtration that is proportional to body weight.
The earliest clinical trial of nesiritide, Vasodilation in the Management of Acute CHF (VMAC), was a comparison study with intravenous nitroglycerin.90 It demonstrated that nesiritide improved hemodynamic function and self-reported symptoms more effectively than intravenous nitroglycerin or placebo (Figs 13A and B). On this basis, nesiritide was approved by the FDA for heart failure and became widely used. Nesiritide has venous, arterial and coronary vasodilator properties. Cardiac output improves and PCWP is reduced. Hypotension occurs in about 4% of patients, and unlike intravenous nitroglycerin, it can be prolonged (~20 minutes) because of nesiritide's relatively longer half-life. The effects of nesiritide on renal function are variable, but generally only a modest or neutral renal effect is observed, though worsening renal function has been reported.91,92
In 2005 Sackner-Bernstein and colleagues reported that nesiritide may be associated with an increased risk of death after treatment for acute decompensated heart failure.93 At about this time, infusions of nesiritide were also being widely performed in outpatient clinics, and the drug came under severe criticism.94,95 Ultimately, an outpatient randomized controlled trial of nesiritide vs. placebo was performed which demonstrated that serial outpatient nesiritide infusions did not provide a demonstrable clinical benefit over standard therapy.96 The drug rapidly fell out of favor.97 Ultimately, the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial was designed to evaluate the effect of nesiritide, in addition to standard care, on rates of self-reported dyspnea at 6 and 24 hours, re-hospitalization for heart failure or death from any cause at 30 days, and renal dysfunction. The study included more than 7,000 patients and concluded that the IV vasodilator nesiritide did not improve survival or re-hospitalization relative to placebo, but had a small, non-significant effect on dyspnea when used in combination with other therapies. It also did not compromise renal function within a month of its use in acute decompensated heart failure. Therefore, the use of nesiritide for patients with acute decompensated heart failure has further waned over the years, while less expensive intravenous vasodilators continue to be employed.
Figs 13a and b: Changes in pulmonary capillary wedge pressure from baseline in response to intravenous nitroglycerin, nesiritide and placebo in patients with heart failure.90
ORAL β-ADRENERGIC BLOCKING DRUGS
There is a fundamental belief that the biologically powerful adrenergic nervous system compensates for the failing heart by increasing myocyte size (hypertrophy), heart rate and force of contraction (inotropy). The sympathetic nervous system also activates the RAAS, thus conserving intravascular volume and redirecting blood flow to vital organs. However, an overly active sympathetic nervous system has repeatedly been shown to be essentially toxic to myocardial cells in both animals and humans.98 There have been numerous large randomized trials supporting the concept that blocking the sympathetic nervous system with β-adrenergic blocking drugs in patients with systolic heart failure slows the progression of systolic heart failure and improves patient survival (Fig. 14).
The importance of dysfunctional adrenergic activation in heart failure was first elucidated by work of Braunwald and colleagues at the National Institutes of Health in the 1960s.99 Since then, there has been an enormous basic and clinical research effort testing the rather counterintuitive concept that blocking the β1 and β2-adrenergic receptors will benefit patients with systolic heart failure.100 It is well known that β-adrenergic receptors downregulate in response to excessive sympathetic drive,101 presumably in an attempt to protect the cardiac myocyte from overstimulation. Such biological behavior suggests that blocking the receptors pharmacologically may also protect the heart.102 Moreover, pheochromocytoma (a classic example of long-term hyperadrenergic activity) is well known to express itself as dilated or hypertrophic cardiomyopathy.103 This provides additional proof of concept that the overly active sympathetic nervous system (SNS) and its dysfunctional status is central to the pathophysiology of heart failure,104–107 similar to the overly active RAAS.
The first use of β-adrenergic blockers to treat patients with heart failure was the product of a series of carefully written case reports from Göteborg, Sweden.108–110 This experience was a source of both great excitement and profound skepticism. Eventually, a small clinical trial (Metoprolol in Dilated Cardiomyopathy [MDC]) was launched, but showed only marginal benefit of metoprolol in patients with heart failure.111 Other clinical trials were performed using bisoprolol (The Cardiac Insufficiency Bisoprolol Study [CIBIS] and CIBIS II)112,113 and metoprolol succinate (the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure [MERIT-HF]).114 Carvedilol, an α1 and non-selective β-adrenergic blocker, was also demonstrated to improve survival in patients with moderate and even very severe heart failure (The Carvedilol Prospective Randomized Cumulative Survival [COPERNICUS] Trial).115 Some would argue that the α1-adrenergic receptor blockade induced by carvedilol provides an additional advantage to standard β-adrenergic blockade,115–117 but this has remained controversial.
Today β-adrenergic blockers are widely used throughout the world to treat patients with systolic heart failure.118 They are considered “evidence-based” therapy. The suggested initial dose and evidence-based maximal dose are shown in Table 2.
Although it is unusual to see patients with heart failure who are naive to either RAAS inhibitors or β-blockers, occasionally the issue of which class of drug to initiate first arises. Experience indicates that either RAAS blockers (i.e., ACE inhibitor or ARB) or a β-blocker may be initiated first,119 but that eventually full-doses of both classes of drugs should be attempted. The titration schedule of β-adrenergic drugs should be slow, that is over several weeks. The magnitude of heart rate reduction is significantly associated with the survival benefit of β-blockers in patients with systolic heart failure, whereas the dose of β-blocker is not.120 There is also a strong correlation between change in heart rate and improvement in LV ejection fraction.121 It appears as though decreased heart rate, improved LV chamber performance and afterload reduction each contribute to enhanced LV ejection fraction with use of carvedilol.122
β-adrenergic blocking drugs are now widely used to treat all stages of heart failure. Some patients admitted to hospital with NYHA class III or IV systolic heart failure may not tolerate β-blockers because of symptomatic hypotension or low cardiac output, but most hospitalized patients with acute heart failure do tolerate these drugs. The continuation of β-blocker therapy in patients hospitalized with acute decompensated systolic heart failure is associated with lower post-discharge mortality risk and improved treatment rates.123 Withdrawal of β-blocker therapy in the hospital is associated with a higher risk. β-blocker therapy before and during hospitalization for acute systolic heart failure is associated with improved outcomes.124 In our experience, the most common documented cause of discontinuance of β-blockers in patients with heart failure is failure to restart β-blockers after they have been stopped during hospitalization.125
Not all patients with systolic heart failure improve with β-blocking therapy. One possibility is that functional improvement from β-blockers may be related to changes in myocardial contractile protein gene expression,126 which could vary from patient to patient. Another possibility is that β-blocking drugs are quite different from each other. Metoprolol and bisoprolol are both β-receptor subtype selective (i.e., β1). Bucindolol, labetalol and carvedilol are each non-selective, and labetalol and carvedilol have α1 blocking properties that produce ancillary vasodilation. Bucindolol, though not generally available, has been intensely studied and has mild vasodilator properties, probably mediated by cGMP. Additionally, bucindolol has meager “inverse agonism”, so there is less negative chronotropism and inotropic effects. Bucindolol can also lower systemic norepinephrine levels substantially in some patients, and therefore has the potential to be a powerful sympatholytic agent. The norepinephrine lowering effects of bucindolol, as well as the clinical response to the drug, are strongly influenced by the pre-synaptic α2c-adrenergic receptors, which modulate exocytosis and exhibit substantial genetic variation in humans. It is believed that a α2c-adrenergic receptor polymorphism affects the sympatholytic effects of bucindolol in patients with systolic heart failure.127 Patients with the α2c-Del 322-325 polymorphism appear to have a marked increase in the sympatholytic response to bucindolol, and these carriers exhibit no evidence of clinical efficacy when treated with bucindolol. This concept is consistent with observations from other studies that indicate a marked decrease in plasma norepinephrine levels as a consequence of certain drug therapy, such as moxonidine, is associated with increased mortality and more heart failure hospitalizations. This seems also true with regard to the response to bucindolol where carriers of the α2c-Del 322-325 variant exhibit very low plasma norepinephrine levels during bucindolol use, and a poor response to treatment. The frequency of this genetic variant is ~0.04 in whites and ~0.40 in blacks.
In addition to their favorable effects on LV performance and patient survival, β-adrenergic blockers, like RAAS blockers, slow the progression of LV remodeling. This occurs in patients with heart failure secondary to an acute myocardial infarction and in patients with chronic heart failure from dilated cardiomyopathy. LV end-diastolic volume tends to improve, the LV becomes less spherical and assumes a more natural ellipsoid shape. Mitral regurgitation is ameliorated or improved, and on average the LV ejection fraction goes up by about 5–7 ejection fraction units. In some cases, there is spectacular reverse remodeling, and in other cases this is less apparent or may not be seen at all. Reverse remodeling of the LV is associated with improved survival. We now have three major heart failure therapeutic strategies aimed at producing reverse remodeling: RAAS blocking drugs, cardiac resynchronization therapy (CRT), and β-adrenergic blocking drugs. Of course, coronary revascularization can also improve LV size and performance in selected patients. These therapies have proven to be powerful drivers of improved patient survival.
Neurohumoral modulating drugs now have a central role in the treatment of patients with systolic heart failure. This was not the case 35 years ago when only digitalis and diuretics were used. Annualized mortality has fallen from approximately 20% to less than 10% per year commensurate with the use of RAAS and sympathetic nervous system blocking drugs. Of course, ICDs and CRT have also importantly contributed to this mortality reduction. The total cardiovascular death rate burden has fallen substantially in accordance with the widespread use of these therapies. Although, the incidence of STEMI (ST segment elevation myocardial infarction) has also fallen dramatically, incident systolic heart failure continues to be a major cause of hospitalization. There is now much better treatment for hypertension and hyperlipidemia. Paradoxically, as people live longer, we are now seeing a wave of heart failure in the elderly, the fastest growing segment of our population. The scourge of heart failure has not gone away, but has rather been shifted to people in their 70s, 80s, and 90s. In the end, prevention of heart failure by life-long control of known risk factors and mechanistic enlightenment though additional genomic studies may reduce the burden of heart failures even more, as systolic heart failure is likely a largely preventable disorder.
We acknowledge the outstanding help of Marisa Tirimacco in the preparation of this manuscript.
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