Asian Cardiovasc Thorac Ann 2000;8:195-203
© 2000 Asia Publishing EXchange Pte Ltd
ACE Inhibition Versus Angiotensin-II Antagonism in Heart Failure
Surendra Kumar, MD,
Dharm Raj Maurya, MD,
Mahesh Chandra, MD
Department of Medicine
King George's Medical College
Lucknow, Uttar Pradesh, India
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For reprint information contact: Mahesh Chandra, MD Tel: 91 522 21 2103 or 39 8298 Fax: 91 522 26 6025 Department of Medicine, King George's Medical College, 11-A J.C. Bose Marg, Lucknow, Uttar Pradesh 226001, India.
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Abstract
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Heart failure is becoming increasingly frequent. Once diagnosed, 5-year survival is less than 50% and a substantial percentage of patients (25% to 50%) die suddenly. Angiotensin-converting enzyme inhibitors are the only agents shown to reduce mortality in heart failure. All angiotensin-converting enzyme inhibitors appear to have similar clinical benefits in heart failure. Therapy should be started with a low dose and titrated up to the target dosage in major trials. Although angiotensin-I receptor antagonists provide more complete inhibition of angiotensin-II effects, they have not been found to be superior to long-acting angiotensin-converting enzyme inhibitors in reducing morbidity and mortality in heart failure. Therefore, in current clinical practice, angiotensin-II antagonists should be used as an alternative to angiotensin-converting enzyme inhibitors when the latter are not tolerated. The combined use of angiotensin-converting enzyme inhibitors and angiotensin-II antagonists is not currently recommended in the treatment of heart failure.
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Introduction
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Congestive heart failure (CHF) is an extremely common clinical syndrome characterized by left ventricular (LV) dysfunction, fluid retention, limited exercise tolerance, and reduced survival. Once the diagnosis of CHF has been made, 5-year survival is less than 50% and a sub-stantial percentage of patients (25% to 50%) die suddenly. Advances in understanding the pathophysiology in this disorder have resulted in new treatment options, although the prognosis remains poor. Prolonged activation of the renin-angiotensin-aldosterone system has several potential adverse effects. In addition to vasoconstriction, it causes myocardial necrosis, acceleration of atheroma, and a decrease in the arrhythmia threshold. Aldosterone also stimulates myocardial collagen deposition. Inhibitors of the renin-angiotensin-aldosterone system, particularly angiotensin-converting enzyme (ACE) inhibitors, are established modes of treatment in all stages of heart failure, which reduce both morbidity and mortality. Recently, angiotensin-receptor antagonists have been introduced, which block the effects of angiotensin II most effectively and have the potential to be superior to ACE inhibitors in CHF. This review deals with the advantages and disadvantages of both groups of drugs in the management of CHF.
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Physiology and Pharmacology of Renin-Angiotensin-Aldosterone System
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Renin is an enzyme that is synthesized, stored, and secreted into the renal arterial circulation by the granular juxta-glomerular cells that lie in the walls of the afferent arterioles as they enter the glomeruli. The active form of renin is a glycoprotein containing 340 amino acids. It is synthesized as a pre-proenzyme of 406 amino acid residues, which is processed to prorenin, a mature but inactive form. The secretion of renin from juxtaglomerular cells is controlled predominantly by 3 pathways; 2 acting locally within the kidney and the 3rd acting through the central nervous system and mediated by norepinephrine release from renal noradrenergic nerves. The first intrarenal mechanism controlling renin release is the macula densa pathway. A change in sodium chloride reabsorption by the macula densa results in transmission to nearby juxta-glomerular cells of chemical signals that modify renin release. The second intrarenal mechanism controlling renin release is the intrarenal baroreceptor pathway. Increases and decreases in blood pressure in the preglomerular vessels inhibit and stimulate renin release, respectively. The third mechanism is the beta-adrenergic receptor pathway that is mediated by the release of norepinephrine from postganglionic sympathetic nerve terminals, acti-vation of beta-l adrenoceptors on juxtaglomerular cells enhances renin secretion. The substrate for renin is an-giotensinogen, an abundant alpha-2 globulin that circulates in the plasma. Angiotensinogen is synthesized primarily in the liver, although the messenger RNA that encodes the protein is also abundant in fat, certain regions of the central nervous system, and kidney.1,2 Angiotensinogen is continuously synthesized and secreted by the liver and its synthesis is stimulated by a number of hormones including glucocorticoids, thyroid hormone, and angio-tensin II itself.3
Angiotensin-converting enzyme was discovered seren-dipitously in plasma as the factor responsible for conver-sion of angiotensin I (decapeptide) to angiotensin II (octapeptide). The traditional view of the renin-angiotensin system is that of a classical endocrine system. Circulating renin of renal origin acts on circulating angiotensinogen of hepatic origin to produce angiotensin I in the plasma. Circulating angiotensin I is converted by plasma ACE and by pulmonary endothelial ACE to angiotensin II. Angiotensin II is then delivered to its target organs via the blood stream, where it induces a physiological re-sponse. Extrinsic ACE is present on the luminal face of vascular endothelium, while intrinsic ACE is present in many tissues including brain, pituitary, heart, kidney, and adrenal gland. Some tissues contain non-renin angio-tensinogen-processing enzymes that convert angio-tensinogen to angiotensin I (non-renin proteases) or directly to angiotensin II (cathepsin G, toxin) and non-ACE angiotensin I-processing enzymes that convert angiotensin I to angiotensin II (cathepsin G, chymostatin-sensitive angiotensin II-generating enzyme, heart chymase). The physiological significance of these pathways is not known.4
The effects of angiotensins are exerted through specific cell surface receptors. In 1989, Whitebread and colleagues5 and Chiu and colleagues6 pharmacologically characterized two subtypes of the angiotensin receptor. These angiotensin receptor subtypes are now designated AT1 and AT2.7 The AT1 receptor has a high affinity for losartan (previously known as DUP 753) and a low affinity for PD 123177 (AT2) and CGP 42112-A. In contrast, the AT2 receptor has a high affinity for PD 123177 and CGP 42112-A, but a low affinity for losartan. To date, all the pharmacological effects of angiotensin II appear to be mediated by AT1 receptors and no functional role for the AT2 receptor has been unequivocally defined. AT1 and AT2 receptors are found in both normal and failing cardiac tissue. They are found on myocytes, endothelial cells, fibroblasts, coronary arterial smooth muscle cells, and peripheral sympathetic nerves. AT1 receptors mediate virtually all effects of angiotensin II in myocytes, even though cardiac tissue may contain over 50% AT2 sites. In endothelial cells, functional responses are predominately via AT1.8
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Renin-Angiotensin-Aldosterone in Heart Failure
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Myocardial failure may develop from many causes.9 These include pressure overload (aortic stenosis, hypertension), volume overload (valvular regurgitation, shunting, pericardial constriction, cardiac tamponade), myocardial abnormalities or loss of myocytes (cardiomyopathy, myocarditis, metabolic abnormalities such as diabetes mellitus), toxins (alcohol, cobalt), ischemia (coronary heart disease), infiltrative and systemic diseases, as well as altered cardiac rhythm (fibrillation, standstill, and electrical asynchrony). These changes cause myocyte hypertrophy or dilatation to meet the load. Hypertrophied cells contract and relax more slowly and may be subject to metabolic limitations.10 In addition, hypertrophied myocardial cells appear to have a shortened lifespan.11,12 This is of considerable prognostic importance because cardiac myocytes appear to have little or no capacity to proliferate. When age-related myocyte loss is added, particularly in association with a late decrease in myocyte contractile activity, failure may ensue with ventricular dilation. Loss of myocytes, whether segmental as in acute myocardial infarction, or diffuse as in myocarditis, sets up a vicious cycle that leads to reactive hypertrophy in the remaining myocytes. As compensatory hypertrophy becomes more marked in some disease states, the unit contractility of the myocardium often declines because of molecular changes in the heart's contractile proteins and activation system. Fatigue and other symptoms of limited cardiac output (exercise limitation, confusion, anorexia) are primarily related to decreased ejection, whereas peripheral and pulmonary edema are related to Na+ and water retention from increased sympathetic tone and increased renin-angiotensin-aldosterone, as shown in Figure 1
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Figure 1. Schema of events in congestive heart failure leading to symptoms. CO = cardiac output, EF = ejection fraction.
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The main underlying mechanisms in CHF are activation of the renin-angiotensin system as a compensatory mechanism with elevation of circulating angiotensin II, norepinephrine, and vasopressin. Elevated circulating and local renin angiotensin systems cause chronic structural myocardial and vascular effects. The renin-angiotensin system is closely related to the bradykinin system and thus indirectly to nitric oxide and endothelial function. Bradykinin has many other effects on the hemostatic system as well as on the myocardium and the vascular system. Therefore, research with specific bradykinin antagonists will give new insights into this system.13
In low cardiac output states and with diuretic therapy, there is activation of the renin-angiotensin system that operates in concert with the activated adrenergic nervous-adrenal medullary system to maintain arterial pressure.13 These two compensatory systems are clearly coupled; stimulation of beta adrenoceptors in the juxtaglomerular apparatus of the kidney as a consequence of heightened adrenergic drive is a principal mechanism responsible for the release of renin in acute heart failure.14 Renin is released by activation of the baroreceptors in the renal vascular bed due to reduction of renal blood flow, and also in patients with severe chronic heart failure following salt restriction and diuretic treatment. The major proportion (90% to 99%) of ACE in the body is in tissues and only 1% to 10% is found in the circulation.15,16 Tissue production of angiotensin II may also occur by a pathway not dependent on ACE (the chymase pathway).
Renin from juxtaglomerular cells of the afferent arterioles of the kidney converts angiotensinogen (a circulating alpha-2 globulin) into angiotensin I. This angiotensin I is converted into angiotensin II in the presence of ACE (plasma and pulmonary endothelial ACE). Angiotensin II works through AT1 receptors (predominantly in the vasculature) and AT2 receptors (predominantly in myocardium) and causes direct vasoconstriction, enhances peripheral noradrenalin, increases sympathetic discharge, and releases catecholamines from the adrenal medulla.17,18 It also releases aldosterone (Na+ retention and K+ depletion) from the adrenal cortex, directly increases Na+ absorption in the proximal tubules, and is a direct renal vasoconstrictor. Angiotensin II increases production of growth factor and the synthesis of extracellular matrix proteins. By these mechanisms, it causes pulmonary and peripheral edema and hence congestive heart failure, hypertension, and vascular and cardiac hypertrophy with remodeling, as shown in Figure 2.
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Figure 2. The renin-angiotensin system and the mechanism of congestive heart failure. Solid arrows show the classic pathways and broken arrows indicate minor alternative pathways. ACE = angiotensin-converting enzyme, Ang = angiotensin, CNS = central nervous system, CV = cardiovascular.
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ACE Inhibitors in Heart Failure
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The essential effect of these agents on the renin-angiotensin system is to inhibit the conversion of the relatively inactive angiotensin I to the active angiotensin II (or the conversion of [des-Asp1] angiotensin I to angiotensin III). Thus, ACE inhibitors attenuate or abolish responses to angio-tensin I but not to angiotensin II. In this regard, ACE inhibitors are highly selective drugs; they do not interact directly with other components of the renin-angiotensin system, and their principal pharmacological and clinical effects seem to arise from suppression of synthesis of angiotensin II. Nevertheless, ACE is an enzyme with many substrates, therefore, inhibition of ACE may induce effects unrelated to reduced levels of angiotensin II. Since ACE inhibitors increase bradykinin levels, and since bradykinin stimulates prostaglandin biosynthesis, bradykinin or prostaglandins may contribute to the pharmacological effects of ACE inhibitors. In addition, ACE inhibitors interfere with both short-loop and longloop negative feedback on renin release. Consequently, ACE inhibitors increase renin release and the rate of formation of angiotensin I. Since the metabolism of angio-tensin I to angiotensin II is blocked by ACE inhibitors, angiotensin I is directed down alternative metabolic routes, resulting in the increased production of peptides such as angiotensin (1–7), as shown in Figure 2
. Whether or not biologically active peptides such as angiotensin (1–7) contribute to the pharmacological effects of ACE in-hibitors, is unknown.
All orally active ACE inhibitors currently available fall into one of three general categories based on chemical structure.19 (1) Sulfhydryl-containing ACE inhibitors that bind to the zinc moiety in ACE, structurally related to captopril (fentiapril, pivalopril, zofenopril, alacepril). (2) Bi-carboxyl-containing ACE inhibitors that bind to the zinc moiety in ACE, structurally related to enalapril (lisinopril, benazepril, quinapril, moexipril, ramipril, spirapril, perindopril, indolapril, pentopril, cilazapril). (3) Phosphorous-containing ACE inhibitors that bind to the zinc moiety in ACE, structurally related to fosinopril. There are currently 9 different ACE inhibitors approved for use in the United States (captopril, enalapril, benazepril, fosinopril, lisinopril, quinapril, ramipril, spirapril, cilazapril) and approximately 16 different ACE inhibitors are employed worldwide.19
The aim of modern therapy for CHF is not only removal of symptoms but also improvement in survival.20 Because ACE inhibitors reduced morbidity and mortality in several large clinical trials in patients with LV dysfunction or manifest heart failure, they are recommended for treatment of CHF as a primary option, unless contraindications are present. The mechanism of action of ACE inhibitors in CHF is hypothetical. The participation of 3 factors was postulated: (1) improved pump function of the failing heart; (2) reduced risk of sudden death; (3) reduced incidence of myocardial infarction.20
Reduction of hemodynamic load (decreased preload and afterload, as they are balanced arterial and venous dilators), anti-ischemic action, and reduction of fibrotic tissue proliferation in failing myocardium are responsible for improvements in heart function. These mechanisms to-gether with potential anti-atherosclerotic, antiaggregative, fibrinolytic, and protective effects on endothelial function are supposed to participate in the reduction of acute myocardial infarction and sudden death. According to Johnston and colleagues,21 treatment with ACE inhibitors suppresses cardiac ACE and is associated with hemo-dynamic improvement, reversal of neurohumoral activa-tion, prevention of ventricular dilatation and remodeling, and reduction of mortality rates. These results suggest that the beneficial effects of ACE inhibitors in treating CHF, preventing ventricular remodeling, and regressing LV hypertrophy may involve not only reducing preload and afterload but also suppressing the local cardiac renin-angiotensin system.21 The contraindications to ACE inhibitors are bilateral renal artery stenosis, connective tissue diseases, and severe renal failure (creatinine > 32.5 mg•L–1).22 The side effects of ACE inhibitors are first-dose hypotension, dry cough, acute renal failure, angioneurotic edema, hyperkalemia, skin rashes, fetopathic potential (oligohydramnios, fetal growth retardation, and fetal death may be due in part to fetal hypotension).23 Other side effects are proteinuria, dysgeusia, neutropenia, glycosuria, and hepatotoxicity. In these situations, ACE inhibitors should be given very cautiously.
Over the past few years, several large prospective ran-domized placebo-controlled clinical trials have examined the usefulness of ACE inhibitors in patients with varying degrees of LV systolic dysfunction (Table l).24–34 The target doses of these drugs in several trials in which a positive effect was demonstrated on mortality as well as other endpoints are given in Table 1.
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Which ACE Inhibitor to Choose?
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There is no compelling reason to favor one ACE inhibitor over another since all ACE inhibitors effectively block the conversion of angiotensin I to angiotensin II and all have similar therapeutic indications, adverse effects, and contraindications. Fosinopril has a balanced dual route of elimination by the liver and kidney. Therefore, it can be given safely in impaired renal function (as can other ACE inhibitors such as temocapril, zofenoprilat, and spirapril) for patients with hypertension and left ventricular hypertrophy, because it produces an adequate reduction in blood pressure and reversal of left ventricular hypertrophy.35 According to Zannad and colleagues36 in 1998, fosinopril (5 to 20 mg daily) is more effective in improving symptoms, delaying events related to worsening of CHF, and produces less orthostatic hypotension than the same dosage of enalapril. Giles37 noted in 1992 that a long-acting ACE inhibitor (lisinopril) had advantages over a short-acting drug (captopril), such as a more sustained increase in exercise tolerance and improvement in LV ejection fraction; it was speculated that these would reduce mortality. Such drugs are very convenient for the patient as they are given in a single daily dose.
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In Whom and for How Long?
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Although there is little disagreement that high-risk acute myocardial infarction patients (elderly, anterior infarction, prior infarction, Killip class II or greater, and asymptomatic patients with evidence of depressed global ventricular function on an imaging study) should receive lifelong treatment with ACE inhibitors. Maximum duration of follow-up was 48 months in the longest trial in patients with CHF.38 Indeed, ACE inhibitors should be preferred for all CHF patients. In the SOLVD trial, addition of enalapril to baseline therapy was found to significantly improve the prognosis in patients with mild to moderate heart failure.38 This extended the findings of the CONSENSUS study and indicated that ACE inhibition would be beneficial to patients with all grades of overt CHF.24 In the SOLVD and SAVE studies, therapy with enalapril or captopril improved prognosis among patients with generally asymptomatic LV dysfunction.27,29 In particular, the risk of development of overt heart failure was reduced. Importantly, a marked anti-ischemic effect of ACE inhibition was identified in both trials.27,29 Clinical data amassed in nearly 9000 patients identify a substantial role for ACE inhibition in patients with all grades of symptomatic heart failure, as well as in those with asymptomatic LV dysfunction (such as often follows myocardial infarction). The data support early intervention with ACE inhibitor therapy alone in asymptomatic cardiac failure and triple combination therapy (ACE inhibitor, diuretic, digoxin) in patients with symptomatic CHF.39 From the studies mentioned, it is clear that an ACE inhibitor is indicated in all patients with LV systolic dysfunction and it is the cornerstone in the treatment of LV dysfunction.
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Angiotensin-II Receptor Antagonists
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There are non-peptide receptor antagonists of angiotensin II. By preventing the effects of angiotensin II, these agents relax smooth muscle and thereby promote vasodilation, increase renal salt and water excretion, reduce plasma volume, and decrease cellular hypertrophy. These agents overcome some of the disadvantages of ACE inhibitors (accumulation of bradykinin and substance P). Two of the adverse effects of an ACE inhibitor (angioedema and cough) have not been associated with angiotensin-II receptor antagonists. AT2 receptors are located predo-minantly in vascular and myocardial tissue and also in brain, kidney, and adrenal glomerulosa cells that secrete aldosterone. AT2 receptors are found in the adrenal medulla and possibly in the central nervous system, but at present, they are not thought to play a role in cardiovascular hemostasis. Saralasin (a peptide angiotensin-II receptor antagonist) has no clinical value because of lack of oral bioavailability and because of partial angiotensin-II agonist activity.
Losartan (previously known as DUP 753) was approved for clinical use in the United States in 1995. Approximately 15 other angiotensin-II receptor antagonists are in various stages of development. The Losartan Hemodynamic Study was a double-blind trial in 134 patients with symptomatic heart failure and impaired LV function (ejection fraction < 40%).40 It showed that oral losartan had beneficial hemodynamic effects (fall in systemic vascular resistance, blood pressure, heart rate, and pulmonary capillary wedge pressure, and a rise in cardiac index) with short-term administration, with additional beneficial hemodynamic effects seen after 12 weeks of therapy. Clear effects were seen with both 25 and 50-mg doses, with the greatest effects seen with 50 mg. Active treatment was well tolerated and excess cough was not reported.40 Angio-tensin-II receptor antagonists are expected to produce similar beneficial effects to those of ACE inhibitors (improvement in LV function, prevention of progressive ventricular dilatation, improved survival, and decreased incidence of myocardial infarction and unstable angina), through blockade of vascular, adrenal, renal, and pre-junctional neuronal angiotensin-II type-1 receptors. Despite similarities, non-renin-angiotensin system effects (notably angioedema and cough) may be less frequent with an angiotensin-II blocker (losartan) therapy. At the tissue level, angiotensin II may still be generated in a patient receiving systemic ACE inhibitor therapy, via other metabolic pathways. Angiotensin-II blockade at the receptor level may be more efficient than ACE inhibitor in blocking undesirable cardiovascular actions of angio-tensin II.41 The available experimental and clinical data indicate that the first ATl receptor inhibitor, losartan, has the same therapeutic potential as ACE inhibitors, but it does not evoke the angiotensin-independent side effects of ACE inhibitors (dry cough and angioedema).42 The losartan pilot study showed that losartan was generally well tolerated and comparable to enalapril in terms of exercise tolerance in the short-term (12 week) study of patients with heart failure.43 Losartan may represent an advance because its efficacy on exercise oxygen-uptake is similar to that of enalapril but not antagonized by aspirin.44 According to Weber,45 losartan (10 to 150 mg daily) can be safely given in hypertensive patients with concomitant illnesses (diabetes mellitus, renal or heart failure). It can be considered for first-line therapy and it is suitable as an alternative in patients already experiencing side effects with other agents.45 Losartan also improved the natriuretic response to atrial natriuretic factor in rats with high-output heart failure, by suppressing previously elevated plasma aldosterone. Therefore, it is useful in the treatment of cardiac edema.46 At the 48th week of follow-up in the elderly, losartan (50 mg daily) was found to be superior to captopril (50 mg 3-times daily) in terms of total mortality and total morbidity, although hospi-talization for CHF was the same for both drugs. Adverse effects (cough, rashes, angioedema, and taste disturbance) occurred in 12% of those receiving losartan compared to 21% of captopril-treated patients. It was recommended that elderly patients with heart failure who are unable to tolerate ACE inhibitors should receive losartan 50 mg daily.47
Thus, the major mechanism of the clinical manifestations of heart failure is activation of the renin-angiotensin system. Of the various agents used in the treatment of heart failure, antagonists of the renin-angiotensin system have been shown to reduce mortality. ACE inhibitors were found to reduce morbidity and mortality in all stages of heart failure. Therapy with ACE inhibitors should be started with low doses and titrated up to the target dose. AT1 receptor antagonists, although providing more complete inhibition of angiotensin-II effects, have not been found to be superior to ACE inhibitors. At present, the role of an AT2 receptor antagonist in the treatment of heart failure is more as an alternative to ACE inhibitors when the latter are not tolerated. The combined use of these two groups of drugs for the treatment of heart failure is still at the experimental stage.
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Asian Cardiovasc Thorac Ann,
December 1, 2001;
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302 - 307.
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Abstract
Introduction
