Ann Thorac Surg 2005;79:1081-1089
© 2005 The Society of Thoracic Surgeons
Review
Role of Angiotensin-Converting Enzyme Inhibitors in the Coronary Artery Bypass Patient
Harold L. Lazar, MDa,b,*
a Department of Cardiothoracic Surgery, Boston University School of Medicine, Boston, Massachussetts
b Boston Medical Center, Boston, Massachussetts
Abbreviations and Acronyms ACEangiotensin-converting enzyme; ANG IIangiotensin II; CABGcoronary artery bypass graft; CHFcongestive heart failure; HOPEHeart Outcomes Prevention Evaluation; MImyocardial infarction; PTCApercutaneous transluminal coronary angioplasty; QUOVADISQuinapril on Vascular Angiotensin-Converting Enzyme and Determinants of Ischemia; SECUREStudy to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E
* Address reprint requests to Dr Lazar, Department of Cardiothoracic Surgery, Boston Medical Center, 88 E Newton St, B402, Boston, MA 02118 (E-mail: harold.lazar{at}bmc.org).
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Abstract
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Angiotensin-converting enzyme inhibitors have been shown to prolong survival and decrease infarct size in patients after acute coronary syndromes. Now there is evidence to suggest that angiotensin-converting enzyme inhibition is beneficial in coronary artery bypass patients. This review will summarize the beneficial effects of angiotensin-converting enzyme inhibition in patients with ischemic heart disease and provide evidence to show that the routine use of angiotensin-converting enzyme inhibition in coronary artery bypass patients can improve clinical outcomes.
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Introduction
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There is growing evidence that activation of the renin angiotensin system increases the risk of arteriosclerosis and its clinical sequelae. Earlier studies in patients with myocardial infarction (MI) and in patients with congestive heart failure (CHF) showed that blocking the renin angiotensin system with angiotensin-converting enzyme (ACE) inhibitors improved ventricular function, prolonged survival, and decreased infarct size [1, 2]. However, the role of ACE inhibitors in the coronary artery bypass graft (CABG) patient was undefined. Most clinicians felt that the beneficial effects of ACE inhibitors were due to their antihypertensive effects and their ability to "unload" the failing myocardium, thereby resulting in a more optimal supply and demand balance. Now we know that ACE inhibitors can improve endothelial function [3, 4], suppress inflammatory response associated with arteriosclerosis [5], limit intimal hyperplasia in venous grafts [6], and play an important role in angiogenesis [7]. Furthermore these pleiotropic effects of ACE inhibitors occur independent from their antihypertensive effects and they may play a major role in reducing ischemic events during and after CABG surgery.
In this article we will cite the evidence to support the use of ACE inhibitors as an adjuvant therapy in all CABG patients. We will show that ACE inhibitors play an important role in decreasing myocardial damage during CABG surgery, and they can lead to a significant reduction in recurrent ischemic events in the years after surgery.
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Detrimental Effects of the Activation of Angiotensin on the Cardiovascular System
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The ACE regulates the balance between the vasodilating properties of bradykinin and the vasoconstrictive and salt-retentive properties of angiotensin II (ANG II) by directly catalyzing the conversion of angiotensin I to ANG II and catalyzing the degradation of bradykinin [8]. Angiotensin II mediates its effects on the vascular system through the angiotensin type 1 receptor, which is expressed on endothelial cells, monocytes, and vascular smooth muscle cells. Vascular cells exposed to ANG II produce increased amounts of super oxide anion, which leads to oxidative stress and reduced endothelial function [9]. Angiotensin II increases the release of cytokines, leukocyte chemo-attractants, adhesion molecules, interleukens, and the C-reactive protein, all of which contribute to the inflammatory process [5]. Angiotensin II also contributes to the development of arteriosclerosis by promoting the transformation of monocytes to lipid-laden macrophages in the presence of oxidized low-density lipoprotein cholesterol [10]. In fact, the ACE has been found in macrophages and fibroproliferative lesions of human atherosclerotic plaques [11]. Increased local tissue ACE has also been associated with vascular smooth muscle proliferation, which leads to changes in growth, remodeling, and restructuring of blood vessel walls [12]. Finally, ANG II may also contribute to acute ischemic events by stimulating the release of plasminogen activator inhibitor-1, which promotes thrombosis and clot progression and may increase the risk of reinfarction [13].
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Vasculoprotective Effects of ACE Inhibition
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Angiotensin-converting enzyme inhibition benefits the cardiovascular system by inhibiting the conversion of angiotensin I to ANG II and preventing the breakdown of bradykinin [14]. Decreasing ANG II levels result in more favorable remodeling of the myocardium and arterial vessel wall by reducing vascular smooth muscle contraction, proliferation, and migration, and by preventing cardiac myocyte growth and matrix synthesis [15, 16]. Fibrinolytic balance is improved by reducing platelet aggregation and decreasing plasminogen activator inhibitor-1 and tissue plasminogen activator levels [17]. Preventing the breakdown of bradykinin helps to decrease oxidative stress and vascular inflammation and preserve endothelial function [18]. The release of nitric oxide is augmented, resulting in the relaxation of vascular smooth muscle and an increase in vasodilation during periods of coronary ischemia, and it also results in the inhibition of platelet aggregation and the expression of adhesion molecules by neutrophils. The improved balance between ANG II and nitric oxide achieved by ACE inhibition may help to reduce the progression of atherosclerotic vascular disease, minimize the effects of acute coronary syndromes, and prevent the long-term complications of hypertensive cardiovascular disease.
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High Versus Low Affinity Tissue ACE Inhibitors
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Approximately 90% of ACE is found in tissues such as blood vessels, the myocardium, and the central nervous system [19]. Only 10% of ACE in the body circulates in the plasma where it is largely responsible for acute changes in blood pressure. It is the local production of ANG II by tissue ACE that is responsible for changes in the myocardium and vascular structures that lead to the development of arteriosclerosis and ischemic events. Angiotensin-converting enzyme inhibitors vary in their affinity to bind tissue ACE. The binding strength of ACE inhibitors to tissue ACE is dependent on the binding of sulfhydryl-, carboxyl-, or phosphinyl-containing groups at the N-terminus of the ACE inhibitor with Zn2+, as well as the binding of the negatively charged C-terminus of the ACE inhibitor with the positively charged carboxylate dock residue of ACE [20].
Radioligand inhibitor binding studies demonstrate that quinaprilat, the active metabolite of quinapril, has the highest ACE-binding affinity in both tissue and plasma [21]. The rank of potency in tissue among ACE inhibitors is as follows: quinaprilat = benazeprilat > ramiprilat > perindoprilat > lisinopril > enalaprilat > fosinopril > captopril. Quinaprilat also has the highest tissue retention of ACE inhibitors. The rank order of tissue retentiveness is quinaprilat > ramipril > lisinopril > enalaprilat > captopril. The effect of tissue binding on clinical outcomes with various ACE inhibitors will be discussed throughout the review.
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ACE Activity and Atherosclerosis
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Now there is abundant data to show that increased ACE activity contributes to the formation of atherosclerotic cardiovascular disease. Miyazaki and colleagues [22] studied the relationship between ANG II and the development of atherosclerotic lesions in the aorta of monkeys fed a high cholesterol diet for 6 months. Angiotensin-converting enzyme activity and ANG II concentration were significantly increased in the aortas of cholesterol-fed monkeys. The ACE inhibitor, trandolapril, significantly decreased the level of ACE activity and the size of the atherosclerotic lesions. Potter and coworkers [23] found that ANG II content was increased in main coronary artery atherectomy samples. Furthermore, they found that the ANG II localized within the macrophages of the atherosclerotic material. Hoshida and colleagues [11] also measured ACE activity of vascular tissue obtained from coronary atherectomy specimens in patients with acute unstable angina and stable ischemic heart disease. Angiotensin-converting enzyme activity was significantly higher in patients with acute coronary syndromes than those with stable disease. This study confirms that increased ACE is actively associated with atherosclerotic lesions. Furthermore, it suggests that increased ACE activity may be related to plaque instability, especially because ACE has been shown to be a local mediator of tissue inflammation. Increased levels of the ACE have been found in macrophages and endothelial cells of human atherosclerotic plaques [24]. The accumulation of the ACE in these inflammatory cells may contribute to plaque instability and may account for the increased amounts of the ACE in atheroma during acute coronary syndromes. Angiotensin-converting enzyme activity has also been found in the conduits used in CABG surgery. Borland and coworkers [25] studied ACE activity and responses to ANG II in saphenous veins and internal mammary arteries (IMAs) in patients who had CABG surgery and now had a cardiotomy in preparation for transplantation. Some of these grafts were nearly 20 years old. Angiotensin-converting enzyme activity was nearly three times higher in saphenous vein grafts compared with the IMA. Saphenous vein grafts were also significantly more responsive to vasoconstriction with ANG II than the IMA. This study suggests that the IMA may be a superior conduit to saphenous veins because of its decreased ACE activity which may prevent atherosclerotic changes.
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Endothelial Function and ACE Inhibition
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Normal endothelium maintains vascular tone, retards adhesion of platelets and leukocytes, inhibits smooth muscle growth, and blocks the accumulation of low-density lipoprotein cholesterol in the vessel walls [26]. Factors that lead to oxidative stress, such as smoking, diabetes, hypertension, and hypercholesterolemia will result in vascular constriction and hypertension, cell adhesion and thrombosis, smooth muscle growth, and lipid accumulation [27]. These changes result in endothelial dysfunction and the development of atherosclerotic plaques. Furthermore, patients with endothelial dysfunction, as determined by brachial artery vasodilation, have been shown to have a significantly higher incidence of cardiovascular events including MIs, strokes, CABGs, percutaneous transluminal coronary angioplasties (PTCAs), and peripheral vascular procedures [28].
Several studies have shown that ACE inhibitor therapy improves endothelial function. In the Trial on Reversing Endothelial Dysfunction (TREND) study, normotensive patients without known coronary disease were randomized to receive either quinapril 40 mg/day or placebos for 6 months [3]. Serial quantitative coronary angiography with intracoronary acetylcholine was used to assess changes in the luminal diameter of epicardial coronary arteries. After 6 months the quinapril-treated patients had significantly better augmentation of coronary blood flow with acetylcholine than the placebo group did, which suggests better preservation of endothelial function. The Brachial Artery Normalization of Forearm Function (BANFF) trial compared the effects of quinapril, enalapril amilodipine, and losartan on blood flow and dilation of the brachial artery in patients with stable coronary artery disease [4]. Although all the agents lowered blood pressure, only the high-affinity tissue ACE inhibitor quinapril produced a significant improvement in endothelial function. Hornig and colleagues [29] sought to determine whether the tissue affinity of ACE inhibitors would impact endothelial function. They compared the effect of quinaprilat (a high-affinity tissue ACE inhibitor) to that of enalaprilat (a low-affinity tissue ACE inhibitor) on radial artery flow in patients with CHF. Quinaprilat significantly improved endothelial flow mediated radial artery vasodilation, whereas enalaprilat did not. The beneficial effect of quinaprilat was mediated by the enhanced availability of nitric oxide. This study adds further proof that high-affinity tissue ACE inhibitors result in better protection of endothelial function.
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ACE Inhibition in the MI Patient
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Numerous studies have shown that treatment with ACE inhibitors after an acute MI improves ventricular function and prolongs survival. In the Cooperative Northern Scandinavian Enalapril Survival Study (CONSENSUS), patients receiving enalapril after an MI had a 40% reduction in 6-month mortality [30]. In the Studies on Left Ventricular Dysfunction (SOLVD) trial, patients with an MI and reduced ejection fraction (<35%) treated with enalapril had a 16% reduction in mortality over 3 years and a 26% reduction in re-hospitalization for recurrent CHF [2]. The Survival and Ventricular Enlargement (SAVE) trial included >2,000 post-MI patients with ejection fractions <40% who were randomized to captopril or placebo and were followed-up for 4 years [1]. The captopril group had a 21% reduction in the risk from death from all cardiovascular causes (p = 0.014), a 22% reduction in the risk for re-hospitalization for recurrent CHF (p = 0.019), and a 25% reduction in the risk for a recurrent MI (p = 0.015). Furthermore these improved outcomes were not related to changes in blood pressure lowering, suggesting that improved endothelial function and decreased oxidative stress may have accounted for the improved results. The Acute Infarction Ramipril Efficacy (AIRE) study [31] and Trandolapril Cardiac Evaluation (TRACE) trial [32] included patients with a recent MI and a moderate reduction in ejection fraction. In the Acute Infarction Ramipril Efficacy trial, patients receiving ramipril had a 27% decrease in mortality. In the Trandolapril Cardiac Evaluation study, trandolapril increased survival by 27%. Angiotensin-converting enzyme inhibitors may not only prolong survival, but can improve left ventricular function after an MI. In the Healing and Early Afterload Reducing Therapy (HEART) trial, patients receiving ramipril immediately after an anterior wall MI had significantly better recovery of ejection fraction as determined by echocardiography [33]. A recent meta-analysis involving more than 10,000 patients summarized the results of ACE inhibitors in patients who have had an acute MI [34]. Patients treated with ACE inhibitors had a 26% lower mortality, a 27% decrease in the rate of hospital readmission for CHF, and a 20% lower reinfarction rate. These benefits were observed early after the MI and persisted long term.
Another mechanism for the beneficial effects of ACE inhibition after an acute MI may be related to their favorable effects on fibrinolysis. In a substudy of the Healing and Early Afterload Reducing Therapy trial, Vaughan and colleagues [35] studied the effect of ramipril on fibrinolytic activity in 120 patients after an anterior MI. After 2 weeks, plasminogen activator inhibitor-1 activity was significantly lower (p = 0.004) in the ramipril group. This suggests that ACE inhibitors may reduce the frequency of recurrent ischemic events after an MI by reducing thrombosis and increasing fibrinolysis.
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ACE Inhibition to Prevent Complications of Atherosclerosis
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The clinical trials cited in the previous section demonstrated that ACE inhibitors reduced morbidity and mortality in patients with MI, CHF, and left ventricular dysfunction. The Heart Outcomes Prevention Evaluation (HOPE) trial sought to determine whether ramipril (the high-tissue affinity ACE inhibitor) would reduce the risk of cardiovascular events in high-risk patients without evidence of left ventricular dysfunction [36]. The inclusion criteria for the 9,541 patients in the study included age >55 years, ejection fraction >40%, and the presence of coronary heart disease, peripheral vascular disease, strokes, or diabetes. Patients were excluded if they had an ejection fraction <40%, CHF, or a stroke or MI within a month of entering the study. Patients were randomized to receive ramipril (10 mg daily) or placebos during a 4.5 year follow-up period. Fewer than half of the study participants had hypertension and 40% had diabetes. Patients receiving ramipril showed a 22% risk reduction in the primary outcome, the combined incidence of MI, stroke, and cardiovascular death (p < 0.0001). The ramipril-treated patients had a 32% reduction in stroke (p < 0.001), a 26% reduction in cardiovascular deaths (p < 0.001), a 20% reduction in nonfatal MI (p < 0.001), and a 16% decrease in all-cause mortality (p < 0.005). The need for either CABG or PTCA was reduced by 15% (p = 0.002), new-onset diabetes by 34% (p < 0.001), complications related to diabetes by 16% (p = 0.03), CHF by 23% (p < 0.01), and worsening angina requiring hospital readmissions by 11% (p = 0.004). The beneficial effects of ACE inhibition was evident in multiple subgroups including men and women patients of all ages with and without evidence of cardiovascular disease, MI, diabetes, hypertension, or cerebrovascular disease. Furthermore, the mean reduction in blood pressure in the ramipril group was only 2 to 3 mm Hg, suggesting that it is the inhibition of tissue ACE-mediated processes and not the activated renin angiotensin system that is responsible for the decrease in ischemic events in these patients. The benefits afforded by ramipril in this study are truly impressive because these patients were already receiving effective anti-ischemic medications, including aspirin, ß-blockers, diuretics, and lipid-lowering agents. The HOPE trial identified new subgroups of patients that could benefit from ACE-inhibitor therapy. These included all diabetic patients with and without clinical cardiovascular disease, patients with coronary artery disease who are normotensive, and patients with coronary artery disease and normal left ventricular function.
The Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE) was a substudy of the HOPE trial, in which the progression of arteriosclerosis was determined by the yearly rate of change in carotid intimal media thickness [37]. In this study, patients receiving 10 mg of ramipril for more than 4.5 years had a 25% reduction in intimal media thickness (p = 0.033) compared with the placebo group. Hosomi and coworkers [38] found that enalapril decreased the progression of intimal media thickness of the carotid artery in patients with type 2 diabetes for more than 2 years. Regression analysis showed that intimal media thickness could be reduced by nearly 1% per year with enalapril.
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ACE Inhibition and the CABG Patient
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Despite the numerous trials showing the benefits of ACE inhibition in patients with known cardiovascular disease, CHF, and an MI, the role of ACE inhibitors in the CABG patient remained undefined. This section will show both experimental and clinical data to suggest that ACE inhibition will also benefit CABG patients.
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Experimental Studies Using ACE Inhibitors During Acute Myocardial Ischemia
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The beneficial effects of ACE inhibitors after an MI and in the HOPE trial were achieved in patients who already had an ischemic event or in those who were at high risk for developing one. This section will review the experimental data suggesting that ACE inhibitors may play an important role in reducing myocardial damage when used during periods of acute ischemia, such as a CABG procedure for unstable angina.
In an isolated rabbit model of 30 minutes of coronary ischemia followed by 120 minutes of reperfusion, Hartman [39] found that infusing ramiprilat before the coronary occlusion reduced myocardial infarct size by 49%. Pre-treatment with either HOE 140 (a potent bradykinin receptor antagonist) or the nitric oxide synthase inhibitor (Ng -nitro-L arginine methyl ester) abolished this protective effect. Furthermore, ramiprilat protected cultured cardiomyocytes exposed to ischemia, which provides additional evidence to show that the beneficial effects of ACE inhibitors occur at the local tissue level. Several experimental studies involving cardioplegic arrest also suggested that ACE inhibitors may be beneficial in reducing myocardial damage after periods of ischemic arrest. Gurevitch and coworkers [40] studied the effects of captopril in isolated rat hearts undergoing warm blood cardioplegic arrest followed by 1 hour of global ischemia and 30 minutes of reperfusion using a modified Lagendorff preparation. The best recovery of positive-developed pressure with time, coronary blood flow, and myocardial oxygen consumption occurred in the hearts that received captopril in both the cardioplegic solution and reperfusate. Engelman and coworkers [41] studied the effects of captopril in isolated porcine hearts undergoing 1 hour of left anterior descending (LAD) occlusion with cardioplegic arrest followed by 1 hour of reperfusion. Captopril given just before LAD occlusion significantly improved both global and regional contractility after 1 hour of reperfusion. Hayashida and coworkers [42] found that isolated rat hearts protected with captopril-enriched warm blood cardioplegia during 60 minutes of ischemic arrest had significantly less release of intracellular adhesion molecules and lactate (p < 0.05), lower left ventricular end-diastolic pressure, and greater coronary blood flow during reperfusion (p < 0.05). Captopril was also found to be beneficial against ischemia-reperfusion injury in a rat, single-lung transplant model [43]. The addition of captopril to the lung preservation solution significantly improved postreperfusion oxygenation, decreased peak airway pressure and wet to dry lung water ratios after 18 hours of cold storage and 2 hours of reperfusion.
Our own laboratory performed an experimental study in intact pigs simulating urgent CABG surgery to determine whether an ACE inhibitor with high-tissue ACE inhibition, such as quinaprilat, would improve endothelial function compared with enalaprilat, a low tissue affinity ACE inhibitor [44]. We also sought to determine whether improvement in endothelial function would correlate with increased cardioplegic protection and determine the mechanism for the actions of ACE inhibitors during cardioplegic arrest on cardiopulmonary bypass. Pigs underwent 90 minutes of coronary occlusion followed by 45 minutes of cardioplegic arrest and 180 minutes of reperfusion. During the period of coronary occlusion, animals received either intravenous enalaprilat, quinaprilat, or saline. Echo-derived wall motion scores were significantly higher (p < 0.0001) and the incidence of ventricular arrhythmias were significantly lower (p < 0.0001) in the groups that received ACE inhibitors, although there was no difference between quinaprilat and enalaprilat. Both ACE inhibitors significantly reduced infarct size from the non-ACE group; however, the quinaprilat-treated animals had a significantly lower area of necrosis than the enalaprilat animals (p < 0.0005). Endothelial-dependent coronary relaxation was best preserved with quinaprilat (p < 0.0001). The beneficial effects of quinaprilat on infarct size and endothelial function were abolished when the bradykinin antagonist HOE 140 was added to the quinaprilat. Similar to the HOPE trial, the beneficial effects of ACE inhibition were seen in doses that had no effect on systolic blood pressure. Our study provided further evidence that ACE inhibitors with higher tissue affinity resulted in better preservation of endothelial function, which resulted in less ischemic injury.
Our results were consistent with other experimental studies that showed high-tissue affinity ACE inhibitors improve endothelial function by a bradykinin-mediated mechanism [39, 45]. The protective effects of bradykinin appear to be mediated by nitric oxide, which modulates guanylate-cyclase and cyclic guanosine monophosphate synthesis [46]. Nitric oxide suppresses P-selectin, an adhesion molecule that contributes to ischemic necrosis by increasing leukocyte adhesiveness to the endothelium. By reducing P-selectin expression, leukocyte adhesiveness is decreased, and blood flow is increased to the ischemic myocardium. In a rabbit model of coronary occlusion and reperfusion, Hoshida and coworkers [46] found that quinaprilat reduced P-selectin expression and significantly decreased infarct size. Similar to our own results, these beneficial effects were achieved in doses that had no effect on mean aortic pressure and were negated by the bradykinin antagonist HOE 140.
The beneficial results achieved with the HOPE trial prompted us to determine whether pretreatment with ACE inhibitors would also minimize ischemic injury during surgical revascularization of ischemic myocardium [47]. Pigs received quinapril (20 mg orally each day for 7 days) followed by our protocol of 90 minutes of coronary occlusion, 45 minutes of cardioplegic arrest, and 180 minutes of reperfusion. Quinapril-treated animals required less cardioversions for ventricular arrhythmias (p < 0.05), had higher wall motion scores (p < 0.05), more complete recovery of endothelial function (p < 0.005), and lower infarct size (p < 0.0001). Similar to our previous study and those of others, these beneficial effects occurred in doses that had no significant changes in blood pressure from the placebo groups. These results strongly suggest that pretreatment with ACE inhibitors before CABG may minimize ischemic injury.
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Clinical Trials With ACE Inhibition in CABG Patients
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Several clinical studies have examined the effects of ACE inhibitors in the CABG patient. The effects of the Quinapril on Vascular Angiotensin-Converting Enzyme and Determinants of Ischemia (QUOVADIS) trial was a randomized, double-blind, placebo-controlled study involving 149 CABG patients [48]. Patients were randomized 27 days before CABG to receive either quinapril (40 mg/d) or placebos for 1 year. Quinapril-treated patients had an 80% reduction in ischemic events (MI, stroke, transient ischemic attack, or recurrence of angina), from 18% to 4% (p = 0.04). The reduction in major ischemic events became evident after the first 6 months and was not associated with any changes in blood pressure from the placebo group. Quinapril was well tolerated and was not associated with any untoward perioperative hemodynamic events. The Angiotensin-Converting Enzyme Inhibition Post-Revascularization Study (APRES) calculated the effects of ramipril in 159 revascularized (130 CABG; 29 PTCA) normotensive patients with moderately depressed (30% to 50%) ejection fractions [49]. Patients received up to 10 mg of ramipril, beginning 5 to 7 days post-CABG and 1 to 2 days post-PTCA for 3 years. Ramipril-treated patients had a 58% risk reduction in the composite endpoint of cardiac death, MI, and CHF (p = 0.03). Ramipril also significantly reduced echo-derived end-diastolic and end-systolic volume indices. Ramipril therapy was well tolerated as no patients had renal or electrolyte abnormalities develop. These beneficial effects were consistent in all patient groups, whether or not a CABG or PTCA was performed. Sirivella and coworkers [50] studied the effects of ACE inhibitors given to postcardiotomy patients with low cardiac output syndrome who required an intraaortic balloon pump and inotropic support. Patients treated with ACE inhibitors had lower hospital mortality (31% vs 14.5%), less morbidity (37% vs 20%), and shorter hospital length of stays (22 days vs 17 days).
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ACE Inhibitors and Graft Patency, Re-Stenosis, and Angiogenesis
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One explanation for the decreased incidence of ischemic events in patients treated with ACE inhibitors may be their ability to limit vein graft intimal hyperplasia, vasoconstriction, and the extension of arteriosclerosis to native vessels. As noted earlier, ANG II is present in atherosclerotic lesions and in the macrophages of atherosclerotic plaques [8, 22, 23]. It is also an important modulator of the proliferation of vascular smooth muscle cells. After CABG surgery, saphenous vein grafts are exposed to increased wall tension, which has been shown to stimulate the proliferation of smooth muscle cells in saphenous vein grafts [51], upregulate the proliferative effects of ANG II, and enhance the vessel wall response to growth-promotion factors that result in intimal hyperplasia [52]. Angiotensin-converting enzyme inhibitors have been shown to limit intimal hyperplasia by as much as 40% in animal models using vein grafts for carotid artery bypass [6]. In the Quinapril on Vascular Angiotensin-Converting Enzyme and Determinants of Ischemia trial, the beneficial effects of reduction of ischemic events were observed after the first 6 months of the study [48]. Hence it is conceivable that by limiting vein graft intimal hyperplasia, ACE inhibitors may also prevent early graft occlusion.
As noted earlier, ACE activity is nearly three times greater in saphenous vein grafts than in the internal mammary artery [25]. Saphenous vein grafts also have greater maximal responses to ANG II than does the internal mammary artery. By preventing vasoconstriction and promoting nitric oxide production, ACE inhibitors may result in less graft spasm and endothelial dysfunction, which may also contribute to improved graft patency, as well as limit the development of atherosclerotic changes in the bypassed distal native vessels.
The same events that lead to occlusion of saphenous vein grafts may also contribute to re-stenosis after PTCA and stent placement. Ribichini and coworkers who have studied in-stent re-stenosis in popliteal arteries, found that the inflammatory process created by stent placement is rich in ACE-positive cells that develop into a fibrocellular lesion that leads to progressive lumen occlusion [53]. Okimoto and colleagues [54] tested this hypothesis in a multi-center, randomized trial in which patients received quinapril for 3 to 6 months after a successful PTCA or stent placement. Patients treated with quinapril had significantly less re-stenosis per patient as assessed by quantitative coronary angiography (34% vs 45%; p < 0.05). These findings suggest that high-tissue affinity ACE inhibitors may also be effective in reducing re-stenosis after PTCA and stent placement.
High-tissue ACE inhibitors may also decrease ischemic events by promoting angiogenesis. Fabre and coworkers [7] used a rabbit model of chronic hind limb ischemia to evaluate the effects of ACE inhibitors on neorevascularization of ischemic tissue. Ten days after ligation of a femoral artery, rabbits received injections of recombinant human vascular endothelial growth factor, quinaprilat, captopril, or placebo. The high-tissue affinity ACE inhibitor quinaprilat stimulated angiogenesis by increasing blood flow reserve, angiographic score, and capillary density in the ischemic limb. The effect of quinaprilat was equal to those animals treated with recombinant human vascular endothelial growth factor and was superior to that of the low-tissue affinity ACE inhibitor captopril, which was similar to the placebo group. This data suggests that another mechanism for the beneficial effects of high-tissue ACE inhibition during ischemia may be its ability to promote angiogenesis.
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ACE Inhibitor Therapy in the CABG Patient
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There is growing evidence that ACE inhibitors should be used in all CABG patients [55]. In the perioperative period, they control hypertension, prevent vasoconstriction, decrease local tissue inflammation, and preserve endothelial function, all of which lead to more optimal myocardial preservation. They minimize thrombotic complications and promote fibrinolysis by decreasing plasminogen activator inhibitor-1 and platelet activation, and increasing tissue plasminogen activator. Pretorius and coworkers [56] have shown that the preoperative use of ACE inhibition attenuates the increase in plasminogen activator inhibitor-1 seen after CABG surgery, potentially reducing the risk of acute graft thrombosis. The anti-atherosclerotic properties of ACE inhibition contribute to improved long-term results, enhanced vein graft patency, and decreased progression of plaque disease in native coronary vessels.
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Contraindications and Side-Effects
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Major contraindications for initiating ACE-inhibitor therapy in CABG patients include a systolic blood pressure of <100 mm Hg, creatinine 
1.5 mg/dL, bilateral renal artery stenosis, angioedema, and intractable cough. Angioedema is rare and occurs in 0.1% of patients. The cough is dry and nonproductive and is related to bradykinin levels in the lung. However, it may be especially worrisome for CABG patients, as it may contribute to sternal instability in the early postoperative period, especially in heavy smokers. In our own clinical practice, <10% of patients will not tolerate ACE inhibitors in the immediate postoperative period because of any of the previously listed factors.
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Selecting an ACE Inhibitor for the CABG Patient
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Currently, there are >10 ACE inhibitors marketed in the United States [57] (see Table 1). All ACE inhibitors have demonstrated efficacy in the management of hypertension and are approved by the Food and Drug Administration for this purpose. Only two ACE inhibitors have been shown in clinical trials to have efficacy in reducing ischemic events after CABG surgery (Table 2). These trials included the study of the high-tissue affinity ACE inhibitors quinapril (in the Quinapril on Vascular Angiotensin-Converting Enzyme and Determinants of Ischemia trial) and ramipril (in the Angiotensin-Converting Enzyme Inhibition Post-Revascularization Study). Only ramipril has been shown to have reduced morbidity and mortality in all types of patient populations studied (ie, CHF and decreased ejection fraction, MI, diabetes and hypertension, stroke, peripheral vascular disease, and post-CABG and PTCA patients). Furthermore, as a result of the findings of the HOPE trial, the Food and Drug Administration allowed a labeling change for ramipril to be indicated for the prevention of MI, stroke, and the prevention of cardiovascular death [58] (Table 1). As a result of these clinical trials and our own experimental studies showing the superiority of high-tissue affinity ACE inhibitors in the perioperative period, our preference is to use either ramipril or quinapril in CABG patients.
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Implementing ACE Inhibitor Therapy in the CABG Patient
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In view of our previous experimental work showing that pretreatment with high-tissue affinity ACE inhibitors minimize ischemic damage during surgical revascularization, we attempt to place all CABG patients on a high-tissue affinity ACE inhibitor before their CABG. In fact, many patients are already receiving an ACE inhibitor prescribed by their internist or cardiologist before surgery. Our own experience with ACE inhibitors before CABG, and those of others, is that systemic vascular resistance is decreased and hypotension may occur in the early postoperative period [59]. However, this is accompanied by a normal or increased cardiac output and index and is easily reversed with short periods of low-dose vasopressor support. Concerns have been raised about the potential antagonism between ACE inhibition and aspirin, because ACE inhibitors increase prostaglandins, which are inhibited by aspirin [60]. It is important to note that in the HOPE trial, in the Quinapril on Vascular Angiotensin-Converting Enzyme and Determinants of Ischemia trial, and in the Angiotensin-Converting Enzyme Inhibition Post-Revascularization Study, the beneficial effects of ACE inhibitors occurred despite the fact that 75% of patients were receiving aspirin therapy [36, 48, 49]. O'Keefe and coworkers [55] have suggested that this problem may be avoided by giving aspirin 12 hours before the ACE inhibitor and reducing the aspirin dose to 81 mg; thereby still obtaining the antiplatelet effects while avoiding the interference with prostaglandin synthesis. Similarly, we have also found that holding the ACE inhibitor for 24 to 48 hours before surgery in nonemergent situations attenuates its vasodilatory effects and reduces the need for vasopressor agents.
In the postoperative period, we will initiate ACE-inhibitor therapy after ß-blockers have been instituted and systolic blood pressure is 100 mm Hg. Our preference is to start with either 2.5 mg of ramipril or 5 to 10 mg of quinapril and increase the dose as tolerated. Usually patients will be discharged on 2.5 to 5.0 mg of ramipril or 10 to 20 mg of quinapril. Serum creatinine levels and signs of increasing cough are carefully monitored. In our experience, 90% of patients will tolerate an ACE inhibitor in the postoperative period. However, if ACE inhibitors cannot be introduced during the patient's hospitalization, their referring physician will be asked to begin ACE-inhibitor therapy as an outpatient. In addition to an ACE inhibitor, all patients are discharged on aspirin, a ß-blocker, and a statin for optimal cardio protection. Yusef [61] has estimated that using these four medications simultaneously in patients with cardiovascular disease can decrease long-term ischemic events by 14%. Individually, the 5-year ischemic event rate was 20% if no medications were used, 15% for aspirin, 11% for ß-blockers, 8% for ACE inhibitors, and 6% for statins.
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Conclusions
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Angiotensin-converting enzyme inhibitor therapy plays an important role in minimizing ischemic events during and after CABG surgery. The cardioprotective effects of these drugs appear to extend beyond their antihypertensive effects and involve decreasing tissue inflammation, preserving endothelial function, suppressing atherosclerotic plaque formation, and promoting angiogenesis. High-affinity tissue ACE inhibitors may be especially effective in achieving these goals. Angiotensin-converting enzyme inhibitor therapy, in addition to statins, aspirin, and ß-blockers, should become part of the adjuvant therapy used by cardiac surgeons to improve clinical outcomes and reduce long-term cardiovascular events in all CABG patients.
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References
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Abstract
Introduction
