ACE inhibitors as cardioprotective agents James B. Young, MD From the Kaufman Center for Heart Failure, The Cleveland Clinic Foundation, Ohio

Cardiovascular Risk Protection ACE inhibitors as cardioprotective agents James B. Young, MD From the Kaufman Center for Heart Failure, The Cleveland Clinic Foundation, Ohio James B. Young, MD The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in certain populations are probably not due to blood pressure reduction alone. These agents are thought to offer cardioprotection by ameliorating the adverse long-term effects of angiotensin II on cardiac tissue and coronary vessels. Preservation of endothelial function and vascular integrity through actions on the bradykinin system may also explain the target-organ protection achieved by ACE inhibitors. This article will review the mechanisms of the renin-angiotensin system and the beneficial effects of interrupting this system by ACE inhibition. An abundance of clinical evidence attests to the value of ACE inhibition in a variety of cardiovascular diseases. Some of this evidence will be reviewed. Actions of the renin-angiotensin system The renin-angiotensin system is essential in regulating blood volume, arterial pressure, and cardiac and vascular function. Sympathetic stimulation via beta adrenoceptors, renal artery hypotension, and decreased sodium delivery to the distal tubules can stimulate the release of renin from the kidney. Once released, renin acts upon circulating angiotensinogen, which then undergoes proteolytic cleavage to form the decapeptide angiotensin I. In response, vascular endothelium releases ACE, which circulates in plasma and cleaves two amino acids from angiotensin I to form the circulating hormone angiotensin II. A tissue renin-angiotensin system independent of systemic functioning also exists; local renin-angiotensin system activity is found throughout blood vessel walls and in the parenchymal cells of most organs. When activated, the tissue renin-angiotensin system causes angiotensin II to influence neighboring cells. Increased ACE activity has been observed in macrophages and in vascular smooth muscle cells of arteriosclerotic plaques. ACE also inactivates bradykinin, a peptide that dilates coronary vessels, exerts natriuretic actions, and improves endothelial function. Bradykinin may also play a role in modulating platelet function. Increases in nitric oxide and other vasodilating substances have also been associated with increased bradykinin. Nitric oxide is important in inhibiting thrombosis and has been linked to atherosclerosis prevention. In addition, bradykinin increases production of tissue plasminogen activator. Because angiotensin II increases production of intrinsic plasminogen activator inhibitor-1, the effect of inactivated bradykinin due to ACE activity impairs fibrinolytic balance. 1 Angiotensin II is responsible for myriad cardiovascular effects and has long been recognized as a potent vasoconstrictor and promoter of protein synthesis and growth. Angiotensin II also promotes type I and type III collagen synthesis, leading to fibrosis and hypertrophy of arterial walls and the left ventricle. It acts via the angiotensin II receptors to constrict resistance vessels, causing an increase in systemic vascular resistance and arterial pressure. Indirect vasoconstrictive properties due to sympathetic nervous system enhancement are also attributed to angiotensin II. Angiotensin II facilitates norepinephrine release in the sympathetic nervous system and inhibits norepinephrine reuptake, enhancing sympathetic adrenergic function. A large body of evidence indicates that angiotensin II stimulates cardiac and vascular hypertrophy. Cardiac myocyte expression of deoxyribonucleic acid is altered by angiotensin II, resulting in myocyte hypertrophy and cellular dysfunction, which leads to hypertrophic cardiomyopathy and cardiac remodeling. In the myocardium, angiotensin II decreases compliance and induces fibroblast proliferation, which is related to the diastolic dysfunction associated with hypertension. Angiotensin II also acts upon the adrenal cortex to release aldosterone and stimulates the release of vasopressin within the kidney. These actions increase retention of 30

sodium and fluid. The renin-angiotensin system influences renal function in other ways as well, including direct vasoconstriction of the efferent arteriole by angiotensin II. Excessive glomerular pressure results when efferent arteriole tone is compromised. 1-3 Interruption of the reninangiotensin system Therapeutic manipulation of the renin-angiotensin system has become an important method of treating hypertension and heart failure. Pharmacologic therapy can be used to decrease arterial pressure, ventricular afterload, blood volume, and ventricular preload and appears to inhibit and possibly reverse cardiac and vascular hypertrophy. ACE inhibitors interrupt the reninangiotensin system and its associated neurohormonal cascade through inhibition of ACE, which, in turn, reduces conversion of angiotensin I to angiotensin II and inhibits the breakdown of bradykinin and other vasoactive substances, such as substance P and enkephalins. The degree to which increased bradykinin levels contribute to the beneficial clinical effects of ACE inhibition is unclear. 4 ACE inhibition does not completely suppress ACE activity and therefore does not entirely block angiotensin II production; there are other pathways by which angiotensin II can be produced. The role of tissue ACE is being investigated in this regard. Some angiotensin II production occurs in the heart and other organs, where it may be unaffected by the action of these drugs. In one study, angiotensin II production within cardiac interstitial fluid was not suppressed by captopril. 5 The reduced inactivation of bradykinin and other vasoactive substances attributed to the use of ACE inhibitors appears to have structural benefits in the heart, endothelium, and kidney. This important effect of ACE inhibitors distinguishes them from the angiotensin receptor blocking agents, which do not interfere directly with kinin breakdown. Hypertension. ACE inhibitors exert an antihypertensive effect and reduce arterial pressure to an extent similar to that of diuretics, beta blocking agents, and calcium antagonists. The primary mechanism by which ACE inhibitors reduce blood pressure is arterial and venous dilatation. ACE inhibitors also suppress aldosterone and have additional renal effects that are thought to help maintain their antihypertensive efficacy without the fluid retention and edema associated with some other vasodilators. There seems to be little relationship between renin levels and the efficacy of ACE inhibitors. ACE inhibitors also increase stroke volume and cardiac output, but do not alter heart rate. Left ventricular hypertrophy and remodeling. Increases in systolic blood pressure and cardiac afterload cause increases in sympathetic tone, aldosterone levels, and angiotensin II synthesis, all of which lead to ventricular remodeling and the development of left ventricular hypertrophy. Once this process is initiated, associated neuroendocrine changes enhance left ventricular hypertrophy. ACE inhibitors have been shown to improve vascular function as measured by maximal forearm blood flow and to restore vascular function to near-normal levels in hypertensive patients. 6 Evidence also shows that ACE inhibition, through blood pressure reduction and reduction in angiotensin II mediated effects on myocyte hypertrophy, is effective in reducing left ventricular hypertrophy. 7 Significant reductions in fibrosis have recently been demonstrated in cardiac biopsy specimens after ACE inhibition. Thirty-five patients with hypertension, left ventricular hypertrophy, and diastolic dysfunction were randomized to receive lisinopril or hydrochlorothiazide. 8 After 6 months, lisinopril was found to lower collagen volume fraction and myocardial hydroxyproline concentration. These effects were associated with an increase in left ventricular peak flow-velocity ratio during early filling and atrial contraction. The changes in fibrosis appear to be independent of blood pressure reduction (Figure 1). Previous investigations showed that ACE inhibition decreases serum markers of tissue collagen synthesis, a mechanism related to fibrosis. The reduction of fibrosis with ACE inhibition is one possible mechanism by which this class of agents may prevent and reverse remodeling in patients with hypertension, reducing subsequent development of heart failure and associated mortality. In this study, however, no regression of left ventricular hypertrophy was observed. Blockade of bradykinin degradation by ACE inhibitors prevents augmentation of prostaglandin synthesis, which may provide protection in left ventricular hypertrophy and heart failure. Heart failure. Left ventricular hypertrophy predisposes to the development of congestive heart failure (CHF), diastolic dysfunction, and arrhythmia. Neuroendocrine changes in heart failure include renin-angiotensin system activation and sympathetic stimulation, which are related to further progression of left ventricular hypertrophy. CHFmediated angiotensin II formation leads to vasoconstriction and volume retention, resulting in additional wall stress, left ventricular dysfunction, and remodeling. ACE inhibition improves cardiac function in patients with heart failure by decreasing vasoconstriction, improving tissue perfusion, reducing 31

Cardiovascular Risk Protection FIGURE 1 Reduction in cardiac fibrosis with lisinopril vs hydrochlorothiazide Change (%) +10 +5 0 5 10 15 p <.05 +2% 9% Left ventricular collagen fraction Source: Brilla CG, Funck RC, Rapp H. 18 P <.001 +9% 16% Myocardial hydroxyproline concentration Lisinopril Hydrochlorothiazide afterload and preload, inhibiting sympathetic stimulation, decreasing angiotensin II levels, and preserving bradykinin levels. As in left ventricular hypertrophy, the remodeling effects of ACE inhibition are beneficial in patients with heart failure. An analysis of a subset of CHF patients in the Studies of Left Ventricular Dysfunction (SOLVD) showed reduced progression of left ventricular dilatation and volume, and reversed left ventricular hypertrophy in patients receiving enalapril compared with placebo. 9 Endothelial dysfunction. ACE inhibition has demonstrated effects on the endothelial wall of arterial vessels, where it reverses hypertrophy and endothelial dysfunction, and may play a role in atherosclerosis development and plaque rupture. The mechanism by which ACE inhibition reduces the risk of myocardial infarction (MI), stroke, and death due to endothelial dysfunction is unclear. Angiotensin II formation in the vessel wall is associated with oxidative stress within the endothelial cell and vascular wall. Bradykinin breakdown also causes decreased nitric oxide production, leading to a reduced ability to inhibit oxidative stress within the endothelial cell. 10 The extent to which systemic ACE inhibition and the accompanying increase in bradykinin may be responsible for vascular benefits continues to be investigated. Some studies suggest that administration of ACE inhibitors with greater activity on tissue ACE is more likely to improve endothelial dysfunction. 11 Renal disease and diabetes. ACE inhibitors have beneficial effects on insulin resistance and glucose levels. Independent of their hemodynamic effects, ACE inhibitors also relax the glomerular efferent arteriole, leading to decreased intraglomerular pressure, reduced proteinuria, and reduced creatinine, thereby decreasing the risk of nephropathy. 12 Research also suggests that the increased insulin sensitivity, decreased hepatic insulin clearance, increased pancreatic blood flow, and antiinflammatory properties observed in animal models with ACE inhibitor treatment may be responsible for reductions in new-onset diabetes mellitus seen in the Captopril Prevention Project (CAPPP) and Heart Outcomes Prevention Evaluation (HOPE). 13,14 Clinical benefits of ACE inhibition Although the exact mechanisms involved in ACE inhibition are still being investigated, many clinical trials conducted during the past decade clearly show the clinical benefits of these agents in a wide variety of patients. The majority of these trials have focused on treatment after MI or in patients with CHF, but clear advantages to ACE inhibition can also be found in patients with left ventricular hypertrophy alone, hypertension, diabetes, renal dysfunction, and stroke. The HOPE trial, completed in 1999, has expanded the parameters of ACE inhibitor use. HOPE included 9,541 patients who were at high risk for a cardiovascular event due to a history of coronary artery disease (CAD), peripheral vascular disease, stroke, or diabetes with at least one cardiovascular risk factor, but did not have CHF, recent MI, recent stroke, or left ventricular dysfunction. The subjects were randomized to ramipril, 10 mg/day, or placebo. The study was terminated early because of a significant 22% reduction in the combined end point of MI, cardiovascular death, or stroke in the ramipril recipients. All-cause mortality was also significantly reduced. The researchers noted that the average systolic blood pressure reduction with ramipril (2 to 3 mm Hg) could not fully explain the benefits observed, although this hypothesis is controversial (Figure 2). 14 Hypertension. ACE inhibitors can be expected to lower blood pressure to a similar degree as other antihy- 32

pertensive drugs. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends that ACE inhibitors be the primary antihypertensive drug therapy in patients with diabetes, patients with CHF, and those with MI and systolic dysfunction (Table). 15 Left ventricular dysfunction. New information from the HOPE study shows definitively that ACE inhibition prevents or causes regression of left ventricular hypertrophy among patients without CHF and with normal or controlled blood pressure. 16 After more than 4 years of followup, 8.1% of the ramipril-treated patients showed electrocardiographic evidence of the persistence or development left ventricular hypertrophy, compared with 9.8% of patients in the placebo group. The effect was independent of blood pressure control. The rate of stroke, cardiovascular death, and MI among patients with prevention or regression of left ventricular hypertrophy was 12.3%, compared with 15.8% among those with development or persistence of left ventricular hypertrophy. The risk of CHF development was 9.3% in patients without left ventricular hypertrophy or regression compared with 15.4% in those with development or persistence of left ventricular hypertrophy. Previously, the SOLVD prevention trial, which included asymptomatic left ventricular hypertrophy patients with ejection fractions less than 35%, demonstrated that ACE inhibition reduced hospitalization risk by 44% compared with placebo. 17 In a meta-analysis, ACE inhibition was found to be more effective in reducing left ventricular mass than diuretics, beta blockers, or calcium antagonists (Figure 3). 7 Additional evidence of the positive effects of ACE inhibition on outcomes FIGURE 2 HOPE trial: Major outcomes with ramipril vs placebo Reduction (%) 35 30 25 20 15 10 5 0 p <.01 MI/ CV CV death/ death Stroke MI among patients with left ventricular dysfunction has been shown in studies involving patients with CHF and previous MI. Heart failure. ACE inhibitors have become primary therapy for all patients with CHF who can tolerate these agents. ACE inhibition was initially thought to be of most benefit in advanced CHF, based on the results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). 18 In that study, patients with New York Heart Association (NYHA) functional class IV heart failure had a 31% reduction in mortality after 1 year of treatment with enalapril. Subsequent studies indicated that ACE inhibition was beneficial in mild and moderate CHF. In the SOLVD treatment trial, the risk of mortality and hospitalization for worsening heart failure was reduced by 16% with enalapril. The benefit was most pronounced in patients with chronic CHF and ejection fractions of 35% or less. The Veterans Administration Cooperative Vasodilator Heart Failure Trial (V-HeFT II) included patients with NYHA functional class II and III heart failure and ejection fractions of less than 45%. 19 It showed a 28% reduction in mortality with enalapril compared with a hydralazineisosorbide combination at 2 years. A meta-analysis of 32 ACE inhibitor trials involving patients with any symptomatic CHF showed that these drugs significantly reduce mortality and hospitalization. 20 The value of angiotensin receptor blockers, which selectively block the AT 1 receptor responsible for the cardiovascular actions of angiotensin II, in the treatment of heart failure is much less clear. In the Evaluation of Losartan in the Elderly II (ELITE II) study, all-cause mortality was not statistically different between patients with NYHA functional class II to IV heart failure who were randomized Stroke CHF CABG Worse angina New diabetes HOPE = Heart Outcomes Prevention Evaluation; MI = myocardial infarction; CV = cardiovascular; CHF = congestive heart failure; CABG = coronary artery bypass graft. Source: Yusuf S, Sleight P, Pogue J, et al. 14 33

Cardiovascular Risk Protection TABLE JNC VI recommendations on drug therapy for subgroups of hypertensive patients Indication Diabetes mellitus Diabetes mellitus with proteinuria Heart failure Isolated systolic hypertension (older patients) MI to the angiotensin receptor blocker losartan or the ACE inhibitor captopril (17.7% versus 15.9%, respectively). 21 In the Valsartan Heart Failure Trial (Val-HeFT), the addition of valsartan to standard heart failure therapy, including an ACE inhibitor, did not result in a reduction in mortality compared with standard heart failure therapy but was associated with a reduction in the rate of hospitalization. 22 A subgroup analysis of Val-HeFT data, however, showed that patients taking valsartan, an ACE inhibitor, and a beta blocker fared worse than patients taking only two neurohormonal antagonists, indicating that aggressive neurohormonal antagonism with three agents may not be advantageous. Data from the ongoing Candesartan Cilexitil in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) should provide additional insight into the role of angiotensin receptor blockers in heart failure. MI prevention and treatment. The American Heart Association and Drug therapy (compelling indications unless contraindicated) ACE inhibitors, alpha blockers,* calcium antagonists, and low-dose diuretics ACE inhibitors ACE inhibitors, diuretics Diuretics (preferred), calcium antagonists (long-acting dihydropyridine) ACE inhibitors (with systolic dysfunction), beta blockers (nonintrinsic sympathomimetic activity) *Alpha blockers are no longer usually recommended because of the increase in cardiovascular events in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). (Pressel SL, Davis BR, Wright JT, et al. Control Clin Trials 2001;22:29.) JNC VI = Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; ACE = angiotensin-converting enzyme; MI = myocardial infarction. American College of Cardiology have recently recommended that ACE inhibitors be used as first-line treatment after MI. 23 ACE inhibition should be started early in stable, high-risk patients, such as those with anterior-wall MI, previous MI, and Killip class II or greater, according to the guidelines. Treatment should be continued indefinitely, FIGURE 3 and long-term ACE inhibition should be considered for all patients with coronary or other vascular disease unless contraindicated. 21 This guideline revision was based on evidence from the HOPE trial discussed previously. 14 Most experts recommend starting ACE inhibitor therapy within 1 day after MI if hypotension is not a concern. Previous investigations have shown success with ACE inhibition after MI. Early studies showed that ACE inhibitors reduced CHF development by as much as 30% and CHF hospitalization by 20% after MI, indicating a substantial effect on morbidity. 24 In the Acute Infarction Ramipril Efficacy (AIRE) study, ramipril given within 1 week of acute MI reduced the incidence of death, severe CHF, reinfarction, or stroke by 19% compared with placebo. 25 In the Survival and Ventricular Enlargement (SAVE) trial, captopril initiated 3 to 16 days after MI in patients with left ventricular dysfunction reduced the risk of death from cardiovascular causes by 21%. 26 Subsequent development of CHF was also reduced significantly. ACE inhibition was also of overall benefit after MI in the Gruppo Italiano per Percentage of change in left ventricular mass index with four antihypertensive drug classes Change in left ventricular mass index (%) 0 5 10 15 20 25 Calcium Beta channel ACE Diuretics blockers blockers inhibitors 7% 6% 9% 13% ACE = angiotensin-converting enzyme. Adapted with permission from Schmieder RE, Martus P, Klingbeil A, et al. 7 p <.01 34

lo Studio della Soppravvivenza nell Infarto Miocardico (GISSI-3), International Study of Infarct Survival (ISIS-IV), and Trandolapril Cardiac Evaluation (TRACE) trials, although the reductions in cardiovascular mortality and morbidity were greatest among subsets of patients with overt CHF or large anterior-wall infarcts. 27-29 Because the HOPE trial excluded patients with a recent MI, CHF, reduced left ventricular ejection fraction, and uncontrolled hypertension, the results suggest that ACE inhibition may be beneficial for primary MI prevention. These results led the Food and Drug Administration to allow prophylactic ramipril therapy for patients meeting HOPE inclusion criteria to reduce the risk of MI and other cardiovascular events. As stated previously, the HOPE study included patients ages 55 years and older with a history of CAD, peripheral vascular disease, diabetes, or a previous stroke who had at least one additional cardiovascular risk factor. Contrary to the HOPE data, the Quinapril Ischemic Event Trial (QUI- ET), in which 49% of subjects had a history of MI, did not show a difference between ACE inhibitor and placebo in preventing cardiovascular events among 1,750 patients with documented CAD. 30 Therefore, the extent to which ACE inhibition prevents MI and other events requires more investigation. Two large trials, the Prevention of Events with ACE Inhibition (PEACE) study, in which trandolapril is being used, and the European Trial of Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA), are being conducted to help resolve the debate; results of these trials are expected in 2003 and 2002, respectively. Diabetes and renal disease. Much evidence shows that ACE inhibition has positive renal effects in patients with type 1 or type 2 diabetes and associated nephropathy. The microalbuminuria common in these patients is known to contribute to development of left ventricular hypertrophy and cardiovascular mortality. An early study showed that captopril slowed renal disease progression and reduced the need for dialysis, renal transplantation, and death by 50% after 2 years of treatment in patients with type 1 diabetes. 31 Two additional trials showed that lisinopril significantly reduced the progression of proteinuria in patients with type 1 diabetes and progression of early nephropathy in patients with type 2 diabetes when compared with a calcium antagonist. 32,33 Strong evidence advocating ACE inhibition in patients with type 1 or type 2 diabetes comes from the Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO)- HOPE substudy. 34 After 4.5 years of treatment, ramipril reduced the development of nephropathy by 24%; reduced the combined end point of overt nephropathy, need for dialysis, or laser therapy by 16%; and slowed the progressive increase in the albumin-to-creatinine ratio. These reductions were most notable in patients with microalbuminuria at baseline. In addition, the EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus (EUCLID) showed a reduction in the progression of retinopathy and the development of proliferative retinopathy in normotensive diabetics treated with lisinopril. 35 The CAPP and HOPE studies indicate that ACE inhibitors may have some effect in reducing the incidence of new-onset diabetes, but more study is needed. Stroke. The recent Perindopril Protection against Recurrent Stroke Study was the first major clinical trial to show that ACE inhibitors can substantially reduce the risk of recurrent stroke. 36 More than 6,000 patients with a history of transient ischemic attack or stroke were randomized to treatment with the ACE inhibitor perindopril or placebo. Over an average of 4 years of follow-up, 307 of the 3,051 patients in the active treatment group had a stroke compared with 420 of the 3,054 patients in the placebo group, a reduction of 28% in the primary end point. Total major vascular events (nonfatal stroke, nonfatal MI, or death from any vascular cause) were reduced by 26%. In the HOPE study, ramipril was associated with a 32% reduction in the risk of stroke and a 61% reduction in the risk of fatal stroke. In addition, significantly fewer ramipril-treated patients had cognitive and functional impairment. 37 Dosing strategy ACE inhibitor dosing has been somewhat controversial. The Assessment of Treatment with Lisinopril and Survival (ATLAS) study has provided some insight, and demonstrates that high-dose ACE inhibition is superior to low-dose treatment and is not associated with a significant increase in adverse effects. 38 In ATLAS, the patients were randomized to receive either 32.5 to 35 mg daily of lisinopril, or 2.5 to 5 mg daily. The average dose in the high-dose group was 22.5 mg daily, and the average dose in the low-dose group was 3 mg daily. All-cause mortality was 44.9% in the low-dose group compared with 42.5% in the high-dose group, and cardiovascular mortality was 40.2% and 37.2%, respectively. The associated risk reductions with high-dose lisinopril were not significant; however, a significant increase in the time to all-cause death and hospitalization, cardiovascular hospitalization, and CHF hospitalization was observed among patients receiving higher doses. The inci- 35

Cardiovascular Risk Protection dence of hospitalization for CHF in the high-dose group was also reduced significantly. 25 In the SOLVD trial, high-dose ACE inhibition reduced mortality by 16% and the combined end point of mortality and hospitalization by 26% compared with placebo. Based on ATLAS and SOLVD, many experts recommend that ACE inhibitors be titrated to higher doses in patients who tolerate them. Conclusion The utility of ACE inhibition has reached far beyond hypertension management. There is clear evidence that ACE inhibitors improve cardiac function and decrease morbidity and mortality after MI, in patients with heart failure, and in patients with diabetes and associated complications. The positive effects of ACE inhibitors in these populations probably go beyond a blood pressure lowering effect, but this issue is still somewhat controversial. 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