Angiotensin-converting enzyme (ACE) inhibitors have been shown reduce mortality in trials of patients with both symptomatic and asymptomatic left ventricular dysfunction (1-6) and after acute myocardial infarction (7-9). Pooled analysis of ACE inhibitor trials in heart failure have also suggested that ACE inhibitors may prevent recurrent myocardial infarction (10). However, it has been estimated that up to one third of patients with congestive cardiac failure may not respond to ACE inhibitor therapy for reasons that are poorly understood (11). Notably, a higher initial renin value, indicating increased activation of the renin-angiotensin system (RAS), does not predict a better response to ACE inhibitor therapy (12-15).
An insertion/deletion polymorphism, consisting of a 287-base pair alu repeat sequence, in intron 16 of the ACE gene, has been shown to predict approximately half of the variance in serum ACE levels between individuals (16). Homozygotes for the deletion allele (DD) have serum ACE levels twice as high on average as those homozygous for the insertion allele (II), whereas heterozygotes (ID) have intermediate levels (16). The effect of the ACE I/D genotype on the response to ACE inhibitor therapy in patients with heart failure was not reported previously. Todd et al. (17) demonstrated that genotype continued to predict residual ACE activity after acute ACE inhibition with enalapril. Therefore, variations in residual levels of enzyme activity during ACE inhibition, mediated by the ACE gene polymorphism, may be important in determining clinical response, as a difference of a few percentage points in residual ACE activity may produce distinctly different amounts of angiotensin II. An interaction between genotype and ACE inhibitor function would have important implications for the prescribing of ACE inhibitors to ensure that all patients receive the full benefits of ACE inhibition, and deleterious effects are kept to a minimum.
Symptomatic hypotension and a deterioration in renal function are important potential side effects of ACE inhibitor therapy in patients with heart failure. The severity of heart failure, the magnitude of the decrease in blood pressure during ACE inhibition, the presence of preexisting hyponatraemia, and the dose of concomitant diuretic therapy are recognised clinical features that predict a decline in renal function (18). The type and dose of ACE inhibitor also may be important. Longer-acting ACE inhibitors (e.g., lisinopril) have a more prolonged hypotensive effect and a more depressant effect on renal function than do short-acting ACE inhibitors (e.g., captopril; 19-22). Nonetheless, it remains difficult to predict in which subjects these side effects will occur.
We attempted to test for interaction between ACE genotype and response to ACE inhibitor therapy in patients with moderate heart failure. The ACE genotype of patients entered into a trial comparing the pressor and renal responses to lisinopril and captopril was assessed, and the responses according to genotype were compared for each ACE inhibitor.
Patients between ages 18 and 80 years with congestive cardiac failure being treated with loop diuretics (≥40 mg furosemide per day or equivalent) were recruited. Patients had to be functionally limited by dyspnoea or fatigue and have an ejection fraction <35% by radionuclide ventriculography. Patients had to be in sinus rhythm to measure accurately the ambulatory blood pressure.
The following exclusions applied: recent myocardial infarction or unstable angina (<8 weeks), recent cardiac surgery or percutaneous transluminal coronary angioplasty (<3 months), recent cerebrovascular event (<6 months), significant valvular outflow obstruction, glomerular filtration rate (GFR) <35 ml/min/1.73 m2, serum creatinine >250 μM, proteinuria >0.5 g/L or a clinically significant abnormality of renal function, including renal artery stenosis, cor pulmonale, or clinically significant lung disease. Patients taking ACE inhibitors, β-blockers, vasodilators, nonsteroidal antiinflammatory drugs, clonidine, allopurinol, procainamide, or probenicid and those with symptomatic postural hypotension before trial entry also were excluded.
This was a prospective, multicentre, randomised, two-way crossover study comparing lisinopril, 10 mg daily, and captopril, 25 mg t.d.s.. There was a single-blind 1-week placebo run-in period to assess compliance. There were then two 6-week double-blind active treatment periods separated by a 2-week single-blind washout period. The centres involved were the Royal Hallamshire Hospital, Sheffield, the Western General Hospital, Edinburgh, and Killingbeck Hospital, Leeds.
Identical unmarked tablets for both drugs (including test doses) and matching placebos were prepared by the Clinical Trials Dispensary at Zeneca Pharmaceuticals. Patients were asked to bring their study medication to each visit to assess compliance. At the beginning of each 6-week phase of active treatment, patients received a test dose of captopril (6.25 mg) or lisinopril (2.5 mg) and were closely monitored in the supine position with regular blood pressure checks for 4 h. Patients experiencing symptomatic hypotension were excluded from the study. Doses of all cardioactive concurrent medication, especially diuretics, were kept constant throughout the study. All patients underwent a full cardiorespiratory examination at each visit with assessment and recording of possible adverse reactions to the study drugs.
Left ventricular ejection fraction (LVEF) was assessed by radionuclide ventriculography (MUGA scan) during the placebo run-in period, and patients with an LVEF >35% were excluded. Glomerular filtration rate (GFR) was measured by the urinary accumulation of technetium 99m [99mTc]-DTPA (diethylenetriaminepentaacetic acid) before and after each 6-week treatment period, and the percentage change from baseline for each ACE inhibitor calculated (23). The [99mTc]-DTPA technique correlates well with determinations of GFR by using inulin and is highly reproducible on different days (24). Twenty-four hour ambulatory blood pressure was monitored by an automatic ambulatory device (Spacelabs model 90207, Spacelabs UK Limited) immediately before the start and end of each active-treatment phase (25). The mean arterial pressure was calculated as one third (systolic pressure - diastolic pressure) + diastolic pressure, and the average value over each 24-h period (MAP) calculated. From this, the change in MAP in response to 6 weeks of treatment with captopril or lisinopril was calculated.
DNA was extracted from whole blood by a standard protocol (Nucleon Kit, Nucleon Biosciences Ltd.), and the ACE genotype was assessed by the polymerase chain reaction (PCR), as described by Rigat et al. (26). By using the method described by Lindpaintner et al. (27), a repeated PCR procedure using primers specific for the I allele was undertaken in all DD subjects to identify possible mistyping of ID heterozygotes.
The trial was approved by local district ethics committees in the three centres, and all patients gave written informed consent. The trial was conducted in accordance with the Declaration of Helsinki, 1989. All surviving subjects to January 1995 gave verbal consent to the measurement of ACE genotype.
The primary end points for this study were the change in GFR (percentage) and MAP (mm Hg) from baseline by ACE genotype to each ACE inhibitor. Changes in blood urea and serum creatinine also were assessed, and the baseline comparability of the genotype groups reviewed. All available data were used to compare responses between the genotype groups (i.e., data were included on subjects who completed only one arm of the two 6-week active-treatment phases).
Carry-over between the first and second treatment periods was assessed by Student's t tests for period effect and treatment-period interaction for all subjects completing both arms of the trial. Paired t tests were used to compare response to and between the ACE inhibitors. Pearson's correlation coefficient is given for the relation between changes in GFR and MAP and between responses to each ACE inhibitor. Analysis of variance was used to assess the significance of changes in the primary end points across the genotype groups. Unpaired t tests also were used to compare genotype groups, and results are presented as difference with 95% confidence intervals between the groups. Significance is taken as the p = 0.05 level except for the tests for carryover, which are taken at p = 0.1, as is the convention.
Forty-one patients were entered into the trial between June 1992 and December 1994, of whom 28 completed the protocol. Twenty-one were randomised to the sequence lisinopril-captopril and 20 to captopril-lisinopril, and of those completing the protocol, there were 14 patients in each sequence group. ACE genotype analysis was performed on the 34 patients who were still alive in January 1995, 26 of whom had completed the protocol. The genotype distribution was 14 DD, 12 ID, and eight II subjects. There was no evidence of carryover in the change in MAP or GFR (Table 1). Mean 24-h systolic and diastolic pressures were 121/67 mm Hg before the first treatment period and 118/69 mm Hg before the second (p = 0.69); for GFR, the corresponding figures were 75.0 and 75.5 ml/min/1.73 m2 (p = 0.29), indicating that the 2-week washout period was adequate.
Results of comparative trial of 6 weeks of lisinopril, 10 mg o.d., or captopril, 25 mg t.d.s., on MAP or GFR in patients with heart failure
Six weeks' therapy with both captopril and lisinopril caused significant reductions in MAP from baseline (captopril: baseline MAP, 88.8 mm Hg; posttreatment MAP, 84.7 mm Hg; p = 0.0002; lisinopril: baseline MAP, 88.9 mm Hg; posttreatment MAP, 83.3 mm Hg; p < 0.0001). Comparing the MAP response between captopril and lisinopril, there was no significant difference between the two drugs [change in MAP (mm Hg): captopril, −4.1; lisinopril, −5.6; difference, 1.5; 95% confidence interval (CI), −1.3 to +4.3; p = 0.28]. There was no correlation between the blood pressure response to captopril and lisinopril in individual subjects (r = 0.30; p > 0.1). There was no statistically significant change in GFR from baseline to either drug (captopril: baseline GFR, 74.5 ml/min/m2; posttreatment GFR, 78.9 ml/min/m2; p = 0.15; lisinopril: baseline GFR, 77.2 ml/min/m2; posttreatment GFR, 72.4 ml/min/m2; p = 0.11). However, the difference in GFR response between captopril and lisinopril was of borderline statistical significance (percentage change in GFR: captopril, +6.8; lisinopril, −4.6; difference, 10.8; 95% CI, −0.3 to 23; p = 0.06.). There was no correlation between the GFR response to captopril and lisinopril in individual subjects (r = −0.12, p > 0.2). Similar results were obtained in both the MAP and GFR responses to both drugs when considering only those subjects who were genotyped [change in MAP (mm Hg): captopril, −4.2; lisinopril, −5.9; difference, 1.7; 95% CI, −1.2 to 4.7; p = 0.24; change in GFR (%): captopril, +7.3; lisinopril, −5.1; difference, 12.4; 95% CI, −0.6 to 25.4; p = 0.06]. There was no correlation between the magnitude of the decrease in MAP and the GFR response to either ACE inhibitor (captopril: r = −0.03; p > 0.2; lisinopril: r = 0.14; p > 0.2).
Pressor and renal responses to 6 weeks of captopril, 25 mg t.d.s., or lisinopril, 10 mg o.d., in patients with heart failure by ACE genotype
There were no major differences apparent between the genotype groups at baseline, although patients with the II genotype tended to be less symptomatic than those from the ID or DD genotype groups (Table 2). Pressor (MAP) and renal (GFR) responses by ACE genotype are shown in Table 3. The change from baseline in blood urea and serum creatinine by genotype group also are shown. There was a significant trend in the pressor response to captopril but not lisinopril by ACE genotype. There was no significant difference in the GFR response between genotype groups to captopril or lisinopril, although on average, II subjects had the least favourable GFR response to both ACE inhibitors (percentage change in GFR II vs. ID/DD groups combined: (a) captopril: II, −0.6; ID/DD, +10.8; difference, 11.4; 95% CI, −8.0 to 30.8; p = 0.26; (b) lisinopril: II, −13.3; ID/DD, −1.6; difference, 11.7; 95% CI, −9.7 to 33.0; p = 0.24. Similarly the increase in blood urea and serum creatinine tended to be greater in subjects with the II genotype.
In a well-characterised group of patients with heart failure (mean LVEF, 24%), the pressor and renal responses to 6 weeks of lisinopril and captopril were measured by using reliable and accurate methods and the results analysed for each drug according to ACE genotype. Both ACE inhibitors caused a significant decrease in mean 24-h blood pressure, which was of similar magnitude (∼5 mm Hg). In keeping with previous comparative studies of short- and long-acting ACE inhibitors (19-22), lisinopril had a more depressant effect on renal function than did captopril. although the difference between the drugs was small in clinical terms and of only borderline statistical significance. There was a significant relation between the pressor response to captopril and ACE genotype (p = 0.02). However, these findings were not replicated in the response to the longer-acting ACE inhibitor lisinopril (p = 0.89). The mean change in renal function tended to be less favourable in II subjects than in ID or DD subjects, and the pattern of response was similar to both drugs. However, there was considerable variance within each group, and these changes failed to achieve statistical significance, except in the change in blood urea with captopril (p = 0.02) and change in serum creatinine with lisinopril, which was of borderline significance (p = 0.07).
The ACE gene polymorphism predicts ∼50% of the variance of serum ACE levels (16) and has been shown to be predict tissue ACE levels in T lymphocytes (28) and myocardial tissue (29). There are relatively few studies on the effect of the ACE gene polymorphism on the response to ACE inhibitors (17,30-33). There also is a paucity of studies examining the direct relation between serum ACE level and the response to ACE inhibition. Johnston et al. (34) reported that serum ACE level predicted the short-term hypotensive response to enalapril in hypertensive patients. Todd et al. (17) studied the short-term hypotensive response to 10 mg enalapril in 27 normotensive volunteers by ACE genotype and found no relation. However, the variance in serum ACE activity between the genotype groups was maintained during ACE inhibition. Therefore, it is possible that ACE genotype continues to predict serum and tissue ACE activity during long-term ACE inhibitor therapy, and thus differences in residual ACE activity may influence the response to these drugs.
It could be expected that if ACE genotype affected the response to ACE inhibitor therapy by influencing residual ACE activity, there would be a clear dose dependence of the physiologic and clinical effects of ACE inhibitors. However, few studies addressed this question directly. Nussberger et al. (35) demonstrated dose dependence of the neurohormonal changes and decrease in pulmonary capillary wedge pressure to quinalapril in patients with heart failure. Brunner et al. (36) demonstrated a significant correlation between systolic pressor response to angiotensin I infusion and plasma levels of concomitantly administered ACE inhibitor. These authors concluded that the pressor response to angiotensin I correlated closely with ACE activity in vivo. Ueda et al. (37) reported that ACE genotype predicted the pressor response to angiotensin I infusion in normotensive volunteers, although this was disputed by two subsequent studies (38,39). Therefore, although the conversion of angiotensin I to angiotensin II is not the rate-limiting step in the circulating renin-angiotensin cascade, these is evidence to suggest a relation between prevailing ACE activity and the response of the RAS to physiologic and pharmacologic stimuli.
In heart failure, the factors governing the renal response to ACE inhibitors are complex, and ACE inhibitors may both improve and impair renal function (40). Angiotensin II-induced glomerular efferent arteriolar constriction acts to maintain renal perfusion, and ACE inhibitors may impair this mechanism, causing a decline in GFR. Conversely, the systemic vasodilatory actions of ACE inhibitors may improve renal plasma flow and so improve the GFR. The pathophysiologic factors that place certain individuals at an increased risk of a decline in renal function are disputed. Fluid and salt depletion, hyponatraemia, and severe heart failure are all known to potentiate the hypotensive response to ACE inhibition and increase the risk of a deterioration in renal function (41). In contrast, preexisting activation of the renin-angiotensin system has not been shown to predict a decline in renal function in response to ACE inhibition in heart failure (12-15). The pattern of response seen in this study suggests that ACE genotype could be a factor influencing the response to ACE inhibitor therapy. The II subjects, with the lowest ACE levels, may be prone to greater decreases in blood pressure and renal function than are ID or DD subjects. A possible mechanism could be through variations in the residual levels of enzyme activity after ACE inhibition, mediated by the ACE genotype, resulting in differing rates of production of the vasoactive hormone angiotensin II. This effect could act at a systemic level or locally within the tissues, such as at a renal paracrine level. Nonetheless, the results of this study are inconclusive, with considerable variance within each genotype group in both pressor and renal responses. This is not surprising, given the variety of factors influencing these parameters. Previous studies of serum and tissue ACE distribution according to genotype demonstrated considerable overlap in ACE expression between the genotype groups (16,28,29). Therefore, unless the relation between ACE expression and response to ACE inhibitor is a very strong one, considerably greater numbers of patients than were available here would be required to demonstrate definitively such a relation. Retrospectively it is possible to estimate that, given the observed difference between II and ID/DD genotype groups in the GFR response to 6 weeks of captopril, and allowing a white distribution of ACE genotype (16,27), 135 subjects would have been required to have 80% power to detect a difference at the 5% significance level.
A greater rate of decline in GFR was reported in subjects with nondiabetic renal disease with the DD genotype (33,42), whereas possession of the II genotype has been associated with a reduced incidence of diabetic nephropathy (43,44). ACE inhibitors have also been shown to slow the progression of renal disease. Therefore, the rate of progression of renal disease may be modulated by the prevailing expression of ACE, for which the I/D polymorphism is a marker. Mizuiri et al. (32) recently studied the response of 27 healthy subjects to a single dose of 50 mg captopril and found a greater decrease in intrarenal vascular resistance in II subjects, implying greater inhibition of renal ACE and renal angiotensin II production in those with the lowest levels of ACE. In our study, the patients had cardiac failure, in which the effects of ACE inhibitors on renal function can be deleterious. There was a nonsignificant trend for the decline in renal function to be most marked in II subjects, and thus, although not conclusive, our findings are compatible with recent work on the influence of the ACE I/D polymorphism on renal pathophysiology.
Two small studies found no relation between ACE genotype and pressor response to ACE inhibition in previously untreated hypertensive subjects (30,31). These findings appear to concur with the lack of relation between pressor response to lisinopril and genotype seen in this study, and it is possible that the apparent influence of ACE genotype on the response to captopril is a chance finding. The patients in this study were all taking a loop diuretic, which is known to activate the RAS. Therefore an influence of the ACE genotype on pressor response is possibly more likely in this study than in previous studies of unselected populations of hypertensive patients (30,31) or normal volunteers (17), in whom activation of the RAS is uncommon, and this may explain the differences observed in the influence of genotype on response to captopril between this and previous studies. It also is possible that short- and long-acting ACE inhibitors interact with prevailing ACE activity in differing ways, possibly with more complete suppression of circulating and tissue ACE activity with the longer-acting ACE inhibitor lisinopril, which could account for the difference in response to the two drugs seen here. Packer et al. (20) noted more pronounced hypotension during long-term ACE inhibition in patients with heart failure in response to enalapril, 10 mg once daily, than to captopril, 50 mg t.d.s. This suggests that there may be differences in the pharmacodynamics of ACE inhibition of short- and long-acting ACE inhibitors. Such differences could possibly explain the different interactions between ACE genotype and the short- and long-acting ACE inhibitors used in this study.
This study has a number of limitations. No baseline hormonal data, including serum ACE level, are available, and it is possible that there were important differences between the genotype groups that were not recorded in the baseline parameters, which may have affected the renal and pressor responses, for example, variations in dietary salt intake, fluid-balance status, or degree of neurohormonal activation. At baseline, the II subjects were, on average, receiving a lower dose of furosemide and had slightly better renal function than the DD or ID subjects (Table 2). These differences, although minor, would be expected to militate against the slightly greater decrease in blood pressure and renal function seen in II subjects; indeed it is possible they may have masked a true difference in the renal response between the genotype groups. As the number of subjects in each genotype group is relatively small, the power of this study confidently to detect or exclude a difference between genotype groups was limited; however, this study does provide important information for the design of future studies in this area. The discriminatory strength of this analysis is strengthened somewhat because the pattern of response to two ACE inhibitors was compared.
This is the first study of the effect of ACE genotype on the long-term response to ACE inhibitor therapy in patients with heart failure. The pattern of response observed suggests the possibility of an interaction between genotype and ACE inhibitor therapy, but it seems unlikely that possession of the DD genotype contributes significantly to the failure of ∼30% of patients with heart failure to improve with these drugs.
Acknowledgment: This study was supported by a grant from Zeneca Pharmaceuticals (U.K.) Ltd.
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