Long-term Angiotensin-converting Enzyme Inhibitor Treatment Research Articles

Long-term prognosis after out-of-hospital cardiac arrest with/without ST elevation myocardial infarction

Aim To describe the 3-year survival of patients after out-of-hospital cardiac arrest (OHCA) taking into account the presence of ST-segment elevation myocardial infarction (STEMI) and evaluating prognostic factors associated with pre-hospital and hospital care. Patient group Over a period of 29 months and with the aid of a questionnaire supplied to 24 rescue stations, we prospectively included 560 individuals (415 men; aged 16–97 years, median 68) for whom cardio-pulmonary resuscitation (CPR) for OHCA of confirmed cardiac etiology was attempted. Results Of 149 hospitalized individuals, 28.2% survived 1 year and 25.5% survived 3 years after OHCA. In the subgroup of patients with STEMI (26 individuals; 17.5%), 57.7% survived 1 year and 53.9% survived 3 years. In the subgroup of patients without STEMI ( n = 123), 22% survived 1 year and 19.5% survived 3 years. The strongest predictors for long-term survival by logistic regression analysis were: age under 70 years, ventricular fibrillation as initial rhythm, CPR without atropine, and STEMI. OHCA occurrence at a public place was an indicator of better survival in the subgroup with STEMI. In the subgroup of patients without STEMI, long-term angiotensin-converting enzyme inhibitor treatment, CPR without atropine, a Glasgow Coma Scale upon hospital admission over 3, no presence of cardiogenic shock, and no manifestations of postanoxic encephalopathy (Fisher's exact test, χ 2 test) were indicators of better survival. Conclusion Among 560 individuals with “primary cardiac” etiology OHCA and initiation of professional CPR, 8% survived 1 year and 7% survived 3 years. A higher survival rate among patients with STEMI was documented.

Impaired bradykinin response to ischaemia and exercise in patients with mild congestive heart failure during angiotensin‐converting enzyme treatment. Relationships with endothelial function, coagulation and inflammation

Inflammation and endothelial dysfunction play important roles in the pathophysiology of congestive heart failure (CHF), and the peptide bradykinin, generated during inflammation, may act as a defence mechanism by inducing vasodilation. Plasma bradykinin levels are increased in experimental heart failure but low in patients with advanced chronic CHF despite treatment with angiotensin-converting enzyme (ACE) inhibitors. It is not currently known how bradykinin behaves in less severe phases of CHF controlled by long-term ACE inhibitor treatment. We studied 10 male patients with clinically stable chronic CHF [New York Heart Association (NYHA) class II] on long-term ACE inhibitor treatment and 10 normal sex- and age-matched control subjects. High performance liquid chromatography/radioimmunoassay methods were used to evaluate plasma levels of bradykinin in relation to an array of parameters of endothelial function, coagulation and inflammation before and after stimuli of forearm arterial occlusion and physical exercise. CHF patients had higher levels of bradykinin (P = 0.008), activated factor XII (P = 0.049), interleukin-6 (P = 0.050) and tumour necrosis factor receptor II (sTNFRII) (P = 0.026) than controls. Arterial occlusion and exercise significantly increased bradykinin and von Willebrand factor levels in controls but not in CHF patients. The increase in brachial artery diameter after arterial occlusion was less in CHF patients (P = 0.036) and inversely related to baseline plasma levels of bradykinin (r = -0.855, P = 0.002) and sTNFRII (r = -0.780, P = 0.008). NYHA class II CHF patients during long-term treatment with ACE inhibitors have increased bradykinin levels and signs of inflammation. They are unable to respond adequately to stimuli of ischaemia and physical exercise which both require vasodilation.

Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X

Angiotensin-converting enzyme (ACE) inhibition has been shown to improve clinical myocardial ischemia in patients with syndrome X (angina pectoris, positive treadmill exercise test, normal coronary angiograms, and no evidence of coronary spasm). This study was conducted to investigate the effects of long-term ACE inhibitors on endothelial nitric oxide (NO) metabolism and coronary microvascular function in patients with syndrome X. After a 2-week washout period, 20 patients with syndrome X were randomized to receive either enalapril, an ACE inhibitor, 5 mg twice daily (n = 10) or placebo (n = 10) in a double-blind design for 8 weeks. Another 6 age- and gender-matched subjects with negative treadmill exercise tests were also studied as controls. Compared with control subjects, patients with syndrome X had significantly reduced coronary flow reserve, reduced plasma levels of nitrate and nitrite (NOx), and a reduced plasma l-arginine to asymmetric dimethylarginine (ADMA) ratio (an index of systemic NO metabolism), as well as reduced endothelial function. These patients also had increased plasma levels of ADMA, which is an endogenous inhibitor of NO synthase and of von Willebrand factor, a marker of endothelial injury. Baseline characteristics including exercise performance and coronary flow reserve were similar between enalapril and placebo groups. After an 8-week treatment period, exercise duration (p = 0.001) and coronary flow reserve (p = 0.001) significantly improved with enalapril but not with placebo. Enalapril treatment, but not placebo, reduced plasma von Willebrand factor (p = 0.03) and ADMA levels (p = 0.01) and increased NOx levels (p = 0.01) and the ratio of l-arginine to ADMA (p <0.01). In patients with syndrome X, the plasma NOx level was positively and ADMA level inversely correlated with coronary flow reserve before and after the treatment. In conclusion, long-term ACE inhibitor treatment with enalapril improved coronary microvascular function as well as myocardial ischemia in patients with syndrome X. This may be related to the improvement of endothelial NO bioavailability with the reduction of plasma ADMA levels.

Effect of angiotensin-converting enzyme inhibitor on left ventricular parameters and circulating brain natriuretic peptide in elderly hypertensives with left ventricular hypertrophy

In the elderly, left ventricular hypertrophy (LVH) is a powerful risk factor for cardiovascular events and cardiovascular death. The purpose of the present study is to investigate the effect of long-term effective blood pressure control with the angiotensin-converting enzyme (ACE) inhibitor temocapril on left ventricular (LV) mass and function indices and the circulating concentration of the cardiac hormone brain natriuretic peptide (BNP) in elderly hypertensives with LVH. Temocapril treatment was administered for 1 year to 11 elderly hypertensives (mean age, 72 years) with LVH. Cardiac dimensions and circulating concentrations of BNP were monitored before initiation of treatment and after 1 year of treatment. At entry, BNP levels were positively correlated with the LV mass index, but were not correlated with the mean blood pressure, LV ejection fraction, or E/A ratio (the ratio of peak transmitral flow velocity in early diastole, peak E, to that in late diastole, peak A). After 1 year, temocapril treatment resulted in effective control of blood pressure. The treatment did not affect the LV ejection fraction, but modestly increased the E/A ratio. Temocapril significantly reduced septal and posterior wall thickness and the LV mass index. BNP significantly declined after 1 year. Changes in BNP were significantly related to changes in the LV mass index, but were not related to changes in the mean blood pressure, LV ejection fraction, or E/A ratio. The results suggest that long-term ACE inhibitor treatment with temocapril can induce the regression of LV mass and reduce elevated plasma BNP in elderly hypertensive patients with LVH. In this study, changes in BNP reflected the magnitude of regression of LVH.

The influence of long-term ACE inhibitor treatment on circulatory responses to stress in human hypertension

The objective of the study was to examine the influence of angiotensin converting enzyme (ACE) inhibition on circulatory responses to standardized stress tests in primary mild to moderate hypertension. Patients (n = 28) received 5 mg ramipril daily or placebo for 6 weeks in a double-blind crossover design, followed by 6 months of open ramipril treatment. Mental stress (a 20-min Stroop’s color word conflict test) and a cold pressor test were performed at the end of each of the three study periods. Noninvasive blood pressure and heart rate were recorded. Ramipril reduced systolic and diastolic blood pressure levels at rest (from 146 ± 3/99 ± 3 with placebo to 135 ± 4/94 ± 3 at 6 weeks, and 136 ± 4/91 ± 3 mm Hg at 6 months, in the laboratory) and during mental stress. Resting heart rates were unchanged by ramipril. Ramipril reduced systolic blood pressure and heart rate responses during mental stress; diastolic blood pressure responses were unchanged. Ramipril reduced cardiac workload (systolic blood pressure × heart rate) levels and responses. Treatment effects at 6 months were generally greater than at 6 weeks. During the cold pressor test systolic and diastolic blood pressure levels were lowered by ramipril, but responses were unchanged. Heart rate responses, however, were reduced. Thus, ramipril reduced cardiac workload levels and responses also during the cold pressor test. These findings show that ACE inhibitors can reduce cardiac workload during stressful situations. If confirmed, this would seem to offer an advantage in the treatment of hypertension.

Reversal of peripheral microvascular dysfunction during long-term treatment with the angiotensin converting enzyme inhibitor fosinopril in congestive heart failure

Background: Treatment with angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure (CHF) improves cardiac and peripheral hemodynamic function and exercise performance. However, studies on the effects of long-term treatment with an ACE inhibitor on the neurogenic and nonneurogenic regulation and structural microangiopathy of the peripheral microvasculature in CHF are lacking. Methods and Results: We investigated the effect of 12 weeks of treatment with the ACE inhibitor fosinopril on peripheral microvascular function in a double-blind, placebo-controlled study of 12 patients treated with fosinopril and 10 patients treated with placebo. All had moderate CHF. Microvascular blood flow and resistance were calculated after application of the local isotope washout method in relaxed and nonrelaxed calf vascular beds in the supine position and during head-up tilt. Skeletal muscle vascular resistance was reduced in the fosinopril group (46 ± 6 to 30 ± 1 mm Hg · mL −1 · 100 g · min ± standard error; P < .05) and differed compared with the effect of placebo ( P < .05) where no change was seen (37 ± 11 to 55 ± 13 mm Hg · mL −1 · 100 g · min; not significant [NS]). Also, skin minimal vascular resistance was reduced during fosinopril treatment (13 ± 0.6 to 11 ± 0.7 mm Hg · mL −1 · 100 g · min; ( P < .05) and differed compared with the effect of placebo ( P < .05) with absence of change (12 ± 1.6 to 14 ± 1.4 mm Hg · mL −1 · 100 g · min; NS). Conclusions: These results suggest that long-term ACE inhibitor treatment with fosinopril in patients with CHF improves hemodynamic status to as far as the peripheral microvascular level in both the relaxed and nonrelaxed microcirculation of the lower leg.

Long-Term Treatment With Angiotensin Converting Enzyme Inhibitor Restores Reduced Calcitonin Gene-Related Peptide-Containing Vasodilator Nerve Function in Mesenteric Artery of Spontaneously Hypertensive Rats

Effects of long-term treatment with angiotensin converting enzyme (ACE) inhibitor on decreased function of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves (CGRP nerves) in mesenteric resistance artery were investigated in spontaneously hypertensive rats (SHR). Eight-week-old SHR were treated for 7 weeks with 0.1% captopril, 0.01% temocapril, 0.05% pindolol or 0.005% hydralazine in drinking water. Long-term treatment with each drug significantly lowered mean blood pressure of SHR. In isolated and perfused mesenteric vascular beds with active tone, periarterial nerve stimulation (PNS) (0.5 to 8 Hz) produced frequency-dependent vasodilations, which were abolished by CGRP(8-37) (CGRP-receptor antagonist) and significantly smaller in SHR than in normotensive Wistar Kyoto rats. Treatment of SHR with captopril and temocapril but not with pindolol and hydralazine resulted in significantly greater PNS-induced vasodilation than in non-treated SHR, but ACE-inhibitor treatment did not affect vasodilation induced by exogenous CGRP. In captopril-treated SHR preparations, PNS evoked significantly larger CGRP-like immunoreactive release than in non-treated SHR. In non-treated 15-week-old SHR preparations, direct perfusion of captopril or temocapril (0.1 μM and 1 μM) did not modify frequency-dependent vasodilation in response to PNS. These results suggest that long-term ACE inhibitor treatment prevents or restores CGRP nerve function reduction in SHR.

The persistent effect of long-term enalapril on pressure natriuresis in spontaneously hypertensive rats.

Long-term angiotensin-converting enzyme inhibitor treatment has been shown to have a persistent antihypertensive effect in spontaneously hypertensive rats (SHR) long after discontinuation of treatment. To test the hypothesis that this persistent effect involves a shift in the pressure-natriuresis relation, we performed experiments in male, anesthetized SHR at 18 wk of age with fixed neural and hormonal influences on the kidney. Renal function was assessed at various levels of arterial pressure using standard clearance techniques. Enalapril (25 mg.kg-1.day-1 in drinking water) was administered from 4 to 14 wk of age and again 3 days before renal function studies. The following four groups of SHR were studied: 1) 10-wk treatment, 2) 10-wk + 3-day treatment, 3) 3-day treatment, and 4) untreated. Groups 1 and 4 had an intact renin-angiotensin system; groups 2 and 3 had the renin-angiotensin system blocked. Mean arterial pressure (MAP, mmHg; means +/- SE) under Inactin anesthesia was 139 +/- 4 (n = 9), 109 +/- 3 (n = 8), 149 +/- 1 (n = 9), and 181 +/- 7 mmHg (n = 9) for each of the four groups, respectively. Glomerular filtration rate was similar in all groups at resting levels of MAP, whereas renal blood flow was elevated in all treatment groups when compared with that in untreated SHR. Pressure-natriuresis, pressure-diuresis, and pressure-fractional sodium excretion curves for the 10-wk treatment group and 3-day only treatment group were shifted leftward to significantly lower pressures by approximately 25 mmHg, compared with the untreated group. The curves for the treated +3-day group were shifted an additional 30 mmHg to the left. The relationship between renal artery pressure (RAP) and renal interstitial hydrostatic pressure was also shifted 25-30 mmHg but only in rats that received the long-term treatment with enalapril. Three-day enalapril had no significant effect on this relationship. These data indicate that the persistent effect of long-term enalapril treatment on arterial pressure in SHR is the result of a shift in the pressure-natriuresis relationship. The mechanism for this effect involves hemodynamic changes that act to improve transmission of RAP to the interstitium, resulting in enhanced sodium excretion for a given level of RAP.

Long-Term Angiotensin-Converting Enzyme Inhibitor Treatment Attenuates Adrenergic Responsiveness Without Altering Hemodynamic Control in Patients Undergoing Cardiac Surgery

Background : The sympathoadrenal and the renin-angiotensin systems are involved in blood pressure regulation and are known to be markedly activated during cardiac surgery. Because unexpected hypotensive events have been reported repeatedly during anesthesia in patients chronically treated with angiotensin-converting enzyme (ACE) inhibitors, the authors questioned whether renin-angiotensin system blockade would alter the hemodynamic control through attenuation of the endocrine response to surgery and/or through attenuation of the pressor effects of exogenous catecholamines. Methods : Patients with preserved left ventricular function undergoing mitral valve replacement or coronary revascularization were divided into two groups according to preoperative drug therapy : patients receiving ACE inhibitors for at least 3 months (ACEI group, n = 22) and those receiving other cardiovascular drug therapy (control group, n = 19). Anesthesia was induced using fentanyl and midazolam. Systemic hemodynamic variables were recorded before surgery, after anesthesia induction, during sternotomy, after aortic cross-clamping, after aortic unclamping, as well as after separation from cardiopulmonary bypass (CPB) and during skin closure. Blood was sampled repeatedly up to 24 h after surgery for hormone analysis. To test adrenergic responsiveness, incremental doses of norepinephrine were infused intravenously during hypothermic CPB and after separation from CPB. From the dose-response curves, pressor (defined as mean arterial pressure changes), and vasoconstrictor (defined as systemic vascular resistance changes) effects were analyzed, and the slopes and the dose of norepinephrine required to increase mean arterial pressure by 20% were calculated (PD 20 ). Results : At no time did the systemic hemodynamics and the need for vasopressor support differ between the two treatment groups. However, for anesthesia induction, significantly less fentanyl and midazolam were given in the ACEI group. Although plasma renin activity was significantly greater in the ACEI group throughout the whole 24-h study period, plasma concentrations of angiotensin II did not differ between the two groups. Similar changes in catecholamines, angiotensin II, and plasma renin activity were found in the two groups in response to surgery and CPB. The pressor and constrictor effects of norepinephrine infusion were attenuated markedly in the ACEI group : the dose-response curves were shifted to the right and the slopes were decreased at the two study periods; PD 20 was significantly greater during hypothermic CPB (0.08 μg/kg in the ACEI group vs. 0.03 μg/kg in the control group ; P < 0.05) and after separation from CPB (0.52 μg/kg in the ACEI group vs. 0.13 μg/kg in the control group ; P < 0.05). In both groups, PD 20 was significantly less during hypothermic CPB than in the period immediately after CPB. Conclusions : Long-term ACE inhibitor treatment in patients with preserved left ventricular function alters neither the endocrine response nor the hemodynamic stability during cardiac surgery. However, a significantly attenuated adrenergic responsiveness associated with incomplete blockade of the plasma renin-angiotensin system supports the hypothesis that inhibition of angiotensin II generation and of bradykinin degradation within the vascular wall mediates some of the vasodilatory effects of ACE inhibitors.

Cardiac and vascular effects of long-term losartan treatment in stroke-prone spontaneously hypertensive rats.

In previous studies in stroke-prone spontaneously hypertensive rats (SHRSP), we demonstrated that early-onset, long-term angiotensin-converting enzyme inhibitor treatment improved cardiac function and metabolism and increased aortic cGMP content even at sub-antihypertensive doses. These effects could be prevented by bradykinin type 2 (B2) receptor blockade with icatibant. In the present study, we studied the effects of long-term oral treatment with the angiotensin type 1 (AT1) receptor antagonist losartan (30 mg/kg per day) on functional and biochemical parameters of the heart and on cGMP content in the aorta in SHRSP treated prenatally and subsequently up to the age of 20 weeks. Losartan prevented the development of hypertension and left ventricular hypertrophy. Cardiac function measured ex vivo in isolated perfused hearts was improved, as demonstrated by significant increases in left ventricular pressure (22.4%), differentiated left ventricular pressure (dP/dtmax) (35.1%), and coronary flow (38%). The release of the intracellular enzymes lactate dehydrogenase and creatine kinase and of lactate into the coronary effluent was reduced by 46.4%, 47.2%, and 63.6%, respectively. In myocardial tissue, the concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 43.2%, 33.1%, and 42.4%, respectively, whereas lactate was decreased by 57.0%. The aortic tissue content of cGMP was increased fivefold. Our results demonstrate that chronic blockade of AT1 receptors with losartan improved cardiac function and metabolism and increased aortic cGMP content in SHRSP to an extent similar to that observed previously after long-term angiotensin-converting enzyme inhibitor treatment at a comparably antihypertensive dose. Prevention of hypertension and cardiac hypertrophy as well as stimulation of non-AT1 receptors are discussed to explain the cardiac and vascular actions of losartan.

Long-term angiotensin-converting enzyme inhibitor treatment attenuates adrenergic responsiveness without altering hemodynamic control in patients undergoing cardiac surgery.

The sympathoadrenal and the renin-angiotensin systems are involved in blood pressure regulation and are known to be markedly activated during cardiac surgery. Because unexpected hypotensive events have been reported repeatedly during anesthesia in patients chronically treated with angiotensin-converting enzyme (ACE) inhibitors, the authors questioned whether renin-angiotensin system blockade would alter the hemodynamic control through attenuation of the endocrine response to surgery and/or through attenuation of the pressor effects of exogenous catecholamines. Patients with preserved left ventricular function undergoing mitral valve replacement or coronary revascularization were divided into two groups according to preoperative drug therapy: patients receiving ACE inhibitors for at least 3 months (ACEI) group, n = 22) and those receiving other cardiovascular drug therapy (control group, n = 19). Anesthesia was induced using fentanyl and midazolam. Systemic hemodynamic variables were recorded before surgery, after anesthesia induction, during sternotomy, after aortic cross-clamping, after aortic unclamping, as well as after separation from cardiopulmonary bypass (CPB) and during skin closure. Blood was sampled repeatedly up to 24 h after surgery for hormone analysis. To test adrenergic responsiveness, incremental doses of norepinephrine were infused intravenously during hypothermic CPB and after separation from CPB. From the dose-response curves, pressor (defined as mean arterial pressure changes), and vasoconstrictor (defined as systemic vascular resistance changes) effects were analyzed, and the slopes and the dose of norepinephrine required to increase mean arterial pressure by 20% were calculated (PD(20)). At no time did the systemic hemodynamics and the need for vasopressor support differ between the two treatment groups. However, for anesthesia induction, significantly less fentanyl and midazolam were given in the ACEI group. Although plasma renin activity was significantly greater in the ACEI group throughout the whole 24-h study period, plasma concentrations of angiotensin II did not differ between the two groups. Similar changes in catecholamines angiotensin II, and plasma renin activity were found in the two groups in response to surgery and CPB. The pressor and constrictor effects of norepinephrine infusion were attenuated markedly in the ACEI group: the dose-response curves were shifted to the right and the slopes were decreased at the two study periods; PD(20) was significantly greater during hypothermic CPB (0.08 micro/kg in the ACEI group vs. 0.03 micro/kg in the control group; P < 0.05) and after separation from CPB (0.52 micro/kg in the ACEI group vs. 0.1 micro/kg in the control group; P < 0.05). In both groups, PD(20) was significantly less during hypothermic CPB than in the period immediately after CPB. Long-term ACE inhibitor treatment in patients with preserved left ventricular function alters neither the endocrine response nor the hemodynamic stability during cardiac surgery. However, a significantly attenuated adrenergic responsiveness associated with incomplete blockade of the plasma renin-angiotensin system supports the hypothesis that inhibition of angiotensin II generation and of bradykinin degradation within the vascular wall mediates some of the vasodilatory effects of ACE inhibitors.

Long-Term Benefits of the Antiproteinuric Effect of Angiotensin-Converting Enzyme Inhibition in Nondiabetic Renal Disease

The long-term (1.5 years) effects of angiotensin-converting enzyme inhibition were evaluated in 22 mostly normotensive patients with nondiabetic renal disease and moderate to severe proteinuria. The nephrotic-range proteinuria of 7.5 g/24 hr fell to 2.9 g/24 hr (-62%) after 2 months' treatment with an angiotensin-converting enzyme inhibitor and remained relatively stable at this level during continued treatment. The antiproteinuric response varied between study days and between individuals. Of note was the fact that the best antiproteinuric response was observed on those study days when no more than the instituted daily sodium intake (50 to 100 mEq/24 hr) was excreted. The sustained reduction in urinary protein excretion was accompanied by an increase in serum albumin and a slight but significant decrease in serum cholesterol. Those patients with the most pronounced initial antiproteinuric response showed less deterioration of renal function, estimated from the slope of the inverse serum creatinine value in time. These data suggest that long-term angiotensin-converting enzyme inhibitor treatment may be beneficial in normotensive patients with nephrotic-range proteinuria, not only to reduce the symptoms of a nephrotic syndrome, but also to prevent further renal damage.