Chronic ACE Inhibitor Therapy Research Articles

Gradual reactivation of vascular angiotensin I to angiotensin II conversion during chronic ACE inhibitor therapy in patients with diabetes mellitus

In chronic heart failure there is gradual reactivation of vascular tissue angiotensin I (AI) to angiotensin II (AII) conversion over time in patients taking chronic ACE inhibitor therapy. However, it remains unknown whether the same overall phenomenon occurs in other patients taking chronic ACE inhibitor therapy, such as patients with type 2 diabetes mellitus. We studied 30 patients with type 2 diabetes mellitus (mean age 43.5 +/- 10.8 years), all of whom received lisinopril (20 mg/day) as part of their normal treatment. Over the course of the 18 month study, we made measurements at 0, 9 and 18 months. These measurements included plasma values for components of the renin-angiotensin-aldosterone system. In addition, we infused AI and AII into the brachial arteries of patients to assess vascular tissue AI to AII conversion. There were no significant changes in plasma renin activity, ACE, AI, AII or aldosterone during the study. In contrast, vascular AI to AII conversion was significantly (p = 0.01) greater at 18 months than at 0 months. There was no change over time in the response to infused AII. We have shown in vivo that vascular tissue AI to AII conversion gradually increases over time in patients with type 2 diabetes being treated with lisinopril. Further studies are required to determine whether this reactivation detracts from the cardioprotective effects of chronic ACE inhibitor therapy in diabetic patients, and if so, how best to overcome it.

Progressive left ventricular hypertrophy after withdrawal of long‐term ACE inhibition following experimental myocardial infarction

Although discontinuation of chronic ACE inhibitor (ACEi) therapy after myocardial infarction (MI) is common in clinical practice, some clinical studies reported an increased incidence of ischemia-related events after withdrawal. To further address this issue, we assessed hemodynamic, neurohormonal and vascular consequences of withdrawing long-term ACEi treatment after experimental MI. Rats were subjected to coronary ligation to induce MI, and received quinapril (15 mg/kg/day) from 2 weeks to 14 months post-MI. Subsequently, surviving rats were randomized to sacrifice at 0, 4, and 6 weeks after ACEi withdrawal. Rats were studied for signs of heart failure, hemodynamics and cardiac function, neurohormones, and vascular edothelial function. After discontinuation of ACEi treatment, plasma aldosterone levels increased between 0-4 weeks without further increment thereafter, suggesting persistent RAAS activation. Acetylcholine-induced aortic relaxation was impaired at 4 and 6 weeks, indicating rapid and sustained development of endothelial vasodilator dysfunction after withdrawal. Moreover, 24% of the rats developed heart failure signs (edema, dyspnea), and 3 rats died, all within 4 weeks after withdrawal. Significantly increased N-ANP levels and lung weights at 4, but not at 6 weeks suggest a transient volume overload. Finally, LV/body weight ratios significantly increased between 0-4 as well as 4-6 weeks, indicating progressive LV hypertrophy. The observed alterations after withdrawing long-term post-MI quinapril treatment in the present study may account for an increased risk for ischemic events. Thus, our findings highlight the potentially harmful effects associated with abrupt discontinuation of long-term post-MI ACE inhibition, and imply careful clinical consideration in this matter.

Improvement of EDHF by Chronic ACE Inhibition Declines Rapidly After Withdrawal in Rats With Myocardial Infarction

Heart failure after myocardial infarction (MI) is associated with endothelial dysfunction. There is conflicting evidence on the exact nature of this endothelial dysfunction and how endothelium-dependent vasodilation is affected by angiotensin-converting enzyme inhibitor (ACE-I) therapy. Furthermore, consequences of acute ACE-I withdrawal are largely unknown. Therefore, we studied the contribution of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) to the effects of ACE-I therapy and its withdrawal on endothelial function in MI rats. Rats were subjected to coronary ligation to induce MI and were assigned to quinapril or vehicle from 2 weeks to 8 months post-MI. In parallel, MI rats treated for 14 months with quinapril were subjected to treatment withdrawal for 0, 4, and 6 weeks. Acetylcholine (ACh)-induced relaxation and underlying endothelium-derived mediators were studied in isolated aortic rings. Long-term quinapril (8 months) resulted in markedly improved endothelium-dependent vasodilation in rats with myocardial infarction, which could be attributed to marked improvement in non-NO/prostanoid-mediated relaxation (ie, EDHF). After 14 months of follow-up, maximum vasodilation was still preserved by quinapril. Withdrawal after 14 months of treatment caused significantly impaired ACh-induced EDHF-mediated relaxation within 4 weeks. A marked reduction in EDHF-mediated relaxation caused this impairment. NO-mediated relaxation was unaffected. These findings highlight the importance of EDHF impairment in development of endothelial dysfunction after myocardial infarction and the possibility of improving EDHF-mediated vasodilation with chronic ACE inhibitor therapy. In addition, withdrawal of chronic ACE inhibition after MI should be considered carefully, as profound endothelial dysfunction may develop rapidly.

The Quinapril Ischemic Event Trial (QUIET): evaluation of chronic ace inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function

Angiotensin-converting enzyme inhibitors improve endothelial function, inhibit experimental atherogenesis, and decrease ischemic events. The Quinapril Ischemic Event Trial was designed to test the hypothesis that quinapril 20 mg/day would reduce ischemic events (the occurrence of cardiac death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary artery bypass grafting, coronary angioplasty, or hospitalization for angina pectoris) and the angiographic progression of coronary artery disease in patients without systolic left ventricular dysfunction. A total of 1,750 patients were randomized to quinapril 20 mg/day or placebo and followed a mean of 27 ± 0.3 months. The 38% incidence of ischemic events was similar for both groups (RR 1.04; 95% confidence interval 0.89 to 1.22; p = 0.6). There was also no significant difference in the incidence of patients having angiographic progression of coronary disease (p = 0.71). The rate of development of new coronary lesions was also similar in both groups (p = 0.35). However, there was a difference in the incidence of angioplasty for new (previously unintervened) vessels (p = 0.018). Quinapril was well tolerated in patients after angioplasty with normal left ventricular function. Quinapril 20 mg did not significantly affect the overall frequency of clinical outcomes or the progression of coronary atherosclerosis. However, the absence of the demonstrable effect of quinapril may be due to several limitations in study design.

Angiotensin II plasma levels during chronic ACE inhibitor therapy are modulated by ACE insertion/deletion gene polymorphism Ralph Winkler, Markus Nauck, Willfried M�rz, Florian Mokler, B�rbel Klein, Rahime G�k, Jochen Senges, Bernhard R. Winkelmann. Herzzentrum Ludwigshafen, Ludwigshafen, Germany, Universit�t Freiburg, Freiburg, Germany

Angiotensin II plasma levels during chronic ACE inhibitor therapy are modulated by ACE insertion/deletion gene polymorphism Ralph Winkler, Markus Nauck, Willfried M�rz, Florian Mokler, B�rbel Klein, Rahime G�k, Jochen Senges, Bernhard R. Winkelmann. Herzzentrum Ludwigshafen, Ludwigshafen, Germany, Universit�t Freiburg, Freiburg, Germany

Chymase-dependent angiotensin II formation in human blood vessels.

The mainstayof this therapeutic strategy is to block the formationof effector peptide, angiotensin II, by inhibition ofangiotensin-converting enzyme (ACE). However,angiotensin II levels have been shown to return topre-treatment levels following chronic ACE inhibi-tor therapy, and reductions in blood pressure greaterthan those observed with ACE inhibitors alone canbe obtained by co-administration of angiotensinreceptor antagonists with an ACE inhibitor.

Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure.

The aim of the study was to assess the incidence and clinical implications of increased plasma angiotensin II despite chronic ACE inhibitor therapy in patients with heart failure. The studied population consisted of 70 patients (mean age 59+/-9 years). Plasma renin activity and plasma concentration of aldosterone, norepinephrine, atrial natriuretic peptide, angiotensin II, tumour necrosis factor, interleukin-6 and interleukin-1B were assessed at 6 months of ACE inhibitor therapy. Mean left ventricular ejection fraction was 24+/-5% and the end-systolic and end-diastolic diameters were 59+/-9 and 71+/-8 mm, respectively. Despite chronic enalapril or captopril therapy, 35 patients (50%) had increased plasma angiotensin II (median 33 pg. ml(-1), range 17-84), while it was in the normal range in the remaining 35 patients (median 10 pg. ml(-1), range 5-15). Plasma renin activity (P=0.005), interleukin-6 (P=0.004), New York Heart Association functional class III-IV (P=0. 006), furosemide dose (P=0.01), lack of beta-blocker therapy (P=0. 04) and norepinephrine (P=0.04) were univariately associated with increased angiotensin II. Multivariate regression analysis identified the plasma renin activity (0.0004), norepinephrine (0.02) and interleukin-6 (0.03) as independent predictors of plasma angiotensin II. During follow-up (35+/-29 months), nine (12.8%) patients died and 13 had new heart failure episodes. Increased plasma angiotensin II, despite ACE inhibitor therapy, was a significant predictor of death or heart failure according to the Kaplan-Meier survival method by log rank test (P=0.002). Fifty per cent of patients with heart failure, ha increased plasma angiotension II despite chronic ACE inhibitor therapy. These patients had higher neurohormonal activation and poor prognosis.

Neurohormonal reactivation in heart failure patients on chronic ACE inhibitor therapy: a longitudinal study.

Angiotensin Converting Enzyme inhibitors reduce mortality in heart failure. One therapeutic mechanism is believed to be the reduction of circulating angiotensin II and aldosterone. However, the Renin-Angiotensin-Aldosterone axis (RAAS) is not uniformly suppressed during therapy for heart failure. This effect has been referred to as 'angiotensin II reactivation' and 'aldosterone escape' and their reactivation may herald clinical deterioration. In the CONSENSUS I trial, correlations were seen between mortality, and angiotensin II and aldosterone. Furthermore, mortality was lower in those with good angiotensin II suppression. Therefore, neurohormonal elevation despite adequate treatment may associate with a poorer prognosis. To follow chronic heart failure patients on ACE inhibitors for 18 months to assess whether or not angiotensin II and aldosterone reactivation are progressive with time, whether reactivation of both occurs simultaneously, and whether different ACE inhibitors have different neurohormonal profiles. We studied 22 patients (M/F 19:3, 72.5+/-7 years) on stable ACE inhibitors. Five times, in 18 months, samples were taken for neurohormones and ACE activity. Mean levels of neurohormones were remarkably stable over time, although captopril takers had generally higher angiotensin II, but lower aldosterone and renin. Aldosterone 'escape' (> 80 pg/ml) occurred in 13/97 samples (13.5%), in 5/22 (23%) individuals. Angiotensin II was elevated > or =10 pg/ml in 8/102 samples (8%), in 6/22 (27%) individuals. Four subjects had isolated angiotensin II reactivation, and three had aldosterone escape alone. On regression analyses between neurohormones in captopril takers there were significant correlations between; renin and angiotensin II (r = 0.62; P<0.02); angiotensin II and aldosterone (r = 0.6; P<0.02); and renin and aldosterone (r = 0.92; P<0.00001). In stable heart failure patients un-suppressed levels of angiotensin II and aldosterone occur despite therapy, but they are not necessarily progressive, nor simultaneous. Furthermore, contemporaneous serum ACE activity makes it unlikely the data presented reflects poor compliance. The results suggest that captopril takers may have different neurohormonal profiles, i.e. higher angiotensin II, and also better correlations between RAAS components, compared to longer acting preparations, although the numbers are small. Our data supports that of Swedberg et al. who showed reductions in both aldosterone and angiotensin II due to ACE inhibitor therapy, but no correlation between ACE activity and angiotensin II and only a limited correlation (r = 0.37) between angiotensin II and aldosterone. This suggests that the interaction between the components of the renin-angiotensin system is not simple and linear. The fact that each phenomenon appears to occur in isolation means that neurohormonal monitoring of individual could provide useful information to direct additional therapy. The RALES study has demonstrated reduced mortality from the addition of spironolactone to an ACE inhibitor emphasising the benefit of enhanced suppression of aldosterone in heart failure. Captopril may be less effective at suppressing the RAAS due to its short duration of action which would logically be associated with a more fluctuating pattern of ACE inhibition. In the presence of high levels of renin and angiotensin I even small differences in ACE activity will produce large variations in angiotensin II levels. Further studies should be directed at understanding the different mechanisms behind angiotensin II and aldosterone generation during ACE inhibition.

Neurohormonal "Escape" During Chronic ACE-Inhibitor Therapy for CHF

Although acute angiotensin-converting-enzyme inhibition has been shown to virtually eliminate angiotensin II (AII) and substantially decrease

948-48 High-dose Lisinopril is More Effective than Low-dose in Suppressing Aldosterone in Patients with Chronic Heart Failure

The optimal dose of ACE inhibitor for the treatment of heart failure is highly controversial and it is uncertain whether the neurohormonal suppression produced by these drugs is dose-dependent. We therefore compared the effects of low-dose and high-dose lisinopril therapy on plasma levels of aldosterone, which causes several important adverse effects including hypokalaemia, hypomagnesaemia and stimulation of myocardial fibrosis. 15 patients with LVEF &lt; 45%, on chronic ACE inhibitor therapy, were given lisinopril 5 mg o.d. and 20 mg o.d. for two weeks each in a randomised order. At the end of each treatment period plasma aldosterone levels were measured, after 30 minutes bed rest, at 6 hours (peak effect) and 22 hours (trough effect) after the dose of lisinopril. The levels of aldosterone on each dose at these timepoints were compared using ANOVA. Lisinopril Dose Mean Plasma Aldosterone Concentration(pg/ml) Peak (6 hours) Trough (22 hours) 5 mg o.d. 163.0 186.7 20 mg o.d. 98.4 118.4 Plasma aldosterone levels were significantly lower during high-dose than during low-dose lisinopril treatment at both 6 hours (p &lt; 0.03) and at 22 hours (p &lt; 0.04). The suppression of aldosterone activity during chronic ACE inhibitor therapy in patients with heart failure is dose-dependent. This provides further evidence that ACE inhibitors should be routinely prescribed in high doses.

Modulation of myocardial sarcoplasmic reticulum Ca(++)-ATPase in cardiac hypertrophy by angiotensin converting enzyme?

Myocardial hypertrophy in response to hemodynamic overload is an established risk factor for cardiovascular morbidity and mortality. Partially, this may be due to alterations in cardiac gene expression, resulting in a more fetal-like myocyte phenotype with a fragile Ca(++)-homeostasis. Depressed expression of the sarcoplasmic reticulum Ca(++)-ATPase is the hallmark of this overload phenotype, contributing to prolonged cytosolic Ca(++)-transients, disturbed diastolic relaxation, altered force-frequency relation, and probably, electrophysiologic instability with susceptibility to malignant arrhythmias. Since angiotensin II is a growth-promoting factor in several cellular systems, the local formation of angiotensin II within the myocardium might contribute to the trophic response and the phenotype shift of overloaded myocardium. Several observations are consistent with this hypothesis: the cardiac expression of ACE and angiotensinogen is enhanced in experimental myocardial overload and in human endstage congestive heart failure; prolonged observations of experimental cardiac overload with hypertrophy-induced putative normalisation of myocardial systolic wall stress demonstrated a renormalization of ventricular tissue ACE activity and of ventricular sarcoplasmic Ca(++)-ATPase expression and activity; normalizing ventricular tissue ACE activity in experimental cardiac overload by chronic nonhypotensive ACE inhibitor therapy caused a parallel partial normalization of hypertrophy and underexpression of sarcoplasmic CA(++)-ATPase. This partial normalization of myocyte Ca(++)-homeostasis in overload hypertrophy by non-hypotensive chronic ACE-inhibition is attenuated by concomitant chronic application of bradykinin-2 receptor blockade, indicating an involvement of altered bradykinin metabolism in the phenotype modulation due to chronic ACE inhibition. While these observations are consistent with a direct influence of local ACE activity on the sarcoplasmic reticulum, the cell type contributing to the enhanced ACE expression in overload and the specific mechanism of this influence are unknown.

Angiotensin-Converting Enzyme Inhibition

Summary: Angiotensin-converting enzyme (ACE) is a widely distributed dipeptidyl carboxydipeptidasc. Using computer analysis of the binding of radiolaheled ACE inhibitors, we have mapped the distribution of ACE in normal animals and in models of disease, and have studied the tissue effects of ACE inhibitors. In the myocardium, ACE is located in vascular and valvular structures as well as in the atria and ventricles. Its concentration is increased in myocardial hypertrophy in the infarct model of heart failure. Chronic ACE-inhibitor therapy prevents myocardial hypertrophy. In the brain, ACE is localized in multiple specific sites where its role is unknown. Following oral ACE-inhibitor treatment, effects are restricted predominantly to areas devoid of blood-brain harrier. Early studies suggest ACE inhibitors enhance cognition. In the testis, ACE is located in the seminiferous tubules where its function is unknown. It is not inhibited following oral ACE-inhibitor treatment. In the kidney and gastrointestinal tract, ACE is in high concentration in the epithelial brush border where its function is unknown. In clinical use ACE inhibitors primarily affect the cardiovascular system. With pharmacological developments, ACE inhibitors targeted for specific organs may have effects predominantly in the brain, heart, reproductive system, or gastrointestinal tract.

Angiotensin-Converting Enzyme Inhibition

Angiotensin-converting enzyme (ACE) is a widely distributed dipeptidyl carboxydipeptidase. Using computer analysis of the binding of radiolabeled ACE inhibitors, we have mapped the distribution of ACE in normal animals and in models of disease, and have studied the tissue effects of ACE inhibitors. In the myocardium, ACE is located in vascular and valvular structures as well as in the atria and ventricles. Its concentration is increased in myocardial hypertrophy in the infarct model of heart failure. Chronic ACE-inhibitor therapy prevents myocardial hypertrophy. In the brain, ACE is localized in multiple specific sites where its role is unknown. Following oral ACE-inhibitor treatment, effects are restricted predominantly to areas devoid of blood-brain barrier. Early studies suggest ACE inhibitors enhance cognition. In the testis, ACE is located in the seminiferous tubules where its function is unknown. It is not inhibited following oral ACE-inhibitor treatment. In the kidney and gastrointestinal tract, ACE is in high concentration in the epithelial brush border where its function is unknown. In clinical use ACE inhibitors primarily affect the cardiovascular system. With pharmacological developments, ACE inhibitors targeted for specific organs may have effects predominantly in the brain, heart, reproductive system, or gastrointestinal tract.