Role Of Angiotensin-converting Enzyme Inhibitors Research Articles

Current Issues on the Angiotensin II Receptor Blocker in Cardiovascular Disease

❙ABSTRACT❙ To reduce cardio-cerebro-vascular and renal morbidity and mortality, the current guidelines on the treatment of hypertension recommend evaluating and managing total cardiovascular risks of the patient with hypertension, not just focused on reducing blood pressure itself. In this point of view, the angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) are considered to be ideal drugs in the treatment of hypertension, because the angiotensin II plays a pivotal role in every stage of cardiovascular disease continuum. Many studies have shown that the ARBs were not only effective in lowering blood pressure, but also had another role in reducing morbidity and mortality of heart failure, myocardial infarction, stroke, diabetic nephropathy, chronic kidney disease, and the recurrence of atrial fibrillation, so called beyond blood pressure lowering effects or pleiotropic effects. However, these favorable effects of ARBs are counter-balanced by some debating issues, myocardial infarction paradox or cancer risk. Furthermore, the issue whether ARBs could replace the role of ACEIs in the treatment of cardiovascular diseases is not resolved yet. Because there have been no randomized studies proving the ARBs are better than ACEIs in terms of cardiovascular morbidity or mortality, the current status of the role of ARBs are an reasonable alternative of ACEIs. In this review, the current issues and status of ARBs will be discussed. (J Korean Soc Hypertens 2012;18(1):17-23)

Stimulation of the AT2 receptor reduced atherogenesis in ApoE−/−/AT1A−/− double knock out mice

AT1 receptor blockers (ARB) and in part ACE inhibitors (ACI) potentially exert beneficial effects on atherogenesis independent of AT1 receptor inhibition. These pleiotropic effects might be related to angiotensin II mediated activation of the AT2 receptor. To analyze this hypothesis we investigated the development of atherosclerosis and the role of ACIs and ARBs in apolipoprotein E-deficient (ApoE−/−) mice and in ApoE/AT1A receptor double knockout mice (ApoE−/−/AT1A−/−). ApoE−/− mice and ApoE−/−/AT1A−/− mice were fed cholesterol-rich diet for 7weeks. Vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation were evident in ApoE−/− mice, but were markedly reduced in ApoE−/−/AT1A−/− mice. Concomitant treatment of ApoE−/−/AT1A−/− mice with either telmisartan or ramipril had no additional effect on blood pressure, vascular oxidative stress, AT2 receptor expression, and endothelial function. Remarkably, atherosclerotic lesion formation was increased in ramipril treated ApoE−/−/AT1A−/− mice compared to untreated ApoE−/−/AT1A−/− mice whereas pharmacological AT1 receptor inhibition with telmisartan had no additional effect on atherogenesis. Moreover, chronic AT2 receptor inhibition with PD123,319 significantly increased plaque development in ApoE−/−/AT1A−/− mice. In additional experiments, direct AT2 receptor stimulation reduced atherogenesis in ApoE−/−/AT1A−/− mice. Taken together, our data demonstrate a relevant antiatherosclerotic role of the AT2 receptor in atherosclerotic mice and provide novel insight in RAS-physiology.

Histological changes in sarcopenia and the possible protective role of angiotensin-converting enzyme inhibitors in male albino rats

Histological changes in sarcopenia and the possible protective role of angiotensin-converting enzyme inhibitors in male albino rats

Systematic Review and Meta-Analysis: Renin-Angiotensin System Inhibitors in the Prevention of Atrial Fibrillation Recurrences. An Unfulfilled Hope

To analyze the published data on the role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II-receptor blockers (ARBs) in secondary prevention of AF. Some post-hoc analyses from trials in different clinical scenarios suggested the efficacy of ACEIs and ARBs in the prevention of new onset atrial fibrillation (AF), while their efficacy in preventing AF recurrences is notably controversial. The authors reviewed all published prospective, randomized vs. placebo or no-treatment studies, concerning the effect of ACEIs and ARBs in the prevention of AF recurrences. Four ACEIs studies accounting for a total of 355 patients and six ARBs studies comprising 4.040 patients were analyzed. The pooled ACEIs data showed a statistical significant effect in preventing AF recurrences. However, the studies did not have a robust follow-up algorithm to recognize AF episodes, and were individually very small. On the contrary, pooled ARBs data did not show any effect in preventing AF recurrences (RR 0.90; 95% CI, 0.75-1.08; p = 0.24). The ARBs analyzed population was much larger in three large prospective, randomized, double-blind, placebo-control trials with transtelephoning monitoring of AF recurrences and neutral results. The meta-analysis of ACEIs and ARBs trials together could suggest a publication bias that may result in an overestimation of the treatment effect. Currently there is no role for ARBs in secondary prevention of AF. With regard to ACEIs, the data are not strong enough for a conclusion, although the efficacy is expected to be the same as that of ARBs.

Acute Kidney Injury After Cardiac Surgery in Infants and Children: Evaluation of the Role of Angiotensin-Converting Enzyme Inhibitors

Children with congenital heart disease who undergo cardiac surgery are vulnerable to acute kidney injury (AKI). This study sought to evaluate the role of angiotensin-converting enzyme (ACE) inhibitors and other nephrotoxic medications in the risk for the development of AKI in neonates and children undergoing cardiac surgery. A retrospective review of all patients younger than 2 years admitted to the cardiac intensive care unit after cardiac surgery from March 2007 to September 2008 was conducted. Patients were included in the review if they received furosemide alone or in combination with an ACE inhibitor. Creatinine clearance was calculated, and the patient's maximal degree of AKI was classified by pRIFLE. A P value less than 0.05 was considered significant. Of the 319 patients who met the inclusion criteria, 149 (47%) received furosemide therapy alone and 170 (53%) received a combination of furosemide and an ACE inhibitor. Patients in the furosemide-only group (age, 5 months) were older than the patients who received both furosemide and an ACE inhibitor (age, 3.8 months; P = 0.024). Despite statistically higher Aristotle scores in the ACE-inhibitor group, the intraoperative variables did not differ between the two groups. Postoperatively, the ACE-inhibitor group had a decreased creatinine clearance (55.3 ml/min/1.73 m(2)) compared with the furosemide group (64.4 ml/min/1.73 m(2); P = 0.015) and an increased incidence of a pRIFLE maximal score of "F" (odds ratio [OR], 1.75; P = 0.033). However, after adjustment for additional risk factors, no difference in the occurrence of AKI resulted (OR, 0.939; P = 0.85) when patients received an ACE inhibitor. More than half of the study population received ACE inhibitors, but this treatment was not associated with an increase in AKI.

Role of angiotensin-converting enzyme inhibitors in visceral angioedema

A rare complication that occurs in patients taking ACE-inhibitors is visceral angioedema. It can affect about 1 in 2500 patients during the first week of exposure [ 1 Brown N.J. Snowden M. Griffin M.R. Recurrent angiotensin-converting enzyme inhibitor-associated angioedema. JAMA. Jul 16 1997; 278: 232-233 Crossref PubMed Google Scholar , 2 Israili Z.H. Hall W.D. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med. Aug 1 1992; 117: 234-242 Crossref PubMed Scopus (887) Google Scholar , 3 Messerli F.H. Nussberger J. Vasopeptidase inhibition and angio-oedema. Lancet. Aug 19 2000; 356: 608-609 Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar ]. The prevalence of angioedema secondary to the use of ACE inhibitors varies anywhere from 0.1 to 0.7 % and usually manifests itself with the involvement of the face, tongue, lips and in rare cases the gastrointestinal wall. Middle aged female patients on an ACE inhibitor presenting with abdominal pain, vomiting, diarrhea, leukocytosis, ascites and small bowel wall thickening on the imaging studies should be examined closely [ 4 Weber M.A. Messerli F.H. Angiotensin-converting enzyme inhibitors and angioedema: estimating the risk. Hypertension. Jun 2008; 51: 1465-1467 Crossref PubMed Scopus (47) Google Scholar , 5 Oudit G. Girgrah N. Allard J. ACE inhibitor-induced angioedema of the intestine: case report, incidence, pathophysiology, diagnosis and management. Can J Gastroenterol. Dec 2001; 15: 827-832 Crossref PubMed Scopus (37) Google Scholar , 6 Gibbs C.R. Lip G.Y. Beevers D.G. Angioedema due to ACE inhibitors: increased risk in patients of African origin. Br J Clin Pharmacol. Dec 1999; 48: 861-865 Crossref PubMed Scopus (116) Google Scholar , 7 Johnsen S.P. Jacobsen J. Monster T.B. Friis S. McLaughlin J.K. Sorensen H.T. Risk of first-time hospitalization for angioedema among users of ACE inhibitors and angiotensin receptor antagonists. Am J Med. Dec 2005; 118: 1428-1429 Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar ]. Multiple invasive and unnecessary procedures can be avoided by raising awareness of this complication. Most of the patients diagnosed with angioedema required hospitalization due to the severity of symptoms and the exclusion of other possible diseases [ [7] Johnsen S.P. Jacobsen J. Monster T.B. Friis S. McLaughlin J.K. Sorensen H.T. Risk of first-time hospitalization for angioedema among users of ACE inhibitors and angiotensin receptor antagonists. Am J Med. Dec 2005; 118: 1428-1429 Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar ].

Insight into Retardation of Aortic Stenosis: A Therapeutic Role for ACE Inhibitors?

Insight into Retardation of Aortic Stenosis: A Therapeutic Role for ACE Inhibitors?

Reviewing the future of renin-angiotensin system blockade: The role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the prevention of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, affecting approximately 250,000 Canadians and accounting for more than 120,000 hospitalizations each year. Atrial remodelling, which is at least partially induced by activation of the renin-angiotensin system (RAS), can be reversed by RAS blockade using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. While RAS antagonists are not considered to be conventional anti-arrhythmic agents, several studies have shown that they may reduce the incidence of AF in patients with heart failure, after myocardial infarction with reduced ejection fraction, and in hypertensive patients. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have also been used in association with amiodarone to facilitate sinus rhythm maintenance after electrical cardioversion. Whether RAS blockade prevents recurrent AF in patients at high cardiovascular risk remains unknown.

Role of Angiotensin-Converting Enzyme Inhibitors in Vascular Modulation: Beyond the Hypertensive Effects

Angiotensin-converting enzyme (ACE) inhibitors are being widely used as antihypertensives by clinicians worldwide. One in every three Americans has hypertension. Hypertension, diabetes, obesity, active smoking, hypercholesterolemia, and inactivity are the major cardiovascular risk factors, which can produce compounding effects on human health, leading to cardiovascular morbidity and mortality. We review the mechanism of action of ACE inhibitors and explain the rationale for using ACE inhibitors not only in hypertensive patients but also in patients with congestive heart failure, acute myocardial infarction, or coronary artery disease. ACE inhibitors can reduce preload and afterload on the heart, prevent ventricular remodeling, and even retard atherogenic changes in the vessel walls. ACE inhibitors can also be helpful in slowing the progression of kidney disease, especially in diabetics. Some studies such as the Heart Outcomes Prevention Evaluation study have shown that ACE inhibitors can reduce the risk of cardiovascular morbidity and mortality, particularly in high-risk individuals. The renin-angiotensin-aldosterone system plays an important role in regulating blood pressure and body volume in the human body. ACE inhibitors and angiotensin-receptor blockers are the two classes of antihypertensives that primarily act on the renin-angiotensin-aldosterone system. We discuss randomized, controlled trials that evaluated different ACE inhibitors and compare them with angiotensin-receptor blockers.

Hypertension and atrial fibrillation

Atrial fibrillation (AF) is an emerging public health problem. The most important risk factor for developing chronic AF is uncontrolled hypertension. Uncontrolled hypertension promotes the initiation and perpetuation of AF through atrial remodeling. Experimental evidence has demonstrated the important role of the renin-angiotensin system in atrial remodeling. Retrospective analysis of several large clinical trials and small prospective trials suggests the beneficial role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in preventing the onset and recurrence of AF in different populations. Several large prospective trials with longer follow-up periods are in progress. These trials may provide definitive evidence for the use of these agents in the prevention of AF.

The role of ACE inhibitors in the treatment of arrhythmias

Several experimental models have been studied to determine the role of angiotensin-converting enzyme (ACE) inhibitors in reducing ischemic and reperfusion arrhythmias. Studies of left main coronary artery occlusion in isolated perfused rat hearts have shown that the ACE inhibitor captopril reduced reperfusion ventricular fibrillation from 100% to 0% and was associated with a reduction in purine overflow and in norepinephrine release. These effects were abolished in the presence of indomethacin. In an anesthetized rat model of acute myocardial infarction (MI), ACE inhibition reduced mean duration of ventricular fibrillation from 1,133 to 135. ACE inhibition at programmed electrical stimulation of the heart in a closed-chest pig model of acute MI reduced the inducibility of sustained, reproducible ventricular tachycardia from a mean of 42 to 8%. In this model, ventricular tachycardia could not be provoked in animals treated with captopril from the time of acute ischemia. Studies on the rate of ventricular ectopy in patients with poor left ventricular function have demonstrated a significant reduction with ACE inhibition. However, while a protective effect has been shown, the mechanism of action is still speculative.

Lessons learned from the ONTARGET and TRANSCEND trials

Cardiovascular disease (CVD) accounts for one of every three deaths in the United States. In recent years, a greater understanding of the renin-angiotensin-aldosterone system's (RAAS) contribution to CVD, particularly in the area of blood pressure regulation, has emerged. Thus, interrupting or blocking the RAAS has become a key component in the treatment of hypertension and other cardiovascular conditions. The role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in reducing CVD in high-risk populations has been demonstrated by two recently completed major trials: the Ongoing Telmisartan Alone and in Combination with Ramipril Global endpoint Trial (ONTARGET) and the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease (TRANSCEND). This article describes these key studies and their outcomes and identifies critical issues that they raise for clinical practice in terms of choosing the most effective therapy for patients with existing CVD.

Physician Characteristics and Knowledge of CKD Management

Many studies suggest that chronic kidney disease (CKD) care is suboptimal in the United States. However, it is not known whether knowledge of CKD management in primary care physicians (PCPs) might have an important role in the suboptimal care and whether PCP characteristics are associated with having adequate knowledge. Cross-sectional study. Self-administered questionnaire sent to a random sample of 1,550 US PCPs in February 2007. PCP characteristics, including age, sex, degree (MD versus DO), primary specialty, board certification, patient volume, percentage of time in patient care spent in the inpatient versus outpatient setting, and number of patients referred to nephrologists in a month. Regression analyses of the association between physician characteristics and overall physician knowledge of CKD management, as well as individual subdomains of CKD knowledge related to recognition of CKD and management of hypertension in the setting of CKD. 470 of 1,453 (32.4%) eligible PCPs returned a completed survey. PCPs show significant variation in their ability to recognize CKD stages 2 to 4, but most have appropriate blood pressure goals in patients with CKD and are knowledgeable of the role of angiotensin-converting enzyme inhibitors in managing proteinuria. For each 10-year increase in age, the odds of showing satisfactory knowledge of CKD management decreased by 26% (odds ratio, 0.74; 95% confidence interval, 0.60 to 0.92). PCPs with the primary specialty of internal medicine had a more than 3-fold greater odds of showing a satisfactory level of knowledge compared with family practice specialists (odds ratio, 3.40; 95% confidence interval, 2.17 to 5.32). The study findings are limited by the potential presence of nonresponse bias, information bias, and results suggesting there are multiple knowledge subdomains that perhaps are not additive. There is need to improve CKD knowledge in PCPs, especially regarding recognition of CKD at an early stage.

ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN MANAGEMENT OF PATIENTS WITH CHRONIC HEART FAILURE

The role of ACE inhibitors in modern pharmacotherapy of patients with chronic heart failure (CHF) is discussed. The actual usage of these highly effective drugs is underlined taking into account high prevalence and social significance of CHF. Necessity of ACE inhibitors usage is confirmed by pharmacodynamic features of these drugs in CHF. The special attention is given to enalapril, that has the biggest evidence base in treatment of CHF patients.

The importance of managing cardiovascular risk in the treatment of hypertension: The role of ACE inhibitors and ARBs

Disclosure: This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. Each participant received an honorarium from Boehringer Ingelheim Pharmaceuticals, Inc. for time and effort involved in participating in the discussion and reviewing the transcript for accuracy of content and readability prior to publication. The participants retained full control of the discussion and the resulting content of this article. The content was not reviewed or changed by Boehringer Ingelheim Pharmaceuticals, Inc. in any way.

In-Stent Restenosis of the Renal Artery in a Single Kidney Patient: The Role of ACEI in the Therapeutic Choice

Renal artery stenosis (RAS) caused by atherosclerotic changes of the renal arteries has become a concern as a cause of end-stage renal failure. Percutaneous balloon angioplasty with or without endovascular stenting is an increasingly accepted procedure at the expense of classical approaches such as aortorenal bypass and other types of surgery. Renal percutaneous transluminal angioplasty and stenting (RPTAS) represent the first therapeutic choice; however, there is doubt regarding the satisfactory long-term outcome for primary RPTAS. Currently, there is no clear evidence whether or not RPTAS prevents further progressive renal function decline because comparisons between interventional randomized studies and medical therapy are still lacking. Despite the fact that the use of angiotensin-converting enzyme inhibitors (ACEIs) may be a potential cause of acute renal failure, clinical data suggest that ACEI therapy is associated with better survival in patient with RAS. In our case, the use of ACEIs has been fundamental for the indirect evaluation of restenosis degree and RPTAS.

Secondary Prevention After Acute Myocardial Infarction and Coronary Revascularisation: Focus on Angiotensin Converting Enzyme Inhibitors

Cardiovascular disease (CVD) is responsible for an estimated one third of all deaths worldwide. One group of patients who are at a particularly high risk of cardiovascular events and death are those with stable coronary artery disease (CAD), especially if they have had a previous myocardial infarction (MI) or revascularisation. Lifestyle changes (smoking, alcohol intake, diet, exercise) and cardiac rehabilitation play an important part in reducing risk of recurrent events. In patients with a history of MI and/or those who underwent myocardial revascularisation these have to be supplemented with medication. Several pharmacological agents are known to improve prognosis in these patients, i.e. beta-blockers, antiplatelet agents, statins, and angiotensin converting enzyme inhibitors (ACEi). The present article focuses mainly on the role of ACEi in the prevention of cardiovascular events in patients with a history of MI or myocardial revascularization.

Use of Statins and Angiotensin Converting Enzyme Inhibitors (ACE-Is) and the Risk of Age-Related Macular Degeneration: Nested Case-Control Study

Age related macular degeneration (AMD) is a progressive degenerative disease affecting central vision. Recent studies have shown that that statins may lower the risk of AMD potentially due to statins' anti-inflammatory and anti-oxidative properties. We sought to further explore this association and also explore the role of angiotensin-converting enzyme inhibitors (ACE-Is) with respect to the development of AMD. We conducted a nested case-control study within a cardiovascular cohort that had undergone revascularization interventions in the Province of Quebec, Canada. Cases were identified as those with an ICD-9 code for AMD. For each case, four controls were randomly chosen from the cohort and matched to the cases by age and calendar time. Conditional logistic regression was used to estimate rate ratios and adjust for potential confounders. Our nested case-control study consisted of 2,867 cases and 11,468. Current users of ACE-Is or statins were at a slightly higher risk of developing AMD (1.19 [1.07-1.33]) and (1.30 [1.17-1.44]) respectively. The results were similar for those using these drugs in the year prior. Based on the results of our study, statin and ACE-I use may be associated with an increase in the risk of AMD. Given that our study is an observational study, further studies are required to confirm or refute these findings.

Angiotensin-Converting Enzyme Inhibitor Attenuates Monocyte Adhesion to Vascular Endothelium through Modulation of Intracellular Zinc

To elucidate an anti-inflammatory role of angiotensin-converting enzyme inhibitors (ACEIs) in cardiovascular disease, we studied the effect of ACEIs in monocyte adhesion to endothelial cells and underlying molecular mechanisms. Treatment of human monocytic THP-1 cells with monocyte chemoattractant protein-1 (MCP-1; 100 ng/ml; 10 min) significantly increased their adhesion to human umbilical vein endothelial cells (HUVECs) under flow condition (P < 0.001). Preincubation of THP-1 cells with imidaprilat (50 nM; 4 h), an active metabolite of imidapril, reduced MCP-1-triggered THP-1 cell adhesion (P < 0.01). Similar effects were obtained with experiments using human peripheral monocytes (P < 0.05). MCP-1 activated protein kinase C (PKC)alpha in THP-1 cells, resulting in the up-regulation of alpha4 and beta2 integrin. Imidaprilat attenuated MCP-1-induced PKC activation and integrin up-regulation in THP-1 cells. Imidaprilat also inhibited THP-1 cell adhesion induced by phorbol 12-myristate 13-acetate (PMA), a potent PKC activator. In attempt to elucidate the mechanisms for the modulation of PKC activity by imidaprilat, we found that MCP-1 or PMA increased labile zinc in THP-1 cells, which was canceled by imidaprilat. Indeed, zinc/pyrithione activated PKC and increased THP-1 cell adhesion. Zinc chelator as well as PKC inhibitor inhibited these processes, suggesting the role for labile zinc in PKC activation and THP-1 cell adhesion. Imidaprilat attenuated zinc/pyrithione-induced PKC activation and THP-1 cell adhesion. These data suggest that ACEI reduces MCP-1 or PMA-triggered monocyte adhesion to activated HUVECs by modulating labile zinc in monocytes. Our findings may point out a novel anti-inflammatory mechanism of ACEIs in atherogenesis.

Contribution of perindopril to cardiology: 20 years of success

Cardiovascular risk factors such as hypertension and diabetes are known to initiate a chain of events that include oxidative stress, endothelial dysfunction, and vascular remodelling, and that if left to progress unchecked, will eventually culminate in end-stage cardiovascular disease. Perindopril is a long-acting lipophilic inhibitor of tissue angiotensin-converting enzyme (ACE) that has been studied in a variety of patient populations, ranging from those with hypertension to more advanced-stage cardiovascular disease. Although the role of ACE inhibitors is well established for patients with hypertension or heart failure, large morbidity–mortality trials have proved the efficacy of perindopril in a comparatively wide range of patients at risk of cardiovascular events, including patients with a history of stroke or transient ischaemic attack, irrespective of whether hypertension was present, and patients with stable coronary artery disease without heart failure or substantial hypertension. In addition, relative to a standard antihypertensive regimen based on a b-blocker/ diuretic, a calcium antagonist/perindopril-based regimen has been shown to provide more effective broad-spectrum prevention of cardiovascular events in hypertensive patients. Early studies revealed that, in addition to sustained 24 h antihypertensive activity with once-daily dosing, perindopril is able to reverse arterial remodelling in hypertensive patients. Furthermore, subanalyses of data from morbidity–mortality trials have shown that reversal of abnormal endothelial function and reductions in central aortic pressure may help to account for benefits observed with perindopril that extend beyond those expected from reductions in brachial blood pressure alone. In summary, although it is already a well-established antihypertensive drug, pivotal clinical trials are still helping to unravel the true potential of perindopril across the cardiovascular continuum.