Modulating atherosclerosis through inhibition or blockade of angiotensin

Angiotensin-convertng enzyme (ACE) inhibitors are well recognized for their benefits in treating hypertension and congestive heart failure and preventing postmyocardial infarction heart failure or left ventricular (LV) dysfunction. Recently, blockade of the angiotensin II type 1 (AT1) receptor was shown to reduce cardiovascular events in hypertensive subjects with LV hypertrophy. Several lines of evidence are now converging to show that ACE inhibitors may affect the atherosclerotic process itself. Emerging clinical data indicate that angiotensin-receptor blockers (ARBs) may possibly modulate atherosclerosis as well. The antiatherogenic properties of ACE inhibitors and ARBs may derive from inhibition or blockade of angiotensin II, now recognized as an agent that increases oxidative stress.Angiotensin-converting enzyme inhibition and angiotensin-receptor blockade also increase endothelial nitric oxide formation, which improves endothelial function. In contrast to the effects of ARBs, the vascular effects of ACE inhibitors may, in part, be mediated by an increase in bradykinin. This article reviews some of the biologic mechanisms whereby ACE inhibitors and ARBs may modulate atherosclerosis.     

Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for hypertension on clinical end points: a cohort study

J Clin Hypertens (Greenwich). 2012; 14:407–414. ©2012 Wiley Periodicals, Inc. Important questions concerning the comparative effectiveness of angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) remain unanswered, including whether they are equally effective in reducing clinical end points and in which populations. An incident cohort of adult patients 18 years and older prescribed an ACE inhibitor or ARB between 2001 and 2008 was identified from Geisinger Clinic, a large community‐based set of medical practices that uses a common electronic health record. Propensity score matching was used to balance the groups on baseline factors. The authors examined differences in mortality and new‐onset coronary disease, chronic kidney disease, stroke, and diabetes for different patient subgroups based on sex and age. A total of 25,035 hypertensive patients newly prescribed an ACE inhibitor or ARB were identified. No differences were found in risk of death, coronary disease, chronic kidney disease, or stroke between those prescribed ACE inhibitors and those prescribed ARBs. Patients prescribed ARBs had a greater rate of new‐onset diabetes (hazard ratio [HR], 1.28; confidence interval [CI], 1.08–1.52), and this was especially true for women (HR, 1.93; CI, 1.22–3.07). Within a large medical‐practice based population, there was no evidence of differential effectiveness between ACE inhibitors and ARBs for most outcomes, with diabetes being the notable exception.     

Adherence to treatment guidelines in the pharmacological management of chronic heart failure in an Australian population

Background To document the pharmacotherapy of chronic heart failure (CHF) and to evaluate the adherence to treatment guidelines in Australian population. Methods The pharmacological management of 677 patients (female 46.7%, 75.5 ± 11.6 years) with CHF was retrospectively analyzed. Results The use of angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB) and β-blockers were 58.2 % and 34.7 %, respectively. Major reasons for non-use of ACE inhibitors/ARBs were hyperkalemia and elevated serum creatinine level. For patients who did not receive β-blockers, asthma and chronic obstructive pulmonary disease were the main contraindications. Treatment at or above target dosages for ACE inhibitors/ARBs and β-blockers was low for each medication (40.3% and 28.9%, respectively). Conclusions Evidenced-based medical therapies for heart failure were under used in a rural patient population. Further studies are required to develop processes to improve the optimal use of heart failure medications.     

Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors

Angioedema is a rare, potentially life-threatening adverse event of renin-angiotensin system inhibitors. The objective of the present study was to determine the risk of angioedema from randomized clinical trials. A PubMed/CENTRAL/EMBASE search was made for randomized clinical trials from 1980 to October 2011 in patients on angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or direct renin inhibitor (DRI). Trials with a total number of patients ≥100 and a duration of ≥8 weeks were included for analysis. Incidence of angioedema was pooled by weighing the incident rate of each trial by the inverse of the variance. Twenty-six trials with 74,857 patients in the ACE inhibitor arm with 232,523 person-years of follow-up, 19 trials with 35,479 patients on ARB with 122,293 person-years of follow-up, and 2 trials with 5,141 patients on DRI with 1,735 person-years of follow-up met the inclusion criteria and were included in the analysis. In head-to-head comparison in 7 trials, risk of angioedema with ACE inhibitors was 2.2 times higher than with ARBs (95% confidence interval [CI] 1.5 to 3.3). With ACE inhibitors and ARBs, incidence of angioedema was higher in heart failure trials compared to hypertension or coronary artery disease trials without heart failure (p <0.0001). Weighted incidence of angioedema with ACE inhibitors was 0.30% (95% CI 0.28 to 0.32) compared to 0.11% (95% CI 0.09 to 0.13) with ARBs, 0.13% (95% CI 0.08 to 0.19) with DRIs, and 0.07% with placebo (95% CI 0.05 to 0.09). In conclusion, incidence of angioedema with ARBs and DRI was <1/2 than that with ACE inhibitors and not significantly different from placebo. Incidence of angioedema was higher in patients with heart failure compared to those without heart failure with ACE inhibitors and ARBs.     

Renin-Angiotensin Inhibition and Outcomes in HFrEF and Advanced Kidney Disease

BackgroundRenin-angiotensin system inhibitors improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, less is known about their effectiveness in patients with HFrEF and advanced kidney disease.MethodsIn the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF), 1582 patients with HFrEF (ejection fraction ≤40%) had advanced kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m²). Of these, 829 were not receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) prior to admission, of whom 214 were initiated on these drugs prior to discharge. We calculated propensity scores for receipt of these drugs for each of the 829 patients and assembled a matched cohort of 388 patients, balanced on 47 baseline characteristics (mean age 78 years; 52% women; 10% African American; 73% receiving beta-blockers). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated comparing 2-year outcomes in 194 patients initiated on ACE inhibitors or ARBs to 194 patients not initiated on those drugs.ResultsThe combined endpoint of heart failure readmission or all-cause mortality occurred in 79% and 84% of patients initiated and not initiated on ACE inhibitors or ARBs, respectively (HR associated with initiation, 0.79; 95% CI, 0.63-0.98). Respective HRs (95% CI) for the individual endpoints of - Respective HRs (95% CI) for the individual endpoints of all-cause mortality and heart failure readmission were 0.81 (0.63–1.03) and 0.63 (0.47–0.85).ConclusionsThe findings from our study add new information to the body of cumulative evidence that suggest that renin-angiotensin system inhibitors may improve clinical outcomes in patients with HFrEF and advanced kidney disease. These hypothesis-generating findings need to be replicated in contemporary patients.     

Effectiveness of angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers on total and cardiovascular mortality and morbidity in primary prevention: A nationwide study based on French Health Insurance Data (SNDS)

Angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) both inhibit the renin‐angiotensin system (RAS) but have different sites of action. Whether clinically meaningful differences exist is still debated. The authors set up a population‐based nationwide retrospective cohort study with at least 5 years of follow‐up based on the comprehensive French Health Insurance Database linked to the French hospital discharge database. Patients aged 50 or above, identified as ARB or ACE inhibitor new users in 2009 (at least one delivery during the year and no such delivery in 2008) were eligible. Exclusion criteria included history of cancer, cardiovascular disease, or chronic renal insufficiency. Main outcome measure was overall mortality. Secondary outcomes were cardiovascular deaths, major cardiovascular events, and major or other cardiovascular events. Out of 407 815 eligible patients, 233 682 (57%) were ARB users; two‐third had no previous exposure to antihypertensive drug. Based on propensity‐score based Cox model, ARB new user group had a better overall (HR: .878, 95%CI, .854 to .902), and cardiovascular (HR: .841, 95%CI, .800 to .84) survival and had a lower risk for major cardiovascular events (HR: .886, 95%CI, .868 to .905). Statistically significant quantitative interactions were detected with diabetes. Considering subgroup analyses, ARBs had a better survival than ACE inhibitors in nondiabetic patients.     

Use of cardiovascular drugs and risk of incident heart failure in patients with atrial fibrillation

Congestive heart failure (CHF) is the most important cause of death in patients with atrial fibrillation (AF). We aimed to study the association between cardiovascular drugs in AF patients and incident CHF. The study population included all adults (n = 120 756) aged ≥45 years diagnosed with AF in Sweden diagnosed for the period 1998‐2006. Outcome was incident congestive heart failure (follow‐up 2007‐2015) in AF patients. Associations between treatment with cardiovascular pharmacotherapies and CHF were evaluated using Cox regression to estimate hazard ratios (HRs) with 95% CIs, after adjustment for age, sociodemographic variables, and comorbidities. During a mean 5.3 years (SD 3.0) of follow‐up, there were 28 257 (23.4%) incident cases of CHF. Treatment with beta‐1‐selective and non‐selective beta‐blockers and statins was associated with lower risks of incident CHF in men, HR, (95% CI); 0.90, (0.87‐0.94); 0.90, (0.84‐0.97), and 0.94, (0.90‐0.99), respectively. Only beta‐1‐selective beta‐blockers were protective in women 0.94 (0.91‐0.98). Treatment with loop diuretics, potassium‐saving agents, ACE inhibitors, and angiotensin receptor blockers was associated with a higher risk of CHF. For men, treatment with heart‐active calcium channel blockers also led to a higher risk of CHF. In conclusion, we found that beta‐blockers, in particular, but also statins were associated with lower risk of incident CHF in patients with AF.     

Angiotensin II receptor blockers in congestive heart failure

The benefits of angiotensin-converting enzyme (ACE) inhibitors for the treatment of congestive heart failure (CHF) are well-established. A newer class of medications, angiotensin II receptor blockers (ARBs), may be a suitable replacement for ACE inhibitors as a result of a more complete inhibition of angiotensin II and better tolerability among patients. To examine the current literature on the efficacy and safety of ARBs in the setting of CHF, a Medline search was conducted of the English language literature for the years 1987 to 2005. Clinical trials that reported data on cardiac outcomes were reviewed. The earlier trials were direct ARB to ACE inhibitor comparisons (ELITE I and ELITE II). These studies indicated that ARBs do not confer an improvement in cardiac outcomes over ACE inhibitors. RESOLVD, Val-HeFT, and the 3 separate trials of the CHARM program investigated the addition of an ARB to standard therapy. The RESOLVD trial showed no significant differences in clinical events among ACE inhibitor, ARB, and their combination. Although no mortality benefit was evident in the Val-HeFT trial, a substantial reduction in CHF rehospitalizations was reported among patients who were not receiving ACE inhibitor therapy. The CHARM-Overall program demonstrated a significant benefit in cardiovascular death and hospital admissions for CHF with the addition of ARB to standard therapy, a benefit that was more pronounced in patients with depressed left ventricular ejection fraction. In the setting of CHF, rates of cardiac outcomes do not differ substantially between ARBs and ACE inhibitors. However, their combination may improve outcomes for patients with CHF.     

Abdominal aortic calcific deposits are associated with increased risk for congestive heart failure: the Framingham Heart Study

Objectives We sought to determine the association of aortic atherosclerosis, detected by calcific deposits in the abdominal aorta seen on lateral lumbar radiographs, with risk for congestive heart failure (CHF). Background Although the association between atherosclerotic coronary heart disease (CHD) and CHF has been extensively studied, there are limited prospective data regarding the association of extracoronary atherosclerosis with CHF. Methods Lateral lumbar radiographs were obtained in 2467 Framingham Heart Study participants (1030 males and 1437 females) free of CHF in 1968. An abdominal aortic calcium (AAC) score was calculated for each subject based on the extent of calcium in the abdominal aorta. Proportional hazards models were used to test for associations between AAC score and CHF risk. Results There were 141 cases of CHF in men and 169 cases in women. In men, the multivariable-adjusted risk for CHF was increased for the second (hazards ratio [HR] 1.5, 95% CI 0.9-2.5) and third (HR 2.2, 95% CI 1.3-3.7) tertiles compared with the lowest tertile. Similarly, in women, the multivariable-adjusted risk for CHF was increased for the second (HR 1.8, 95% CI 1.1-2.9) and third (HR 3.2, 95% CI 2.0-5.1) tertiles compared with the lowest tertile. After further adjustment for CHD occurring prior to the onset of CHF, risk remained significantly increased for both men and women. Conclusions Atherosclerosis of the abdominal aorta is an important risk factor for CHF, independent of CHD and other risk factors. Noninvasive detection and quantification of atherosclerosis may be useful in identifying high-risk individuals likely to benefit from strategies aimed at preventing CHF. The possibility of a link between AAC and vascular compliance deserves further study. (Am Heart J 2002;144:733-9.)     

Daytime sleepiness predicts mortality and cardiovascular disease in older adults. The Cardiovascular Health Study Research Group

INTRODUCTION: As part of the baseline examination in the Cardiovascular Health Study, sleep disturbance symptoms including snoring and daytime sleepiness, were assessed as potential risk factors or precipitants of cardiovascular disease (CVD). Because of the association of sleep disturbance with poorer health and the possible associations of sleep apnea with CVD, we hypothesized that those with poorer sleep or daytime sleepiness may be at increased risk of mortality or incident CVD. SETTING: Participants (n = 5888) were recruited in 1989, with an additional minority cohort recruited in 1993, in four US communities for a cohort study designed to evaluate risk factors for cardiovascular disease. METHODS: An interview-administered questionnaire regarding health and sleep habits with ongoing ascertainment of total mortality and cardiovascular disease morbidity and mortality, including total CVD morbidity and mortality, incident myocardial infarction, and congestive heart failure. RESULTS: Daytime sleepiness was the only sleep symptom that was significantly associated with mortality in both men and women. The unadjusted hazard ratio was 2.12 (1.66, 2.72) in women and 1.40 (1.12, 1.73) in men. Men who reported difficulty falling asleep also had an increased mortality rate (HR = 1.43 (1.14, 1.80)) which was not seen in women. The risks were attenuated with adjustment for age but remained significant for daytime sleepiness in women (HR = 1.82 (1.42, 2.34)) and for difficulty falling asleep in men. (HR = 1.29 (1.03, 1.63)). Frequent awakenings, early morning awakening, and snoring were not associated with a significantly increased risk of mortality in these older men and women. Crude event rates were evaluated for total incident cardiovascular morbidity and mortality, incident myocardial infarction, and incident congestive heart failure (CHF). Incident CVD rates were higher in both men and women with daytime sleepiness. The aged adjusted HR was 1.35 (95% CI = 1.03, 1.76) in men and was 1.66 (95% CI = 1.28, 2.16) in women. Incident CVD was not higher in those with any other sleep disturbance including snoring. The risk of CVD events associated with daytime sleepiness was attenuated but remained significant in women after adjustment for age. Incident myocardial infarction (MI) rates were also higher in women with daytime sleepiness but were not significantly higher in men. Incident CHF rates were increased in both men and women with daytime sleepiness. In men, the age adjusted HR was 1.49 (95% CI, 1.12- 1.98) and in women, was 2.21 (95% CI, 1.64-2.98). Women reporting both daytime sleepiness and frequent awakening had a hazard ratio of 2.34 (95% CI, 1.66-3.29) for incident CHF compared with those with daytime sleepiness but without frequent awakening. This interaction was not found in men. CONCLUSIONS: In this study, daytime sleepiness was the only sleep disturbance symptom that was associated with mortality, incident CVD morbidity and mortality, MI, and CHF. These findings were stronger in women than men, i.e., the associations persisted for mortality, CVD, and CHF in women after adjustment for age and other factors. Thus, a report of daytime sleepiness identifies older adults at increased risk for total and cardiovascular mortality, and is an independent risk factor in women.     

The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis

Oral anti-diabetic agents have been associated with adverse cardiovascular events in type 2 diabetes (DM2). We investigated the risk of coronary artery disease (CAD), congestive heart failure (CHF), and mortality using multivariable Cox models in a retrospective cohort of 20,450 DM2 patients from our electronic health record (EHR). We observed no differences in CAD risk among the agents. Metformin was associated with a reduced risk of CHF (HR 0.76, 95% CI 0.64–0.91) and mortality (HR 0.54, 95% CI 0.46–0.64) when compared to sulfonylurea. Pioglitazone was also associated with a lower risk of mortality when compared to sulfonylurea (HR 0.59, 95% CI 0.43–0.81). No other significant differences were found between the oral agents. In conclusions, our results did not identify an increased CAD risk with rosiglitazone in clinical practice. However, the results do reinforce a possible increased risk of adverse events in DM2 patients prescribed sulfonylureas.     

ACE-Inhibition and Angiotensin II Receptor Blockers in Chronic Heart Failure: Pathophysiological Consideration of the Unresolved Battle

Reducing the effects of angiotensin II by blockade of AT1-receptors may be superior to inhibition of angiotensin II formation by angiotensin converting enzyme (ACE) inhibitors in chronic heart failure (CHF) patients. However, the results of several trials did not fulfil this expectation. In both ELITE II with symptomatic CHF patients and in OPTIMAAL involving high risk patients after acute myocardial infarction, angiotensin II type I (AT1) receptor blocker (ARB) losartan did not prove to be superior to captopril. There are several potential reasons, why ARBs did not fare better than ACE inhibitors. Although AT1-receptor blockade may block the effects of non-ACE pathways of tissue angiotensin II formation, no clinical evidence is available that a more powerful inhibition of the tissue renin-angiotensin system brings improved survival. The choice of patients for clinical trials of HF therapy is not based on the level of neurohumoral activation. Thus, the more effective attenuation of angiotensin II action with ARBs may not bring additional benefits. The potential antiremodeling effect of ARBs through the stimulation of AT2 receptors by angiotensin II could be counterbalanced by a failure of AT1-receptor blockers to enhance bradykinin, nitric oxide and prostacyclin formation with antigrowth properties. Although ACE-inhibitors seem to have slightly better results at present than AT1 blockers in the battle on heart failure patient, future trials will decide which is the definitive winner.     

Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure.

In previous analyses of the occurrence of central (CSA) and obstructive sleep apnea (OSA) in patients with congestive heart failure (CHF), only men were studied and risk factors for these disorders were not well characterized. We therefore analyzed risk factors for CSA and OSA in 450 consecutive patients with CHF (382 male, 68 female) referred to our sleep laboratory. Risk factors for CSA were male gender (odds ratio [OR] 3.50; 95% confidence interval [CI], 1.39 to 8.84), atrial fibrillation (OR 4.13; 95% CI 1.53 to 11. 14), age > 60 yr (OR 2.37; 95% CI 1.35 to 4.15), and hypocapnia (PCO(2 )< 38 mm Hg during wakefulness) (OR 4.33; 95% CI 2.50 to 7. 52). Risk factors for OSA differed by gender: in men, only body mass index (BMI) was significantly associated with OSA (OR for a BMI > 35 kg/m(2), 6.10; 95% CI 2.86 to 13.00); whereas, in women, age was the only important risk factor (OR for age > 60 yr, 6.04; 95% CI 1.75 to 20.0). We conclude that historical information, supplemented by a few simple laboratory tests may enable physicians to risk stratify CHF patients for the presence of CSA or OSA, and the need for diagnostic polysomnography for such patients. Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure.     

Effect of heart failure program on cardiovascular drug utilization and dosage in patients with chronic heart failure

BACKGROUND: Utilization and dosage of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF) remain low. Recent data suggest that care of patients with CHF in specialized heart failure programs is associated with improved clinical outcomes. HYPOTHESIS: Specialized heart failure care is associated with better utilization and higher dose of cardiovascular drugs. METHODS: Data from 133 patients with CHF referred to a heart failure program were analyzed. Mean functional class 3.1 +/- 0.5, left ventricular ejection fraction 19 +/- 8. Utilization and doses of cardiovascular drugs were examined at initial evaluation and at last visit, after an average period of 17 +/- 14 months. Hospitalization and survival data were determined. RESULTS: Utilization of ACE inhibitors and angiotensin-receptor blockers increased from 87 to 100% (p < 0.001). Average daily dose increased by 60%, from the equivalent of captopril 105 +/- 78 mg to 167 +/- 86 mg (p < 0.001). Utilization of the following drugs increased significantly: beta blockers (16-37%, p < 0.001), metolazone (10-23%, p = 0.007), spironolactone (1-36%, p < 0.001), amiodarone (7-15%, p = 0.05), hydralazine (1-9%, p = 0.004), and nitrates (20-33%, p = 0.03). One-year survival was 90%. The 3- and 6-month hospitalization rates for heart failure were 4 and 7%, and for all cardiovascular causes they were 6 and 11%, respectively. CONCLUSIONS: Care of patients with CHF in a specialized heart failure program was associated with significant increase in the utilization and doses of all beneficial cardiovascular drugs, especially ACE inhibitors. It was also associated with excellent clinical outcomes.