Tissue angiotensin‐converting enzyme inhibitors: Are they more effective than serum angiotensin‐converting enzyme inhibitors?

Since their discovery in the 1980s, angiotensin-converting enzyme (ACE) inhibitors have been shown to decrease angiotensin formation, prevent breakdown of bradykinin, and may also act on peptides of the renin-angiotensin system. They are effective in reducing the risk of heart failure, myocardial infarction, and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure, and have been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure. They may preserve endothelial function and counteract initiation and progression of atherosclerosis. Broadly, ACE inhibitors can be divided into tissue specific or serum ACE inhibitors. Tissue-specific ACE inhibitors as a group are not superior to serum ACE inhibitors in the treatment of coronary artery disease. Pending direct comparator clinical trials between a tissue ACE inhibitor and a plasma ACE inhibitor, both ramipril and perindopril can be recommended for secondary risk prevention, based on the evidence.     

Acute effects of caffeine on blood pressure and wave reflections in healthy subjects: should we consider monitoring central blood pressure?

BACKGROUND: Data concerning blood pressure changes, acutely induced by caffeine consumption, are conflicting. Furthermore, limited data exist regarding central hemodynamic response to caffeine ingestion by healthy young subjects. We investigated the acute effect of coffee (80 mg of caffeine) and decaffeinated coffee on peripheral and central hemodynamics, as well as on wave reflections. SUBJECTS: For this purpose, 16 healthy volunteers (eight females and eight males, mean age 29+/-3.2 years) were investigated. METHODS: Repeated measurements were performed at baseline and 30, 60, 90 and 120 min after oral administration of each beverage in a double-blind crossover design. Aortic blood pressures, augmentation index (AI) and pressure (AP) and timing of reflected waves were evaluated by using applanation tonometry and pulse wave analysis. RESULTS: Regular coffee increased central systolic (SBP) and diastolic pressure (DBP) from 96.2+/-9.9 to 101.1+/-10.1 mmHg, p=0.011 and from 72.6+/-9.4 to 76.5+/-9.0 mmHg, p=0.027, respectively, but no change was observed following consumption of decaffeinated coffee. Peripheral systolic blood pressure did not change significantly after the administration of either coffee. Augmentation index increased significantly following regular coffee consumption. The change in AI was significantly higher following regular compared to decaffeinated coffee consumption as shown by analysis of variance (ANOVA) for repeated measures (p=0.001). CONCLUSIONS: These caffeine effects reveal an unfavourable effect on wave reflections and therefore on left ventricular (LV) pulsatile afterload. It also revealed a significant acute effect of caffeine consumption on central hemodynamics which is not observed at peripheral pressures.     

Are clinical endpoint benefits of angiotensin converting enzyme inhibitors independent of their blood pressure effects?

Both basic and experimental data indicate that the renin-angiotensin system through angiotensin II mediates its classic hemodynamic role, but also has a significant deleterious role in a number of cardiac, vascular, and renal disorders. Indeed, evidence indicates that angiotensin II negatively impacts endothelial function, cardiac remodeling, vessel wall hypertrophy, atherosclerosis, and progressive renal disease. Newer data point to a significant role for angiotensin II in inflammation and in inducing plasminogen activator inhibitor. This widespread negative effect can be countered by newer antihypertensive drugs, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers. Both small and large clinical trials suggest a large benefit of such drugs on not only organ-specific endpoints such as renal disease or proteinuria, but on global cardiovascular events. It does appear that when blood pressure is significantly elevated, lowering blood pressure does indeed provide protection for larger endpoints such as stroke. However, at lower blood pressure levels, a hemodynamically independent effect is likely to be contributing to the positive effects. We should embrace these effects and champion them for our patients.     

Do angiotensin II receptor antagonists substitute angiotensin converting enzyme inhibitors in the treatment of high blood pressure?

Angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (AIIA) are both pharmacological groups that inhibit the actions of angiotensin II. ACEI prevent the formation of angiotensin II from angiotensin I, whereas A II A inhibit the final crucial step of angiotensin II binding with the AT1 receptor site. A similar antihypertensive efficacy has been described for both groups but A II A drugs have a better safety profile above all due to the absence of dry cough. Despite the fact that evidence with ACEI is more conclusive, A II A seems to achieve the same protective effects on the target organ damage in hypertensive patients. At present, ACEI are the drugs of choice in the treatment of patients with cardiac dysfunction and failure. The information of ongoing trials with A II A will be of great value in deciding the optimal treatment for hypertensive patients with different cardiovascular diseases.     

Is blood pressure the major determinant of left ventricular mass in subjects over 50 years of age?

The weak relation of systolic blood pressure to left ventricular (LV) mass in hypertension has frequently been regarded as evidence of non-hemodynamic stimuli to muscle growth. Anyway, left ventricular hypertrophy (LVH) is associated with a significantly increased risk for cardiovascular events. Data were obtained from M-mode echocardiograms in 10 normotensives and 58 hypertensives over 50 years (range 50-85 years); 18 hypertensives; were without (LVH -) and 40 were with LVH (LVH +) - when LV mass, normalized for body surface area, was calculated according to the Penn's Convention. Cardiac output was derived by Teicholz formula for LV volumes. End-systolic stress/end-systolic dimension ratio (ESS/ ESD r), an index of myocardial contractility, was calculated as previously validated in the literature. We found that, in subjects ranging from 50 to 85 years of age, the presence of LV hypertrophy is not necessarily associated with raised blood pressure levels. Systolic function was substantially preserved among the study groups, irrespective of their age, hypertensive condition and/or presence of LVH. The increased wall thickness in subjects with LVH was associated with a significant reduction in wall stress (thus suggesting an adequateness of the compensatory role of LVH - at least at the observed stage of the hypertrophy process) and with a significant decrease of the contractile performance. On the multivariate analysis, the observed relation of LV mass to blood pressure and myocardial contractility (r = 0.621, P < 0.001) may explain some apparently conflicting findings, such as the lack of LV hypertrophy in a number of hypertensive patients.     

Beyond ONTARGET: angiotensin‐converting enzyme inhibition and angiotensin II receptor blockade in combination,a lesser evil in some?

Aim: Following the recent Ongoing Telmistartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) finding of adverse renal outcomes, dual renin‐angiotensin blockade has fallen out of favour, despite antihypertensive and antiproteinuric efficacy. However, in high‐risk severe hypertension, not studied in ONTARGET, whether combination treatment should be withheld or withdrawn is not clear. We examine the renal effects of angiotensin‐converting enzyme inhibitor (ACE‐I) and angiotensin II receptor blocker (ARB) monotherapy versus combination therapy in patients with type 2 diabetes and varying degrees of hypertension. Methods: Subjects attending a hospital diabetes centre were selected as case (combination therapy, n = 120) and control (monotherapy, n = 480). Subjects were matched for age, gender, ethnicity, estimated glomerular filtration rate (eGFR), blood pressure (BP) and study duration. Patients were stratified by BP, hypertension stage 1 (BP < 160/100, n = 506) and stage 2 (≥160/100, n = 94), and by treatment group. Data were analysed for the primary renal outcome of eGFR decline ≥20 ml/min, over a median of 3.7 years. Results: In keeping with the ONTARGET study, for stage 1 hypertension, combination treatment is significantly worse than monotherapy for the primary outcome of eGFR decline ≥20 ml/min (20 vs. 10.7%, p = 0.01). In contrast, for stage 2 hypertension, this endpoint was reached less often for combination versus monotherapy (12.0 vs. 23.2%, p = 0.2). Combination treatment was also not detrimental in patients with proteinuria or eGFR < 60 ml/min and was associated with fewer macrovascular events. Conclusion: Given that hypertension control is paramount and in the spirit of primum non nocere, these data are reassuring should clinicians choose to use ACE‐I and ARB combination therapy in the very hypertensive diabetic patient.     

Does sodium sensitivity affect nocturnal blood pressure variation in outpatients with hypertension?

We investigated the relationship between sodium sensitivity and diurnal variation of blood pressure in outpatients with hypertension. Twenty hypertensives were maintained on both a regular sodium diet for a period of 2 weeks and a low salt (7 g/day) diet for a period of one or two weeks. Ambulatory blood pressure was recorded at thirty minute intervals for 24 hours by automatic device before and during low salt diet. Patients were classified by nocturnal fall in blood pressure. 14 patients were classified as sodium sensitive, whereas 6 were classified as non-sodium sensitive on the basis of a > or = 0 in salt sensitive index caused by sodium restriction. Incidence of reversed dipper and non-dipper in systolic blood pressure was reduced by sodium restriction, however, dipper and extreme dipper were increased. In conclusion, the results of this study show that patients with high sodium sensitivity index have strong sodium sensitivity and non-dipper is not always changed by sodium restriction.     

Does stage‐based smoking cessation advice in pregnancy result in long‐term quitters? 18‐month postpartum follow‐up of a randomized controlled trial

AIMS: To evaluate the effect on quitting smoking at 18 months postpartum of smoking cessation interventions based on the Transtheoretical Model (TTM) delivered in pregnancy compared to current standard care. It has been claimed that TTM-based interventions will continue to create quitters after the end of the intervention period. DESIGN: Cluster randomized trial. SETTING: Antenatal clinics in general practices in the West Midlands, UK. PARTICIPANTS: A total of 918 pregnant smokers originally enrolled in the trial, of which 393 women were followed-up at 18 months postpartum. INTERVENTIONS: One hundred general practices were randomized into the three trial arms. Midwives in these practices delivered three interventions: A (standard care), B (TTM-based self-help manuals) and C (TTM-based self-help manuals plus sessions with an interactive computer program giving individualized smoking cessation advice). MEASUREMENTS: Self-reported continuous and point prevalence abstinence since pregnancy. FINDINGS: When combined together, there was a slight and not significant benefit for both TTM arms compared to the control, with an odds ratio (OR) 95% confidence interval (CI) of 1.20 (0.29-4.88) for continuous abstinence. For point prevalence abstinence, the OR (95%CI) was 1.15 (0.66-2.03). Seven of the 54 (13%) women who had quit at the end of pregnancy were still quit 18 months later, and there was no evidence that the TTM-based interventions were superior in preventing relapse. CONCLUSIONS: The TTM-based interventions may have shown some evidence of a short-term benefit for quitting in pregnancy but no benefit relative to standard care when followed-up in the longer-term.     

Low‐grade systolic murmurs in healthy middle‐aged individuals: innocent or clinically significant? A 35‐year follow‐up study of 2014 Norwegian men

Abstract. Bodegard J, Skretteberg PT, Gjesdal K, Pyörälä K, Kjeldsen SE, Liestøl K, Erikssen G, Erikssen J (Oslo University Hospital, Oslo; University of Oslo, Oslo; University of Eastern Finland, Kuopio; University of Oslo, Oslo; Oslo University Hospital, Oslo). Low‐grade systolic murmurs in healthy middle‐aged individuals: innocent or clinically significant? A 35‐year follow‐up study of 2014 Norwegian men. J Intern Med 2012; 271 : 581–588. Objective. To determine whether a low‐grade systolic murmur, found at heart auscultation, in middle‐aged healthy men influences the long‐term risk of aortic valve replacement (AVR) and death from cardiovascular disease (CVD). Setting and subjects. During 1972–1975, 2014 apparently healthy men aged 40–59 years underwent an examination programme including case history, clinical examination, blood tests and a symptom‐limited exercise ECG test. Heart auscultation was performed under standardized conditions, and murmurs were graded on a scale from I to VI. No men were found to have grade V/VI murmurs. Participants were followed for up to 35 years. Results. A total of 1541 men had no systolic murmur; 441 had low‐grade murmurs (grade I/II) and 32 had moderate‐grade murmurs (grade III/IV). Men with low‐grade murmurs had a 4.7‐fold [95% confidence interval (CI) 2.1–11.1] increased age‐adjusted risk of AVR, but no increase in risk of CVD death. Men with moderate‐grade murmurs had an 89.3‐fold (95% CI 39.2–211.2) age‐adjusted risk of AVR and a 1.5‐fold (95% CI 0.8–2.5) age‐adjusted increased risk of CVD death. Conclusions. Low‐grade systolic murmur was detected at heart auscultation in 21.9% of apparently healthy middle‐aged men. Men with low‐grade murmur had an increased risk of AVR, but no increase in risk of CVD death. Only 1.6% of men had moderate‐grade murmur; these men had a very high risk of AVR and a 1.5‐fold albeit non‐significant increase in risk of CVD death.     

Does modifying electrode placement of the 12 lead ECG matter in healthy subjects?

Background

Limb electrodes for the 12 lead ECG are routinely placed on the torso during exercise stress testing or when limbs are clinically inaccessible. It is unclear whether such electrode modification produces ECG changes in healthy male or female subjects that are clinically important according to the 2009 AHA, ACCF, HRS guidelines. We therefore measured whether ECG modification produced clinically important or false positive ECG changes e.g., appearance of Q waves in leads V_1-3, ST changes greater than 0.1 mV, T wave changes greater than 0.5 mV (frontal plane) or 1 mV (transverse plane), QRS axis shifts or alterations to QTc/P-R/QRS intervals.

Methods

The 12 lead ECG was measured in 18 healthy and semi-recumbent subjects using the standard and Takuma modified limb placements.

Results

In the frontal plane we demonstrate that the modification of limb electrode placement produces small Q, R and T wave amplitude and QRS axis changes that are statistically but not clinically significant. In the transverse plane it produces no statistically or clinically significant changes in the ECG or in ST segment morphology, P-R, QRS or QTc intervals.

Conclusions

We provide better and more robust evidence that routine modification of limb electrode placement produces only minor changes to the ECG waveform in healthy subjects. These are not clinically significant according to the 2009 guidelines and thus have no effect on the clinical specificity of the 12 lead ECG.     

Does short sleep duration in daily life affect morning home blood pressure? Evaluation in Japanese people

A short sleep duration is expected to elevate blood pressure the next morning, but no report has evaluated this in detail using home blood pressure measurement. In this study, the relation between sleep duration and morning and evening home blood pressure and heart rate during seven consecutive days was evaluated. From 630 volunteers not receiving antihypertensive agents, we selected 478 subjects (318 male, 160 female; mean age: 39.0 years) whose 2-7 days of data consisted of 7-8 hours sleep duration (proper sleep period phase; mean sleep duration: 7.3 +/- 0.3 hours) and less than 7 hours (short sleep period phase; 5.7 +/- 4.9 hours). In the morning, systolic blood pressure and heart rate in the short sleep period phase (117.7 +/- 14.9 mmHg, 67.3 +/- 9.6/min) were significantly (p < 0.01) higher than those in the proper sleep period phase (116.9 +/- 14.9 mmHg, 66.5 +/- 9.1/min). However, there was no difference in morning diastolic blood pressure. Although the difference in morning systolic blood pressure had disappeared by the time of measurement before going to bed, the difference in heart rate was maintained (proper sleep period phase: 70.4 +/- 10.2/min, short sleep period phase: 71.7 +/- 10.7/min, p < 0.01). In conclusion, days with sleep duration of less than 7 hours showed higher morning systolic blood pressure and heart rate compared with days with sleep duration between 7 and 8 hours, but no difference was found in diastolic blood pressure. Moreover, although the difference in morning systolic blood pressure had disappeared at night, the difference in heart rate was still maintained.     

Does cirrhosis affect quality of life in hepatitis C virus‐infected patients?

Background: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and is associated with impairments in health‐related quality of life. Aims: To evaluate quality of life (QOL) in cirrhotic (compensated and decompensated) and non‐cirrhotic patients with chronic HCV infection, using preference‐based (utilities) and non‐preference‐based methods of evaluating QOL. Methods: In a tertiary care setting, 271 patients completed a self‐administered time trade‐off utility instrument, the Health Utility Index Mark 2 and Mark 3, and the Hepatitis Quality of Life Questionnaire Version 2. Mean QOL scores were compared across HCV disease stages and sociodemographical categories. We examined the association between QOL and disease stage using linear regression adjusting for age, education, marital status, log income and Charlson comorbidity scores. Mean utility scores were compared across disease stages using a propensity score method. Results: Mean utilities were lower than general population norms (0.81–0.92) and ranged from 0.62 to 0.82 in non‐cirrhotic patients (n=197), 0.56–0.84 in compensated cirrhotic patients (n=17) and 0.55–0.76 for decompensated cirrhotic patients (n=57). No significant association found was between disease stage and utility for current health status. Higher income, fewer comorbidities and living in a married or common‐law relationship were significantly associated with higher utilities and better QOL. No significant difference in utilities was found between disease stages using propensity score matching. Conclusions: Our study confirms that changes in HCV disease stage explain only small changes in QOL and suggests that factors such as underlying comorbidities, income and marital status have a greater effect on QOL than disease stage.