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Background Sarcopenia is rarely diagnosed and is not recorded electronically in routine clinical care, posing challenges to trial recruitment. We describe the performance of four components of a strategy to efficiently recruit participants with sarcopenia to a trial of perindopril and/or leucine for sarcopenia: primary care vs. hospital recruitment, a comparison of central vs. local telephone pre‐screening, performance of a questionnaire on physical function conducted as part of the pre‐screening telephone call, and performance of bioimpedance measurement to identify low muscle mass. Methods Hospital‐based recruitment took place through inpatient and outpatient geriatric medicine services. Local research nurses reviewed medical notes and approached potentially eligible patients. Primary care recruitment reviewed primary care lists from collaborating practices, sending mailshots to patients aged 70 and over who were not taking angiotensin‐converting enzyme inhibitors. Telephone pre‐screening was conducted either by research nurses at each site or centrally by Tayside Clinical Trials Unit. The 10‐point SARC‐F questionnaire was used for pre‐screening. De‐identified recruitment information was held on a central electronic tracking system and analysed using SPSS. Bioimpedance was measured using the Akern BIA 101 system, with the Sergi equation used to estimate lean mass. Results Fourteen UK sites recruited to the trial. The 1202 sets of notes in hospital‐based care were reviewed at these sites; 7 participants (0.6% of total notes screened) were randomized. From primary care, 13 808 invitations were sent; 138 (1.0% of total invited) were randomized. 633/2987 primary care respondents were pre‐screened centrally; the mean number of calls per respondent was 2.3. For 10 sites where central and local pre‐screening could be compared, the conversion rate from pre‐screening to randomization was 18/588 (3.1%) for centralized calls, compared with 73/1814 (4.0%) for local pre‐screening calls (P = 0.29). A weak relationship was seen between higher (worse) SARC‐F score at screening and lower likelihood of progression to randomization (r = −0.08, P = 0.03). Muscle mass estimates generated using the Sergi equation were systematically biased, and a recalibrated equation for bioimpedance‐estimated muscle mass was derived. Conclusions Primary care recruitment led to higher response rates and overall numbers randomized than hospital‐based recruitment. Centralized pre‐screening saved local research nurses' time but did not improve conversion to randomization. SARC‐F did not help to target screening activity in this sarcopenia trial, and a recalibration of the equation for estimating muscle mass from bioimpedance measures may improve accuracy of the screening process.

Purpose: To scan a volunteer population using 3.0T magnetic resonance imaging (MRI). MRI of the left ventricular (LV) structure and function in healthy volunteers has been reported extensively at 1.5T. Materials and Methods: A population of 1528 volunteers was scanned. A standardized approach was taken to acquire steady-state free precession (SSFP) LV data in the short-axis plane, and images were quantified using commercial software. Six observers undertook the segmentation analysis. Results: Mean values (±standard deviation, SD) were: ejection fraction (EF) = 69 ± 6%, end diastolic volume index (EDVI) = 71 ± 13 ml/m, end systolic volume index (ESVI) = 22 ± 7 ml/m, stroke volume index (SVI) = 49 ± 8 ml/m, and LV mass index (LVMI) = 55 ± 12 g/m. The mean EF was slightly larger for females (69%) than for males (68%), but all other variables were smaller for females (EDVI 68v77 ml/m, ESVI 21v25 ml/m, SVI 46v52 ml/m, LVMI 49v64 g/m, all P < 0.05). The mean LV volume data mostly decreased with each age decade (EDVI males: –2.9 ± 1.3 ml/m, females: –3.1 ± 0.8 ml/m; ESVI males: –1.3 ± 0.7 ml/m, females: –1.7 ± 0.5 ml/m; SVI males: –1.7 ± 0.9 ml/m, females: –1.4 ± 0.6 ml/m; LVMI males: –1.6 ± 1.1 g/m, females: –0.2 ± 0.6 g/m) but the mean EF was virtually stable in males (0.6 ± 0.6%) and rose slightly in females (1.2 ± 0.5%) with age. Conclusion: LV reference ranges are provided in this population-based MR study at 3.0T. The variables are similar to those described at 1.5T, including variations with age and gender. These data may help to support future population-based MR research studies that involve the use of 3.0T MRI scanners. J. Magn. Reson. Imaging 2016;44:1186–1196.

Aims Controversy exists regarding the importance of glycaemic control in patients with type 2 diabetes mellitus (T2DM) and chronic heart failure (CHF) based on conflicting reports using single baseline glycosyated haemoglobin (HbA1c). Using the time-weighted mean of serial HbA1c measurements has been found to be a better predictor of diabetic complications as it reflects the glycaemic burden for that individual over time. We therefore sought to confirm this in a large cohort of patients with T2DM and incident CHF. Methods and results A time-weighted mean HbA1c was calculated using all HbA1c measurements following CHF diagnosis. Patients were grouped into five categories of HbA1c (≤6.0%, 6.1–7.0%, 7.1–8.0%, 8.1–9.0%, and >9.0%). The relationship between time-weighted mean HbA1c and all-cause death after CHF diagnosis was assessed. A total of 1447 patients with T2DM met the study criteria. During a median follow-up of 2.8 years, there were 826 (57.1%) deaths, with a crude death rate of 155 deaths per 1000 person-years [95% confidence interval (CI) 144–166]. A Cox regression model, adjusted for all significant predictors, with the middle HbA1c category (7.1–8.0%) as the reference, showed a U-shaped relationship between HbA1c and outcome [HbA1c 9.0%, HR 1.8, 95% CI 1.4–2.3]. Further analysis revealed a protective effect of insulin sensitizers (i.e. metformin) (HR 0.7, 95% CI 0.61–0.93) but not other drug classes. Conclusions In patients with T2DM and CHF, our study shows a U-shaped relationship between HbA1c and mortality, with the lowest risk in patients with modest glycaemic control (HbA1c 7.1–8.0%) and those treated with insulin sensitizers.

Plasma BNP and high-sensitivity cardiac troponin-T (hs-TnT) are elevated by both ischaemia and LV systolic dysfunction (LVSD). As a result, it is unknown whether BNP and/or hs-TnT could be useful biomarkers to identify ischaemia in the presence of LVSD.Three separate patient populations were studied. Study A (n = 500) involved consecutive patients undergoing clinically indicated myocardial perfusion scintigraphy, study B (n = 100) included patients with vascular disease but no known cardiac disease, and study C (n = 300) recruited primary prevention patients with controlled risk factors. Levels of BNP and hs-TnT were measured prior to the stress testing to detect myocardial ischaemia. The prevalence of myocardial ischaemia was 28.2, 28, and 6.3% in study A, B, and C, respectively. For BNP, area under curve (AUC) values to identify ischaemia in the presence and absence of coincidental LVSD were: 0.73 vs. 0.63 (study A), 0.90 vs. 0.81 (study B), and 0.83 vs. 0.80 (study C). Equivalent figures for hs-TnT were: 0.64 vs. 0.60 (study A), 0.75 vs. 0.68 (study B), and 0.53 vs. 0.68 (study C). BNP and hs-cTnT, when combined together, performed better with an AUC of 0.75 vs. 0.65 (study A), 0.91 vs. 0.92 (study B), and 0.84 vs. 0.83 (study C).In three separate populations a consistent finding is that BNP is increased further by myocardial ischaemia even in the presence of LVSD. A disproportionately high BNP for the degree of LVSD might be due to (unsuspected) ischaemia, and a disproportionately low BNP could be useful as a 'rule out' test for ischaemia even in the presence of LVSD.

Reason for withdrawal from publication The Editor/CRG withdrew this protocol as the current author team are unable to progress to the final review stage.

Aims Chronic heart failure (CHF) is an insulin-resistant state. The degree of insulin resistance (IR) correlates with disease severity and is associated with reduced exercise capacity. In this proof of concept study, we have examined the effect of metformin on IR and exercise capacity in non-diabetic CHF patients identified to have IR. Methods and results In a double-blind, placebo-controlled study, 62 non-diabetic IR CHF patients (mean age, 65.2 ± 8.0 years; male, 90%; left ventricular ejection fraction, 32.6 ± 8.3%; New York Heart Association class I/II/III/IV, 11/45/6/0) were randomized to receive either 4 months of metformin (n = 39, 2 g/day) or matching placebo (n = 23). IR was defined by a fasting insulin resistance index (FIRI) ≥2.7. Cardiopulmonary exercise testing and FIRI were assessed at baseline and after 4 months of intervention. Compared with placebo, metformin decreased FIRI (from 5.8 ± 3.8 to 4.0 ± 2.5, P < 0.001) and resulted in a weight loss of 1.9 kg (P < 0.001). The primary endpoint of the study, peak oxygen uptake (VO2), did not differ between treatment groups. However, metformin improved the secondary endpoint of the slope of the ratio of minute ventilation to carbon dioxide production (VE/VCO2 slope), from 32.9 ± 15.9 to 28.1 ± 8.8 (P = 0.034). In the metformin-treated group, FIRI was significantly related to the reduction of the VE/VCO2 slope (R = 0.41, P = 0.036). Conclusion Metformin treatment significantly improved IR but had no effect on peak VO2, the primary endpoint of our study. However, metformin treatment did result in a significant improvement in VE/VCO2 slope. Trial registration: NCT00473876.

Basic research and clinical studies have implicated a role for hyperuricemia and for xanthine oxidoreductase (XOR), the enzyme that generates uric acid (UA), in not only gout but also vascular diseases. At present, asymptomatic hyperuricemia (i.e., in the absence of gout, urate nephrolithiasis, or tumor lysis syndrome) is not an indication for therapy. With the rise over the past several decades in prevalence of both gout and hyperuricemia, clarifying the potential adverse effects of hyperuricemia (in patients with and without gout) is of public health importance. UA is not simply an inert end-product of purine metabolism in humans, but rather has potential antioxidant, pro-oxidant, and pro-inflammatory effects. However controversy remains as to which, if any, of these effects are of clinical relevance in development and complications of human vascular diseases in gout and asymptomatic hyperuricemia. Clearly, not all individuals with hyperuricemia develop gout, and studies to date have also been unable to clarify in which subjects hyperuricemia may have detrimental effects on the vasculature. Further, studies of urate-lowering therapy with XOR inhibition or uricosuric agents have not been able to definitively identify whether any such effects may be mediated by UA versus XO. Adequately sized, prospective randomized clinical trials of sufficient duration, and employing appropriate biomarkers, now appear critical to resolve the putative toxic roles of UA and XO in the human arterial circulation.

BACKGROUND AND PURPOSE Expression of inducible NOS (iNOS) is important in certain inflammatory diseases. We determined if the hormone aldosterone, a mineralocorticoid receptor (MR) agonist, affects LPS activation of iNOS expression in rat aortic smooth muscle cells (RASMC). EXPERIMENTAL APPROACH Cultured RASMC were treated with LPS, with or without agonists/antagonists of steroid receptors. iNOS expression was determined by nitrite assays on culture medium removed from treated cells and by immunoblotting of cell protein extracts. KEY RESULTS LPS (1 µg·mL−1) increased nitrite and iNOS protein above that in control (untreated) cells. These effects of LPS were reduced by aldosterone (0.1–10 µM). The MR antagonists, eplerenone (10 µM) and spironolactone (10 or 50 µM), did not inhibit these actions of 1 µM aldosterone, but the latter were prevented by 10 µM mifepristone, a glucocorticoid (GR) and progestogen receptor (PR) antagonist. Mifepristone also prevented the reduction of LPS-induced nitrite increase produced by 1 µM dexamethasone (GR agonist) and 10 µM progesterone (PR agonist). Spironolactone (10–50 µM) by itself decreased LPS-induced increases in nitrite and iNOS protein. Mifepristone (10 µM) partially reversed these effects of 10 µM spironolactone, but not those of 50 µM; the effects of 50 µM spironolactone were also unchanged when mifepristone was increased to 50 µM. CONCLUSIONS AND IMPLICATIONS This pharmacological profile suggests that aldosterone, and possibly 10 µM spironolactone, use mechanisms that are dependent on PR and/or GR, but not MR, to inhibit iNOS induction in RASMC. With 50 µM spironolactone, other inhibitory mechanisms requiring further investigation may become predominant.

Dysregulation of the renin-angiotensin-aldosterone system has been associated with a number of age-related pathologies including hypertension, heart failure and chronic kidney disease. More recently, it has been suggested that alterations within the RAAS may contribute to the development of sarcopenia and subsequent decline in physical function. There is growing interest in developing interventions to prevent age-associated decline in muscle function. We postulate that inhibition of the RAAS with the mineralocorticoid antagonist spironolactone may have a role in countering the effects of physical impairment in older people by improving skeletal muscle function. Spironolactone may prevent skeletal myocyte apoptosis, improve vascular endothelial function and enhance muscle contractility by increasing muscle magnesium and sodium-potassium pumps. This article will review the literature underpinning the hypothesis that spironolactone may have a role in maintaining muscle function in older people.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Guidelines recommend that the therapeutic goal of urate-lowering therapy (ULT) is to achieve a urate concentration of ≤6 mg dl−1. • High-dose allopurinol is associated with reduced cardiovascular events and mortality in heart failure patients. WHAT THIS STUDY ADDS • Less than 50% of patients taking allopurinol reached target urate concentration. • Higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality in all patients on allopurinol treatment. AIMS To characterize patients with urate measurements by urate-lowering therapy (ULT) use and to study the impact of allopurinol treatment on cardiovascular and mortality outcomes. METHODS A cohort study using a record-linkage database. The study included 7135 patients aged ≥60 years with urate measurements between 2000 and 2002 followed up until 2007. A Cox regression model was used. The association between urate levels, dispensed allopurinol and cardiovascular hospitalization and mortality was determined. RESULTS Six thousand and forty-two patients were not taking ULT and 45.9% of those (2774 of 6042) had urate concentrations ≤6 mg dl−1. Among 1035 allopurinol users, 44.7% (45.6% for men and 43.3% for women) reached target urate concentration. There was no significant increased risk of cardiovascular events for allopurinol users when compared with non-ULT users [adjusted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.95–1.26] and the non-ULT group with urate >6 mg dl−1 (adjusted HR 1.07, 95% CI 0.89–1.28). Within the allopurinol use cohort, cardiovascular event rates were 74.0 (95% CI 61.9–86.1) per 1000 person years for the 100 mg group, 69.7 (49.6–89.8) for the 200 mg group and 47.6 (38.4–56.9) for the ≥300 mg group. Compared with low-dose (100 mg) users, high-dose (≥300 mg) users had significant reductions in the risk of cardiovascular events (adjusted HR 0.69, 95% CI 0.50–0.94) and mortality (adjusted HR 0.75, 95% CI 0.59–0.94). CONCLUSIONS Less than 50% of patients taking allopurinol reached target urate concentration. Higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality.

Purpose: To optimize the contrast agent dose and delivery rate used in a novel whole-body magnetic resonance angiography (MRA) protocol using a 3.0T MR scanner. Materials and Methods: Six groups of 20 consenting volunteers underwent whole-body MRA, with each group receiving a different contrast dose and contrast delivery rate. The arterial tree was divided into 16 segments and the image quality at each of the anatomical locations, covering the whole body, was assessed. Qualitative analysis was carried out using a scoring assessment of image quality, and quantitative assessments were performed by measuring contrast-to-noise (CNR) and a signal-to-noise (SNR) index. Results: Reducing the contrast dose from 40 mL to 25 mL was found to significantly increase the CNR in several vessels of interest in the arterial tree. There was also a significant increase in the qualitative image quality score (P < 0.001). Conclusion: This study demonstrates that reducing the contrast dose at 3.0T can result in an increase in the CNR in the vessels of interest without significantly affecting the SNR. J. Magn. Reson. Imaging 2009;30:1059–1067. © 2009 Wiley-Liss, Inc.

Objectives The demand–control (D–C) model of job strain has generated a considerable body of empirical support in predicting psychological health outcomes in the context of work. This study aimed to extend previous work using the D–C model of job strain to predict caregiver burden and satisfaction in the informal caregivers of patients with heart failure. Design and method Data were gathered from 60 caregiver/patient dyads in a cross-sectional design. Patients with chronic stable heart failure were recruited from out-patient clinics. The dependent variables were caregiver burden and satisfaction. Demand and control were measured using both patient- and caregiver-derived measures. Results The D–C model accounted for 15 and 19% of the variance in caregiver burden, after controlling for age, gender and relationship to the patient. Lower control was associated with higher burden. The D–C model did not predict caregiver satisfaction. Conclusion The D–C model was associated with caregiver burden, but not satisfaction in caregivers, with control being the dominant predictor. Research linking the theory and findings from job strain and informal caregiving studies may elucidate both fields of research. Using the demand–control model of job strain to predict caregiver burden and caregiver satisfaction in the informal caregivers of heart failure patients.

Many studies have shown a strong correlation between urate levels and cardiovascular disease. The formation of urate is complex as the same enzyme that produces urate, xanthine oxidase (XO) also catalyzes the formation of reactive oxygen species (ROS). There is some evidence that the urate molecule has free radical scavenging properties in vitro and acute infusions of urate improve endothelial function in at-risk populations. High levels of ROS are clearly linked to worse outcome in a variety of conditions. Allopurinol has been the archetypal XO inhibitor for over 40 years. Small studies have demonstrated its beneficial effects, mainly in heart failure but also in a variety of other cohorts of patients with cardiovascular risk. It is a safe agent, provided suitable patients are chosen and monitored carefully. Newer promising agents like oxypurinol have not shown the expected benefits in larger multicentered studies. This review looks at the biology of urate, its role in cardiovascular disease, the possible mechanisms by which XO inhibitors exert their beneficial effect on endothelial dysfunction, and examines the possible causes for the failure of newer agents to live up to expectations.

Objectives: To determine the predictive power of B-type natriuretic peptide (BNP) regarding death in older, functionally impaired patients with multiple comorbidity. Design: Prospective cohort study. Setting: Specialist geriatric assessment clinic and day hospital. Participants: Two hundred ninety-nine older, functionally impaired patients, mean age 79 at enrollment. Measurements: Full clinical history and examination, baseline BNP, and echocardiography. Date and cause of death were ascertained from Scottish death records. Kaplan-Meier survival curves were constructed for quartiles of log (BNP), and the contribution of BNP to prediction of death was investigated. Results: The follow-up period ranged from 3.9 to 5.2 years (mean 4.4 years). BNP was a powerful independent predictor of all-cause and cardiovascular mortality. BNP was a more powerful predictor than blood pressure, diabetes mellitus, smoking, echocardiographic left ventricular hypertrophy, left ventricular systolic dysfunction, or age. BNP predicted death in those with and without a previous cardiovascular event at baseline. Conclusion: BNP has significant predictive power for death in older, functionally impaired patients.

The authors sought to determine the prevalence of diastolic heart failure (DHF) in patients hospitalized with their first stroke, transient ischemic attack, or new onset of peripheral vascular disease. A total of 216 prospective consecutive stroke, transient ischemic attack, and peripheral vascular disease patients (vascular group) were identified at their first noncardiac presentation to a hospital and compared with 164 age-matched control patients (nonvascular group). DHF was clinically defined as the presence of left ventricular ejection fraction>or=45% on echocardiography. DHF occurred in 40% and 73% of vascular and control patients, respectively, with symptomatic heart failure. Overall, it was found in 12% of vascular (10% of stroke/transient ischemic attack, 16% of peripheral vascular disease) and 11% of control patients. Advancing age and female gender were independently associated with the presence of DHF in vascular patients (p

Background: Heart failure (HF) is difficult to diagnose and treat in older patients. Symptoms may be non-specific and the presence of co-morbidities and polypharmacy complicate treatment strategies. There are, however, few data to quantify the extent of these problems in the very elderly. Methods: A retrospective study of 116 patients (median age 86; range 65–98) with an established diagnosis of HF during their hospital admission. Main outcome measures: the accuracy of diagnosis of heart failure according to the European Society of Cardiology (ESC) definition. The aetiology and frequency of associated co-morbidities and the nature of drug treatment. Results: The specificities of clinical signs, chest X-rays and abnormal ECGs for heart failure (ESC definition) were 50%, 20% and 9%, respectively. Only 28% of patients were admitted for worsening symptoms which could be attributed to HF. None of the patients had HF as their only medical problem. Co-morbidities included chest disease (30%), incontinence (29%), cerebrovascular disease (26%), musculoskeletal problems (41%). Barthel (activities of daily living) score was ≤16/20 in 35%. Mental state questionnaire (MSQ) score was ≤7/10 in 38%. Ninety percent were taking four or more different medications. Thirty-nine percent were on psychotropic drugs. On discharge, a total of 88% of patients returned home to live independently and 35% were monitored by regular day hospital attendance. Conclusion: Heart failure in frail elderly patients is often compounded by other major illnesses and polypharmacy which have a profound impact on their functional status. This has implications for the most effective targeting of evidence based treatment.

Aims Smoking is a major risk factor for developing atherosclerosis. In order to understand the vascular abnormalities observed in smokers, we investigated vascular responsiveness in cigarette smokers. Methods We performed two consecutive matched group comparative studies to investigate vascular responsiveness using venous occlusion plethysmography. The mean effects of three incremental doses of each vasoactive agent are presented. Both studies compared smokers with nonsmokers. Results The first investigated 68 subjects (smokers = 29; mean ± s.d. ages; 24 ± 6 vs 25 ± 5 years; P = NS) and found smoking was associated with a significant blunting of the flow ratio between treated and untreated arms to endothelium-dependent vasodilatation to acetylcholine (mean ± s.d., nonsmokers vs smokers) 4.07 ± 2.18 vs 3.42 ± 1.79 (P = 0.04, 95% CI 0.02, 1.12). By contrast, there was no significant difference in the responses to the endothelium-independent vasodilators sodium nitroprusside and verapamil. Smoking was also associated with a significant impairment in endothelium-dependent vasoconstriction induced by monomethyl-l-arginine (L-NMMA) 0.78 ± 0.22 vs 0.87 ± 0.21 (P = 0.006, 95% CI −0.14, −0.02) and a trend to blunted endothelium-independent vasoconstrictor responses to noradrenaline. In the second study we investigated the response to angiotensin I and II in 23 subjects (smokers=12; mean ± s.d. ages; 34 ± 10 vs 32 ± 11 years). There was significant impairment in smokers of the mean vasoconstrictor response to angiotensin I 0.51 ± 0.15 vs 0.59 ± 0.16 (nonsmokers vs smokers; P = 0.003, 95% CI −0.13, −0.03) and a nonsignificant trend towards impairment of the response to angiotensin II. Conclusions Cigarette smoking in male volunteers is associated with blunted basal and stimulated nitric oxide bioactivity. Endothelial independent vasodilator responses (to nitroprusside and verapamil) were unaltered in smokers. A defect in the vasoconstrictor response to angiotensin I was also seen.

Aims Allopurinol improves endothelial function in chronic heart failure by reducing oxidative stress. We wished to explore if such an effect would attenuate autonomic dysfunction in CHF in line with many other effective therapies in CHF. Methods We performed a prospective, randomized, double-blind cross-over study in 16 patients with NYHA Class II-IV chronic heart failure (mean age 67 ± 10 years, 13 male, comparing allopurinol (2 months) at a daily dose of 300 mg (if creatinine 150 µmol l−1) with matched placebo. Mean heart rate and dysrhythmia counts were recorded from 24 h Holter tapes at monthly intervals for 6 months. We assessed autonomic function using standard time domain heart rate variability parameters (HRV): SDNN, SDANN, SDNN index, rMSSD and TI. Results Allopurinol had no significant effect on heart rate variability compared with placebo; the results are expressed as a difference in means ± s.d. with 95% confidence interval (CI) between allopurinol and placebo: SDNN mean=6.5 ± 4.8 ms, P = 0.18 and 95% CI (−3.7, 17); TI mean=−2.1 ± 1.4, P = 0.16 and 95% CI (−5.2, 0.8); SDANN mean=−2.8 ± 7 ms, P = 0.68 and 95% CI (−18, 12); SDNNi mean=2 ± 6.6, P = 0.7 and 95% CI (−12, 16); RMSSD mean=−0.9 ± 2, P = 0.68 and 95% CI (−5.6, 3.7). For mean heart rate the corresponding results were 0.9 ± 1.4, P = 0.5 and 95% CI (−2, 3.8). Log 24 h ventricular ectopic counts (VEC) were 0.032 ± 0.37, P = 0.7 and 95% CI (−0.1, 0.2). Patient compliance with study medication was good since allopurinol showed its expected effect of reducing plasma uric acid (P

1. Cardiac death is due not only to coronary artery disease, but also to left ventricular (LV) abnormalities (fibrosis, dysfunction) and arrhythmogenic triggers, such as autonomic imbalance. 2. Nitric oxide deficiency could be a key mediator leading not only to coronary atherosclerosis, but also to LV abnormalities and autonomic imbalance. 3. It may be possible to screen for the above abnormalities (e.g. echocardiography and brain natriuretic peptide levels for LV abnormalities, 24 h tapes for autonomic imbalance and QT interval analysis). 4. Once individuals are identified as being at high risk, a range of interventions is possible (e.g. intensive statin therapy or angiotensin-converting enzyme inhibitors if LV abnormalities or autonomic imbalance are found).

Background: 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. Aims: 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. Methods and results: 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 ≥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). Conclusion: 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.

Aims We wished to see if renin release in man was inhibited by nitric oxide blockade, suggesting a role for nitric oxide in renin release. Evidence from animal studies has shown variable effects on renin release depending on the model and stimulus used. Methods Ten normal male volunteers, received either l-NMMA as a front loaded infusion (4 mg kg−1 bolus, with 4 mg kg−1 infusion), or placebo, followed by an intravenous bolus of 5 mg frusemide to stimulate renin. To investigate whether any alteration in renin release was due to the pressor effect of the l-NMMA, the experiment was repeated using an equipressor dose of phenylephrine (0.5 μg kg−1 min−1 ). Results l-NMMA caused the expected increase in mean arterial pressure (96±2.6 vs 89±3.3 mmHg P

Aims To assess the role of direct AT1 receptor antagonism in baroreceptor modulation in man, and to perform a direct comparison of Ang II blockade at the receptor level with that of ACE inhibition. Methods Ten healthy male volunteers [mean age (s.d.) 23 (6.9)] pretreated with frusemide therapy (40 mg day−1 for 3 days prior to each visit) were studied on 3 separate days, 10 days apart, in a placebo-controlled, randomized, double-blind, cross-over fashion. On each study day, subjects were randomly given either a single-dose of enalapril 20 mg, losartan 50 mg or placebo. Baroreceptor function was assessed by measuring changes in blood pressure (BP), pulse interval (RR Int) and heart rate (HR) in response to incremental doses of intravenous phenylephrine infusions (0.2–3.6 μg kg−1 min−1 ). Results In response to phenylephrine, no significant differences in BP responses were observed with any of the study medications but reflex heart rate responses were significantly increased with both enalapril and losartan compared with placebo (P

Aims The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using NG-monomethyl-l-arginine (l-NMMA) on systemic and pulmonary haemodynamics. Methods Ten normal male volunteers 26±1.6 years were studied on two separate occasions in a double-blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of l-NMMA (4 mg kg−1 h−1 ) with a front loaded bolus (4 mg kg−1 ) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion (t0 ) and after 4, 8, and 12 min (t1, t2 and t3 ). Results Infusion of l-NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t1 and persisted during the entire infusion period. Conclusions These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.

Raised plasma concentrations of atrial natriuretic peptide (ANP) have been reported in patients with Type 1 (insulin dependent) diabetes mellitus (DM) who have poor glycaemic control and are associated with the presence of microalbuminuria. To test the hypothesis that elevations in plasma ANP concentration increase urinary albumin excretion in Type 1 DM, we have studied the effects of intravenous infusions of ANP in eight such subjects with established microalbuminuria. Blood glucose was maintained between 4 and 7 mmol l-1 in all subjects for the duration of studies; after euglycaemia had been established, a standard oral water load (20 ml kg-1 plus replacement of urinary losses) was given. Once steady state diuresis was attained, subjects received intravenous infusion of either placebo (0.9% saline), low dose (2.5 pmol kg-1 min-1) or high dose (5.0 pmol kg-1 kg min-1) ANP solution in a randomized, double-blind protocol. Infusion of ANP caused a dose-dependent increase in urinary albumin excretion rate (placebo, 11.3 (SD 8.9) to 8.7 (SD 6.8) micrograms min-1; low dose ANP, 12.4 (SD 9.9) to 26.5 (SD 27.5) micrograms min-1, p < 0.01; high dose ANP 10.3 (SD 7.3) to 36.6 (SD 28.5) micrograms min-1, p < 0.001, ANOVA). Only high dose ANP caused an increase in urine flow. Blood glucose remained unchanged in all studies. We conclude that intravenous infusions of ANP cause a dose-dependent increase in urinary albumin excretion rate in Type 1 DM subjects with microalbuminuria. These data support the hypothesis that ANP has albuminuric actions which may contribute to microalbuminuria in Type 1 DM.

Previous studies in heart failure (CHF) after temporary diuretic withdrawal have suggested that perindopril is associated with no first dose hypotension in comparison with other ACE inhibitors (ACEI) or placebo. The aim of this study was to explore further the profile of perindopril during chronic dosing.We report the effects of acute and chronic (8 weeks) treatment with the ACE inhibitor perindopril (Per, 2--4 mg daily) or placebo (P) in a double-blind parallel group study of 24 diuretic treated patients (17M; 67 +/- 8 years, 80 +/- 17 kg) with ischaemic cardiomyopathy (fractional shortening, 19 +/- 5%; radionuclide ejection fraction, 31 +/- 3%). Baseline biochemical, hormonal (ACE, Ang I, Ang II), isotopic renal function (GFR, ERPF, ECFV), pretreatment diuretic dose and heart failure scores were similar between groups. Concomitant cardiac treatments remained unchanged and diuretic withdrawal was not used to introduce treatment.There were no significant effects on electrolytes, liver function tests, serum or erythrocyte magnesium. There was no significant first dose fall in SBP over 6 h) (P, baseline 137 +/- 18; min 115 +/- 16 mmHg; Per, baseline 137 +/- 15; min 118 +/- 17 mmHg). Neither supine nor erect BP was significantly affected by chronic treatment (P, erect baseline 134 +/- 23/76 +/- 10 to 124 +/- 41/74 +/- 10 mmHg; Per, baseline 135 +/- 21/76 +/- 14 to 128 +/- 22/70 +/- 12 mmHg, P=NS). Active treatment was associated with significant ACE inhibition (P, baseline 47 +/- 17 to 43 +/- 17; Per baseline 49 +/- 15 to 14 +/- 7); aldosterone (P, baseline 337 +/- 179 to 375 +/- 306; Per, baseline 335 +/- 357 to 293 +/- 155 pg ml(-1)) and Ang II suppression (P, baseline 9 +/- 9 to 20 +/- 39; Per baseline 10 +/- 9 to 3 +/- 3 pM). Isotopic renal function was unaffected by either treatment.At this dose (2-4 mg orally) chronic perindopril therapy has no significant effect on blood pressure or renal function. Sustained neurohormonal suppression of ACE and AII occurred without evidence of AII reactivation. A lack of effect on BP at these doses may make perindopril suitable for study in unstable patients with acute HF or useful in those patients where there are concerns over ACEI induced hypotension.

Nitric oxide is an endogenous vasodilator produced from L-arginine and oxygen by stereospecific enzymes. L-arginine itself can act as a vasodilator when administered at high doses to humans. This effect has been attributed by some to provision of extra substrate for production of nitric oxide. This work compares L-arginine-induced vasodilation with that caused by D-arginine, hyperosmolar sodium chloride and by other cationic amino acids in the resting forearm vasculature of normal subjects. By these means we identify whether L-arginine-induced vasodilation has a component related to stereospecific provision of substrate for nitric oxide production, or whether it can be accounted for by other phenomena. Effects of hyperosmolar sodium chloride and both L and D isomers of arginine, lysine and ornithine on forearm blood flow in eight normal male subjects were compared by bilateral forearm venous occlusion plethysmography. Vasodilator responses to saline and each amino acid were compared as the area under dose-response curves with single-factor analysis of variance (ANOVA). The magnitude of vasodilation obtained with the D isomers of each amino acid was compared with the L counterpart by application of single-factor ANOVA to the appropriate areas under dose-response curves. All three cationic amino acids increased forearm blood flow. Part of the increase could be related to the high osmolality of infusates-comparison with equiosmolar sodium chloride solutions shows that ornithine does not differ significantly as a vasodilator (P > 0.4), but that arginine and lysine have greater vasodilator effects than can be accounted for by osmolality alone (P < 0.001). The D isomers of arginine and lysine were more potent dilators than their L counterparts (arginine P < 0.03, lysine P < 0.02). The vasodilator effects of arginine in the forearm vascular bed at rest are not stereospecific, they are common to other cationic amino acids, greater for D isomers and occur only when normal plasma concentrations are raised far above the physiological range. These features suggest that the vasodilator effect of arginine is in part physical and related to the presence of the molecule in the vessel lumen. They do not suggest that increased provision of substrate, with a consequence of increased nitric oxide production, is the principal basis of L-arginine-induced vasodilation in normal humans.

The responses of renal haemodynamic and natriuretic indices to the oral prostaglandin synthetase inhibitor indomethacin (200 mg), to infused angiotensin II (1 ng min-1 kg-1) and to the combination of the two were studies in placebo-controlled fashion in eight normal male subjects both prior to and following administration of intravenous frusemide (20 mg). As compared with placebo, angiotensin II infusion alone caused significant reductions in absolute rate of sodium excretion, fractional sodium excretion, urine flow rate and effective renal plasma flow (all P < 0.001 vs placebo) but had no effect on glomerular filtration rate. The only change observed in these parameters with indomethacin alone was a small but significant reduction in urine flow rate (P < 0.005 vs placebo). As compared with the effects of angiotensin II alone, indomethacin pre-treatment followed by angiotensin II infusion led to much greater falls in absolute rate of sodium excretion, fractional sodium excretion, urine flow rate and effective renal plasma flow (all P < 0.0001 vs placebo) associated with a significant reduction in glomerular filtration rate (P < 0.0001) not observed with angiotensin II alone. Frusemide administration at the midpoint of each study limb resulted in each case in a prompt 15 to 20 fold increase in natriuresis. The renal haemodynamic and natriuretic effects of angiotensin II, indomethacin and their combination were not qualitatively different from those observed in the pre-frusemide phase. Our findings provide a clear demonstration in man of the important homeostatic role of renal prostaglandins in preserving renal function, particularly glomerular filtration, under conditions of elevated circulating angiotensin II.

The relative risk of dying from a myocardial infarction according to diuretic therapy was estimated in a case control study for 189 cases, 144 dead controls and 349 living controls. The controls were matched for age (±2.5 years), sex and general practice. The study was community-based; the cases were identified from death certificates and the death certificates of the dead controls had no mention of ischaemic heart disease. The relative risk was estimated from the odds ratio and was similar whether dead or living controls were considered. Against all controls combined, the odds ratio for dying while taking a potassium-losing diuretic at 1 month prior to death (R1) was 1.5 (95 per cent CI 0.9, 2.4) and for a combined potassium-losing + sparing diuretic (RL+S) was 2.0 (95 per cent CI 1.1, 3.4). Potassium-sparing diuretics may be given more frequently to patients at greater risk of dying, thus masking a benefit, but the data could not provide evidence for a benefit from the addition of a potassium-sparing diuretic.

1. Atrial natriuretic factor (ANF) has an inhibitory effect on angiotensin II and ACTH stimulated aldosterone secretion in man. The selectivity of this aldosterone suppressing effect of ANF is unclear in man. The present study investigated the effect of ANF on the increase in plasma aldosterone due to metoclopramide in man. 2. Eight normal male volunteers were studied on three occasions. Metoclopramide (10 mg slow i.v.) was given on all study days and each volunteer was randomised to receive 45 min infusion of either 5% D-glucose (placebo) or ANF (99-126) 3 or 15 pmol kg-1 min-1. 3. Metoclopramide increased plasma aldosterone to approximately 170% of baseline levels (P less than 0.01). Concomitant infusion of ANF 3 pmol kg-1 min-1 and 15 pmol kg-1 min-1 significantly attenuated this rise in plasma aldosterone to approximately 130% (P less than 0.05) and 110% (P less than 0.01) of baseline values respectively. 4. It is suggested, in the light of previous findings, that the inhibitory effect of ANF represents a non-selective action of ANF on aldosterone release.

The mechanism of the antihypertensive effect of alpha-methyldopa was compared with clonidine by administering equipotent single doses of clonidine (0.2 mg) and alpha-methyldopa (750 mg) to nine hypertensive patients. Plasma noradrenaline was followed for 8 h thereafter as an index of peripheral sympathetic activity. alpha-Methyldopa and clonidine produced the same hypotensive response at 6 and 8 h after dosing with a similar fall in plasma noradrenaline levels at these times. Linear regression analysis between the systolic blood pressure fall and the corresponding plasma noradrenaline fall, showed that the slopes of the two regression lines were similar for alpha-methyldopa as for clonidine. Equipotent doses of alpha-methyldopa and clonidine produce the same fall in plasma noradrenaline. This supports the current hypothesis that an alpha-methyldopa metabolite acts centrally, like clonidine, to reduce peripheral sympathetic activity.

1 Individual systolic time intervals (STI) v heart rate regression equations were determined using small doses of intravenous atropine in seven patients with angina pectoris. 2 Regression lines of the form LVET = A + B.HR and QS2 = C + D.HR were calculated. There was no significant correlation between PEP and HR. The values of parameters A C and D were significantly different from a group of previously studied normal volunteers. 3 STI changes were recorded for 5 h after the application of GTN or placebo ointment. The active drug caused shortening of LVET and QS2 with the peak effect occurring between 105 and 180 min. After 180 min neither LVET nor QS2 were significantly shortened. There was no significant effect on PEP or heart rate.

1. Laser Doppler flowmetry was used in six normal volunteers to record changes in fingertip skin blood flow after the administration of prazosin to block postsynaptic alpha 1-adrenoceptors. 2. Prazosin (0.5 mg orally) did not alter systolic or diastolic blood pressure or heart rate. 3. Prazosin did significantly increase basal skin blood flow 2 h after its administration but this effect was no longer evident after contralateral hand warming. Prazosin markedly reduced the skin vasoconstrictor response to deep inspiration and to contralateral hand cooling. 4. This study suggests that postsynaptic alpha 1-adrenoceptors are involved in maintaining skin vasoconstrictor tone at rest and are also involved in the rapid skin vasoconstriction seen in response to a deep inspiration and to contralateral hand cooling.

1. The effects of noradrenaline (0.025 micrograms kg-1 min-1) and atrial natriuretic factor (0.04 micrograms kg-1 min-1) alone, and in combination, were studied in eight healthy salt replete men. 2. Atrial natriuretic factor increased urinary sodium excretion and flow rate without changing glomerular filtration rate or systemic haemodynamics. 3. Noradrenaline decreased urinary sodium excretion without changing glomerular filtration rate, urinary flow rate or systemic haemodynamics. 4. When atrial natriuretic factor was administered against a background infusion of noradrenaline the natriuretic response to the peptide was significantly attenuated. 5. Further analysis showed that this attenuation was due to the additive antinatriuretic effect of noradrenaline rather than to a specific interaction between atrial natriuretic factor and noradrenaline. 6. The possible significance of this interplay between noradrenaline and atrial natriuretic factor is discussed in the context of experimental evidence for an important role of the sympathetic nervous system in modulating the renal effects of atrial natriuretic factor in animals.

The adrenergic nervous system plays an important role in the control of insulin release and animal work suggests that this is mediated by way of alpha 2 adrenoceptors. A specific alpha 2 adrenoceptor antagonist (idazoxan) is now available for use in man and we have studied its effects on insulin release in normal volunteers (a) during the infusion of adrenaline (0.05 micrograms/kg/min) and (b) after an intravenous dose of glucose (20 g). The infusion of adrenaline alone had no significant effect on insulin release while in the presence of idazoxan, insulin release was markedly stimulated by adrenaline. Despite this, adrenaline-induced hyperglycaemia was unaffected by pretreatment with idazoxan. In the second study, pretreatment with either idazoxan or a specific alpha 1 antagonist (prazosin) had no significant effect on either glucose tolerance, glucose-induced insulin release or glucose-induced suppression of glucagon. Intravenous glucose also had no significant effect on pancreatic polypeptide levels. Therefore the effect of adrenaline on insulin release is mediated by way of inhibitory alpha 2 adrenoceptors in the pancreas, while the release of insulin in response to glucose in a resting subject is independent of the alpha-adrenergic system.

1. Considerable data from animal studies suggest that angiotensin II exerts a facilitatory effect on noradrenaline release. We sought evidence for such an effect in man by examining how a subpressor dose of angiotensin II (1.5 ng kg-1 min-1) influences the haemodynamic and plasma noradrenaline responses to physiological stimulation of the sympathetic nervous system. 2. The physiological stimuli investigated were a cold pressor test, the response to standing from lying, bicycle exercise and forearm isometric exercise. 3. The presence of the angiotensin II infusion had no effect on the systolic blood pressure, diastolic blood pressure, heart rate or plasma noradrenaline responses to stimulation of the sympathetic nervous system. 4. We have therefore found no evidence to support the enhancement of noradrenaline release by this low dose of angiotensin II in man.