Allan D. Struthers

C-Type Natriuretic Peptide

C-type natriuretic peptide is a 22-amino acid peptide that was initially identified in the central nervous system. The distribution of C-type natriuretic peptide, which has structural homology with atrial and brain natriuretic peptides, is wide and includes the endothelium, myocardium, gastrointestinal, and genitourinary tracts. The biological effects of this peptide are being elucidated in a number of sites in a number of species; however, the novel endothelial site of production of C-type natriuretic peptide and the proximal situation of its receptor in vascular smooth muscle suggest that this vascular natriuretic peptide system may play a role in concert with other local systems in the control of vascular tone.

High-Dose Allopurinol Reduces Left Ventricular Mass in Patients With Ischemic Heart Disease

OBJECTIVESnThis study sought to ascertain if high-dose allopurinol regresses left ventricular mass (LVM) in patients with ischemic heart disease (IHD).nnnBACKGROUNDnLV hypertrophy (LVH) is common in patients with IHD including normotensive patients. Allopurinol, a xanthine oxidase inhibitor, has been shown to reduce LV afterload in IHD and may therefore also regress LVH.nnnMETHODSnA randomized, double-blind, placebo-controlled, parallel group study was conducted in 66 patients with IHD and LVH, comparing 600 mg/day allopurinol versus placebo therapy for 9 months. The primary outcome measure was change in LVM, assessed by cardiac magnetic resonance imaging (CMR). Secondary outcome measures were changes in LV volumes by CMR, changes in endothelial function by flow-mediated dilation (FMD), and arterial stiffness by applanation tonometry.nnnRESULTSnCompared to placebo, allopurinol significantly reduced LVM (allopurinol -5.2 ± 5.8 g vs. placebo -1.3 ± 4.48 g; p = 0.007) and LVM index (LVMI) (allopurinol -2.2 ± 2.78 g/m(2) vs. placebo -0.53 ± 2.5 g/m(2); p = 0.023). The absolute mean difference between groups for change in LVM and LVMI was -3.89 g (95% confidence interval: -1.1 to -6.7) and -1.67 g/m(2) (95% confidence interval: -0.23 to -3.1), respectively. Allopurinol also reduced LV end-systolic volume (allopurinol -2.81 ± 7.8 mls vs. placebo +1.3 ± 7.22 mls; p = 0.047), improved FMD (allopurinol +0.82 ± 1.8% vs. placebo -0.69 ± 2.8%; p = 0.017) and augmentation index (allopurinol -2.8 ± 5.1% vs. placebo +0.9 ± 7%; p = 0.02).nnnCONCLUSIONSnHigh-dose allopurinol regresses LVH, reduces LV end-systolic volume, and improves endothelial function in patients with IHD and LVH. This raises the possibility that allopurinol might reduce future cardiovascular events and mortality in these patients. (Does a Drug Allopurinol Reduce Heart Muscle Mass and Improve Blood Vessel Function in Patients With Normal Blood Pressure and Stable Angina?; ISRCTN73579730).

Effect of Vitamin D Supplementation on Markers of Vascular Function: A Systematic Review and Individual Participant Meta-Analysis

Background Low 25‐hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear. Methods and Results We conducted a systematic review and individual participant meta‐analysis to examine the effect of vitamin D supplementation on flow‐mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo‐controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial‐level meta‐analysis was performed using random‐effects models; individual participant meta‐analyses used a 2‐stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial‐level meta‐analysis, and 24 trials (2051 participants) contributed to individual‐participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial‐level meta‐analysis showed no significant effect of supplementation on macrovascular measures (flow‐mediated dilatation, 0.37% [95% confidence interval, −0.23 to 0.97]; carotid‐femoral pulse wave velocity, 0.00 m/s [95% confidence interval, −0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial‐level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues. Conclusions Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis.

Health care delivery for chronic congestive heart failure in the United Kingdom

&NA; Since the United Kingdom has fewer cardiology specialists than other countries, the United Kingdom cardiologist cannot provide direct care for all patients with chronic congestive heart failure (CHF). Most CHF care is provided by general practitioners, physicians or geriatricians. A survey of 100 CHF patients attending a health center revealed that these patients visited their general practitioners 270 times in 1 year, compared with only 34 outpatient visits. The cardiologist mainly provides echocardiography. The accurate diagnosis of mild CHF became imperative with the advent of angiotensin converting enzyme (ACE) inhibitors. Results of a survey showed that although 1.6% of the population are taking diuretics for CHF, only 0.84% of the population have left ventricular systolic dysfunction on echocardiography. An estimated 22 echocardiograms per 1000 population per year are required (10 for structural reasons, three for suspected new CHF, three to identify patients with a low left ventricular ejection fraction and six to identify left ventricular hypertrophy in hypertensive patients). However, district general hospitals in Scotland can only provide 3.3‐6 echocardiograms per 1000 population per year. The elderly CHF patient may not receive adequate treatment because of the lack of resources and a dislike of ‘overinvestigating’ or ‘overtreating’ the elderly. The benefits of echocardiography and ACE inhibitor therapy for all patients with CHF should be stressed.

Leucine and ACE inhibitors as therapies for sarcopenia (LACE trial): study protocol for a randomised controlled trial

BackgroundSarcopenia (the age-related loss of muscle mass and function) is a major contributor to loss of mobility, falls, loss of independence, morbidity and mortality in older people. Although resistance training is effective in preventing and reversing sarcopenia, many older people are sedentary and either cannot or do not want to exercise. This trial examines the efficacy of supplementation with the amino acid leucine and/or angiotensin converting enzyme inhibition to potentially improve muscle mass and function in people with sarcopenia. Promising preliminary data exist from small studies for both interventions, but neither has yet been tested in adequately powered randomised trials in patients with sarcopenia.MethodsLeucine and ACE inhibitors in sarcopenia (LACE) is a multicentre, masked, placebo-controlled, 2u2009×u20092 factorial randomised trial evaluating the efficacy of leucine and perindopril (angiotensin converting enzyme inhibitor (ACEi)) in patients with sarcopenia. The trial will recruit 440 patients from primary and secondary care services across the UK. Male and female patients aged 70xa0years and over with sarcopenia as defined by the European Working Group on Sarcopenia (based on low total skeletal muscle mass on bioimpedance analysis and either low gait speed or low handgrip strength) will be eligible for participation. Participants will be excluded if they have a contraindication to, or are already taking, an ACEi, angiotensin receptor blocker or leucine. The primary clinical outcome for the trial is the between-group difference in the Short Physical Performance Battery score at all points between baseline and 12xa0months. Secondary outcomes include appendicular muscle mass measured using dual-energy X-ray absorptiometry, muscle strength, activities of daily living, quality of life, activity using pedometer step counts and falls. Participants, clinical teams, outcomes assessors and trial analysts are masked to treatment allocation. A panel of biomarkers including microRNAs, neurohormones, genetic polymorphisms and markers of inflammation relevant to muscle pathophysiology will be measured to explore predictors of response and further elucidate mechanisms underlying sarcopenia. Participants will receive a total of 12xa0months of either perindopril or placebo and either leucine or placebo.DiscussionThe results will provide the first robust test of the overall clinical and cost-effectiveness of these novel therapies for older patients with sarcopenia.Trial registrationISRCTN, ISRCTN90094835. Registered on 18 February 2015.

Development and Validation of a Path Length Calculation for Carotid-Femoral Pulse Wave Velocity Measurement: A TASCFORCE, SUMMIT, and Caerphilly Collaborative Venture.

Current distance measurement techniques for pulse wave velocity (PWV) calculation are susceptible to intercenter variability. The aim of this study was to derive and validate a formula for this distance measurement. Based on carotid femoral distance in 1183 whole-body magnetic resonance angiograms, a formula was derived for calculating distance. This was compared with distance measurements in 128 whole-body magnetic resonance angiograms from a second study. The effects of recalculation of PWV using the new formula on association with risk factors, disease discrimination, and prediction of major adverse cardiovascular events were examined within 1242 participants from the multicenter SUMMIT study (Surrogate Markers of Micro- and Macrovascular Hard End-Points for Innovative Diabetes Tools) and 825 participants from the Caerphilly Prospective Study. The distance formula yielded a mean error of 7.8 mm (limits of agreement =−41.1 to 56.7 mm; P<0.001) compared with the second whole-body magnetic resonance angiogram group. Compared with an external distance measurement, the distance formula did not change associations between PWV and age, blood pressure, or creatinine (P<0.01) but did remove significant associations between PWV and body mass index (BMI). After accounting for differences in age, sex, and mean arterial pressure, intercenter differences in PWV persisted using the external distance measurement (F=4.6; P=0.004), whereas there was a loss of between center difference using the distance formula (F=1.4; P=0.24). PWV odds ratios for cardiovascular mortality remained the same using both the external distance measurement (1.14; 95% confidence interval, 1.06–1.24; P=0.001) and the distance formula (1.17; 95% confidence interval, 1.08–1.28; P<0.001). A population-derived automatic distance calculation for PWV obtained from routinely collected clinical information is accurate and removes intercenter measurement variability without impacting the diagnostic utility of carotid–femoral PWV.

Atrial Natriuretic Peptide

Publisher Summary The natriuretic peptide system consists of three peptides with similar structures. These peptides cause a wide range of actions in the kidney, the vasculature, the heart, and the central nervous system. Atrial natriuretic peptide (ANP) has subsequently been the subject of extensive investigation. This peptide is secreted from the cardiac atria and has profound natriuretic and diuretic properties, as well as vasodilatory effects. Brain natriuretic peptide (BNP) was subsequently discovered in porcine brain, but in humans, this peptide is secreted extensively from the heart, predominantly from the ventricles. It has actions similar to those of ANP and has more recently been called B-type natriuretic peptide. The recognized natriuretic, diuretic, and vasodilatory properties of natriuretic peptides make them very attractive as therapeutic agents for both hypertension and heart failure. In contrast with loop diuretics and many vasodilators, natriuretic peptides have the advantage of causing inhibition rather than stimulation of the rennin–angiotensin–aldosterone (RAAS) system.

Disconnection of pulmonary and systemic arterial stiffness in COPD

Background Both pulmonary arterial stiffening and systemic arterial stiffening have been described in COPD. The aim of the current study was to assess pulse wave velocity (PWV) within these two arterial beds to determine whether they are separate or linked processes. Materials and methods In total, 58 participants with COPD and 21 healthy volunteers (HVs) underwent cardiac magnetic resonance imaging (MRI) and were tested with a panel of relevant biomarkers. Cardiac MRI was used to quantify ventricular mass, volumes, and pulmonary (pulse wave velocity [pPWV] and systemic pulse wave velocity [sPWV]). Results Those with COPD had higher pPWV (COPD: 2.62 vs HV: 1.78 ms−1, p=0.006), higher right ventricular mass/volume ratio (RVMVR; COPD: 0.29 vs HV: 0.25 g/mL, p=0.012), higher left ventricular mass/volume ratio (LVMVR; COPD: 0.78 vs HV: 0.70 g/mL, p=0.009), and a trend toward a higher sPWV (COPD: 8.7 vs HV: 7.4 ms−1, p=0.06). Multiple biomarkers were elevated: interleukin-6 (COPD: 1.38 vs HV: 0.58 pg/mL, p=0.02), high-sensitivity C-reactive protein (COPD: 6.42 vs HV: 2.49 mg/L, p=0.002), surfactant protein D (COPD: 16.9 vs HV: 9.13 ng/mL, p=0.001), N-terminal pro-brain natriuretic peptide (COPD: 603 vs HV: 198 pg/mL, p=0.001), and high-sensitivity troponin I (COPD: 2.27 vs HV: 0.92 pg/mL, p<0.001). There was a significant relationship between sPWV and LVMVR (p=0.01) but not pPWV (p=0.97) nor between pPWV and RVMVR (p=0.27). Conclusion Pulmonary arterial stiffening and systemic arterial stiffening appear to be disconnected and should therefore be considered independent processes in COPD. Further work is warranted to determine whether both these cause an increased morbidity and mortality and whether both can be targeted by similar pharmacological therapy or whether different strategies are required for each.

Acceptability and feasibility of magnetic femoral nerve stimulation in older, functionally impaired patients.

ObjectiveMagnetic femoral nerve stimulation to test muscle function has been largely unexplored in older people. We assessed acceptability, feasibility, along with reproducibility and correlation with other physical function measures.ResultsStudy 1 recruited older people with sarcopenia. Stimulation was performed at baseline and 2xa0weeks along with six minute walk (6MW), maximum voluntary quadriceps contraction, short physical performance battery and grip strength. Acceptability was measured using visual analog scales. Study 2 used baseline data from a trial of older people. We correlated stimulation results with 6MW, maximal voluntary contraction and muscle mass. Maximum quadriceps twitch tension was measured in both studies, evoked using biphasic magnetic stimulation of the femoral nerve. In study 1 (nu2009=u200912), magnetic stimulation was well tolerated with mean discomfort rating of 9% (range 0–40%) on a visual analog scale. Reproducibility was poor (intraclass correlation coefficient 0.06; pu2009=u20090.44). Study 2 (nu2009=u200964) showed only weak to moderate correlations for maximum quadriceps twitch tension with other measures of physical function (6xa0minute walk test ru2009=u20090.24, pu2009=u20090.06; maximal voluntary contraction ru2009=u20090.26; pu2009=u20090.04). We conclude that magnetic femoral nerve stimulation is acceptable and feasible but poorly reproducible in older, functionally impaired people.