Design and rationale for the randomised, double-blinded, placebo-controlled Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) crossover study

Background: Glucagon-like peptide-1 is an incretin hormone essential for normal human glucose homeostasis. Expression of the glucagon-like peptide-1 receptor in the myocardium has fuelled growing interest in the direct and indirect cardiovascular effects of native glucagon-like peptide-1, its degradation product glucagon-like peptide-1(9-36), and the synthetic glucagon-like peptide-1 receptor agonists. Preclinical studies have demonstrated cardioprotective actions of all three compounds in the setting of experimental myocardial infarction and left ventricular systolic dysfunction. This has led to Phase 2 trials of native glucagon-like peptide-1 and incretin-based therapies in humans with and without Type 2 diabetes mellitus. These studies have demonstrated the ability of glucagon-like peptide-1, independent of glycaemic control, to positively modulate the metabolic and haemodynamic parameters of individuals with coronary artery disease and left ventricular systolic dysfunction. We aim to add to this growing body of evidence by studying the effect of chronic glucagon-like peptide-1 receptor activation on exercise-induced ischaemia in patients with chronic stable angina managed conservatively or awaiting revascularisation. The hypothesis being liraglutide, a subcutaneously injectable glucagon-like peptide-1 receptor agonist, is able to improve exercise haemodynamics in patients with obstructive coronary artery disease when compared with saline placebo. Methods and design The Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) trial is an investigator-initiated single-centre randomised double-blinded placebo-controlled crossover proof-of-principle physiological study. Primary endpoints are change in rate pressure product at 0.1 mV ST-segment depression and change in degree of ST-segment depression at peak exercise during sequential exercise tolerance testing performed over a 6-week study period in which 26 patients will be randomised to either liraglutide or saline with crossover to the opposing regimen at week 3. Discussion The study will be conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The local Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency have approved the study. Trial registration National Institute of Health Research Clinical Research Network (NIHR CRN) Portfolio ID 11112 and ClinicalTrials.gov Identifier NCT02315001

Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart

Aims Glycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3α and 9 of GSK-3β respectively, required for inactivation by upstream kinases. Methods and results Between 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts. Conclusion Expression of inactivation-resistant GSK-3α/β does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3α/β, may enable a sustained cardiac response to chronic β-agonist stimulation while preventing pathological remodelling

Novel United Kingdom prognostic model for 30-day mortality following transcatheter aortic valve implantation

Objective Existing clinical prediction models (CPM) for short-term mortality after transcatheter aortic valve implantation (TAVI) have limited applicability in the UK due to moderate predictive performance and inconsistent recording practices across registries. The aim of this study was to derive a UK-TAVI CPM to predict 30-day mortality risk for benchmarking purposes. Methods A two-step modelling strategy was undertaken: first, data from the UK-TAVI Registry between 2009 and 2014 were used to develop a multivariable logistic regression CPM using backwards stepwise regression. Second, model-updating techniques were applied using the 2013–2014 data, thereby leveraging new approaches to include frailty and to ensure the model was reflective of contemporary practice. Internal validation was performed by bootstrapping to estimate in-sample optimism-corrected performance. Results Between 2009 and 2014, up to 6339 patients were included across 34 centres in the UK-TAVI Registry (mean age, 81.3; 2927 female (46.2%)). The observed 30-day mortality rate was 5.14%. The final UK-TAVI CPM included 15 risk factors, which included two variables associated with frailty. After correction for in-sample optimism, the model was well calibrated, with a calibration intercept of 0.02 (95% CI −0.17 to 0.20) and calibration slope of 0.79 (95% CI 0.55 to 1.03). The area under the receiver operating characteristic curve, after adjustment for in-sample optimism, was 0.66. Conclusion The UK-TAVI CPM demonstrated strong calibration and moderate discrimination in UK-TAVI patients. This model shows potential for benchmarking, but even the inclusion of frailty did not overcome the need for more wide-ranging data and other outcomes might usefully be explored

Renal artery sympathetic denervation:observations from the UK experience

Background: Renal denervation (RDN) may lower blood pressure (BP); however, it is unclear whether medication changes may be confounding results. Furthermore, limited data exist on pattern of ambulatory blood pressure (ABP) response—particularly in those prescribed aldosterone antagonists at the time of RDN. Methods: We examined all patients treated with RDN for treatment-resistant hypertension in 18 UK centres. Results: Results from 253 patients treated with five technologies are shown. Pre-procedural mean office BP (OBP) was 185/102 mmHg (SD 26/19; n = 253) and mean daytime ABP was 170/98 mmHg (SD 22/16; n = 186). Median number of antihypertensive drugs was 5.0: 96 % ACEi/ARB; 86 % thiazide/loop diuretic and 55 % aldosterone antagonist. OBP, available in 90 % at 11 months follow-up, was 163/93 mmHg (reduction of 22/9 mmHg). ABP, available in 70 % at 8.5 months follow-up, was 158/91 mmHg (fall of 12/7 mmHg). Mean drug changes post RDN were: 0.36 drugs added, 0.91 withdrawn. Dose changes appeared neutral. Quartile analysis by starting ABP showed mean reductions in systolic ABP after RDN of: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively (p < 0.001 for trend). Use of aldosterone antagonist did not predict response (p < 0.2). Conclusion: In 253 patients treated with RDN, office BP fell by 22/9 mmHg. Ambulatory BP fell by 12/7 mmHg, though little response was seen in the lowermost quartile of starting blood pressure. Fall in BP was not explained by medication changes and aldosterone antagonist use did not affect response

CXCR2 Inhibition – a novel approach to treating CoronAry heart DiseAse (CICADA): study protocol for a randomised controlled trial

Abstract Background There is emerging evidence of the central role of neutrophils in both atherosclerotic plaque formation and rupture. Patients with lower neutrophil counts following acute coronary syndromes tend to have a greater coronary flow reserve, which is a strong predictor of long-term cardiovascular health. But so far, no data are available regarding the impact of neutrophil inhibition on cardiovascular clinical or surrogate endpoints. Therefore, the aim of this study is to investigate the effects of AZD5069, a cysteine-X-cysteine chemokine receptor 2 (CXCR2) inhibitor, on coronary flow reserve and coronary structure and function in patients with coronary artery disease. Methods/Design Ninety subjects with coronary artery disease undergoing percutaneous coronary intervention will be included in this investigator-driven, randomised, placebo-controlled, double-blind, phase IIa, single-centre study. Participants will be randomised to receive either AZD5069 (40 mg) administered orally twice daily or placebo for 24 weeks. Change in coronary flow reserve as determined by 13N-ammonia positron emission tomography-computed tomography will be the primary outcome. Change in the inflammatory component of coronary plaque structure and the backward expansion wave, an invasive coronary physiological measure of diastolic function, will be assessed as secondary outcomes. Discussion Cardiovascular surrogate parameters, such as coronary flow reserve, may provide insights into the potential mechanisms of the cardiovascular effects of CXCR2 inhibitors. Currently, ongoing trials do not specifically focus on neutrophil function as a target of intervention, and we therefore believe that our study will contribute to a better understanding of the role of neutrophil-mediated inflammation in coronary artery disease. Trial registration EudraCT, 2016-000775-24 . Registered on 22 July 2016. International Standard Randomised Controlled Trial Number, ISRCTN48328178 . Registered on 25 February 2016