Renal and Cardiovascular Effects of sodium–glucose cotransporter 2 (SGLT2) inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF):protocol for a randomised controlled double-blind cross-over trial

Introduction: Type 2 diabetes (T2D) and heart failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium-glucose co-transporter 2 (SGLT2) inhibitors and their use in patients with HF. Data on the effect of SGLT2 inhibitor use with diuretics is limited. We hypothesise that SGLT2 inhibition may augment the effects of loop diuretics. We hypothesise that the benefits of SGLT2 inhibitors extend beyond those of their metabolic (glycaemic parameters and weight loss) and haemodynamic parameters; that the effects of SGLT2 inhibitors as an osmotic diuretic and on natriuresis may underlie the cardiovascular and renal benefits demonstrated in the recent EMPA-REG study.Methods and Analysis: To assess the effect of SGLT2 inhibitors when used in combination with a loop diuretic, the RECEDE-CHF trial is a single centre, randomised double-blind, placebo-controlled, crossover trial conducted in a secondary care setting within NHS Tayside, Scotland. 34 eligible participants, aged between 18 to 80 years, with stable T2D and CHF will be recruited. Renal physiological testing will be performed at two points (week 1 and week 6) on each arm to assess the effect of 25 mg empagliflozin, on the primary and secondary outcomes. Participants will be enrolled in the trial for a total period between 14 to 16 weeks. The primary outcome will assess the effect of empagliflozin versus placebo on urine output. The secondary outcomes are to assess the effect of empagliflozin on glomerular filtration rate, cystatin C, urinary sodium excretion, urinary protein/creatinine ratio, and urinary albumin/creatinine ratio when compared to placebo.Ethics and Dissemination: Ethics approval was obtained by the East of Scotland Research Ethics Service. Results of the trial will be submitted for publication in a peer-reviewed journal.Registration Details: clinicaltrials.gov: NCT03226457. Registered: July 17, 2017

Efficacy of noninvasive cardiac imaging tests in diagnosis and management of stable coronary artery disease

Ify R Mordi,1,2 Athar A Badar,2 R John Irving,2 Jonathan R Weir-McCall,1 J Graeme Houston,1 Chim C Lang1,2 1Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK; 2Department of Cardiology, Ninewells Hospital and Medical School, Dundee, UK Abstract: The aim of this review was to discuss the current literature regarding the utility of noninvasive imaging in diagnosis and management of stable coronary artery disease (CAD) including recent data from large randomized trials assessing diagnosis and prognosis. Current guidelines recommend revascularization in patients with refractory angina and in those with potential prognostic benefit. Appropriate risk stratification through noninvasive assessment is important in ensuring patients are not exposed to unnecessary invasive coronary angiograms. The past 20 years have seen an unprecedented expansion in noninvasive imaging modalities for the assessment of stable CAD, with cardiovascular magnetic resonance and computed tomography complementing established techniques such as myocardial perfusion imaging, echocardiography and exercise electrocardiogram. In this review, we examine the current state-of-the-art in noninvasive imaging to provide an up-to-date analysis of current investigation and management options. Keywords: angina, noninvasive imaging, SPECT, stress echo, cardiovascular magnetic resonance, CT coronary angiograph

Clinical Determinants and Prognostic Implications of Renin and Aldosterone in Patients with Symptomatic Heart Failure

Aims Activation of the renin-angiotensin-aldosterone system plays an important role in the pathophysiology of heart failure (HF) and has been associated with poor prognosis. There are limited data on the associations of renin and aldosterone levels with clinical profiles, treatment response, and study outcomes in patients with HF. Methods and results We analysed 2,039 patients with available baseline renin and aldosterone levels in BIOSTAT-CHF (a systems BIOlogy study to Tailored Treatment in Chronic Heart Failure). The primary outcome was the composite of all-cause mortality or HF hospitalization. We also investigated changes in renin and aldosterone levels after administration of mineralocorticoid receptor antagonists (MRAs) in a subset of the EPHESUS trial and in an acute HF cohort (PORTO). In BIOSTAT-CHF study, median renin and aldosterone levels were 85.3 (percentile(25-75) = 28-247) mu IU/mL and 9.4 (percentile(25-75) = 4.4-19.8) ng/dL, respectively. Prior HF admission, lower blood pressure, sodium, poorer renal function, and MRA treatment were associated with higher renin and aldosterone. Higher renin was associated with an increased rate of the primary outcome [highest vs. lowest renin tertile: adjusted-HR (95% CI) = 1.47 (1.16-1.86), P = 0.002], whereas higher aldosterone was not [highest vs. lowest aldosterone tertile: adjusted-HR (95% CI) = 1.16 (0.93-1.44), P = 0.19]. Renin and/or aldosterone did not improve the BIOSTAT-CHF prognostic models. The rise in aldosterone with the use of MRAs was observed in EPHESUS and PORTO studies. Conclusions Circulating levels of renin and aldosterone were associated with both the disease severity and use of MRAs. By reflecting both the disease and its treatments, the prognostic discrimination of these biomarkers was poor. Our data suggest that the "point" measurement of renin and aldosterone in HF is of limited clinical utility

The future of pharmacogenetics in the treatment of heart failure

Heart failure is a common disease with high levels of morbidity and mortality. Current treatment comprises β-blockers, ACE inhibitors, aldosterone antagonists and diuretics. Variation in clinical response seen in patients begs the question of whether there is a pharmacogenetic component yet to be identified. To date, the genes most studied involve the β-1, β-2, α-2 adrenergic receptors and the renin-angiotensin-aldosterone pathway, mainly focusing on SNPs. However results have been inconsistent. Genome-wide association studies and next-generation sequencing are seen as alternative approaches to discovering genetic variations influencing drug response. Hopefully future research will lay the foundations for genotype-led drug management in these patients with the ultimate aim of improving their clinical outcome.</p

A network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic heart failure

Aims Heart failure (HF) is frequently caused by an ischaemic event (e.g. myocardial infarction) but might also be caused by a primary disease of the myocardium (cardiomyopathy). In order to identify targeted therapies specific for either ischaemic or non‐ischaemic HF, it is important to better understand differences in underlying molecular mechanisms. Methods and results We performed a biological physical protein–protein interaction network analysis to identify pathophysiological pathways distinguishing ischaemic from non‐ischaemic HF. First, differentially expressed plasma protein biomarkers were identified in 1160 patients enrolled in the BIOSTAT‐CHF study, 715 of whom had ischaemic HF and 445 had non‐ischaemic HF. Second, we constructed an enriched physical protein–protein interaction network, followed by a pathway over‐representation analysis. Finally, we identified key network proteins. Data were validated in an independent HF cohort comprised of 765 ischaemic and 100 non‐ischaemic HF patients. We found 21/92 proteins to be up‐regulated and 2/92 down‐regulated in ischaemic relative to non‐ischaemic HF patients. An enriched network of 18 proteins that were specific for ischaemic heart disease yielded six pathways, which are related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. We identified five key network proteins: acid phosphatase 5, epidermal growth factor receptor, insulin‐like growth factor binding protein‐1, plasminogen activator urokinase receptor, and secreted phosphoprotein 1. Similar results were observed in the independent validation cohort. Conclusions Pathophysiological pathways distinguishing patients with ischaemic HF from those with non‐ischaemic HF were related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. The five key pathway proteins identified are potential treatment targets specifically for patients with ischaemic HF

Genetic Risk and Atrial Fibrillation in Patients with Heart Failure

Aims: To study the association between an atrial fibrillation (AF) genetic risk score with prevalent AF and all-cause mortality in patients with heart failure. Methods and results: An AF genetic risk score was calculated in 3759 European ancestry individuals (1783 with sinus rhythm, 1976 with AF) from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) by summing 97 single nucleotide polymorphism (SNP) alleles (ranging from 0–2) weighted by the natural logarithm of the relative SNP risk from the latest AF genome-wide association study. Further, we assessed AF risk variance explained by additive SNP variation, and performance of clinical or genetic risk factors, and the combination in classifying AF prevalence. AF was classified as AF or atrial flutter (AFL) at baseline electrocardiogram and/or a history of AF or AFL. The genetic risk score was associated with AF after multivariable adjustment. Odds ratio for AF prevalence per 1-unit increase genetic risk score was 2.12 (95% confidence interval 1.84–2.45, P = 2.15 × 10−24) in the total cohort, 2.08 (1.72–2.50, P = 1.30 × 10−14) in heart failure with reduced ejection fraction (HFrEF) and 2.02 (1.37–2.99, P = 4.37 × 10−4) in heart failure with preserved ejection fraction (HFpEF). AF-associated loci explained 22.9% of overall AF SNP heritability. Addition of the genetic risk score to clinical risk factors increased the C-index by 2.2% to 0.721. Conclusions: The AF genetic risk score was associated with increased AF prevalence in HFrEF and HFpEF. Genetic variation accounted for 22.9% of overall AF SNP heritability. Addition of genetic risk to clinical risk improved model performance in classifying AF prevalence

Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status

Rationale: The diabetes drug metformin is under investigation in cardiovascular disease but the molecular mechanisms underlying possible benefits are poorly understood. Objective: Here we have studied anti-inflammatory effects of the drug and their relationship to anti-hyperglycaemic properties. Methods and Results: In primary hepatocytes from healthy animals, metformin and the IKKβ inhibitor BI605906 both inhibited TNFα-dependent IκB degradation and expression of pro-inflammatory mediators IL-6, IL-1b, and CXCL1/2. Metformin suppressed IKKα/β activation, an effect which could be separated from some metabolic actions, in that BI605906 did not mimic effects of metformin on lipogenic gene expression, glucose production and AMPK activation. Equally AMPK was not required either for mitochondrial suppression of IκB degradation. Consistent with discrete anti-inflammatory actions, in macrophages metformin specifically blunted secretion of pro-inflammatory cytokines, without inhibiting M1/M2 differentiation or activation. In a large treatment naïve diabetes population cohort, we observed differences in the systemic inflammation marker, Neutrophil to Lymphocyte Ratio (NLR), following incident treatment with either metformin or sulfonylurea monotherapy. Compared to sulfonylurea exposure, metformin reduced the mean log-transformed NLR after 8-16 months by 0.09 units (95% CI=0.02-0.17, p=0.013), and increased the likelihood that NLR would be lower than baseline after 8-16 months (OR 1.83, 95% CI=1.22-2.75, p=0.00364). Following up these findings in a double blind placebo controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin suppressed plasma cytokines including the ageing-associated cytokine CCL11. Conclusions: We conclude that anti-inflammatory properties of metformin are exerted irrespective of diabetes status. This may accelerate investigation of drug utility in non-diabetic cardiovascular disease groups