Microvascular Disease with Heart Failure with Reduced and Preserved Ejection Fraction in Patients with Type 2 Diabetes

Aims: Identification of patients with type 2 diabetes (T2D) at increased risk of incident heart failure (HF) beyond traditional risk factors such as prior myocardial infarction (MI) might allow selection of patients who would benefit from preventative treatment. Microvascular disease (MiVD) is thought to play a pathophysiological role in the development of HF in T2D; however, its association with new-onset HF with reduced or preserved ejection fraction has not been specifically defined. Methods and results: Patients in the Genetics of Diabetes Audit and Research Tayside Scotland study were linked to echocardiography, prescriptions, and clinical outcomes. In total, 9141 patients with T2D were identified for analysis. Clinical variables and the presence of retinopathy, nephropathy, and neuropathy were assessed. Cumulative incidence was calculated for the association of both individual and the total number of MiVD states and incident HF. Median follow-up was 9.3 years. In total, there were 900 HF events. The presence of any MiVD was independently associated with both HF with reduced ejection fraction (hazard ratio 1.40; 95% confidence interval 1.11–1.76, P = 0.004) and HF with preserved ejection fraction (hazard ratio 1.38; 95% confidence interval 1.10–1.72, P = 0.005), with a stepwise association between the number of MiVD states and risk of incident HF (P for trend &lt;0.001). Similar associations were found in sensitivity analyses limited to patients without a prior MI, and using competing risks analysis. Conclusions: Individuals with T2D and with MiVD are at risk of incident HF independent of a history of prior HF or MI. Patients with MiVD could benefit from screening for HF and individualized therapy with treatments that lower HF risk.</p

Potential mechanisms for the effects of far-infrared on the cardiovascular system:a review

Far-infrared (FIR) is a form of thermal radiation, which may have beneficial effects on cardiovascular health. Clinical studies suggest that FIR irradiation may have therapeutic effects in heart failure, myocardial ischaemia and may improve flow and survival of arteriovenous fistula. Animal studies have suggested a wide range of potential mechanisms involving endothelial nitric oxide synthase and nitric oxide bioavailability, oxidative stress, heat shock proteins and endothelial precursor cells. However, the exact cellular and molecular mechanism of FIR on the cardiovascular system remains elusive. The purpose of this review is to discuss the current literature, focusing on mechanistic studies involving the cardiovascular system, and with a view to highlighting areas for future investigation.<br/

Allopurinol treatment adversely impacts left ventricular mass regression in patients with well-controlled hypertension

Objectives: Previous studies have demonstrated that high dose allopurinol is able to regress Left Ventricular (LV) mass in cohorts with established cardiovascular disease. The aim of this study was to assess whether treatment with high dose allopurinol would regress LV mass in a cohort with essential hypertension, LV hypertrophy and well- controlled blood pressure but without established cardiovascular disease.Methods: We conducted a mechanistic proof-of-concept randomised, placebo controlled, double-blind trial of allopurinol (600mg/day) versus placebo on LV mass regression. Duration of treatment was 12 months. LV mass regression was assessed by Cardiac Magnetic Resonance. Secondary outcomes were changes in endothelial function (flow mediated dilatation), arterial stiffness (pulse wave velocity) and biomarkers of oxidative stress. Results: 72 patients were randomised into the trial. Mean baseline urate was 362.2 ± 96.7umol/L. Despite good blood pressure control, LV mass regression was significantly reduced in the allopurinol cohort compared to placebo (LV mass -0.37 ± 6.08 g vs -3.75 ± 3.89 g; p=0.012). Oxidative stress markers (Thiobarbituric acid reactive substances) were significantly higher in the allopurinol group vs placebo (0.26 ± 0.85uM vs -0.34 ± 0.83uM; p=0.007). Other markers of vascular function were not significantly different between the two groups.Conclusions: Treatment with high dose allopurinol in normo-uricemic controlled hypertensive patients and LV hypertrophy is detrimental. It results in reduced LV mass regression and increased oxidative stress over a 12-month period. This may be due to an adverse impact on redox balance. Cohort selection for future cardiovascular trials with allopurinol is crucial.<br/

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

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

Metformin:still the sweet spot for CV protection in diabetes?

Metformin remains the first-line drug treatment for type 2 diabetes (T2D) in most guidelines not only because it achieves significant reduction in HbA1c but also because of a wealth of clinical experience regarding its safety and observational data that has shown that metformin use is associated with lower mortality rates when compared to sulphonylureas or insulin. Recently other diabetes drugs, particularly SGLT2 inhibitors (SGLT2i) and GLP1 receptor agonists (GLP1RA), have attracted considerable attention for their cardioprotective benefits reported in cardiovascular outcome trials (CVOTs). Randomised control trials on these newer drugs are on a larger scale but have shorter follow-up than UKPDS, the main study supporting metformin use. In a recent change to the European Society of Cardiology guidelines, metformin was replaced by SGLT2i and GLP1RA as first-line for T2D with atherosclerotic cardiovascular disease, whereas American Diabetes Association and UK-wide guidelines maintain metformin as first choice drug pharmacotherapy for all T2D. A definitive evidence-base for prioritisation of these drugs is currently missing because there are no head-to-head clinical trial data. Without such trials being forthcoming, innovative, pragmatic and low-cost 'real-world' trial approaches based on electronic health records may need to be harnessed to determine the correct priority, combinations of drugs and/or identify-specific patient populations most likely to benefit from each one.</p