In patients with non–ST-segment elevation acute coronary syndrome (NSTEACS), coronary pathology ranges from normal vessels to severe obstructive disease. In NSTEACS patients where invasive coronary angiography (ICA) is recommended, it is unknown whether a non-invasive coronary computed tomography angiography (CCTA) may be used for patient triage. The Very Early Computerized Tomography to Organize Revascularization in patients with NSTEACS (VECTOR) study was a pilot study that assessed whether CCTA can be used to safely discharge NSTEACS patients without obstructive coronary artery disease. An initial CCTA categorized all patients into CCTA groups: CTnon−obstructive, (without stenosis ≥ 50

Objectives The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 x 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT). Methods Symptomatic, optimally treated HFrEF patients with LVEF <= 40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years. Results As of May 2020, 296 patients have been randomized at 20 centers in Denmark. Conclusion The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

BACKGROUND In patients with non-ST-segment elevation acute coronary syndrome (NSTEACS), coronary pathology may range from structurally normal vessels to severe coronary artery disease. OBJECTIVES The purpose of this study was to test if coronary computed tomography angiography (CTA) may be used to exclude coronary artery stenosis $50% in patients with NSTEACS. METHODS The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial (NCT02061891) evaluated the outcome of patients with confirmed NSTEACS randomized 1:1 to very early (within 12 h) or standard (48 to 72 h) invasive coronary angiography (ICA). As an observational component of the trial, a clinically blinded coronary CTA was conducted prior to ICA in both groups. The primary endpoint was the ability of coronary CTA to rule out coronary artery stenosis ($50% stenosis) in the entire population, expressed as the negative predictive value (NPV), using ICA as the reference standard. RESULTS Coronary CTA was conducted in 1,023 patients-very early, 2.5 h (interquartile range [IQR]: 1.8 to 4.2 h), n = 583; and standard, 59.9 h (IQR: 38.9 to 86.7 h); n = 440 after the diagnosis of NSTEACS was made. A coronary stenosis $50% was found by coronary CTA in 68.9% and by ICA in 67.4% of the patients. Per-patient NPV of coronary CTA was 90.9% (95% confidence interval [CI]: 86.8% to 94.1%) and the positive predictive value, sensitivity, and specificity were 87.9% (95% CI: 85.3% to 90.1%), 96.5% (95% CI: 94.9% to 97.8%) and 72.4% (95% CI: 67.2% to 77.1%), respectively. NPV was not influenced by patient characteristics or clinical risk profile and was similar in the very early and the standard strategy group. CONCLUSIONS Coronary CTA has a high diagnostic accuracy to rule out clinically significant coronary artery disease in patients with NSTEACS. (C) 2020 by the American College of Cardiology Foundation.

Current guidelines recommend angiotensin receptor blocker neprilysin inhibitors (ARNI) (sacubitril/valsartan) as a replacement for angiotensin-converting-enzymeinhibitor (ACE-I) in heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal medical therapy. The effects of ARNIs have not previously been assessed in a systematic review. We searched for relevant trials until October 2019 in CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, CNKI, VIP, WanFang and CBM. Our primary outcomes were all-cause mortality and serious adverse events. We systematically assessed the risks of random errors and systematic errors. PROSPERO registration: CRD42019129336. 48 trials randomising 19 086 participants were included. The ARNI assessed in all trials was sacubitril/valsartan. ACE-I or ARB were used as control interventions. Trials randomising HFrEF participants (27 trials) and heart failure with preserved ejection fraction (HFpEF) participants (four trials) were analysed separately. In HFrEF participants, meta-analyses and Trial Sequential Analyses showed evidence of a beneficial effect of sacubitril/valsartan when assessing all-cause mortality (risk ratio (RR), 0.86; 95% CI, 0.79 to 0.94) and serious adverse events (RR, 0.89; 95% CI, 0.86 to 0.93); and the results did not differ between the guideline recommended target population and HFrEF participants in general. We found no evidence of an effect of sacubitril/valsartan in HFpEF participants. Sacubitril/valsartan compared with either ACE-I or ARB seems to have a beneficial effect in patients with HFrEF. Our results indicate that sacubitril/valsartan might be beneficial in a wider population of patients with heart failure than the guideline recommended target population. Sacubitril/valsartan does not seem to show evidence of a difference compared with valsartan in patients with HFpEF.

Heart failure is a highly prevalent disease with a global prevalence of 37 million, and the prevalence is increasing. Patients with heart failure are at an increased risk of death and morbidity. Traditionally, patients with heart failure have been treated with a beta-blocker in addition to an inhibitor of the renin-angiotensin-aldosterone system. However, new drugs are currently being added to the recommended guideline therapy. The latest drug to be added combines inhibition of the renin-angiotensin-aldosterone system pathway with inhibiting the neprilysin enzyme and is therefore classified as an ARNI. Our objective is to identify the beneficial and harmful effects of ARNIs in the treatment of patient with heart failure. This protocol for a systematic review was undertaken using the recommendations of the Cochrane, the Preferred Report Items of Systematic reviews with Meta-Analysis Protocols, and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the use of ARNIs in the treatment of patients with heart failure. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP), and BIOSIS to identify relevant trials. We will also search for grey literature and unpublished trials. Extracted data will be analysed using Review Manager 5, STATA 5, and Trial Sequential Analysis. Our primary outcomes will be all-cause mortality and serious adverse events. We will create a ‘Summary of Findings’ table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the GRADE assessment. The present systematic review will have the potential to aid clinicians in decision-making and thereby, benefit patients with heart failure. PROSPERO CRD42019129336

Background: The optimal timing of invasive coronary angiography (ICA) and revascularization in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is not well defined. We tested the hypothesis, that a strategy of very early invasive coronary angiography (ICA) and possible revascularization within 12 hours of diagnosis, is superior to an invasive strategy performed within 48-72 hours in terms of clinical outcomes. Methods: Patients admitted with clinical suspicion of NSTE-ACS in the Capital Region of Copenhagen, Denmark were screened for inclusion in the VERDICT trial (ClinicalTrials.gov NCT02061891). Patients with ECG changes indicating new ischemia and/or elevated troponin, in whom ICA was clinically indicated and deemed logistically feasible within 12 hours, were randomized 1:1 to ICA within 12 hours or standard invasive care within 48-72 hours. The primary endpoint was a combination of all-cause death, non-fatal recurrent myocardial infarction, hospital admission for refractory my...

Background Edoxaban, an oral factor Xa inhibitor, is non-inferior for prevention of stroke and systemic embolism in patients with atrial fibrillation and is associated with less bleeding than well controlled warfarin therapy. Few safety data about edoxaban in patients undergoing electrical cardioversion are available.Methods We did a multicentre, prospective, randomised, open-label, blinded-endpoint evaluation trial in 19 countries with 239 sites comparing edoxaban 60 mg per day with enoxaparin-warfarin in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. The dose of edoxaban was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, low bodyweight [<= 60 kg], or concomitant use of P-glycoprotein inhibitors) were present. Block randomisation (block size four)-stratified by cardioversion approach (transoesophageal echocardiography [TEE] or not), anticoagulant experience, selected edoxaban dose, and region-was done through a voice-web system. The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular mortality, analysed by intention to treat. The primary safety endpoint was major and clinically relevant non-major (CRNM) bleeding in patients who received at least one dose of study drug. Follow-up was 28 days on study drug after cardioversion plus 30 days to assess safety. This trial is registered with ClinicalTrials.gov, number NCT02072434.Findings Between March 25, 2014, and Oct 28, 2015, 2199 patients were enrolled and randomly assigned to receive edoxaban (n= 1095) or enoxaparin-warfarin (n= 1104). The mean age was 64 years (SD 10 . 54) and mean CHA(2)DS(2)-VASc score was 2.6 (SD 1.4). Mean time in therapeutic range on warfarin was 70.8% (SD 27.4). The primary efficacy endpoint occurred in five (<1%) patients in the edoxaban group versus 11 (1%) in the enoxaparin-warfarin group (odds ratio [OR] 0.46, 95% CI 0.12-1.43). The primary safety endpoint occurred in 16 (1%) of 1067 patients given edoxaban versus 11 (1%) of 1082 patients given enoxaparin-warfarin (OR 1.48, 95% CI 0.64-3.55). The results were independent of the TEE-guided strategy and anticoagulation status.Interpretation ENSURE-AF is the largest prospective randomised clinical trial of anticoagulation for cardioversion of patients with non-valvular atrial fibrillation. Rates of major and CRNM bleeding and thromboembolism were low in the two treatment groups.Funding Daiichi Sankyo provided financial support for the study.

SummaryBackgroundChronic heart failure (HF) is characterized by reduced serum T3 levels and increased activity of the T3 degrading enzyme deiodinase D3. This may result in an intracellular composition of the cardiomyocyte mimicking that of hypothyroidism. Short‐term T3‐administration to systolic HF patients might be beneficial.QuestionDoes long‐term treatment with T3 have a beneficial effect on cardiac function and neurohormonal activation in chronic systolic HF patients with serum T3 levels below 1·6 nmol/l?DesignA randomized, double‐blind, cross‐over, placebo‐controlled intervention study with oral T3 treatment twice daily for 3 months. The T3 dose was uptitrated to a final dose avoiding reduced TSH levels.Primary end‐pointLeft‐ventricular ejection fraction (LVEF).MethodsCardiac imaging was performed using multiple gated tomographic radionuclide ventriculography (MUGA‐SPECT). Neurohormonal stimulation was evaluated by plasma measurements of natriuretic peptides, aldosterone, renin, noradrenalin and copeptin levels. The patients were monitored for potential cardiac arrhythmias at the start of each treatment period.ResultsThirteen patients completed the protocol. Mean LVEF was 43%, range: 37–52 and serum T3 levels 1·4 nmol/l (0·9–1·6). The T3 dose was 20 μg per day (10–40). TSH levels did not change between groups, whereas serum T3 levels increased in the active arm. Cardiac function as measured by LVEF, end‐diastolic and end‐systolic volumes and cardiac output did not change during T3‐treatment and neither did the neurohormonal profile. There were no side‐effects in terms of cardiac arrhythmias and no change in resting heart rate.ConclusionsThis study does not support the hypothesis that oral T3 treatment might be beneficial to patients with chronic, stable systolic HF with a modest degree of reduced LVEF and low‐normal serum T3 concentrations. The study included both functional studies of heart contractility as well as measures of the neurohormonal activation.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Aim α‐Defensins are part of the innate immune system. Low‐grade inflammation seems to play a crucial role in development and progression of chronic heart failure (CHF). The aims of the present study were to compare plasma levels of α‐defensins in CHF patients and healthy controls and to examine the predictive ability of α‐defensins, alone and combined with N‐terminal pro brain natriuretic peptide (NT‐proBNP), with respect to all‐cause mortality. Methods and results In a prospective observational study lasting 2.6 years we examined the prognostic value of plasma α‐defensins with respect to mortality in 194 CHF patients, and compared plasma levels with those of 98 age‐matched healthy controls. α‐Defensin levels were twice as high among CHF patients in New York Heart Association (NYHA) functional class III–IV than in patients in NYHA class I–II and healthy controls ( P = 0.001). The absolute increase in risk of mortality for patients with α‐defensin levels in the upper tertile vs. the lowest tertile was 30% ( P = 0.002). After adjusting for potential confounders including NT‐proBNP, plasma α‐defensins remained independently associated with an increased risk of all‐cause mortality (hazard ratio 1.65, 95% confidence interval 1.19–2.28, P = 0.002) per 1 standard deviation increment in Ln (natural logarithm)‐transformed α‐defensin values. The combination of high α‐defensins and NT‐proBNP levels provided incremental prognostic information independent of well‐known prognostic biomarkers in heart failure. Conclusion Plasma α‐defensins appear to have prognostic information regarding mortality among patients with CHF and seem to provide incremental information to established clinical risk markers.

BACKGROUND:Low-grade inflammation has been associated with cardiovascular disease (CVD) and chronic heart failure (CHF). The aim of the present study was to investigate the potential usefulness of the inflammatory protein calprotectin as a biomarker in CHF.METHODS:Plasma calprotectin was measured in 193 CHF patients with left ventricular function <45% and in 100 healthy controls at baseline. Patients with CHF were followed for a median period of 2.6 years according to mortality.RESULTS:The levels of plasma calprotectin were significantly increased in the CHF patients compared to the control group (P < 0.01), primarily due to elevated levels in the patients with New York Heart Association (NYHA) class III and IV. Furthermore, plasma calprotectin was a superior biomarker of high NYHA classes than other parameters reflecting CHF severity, OR 2.2 (1.1-4.3) (P = 0.019). After the follow-up period, 46 patients had died. Plasma calprotectin levels did not predict mortality in CHF patients.CONCLUSIONS:Plasma calprotectin is increased in CHF patients, indicating that inflammatory activity is upregulated in CHF and may be associated with the severity of CHF.

The objective of the present study was to test the hypothesis that circulating levels of insulin-like growth factor-I (IGF-I) are inversely associated with inflammatory processes in an elderly background population.

Background: Low grade inflammation is of pathogenic importance in the development of cardiovascular disease (CVD) and type 2 diabetes. The inflammation marker YKL-40 correlates with insulin resistance and is highly expressed in atherosclerotic plaques. We aimed to investigate whether YKL-40 could predict overall and cardiovascular (CV) mortality in a 50+ years population without known CVD.Methods: A representative population sample of 639 individuals aged 50-89 years was recruited from general practices. Examination at baseline included echocardiography and blood and urine samples for CV risk factors and markers including lipids, high sensitive C-reactive protein (hsCRP), N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) and urinary albumin/creatinine-ratio (UACR). Median follow-up period was 5.0 (0.17-5.28) years.Results: In subjects without diabetes and CVD at baseline, increasing YKL-40 levels independently predicted overall and CV mortality rate with hazard ratios of 1.58 (95% confidence interval (CI), 1.12-2.23, p = 0.009) and 1.57 (95% CI, 1.00-2.46, p = 0.049) after adjustment for age, sex, smoking, total cholesterol, hsCRP, NT-proBNP and UACR. In combined Kaplan-Meier analyses, baseline values of both YKL-40 and UACR above median significantly predicted increased cumulative overall and CV mortality rates in subjects without diabetes or CVD at baseline (30.6% vs. <= 8%, respectively 10.6% <= 3%, p<0.0001).Conclusions: YKL-40 seems to be an independent predictor of overall and CV mortality in an elderly part of the general population without diabetes and CVD. YKL-40 and UACR are both independent predictors, that seem to predict overall and CV mortality in a synergistic way. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND:IGF1 is believed to influence ageing and development of cardiovascular disease (CVD) through complex mechanisms. Reduced IGF1 levels might be causally associated with conditions accompanying ageing including development of CVD. However, in animal models reduced GH-IGF1 signalling increases lifespan. Reduced IGF1 activity might also be associated with longevity in humans.OBJECTIVE:The objective was to investigate if plasma IGF1 levels were associated with all cause mortality, and the development of chronic heart failure (CHF) and a major CV event.PATIENTS AND DESIGN:A population based study of 642 individuals, aged 50-89 years. Development of CHF was evaluated in 576 individuals with normal systolic function assessed by echocardiography and without the history of CHF or myocardial infarction. Development of the first major CV event was evaluated in 504 individuals with normal systolic function and without prevalent CVD. Outcomes were ascertained after 5 years using hospital discharge diagnoses.RESULTS:Adjustment for risk factors IGF1 values in the fourth quartile versus values below the fourth quartile was associated with increased mortality (n=103), hazard ratio (HR) 1.52 (95% confidence interval (CI) 1.01-2.28; P=0.044). IGF1 in the fourth quartile was also independently associated with risk of development of CHF (n=19), HR 5.02 (95% CI 2.00-12.64; P=0.001) but showed no association with the overall incidence of major CV events (n=58), HR 1.05 (95% CI 0.59-1.90; P=0.861).CONCLUSIONS:High IGF1 levels were independently associated with increased all cause mortality and risk of development of CHF, whereas no relation with the overall incidence of CVD was observed.

Objectives. Congestive heart failure (CHF) has been associated with elevated biomarker levels reflecting chronic low-grade inflammation. YKL-40 is a biomarker with increasing levels in patients with cardiovascular disease (CVD) of increasing severity. Furthermore, YKL-40 is associated with all-cause and cardiovascular mortality. We investigated plasma YKL-40 levels in patients with CHF and evaluated the possible predictive value with respect to overall mortality and recurrent cardiovascular outcomes. Design. Plasma YKL-40 was measured in 194 CHF patients and in 117 age-matched individuals without CVD. Results. Median YKL-40 levels were approximately 77% higher in patients with CHF (106 (IQR, 66-184) ng/ml vs. 60 (IQR, 42-97) ng/ml, p < 0.0001). We found a trend towards an association of YKL-40 levels with urinary albumin/creatinine ratio (UACR) (beta = 0.12, p = 0.08). YKL-40 levels were not predictive of overall mortality (p = 0.59), major cardiovascular events (p = 0.23) or events of incompensation (p = 0.56). Conclusions. Plasma YKL-40 levels are elevated in patients with CHF but show no association with other clinical or paraclinical variables. YKL-40 levels were not predictive of overall mortality or incident cardiovascular events. Most likely, elevated YKL-40 levels in CHF patients are explained by the presence of concomitant diseases but a role of YKL-40 in low-grade inflammation is not excluded.

Objectives: Insulin-like growth factor I (IGF-I) is an anabolic growth factor that seems to increase cardiac contractility. Reduced levels of IGF-I may be implicated in progression of CHF. The objective was to compare plasma IGF-I in CHF patients with healthy controls. and to examine the associations between baseline IGF-I levels, cardiac contractility and the prognosis as judged by all cause mortality and progression of CHIF requiring admission to hospital.Methods: A prospective study comprising 194 CHF outpatients, and 169 matched controls. All patients and controls underwent echocardiographic examination at baseline. Patients were followed for a median of 30 months.Results: There was no difference in IGF-I levels between patients and controls (median and interquartile range), 78 (58-91) vs. 77 (57-94) ng/mL (P = 0.92). Age-adjusted IGF-I levels were not related to left ventricular ejection fraction (LVEF) (P = 0.58) or levels of N-terminal B-Type natriuretic peptide (NT-proBNP) (P = 0.42).During follow-up 44 patients died and 94 were admitted to hospital due to worsening of CHF. Adjusted for cardiovascular risk factors (age, gender, NT-proBNP, lipids, diabetes mellitus, blood pressure, renal function and LVEF) IGF-I levels did not influence the overall mortality risk or the admission rate to hospital, hazard ratio (HR) (95% confidence intervals) 1.05 (0.75-1.47) (P = 0.77) and 1.00 (0.80-1.26) (P = 0.96), respectively per each SD increase in log IGF-I levels.Conclusions: IGF-I levels were not reduced in patients with CHF and did not influence cardiac status at baseline or the prognosis. (C) 2009 Elsevier Ltd. All rights reserved.

BACKGROUND AND OBJECTIVE:Measurements of Insulin-Like Growth Factor-I (IGF-I) play a pivotal role in the evaluation of the growth hormone-IGF-I axis. Due to assay variation IGF-I reference ranges are assay specific. We provide serum IGF-I reference ranges for adult men and women obtained by a commercially available assay.METHOD:IGF-I was measured by an enzyme-linked immunosorbent assay (R&D Systems). Assay precision was evaluated in low, medium and high IGF-I pools and in single samples from outpatients. The reference ranges were obtained in 724 healthy Caucasians, mean age 48 years (range 19-91).RESULTS:IGF-I was measured higher in serum compared to plasma samples (p<0.001, R2=0.96). To convert EDTA plasma values to serum values a factor of 1.22 was calculated. The intraassay coefficients of variation (CV) for the low: 56.4+/-2.7 ng/mL, medium: 179.7+/-5.9 ng/mL and high pool: 445.61+/-3.2 ng/mL (mean 1 SD) were 5, 3 and 3%. Interassays CVs for the low, medium and high pool varied between 7-10, 5-7, and 6-9%. Reproducibility between 4 different lots showed a intraclass CV of 0.99 (95%CI 0.98-0.96). Logarithmically transformed IGF-I levels were linearly associated with age with a 13% reduction in IGF-I per decade in females and 11% in males.CONCLUSION:We have provided IGF-I reference ranges obtained by an assay that showed variations and reproducibility that was considered of sufficient high quality for clinical and scientific use.