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Abstract Aims In patients with chronic heart failure with reduced ejection fraction (HFrEF), myocardial ketone metabolism is increased and short‐term treatment with the ketone body 3‐hydroxy butyrate (3‐OHB) has beneficial haemodynamic effects. In patients with HFrEF, we investigated whether the level of circulating 3‐OHB predicted all‐cause mortality and sought to identify correlations between patient characteristics and circulating 3‐OHB levels. Methods and results We conducted a cohort study in 218 patients with HFrEF. Plasma 3‐OHB levels were measured using high‐performance liquid chromatography tandem mass spectrometry. Data on all‐cause mortality were obtained by reviewing the patients' medical records, which are linked to the national ‘Central Person Registry’ that registers the timing of all deaths in the country. Mean left ventricular ejection fraction was 35 ± 8.6%, mean age was 67 ± 10 years, 54% were New York Heart Association II, and 27% had type 2 diabetes mellitus. Median follow‐up time was 7.3 (interquartile range 6.3–8.4) years. We observed large variations in 3‐OHB levels between patients (median 59 μM, range: 14–694 μM). Patients with 3‐OHB levels above the median displayed a markedly increased risk of death compared with those with low levels {hazard ratio [HR]: 2.1 [95% confidence interval (CI): 1.3–3.5], P = 0.003}. In a multivariate analysis, 3‐OHB predicted mortality independently of known chronic heart failure risk factors [HR: 1.004 (95% CI: 1.001–1.007), P = 0.02] and with a similar statistical strength as N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) [HR: 1.0005 (95% CI: 1.000–1.001), P = 0.02]. For every 100 μmol increase in plasma 3‐OHB, the hazard of death increased by 49%. The following factors significantly predicted 3‐OHB levels in the univariate analysis: free fatty acids (FFAs) [β: 238 (95% CI: 185–292), P 0.001]. Conclusions In patients with HFrEF, circulating 3‐OHB was a strong predictor of all‐cause mortality independently of NT‐proBNP. Circulating FFAs were the best predictor of 3‐OHB levels.

Abstract Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia–reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer’s acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P

Background The heart can metabolize the microbiota‐derived short‐chain fatty acid butyrate. Butyrate may have beneficial effects in heart failure, but the underlying mechanisms are unknown. We tested the hypothesis that butyrate elevates cardiac output by mechanisms involving direct stimulation of cardiac contractility and vasorelaxation in rats. Methods and Results We examined the effects of butyrate on (1) in vivo hemodynamics using parallel echocardiographic and invasive blood pressure measurements, (2) isolated perfused hearts in Langendorff systems under physiological conditions and after ischemia and reperfusion, and (3) isolated coronary arteries mounted in isometric wire myographs. We tested Na‐butyrate added to injection solutions or physiological buffers and compared its effects with equimolar doses of NaCl. Butyrate at plasma concentrations of 0.56 mM increased cardiac output by 48.8±14.9%, stroke volume by 38.5±12.1%, and left ventricular ejection fraction by 39.6±6.2%, and lowered systemic vascular resistance by 33.5±6.4% without affecting blood pressure or heart rate in vivo. In the range between 0.1 and 5 mM, butyrate increased left ventricular systolic pressure by up to 23.7±3.4% in isolated perfused hearts and by 9.4±2.9% following ischemia and reperfusion, while reducing myocardial infarct size by 81.7±16.9%. Butyrate relaxed isolated coronary septal arteries concentration dependently with an EC50=0.57 mM (95% CI, 0.23–1.44). Conclusions We conclude that butyrate elevates cardiac output through mechanisms involving increased cardiac contractility and vasorelaxation. This effect of butyrate was not associated with adverse myocardial injury in damaged hearts exposed to ischemia and reperfusion.

[This corrects the article DOI: 10.1371/journal.pmed.1004238.].

BackgroundMigraine carries risk of myocardial infarction (MI) and stroke. The risk of premature MI (i.e., among young adults) and stroke differs between men and women; previous studies indicate that migraine is mainly associated with an increased risk of stroke among young women. The aim of this study was to examine impact of migraine on the risk of premature (age ≤60 years) MI and ischemic/hemorrhagic stroke among men and women.Methods and findingsUsing Danish medical registries, we conducted a nationwide population-based cohort study (1996 to 2018). Redeemed prescriptions for migraine-specific medication were used to identify women with migraine (n = 179,680) and men with migraine (n = 40,757). These individuals were matched on sex, index year, and birth year 1:5 with a random sample of the general population who did not use migraine-specific medication. All individuals were required to be between 18 and 60 years old. Median age was 41.5 years for women and 40.3 years for men. The main outcome measures to assess impact of migraine were absolute risk differences (RDs) and hazard ratios (HRs) with 95% confidence intervals (CIs) of premature MI, ischemic, and hemorrhagic stroke, comparing individuals with migraine to migraine-free individuals of the same sex. HRs were adjusted for age, index year, and comorbidities. The RD of premature MI for those with migraine versus no migraine was 0.3% (95% CI [0.2%, 0.4%]; p < 0.001) for women and 0.3% (95% CI [-0.1%, 0.6%]; p = 0.061) for men. The adjusted HR was 1.22 (95% CI [1.14, 1.31]; p < 0.001) for women and 1.07 (95% CI [0.97, 1.17]; p = 0.164) for men. The RD of premature ischemic stroke for migraine versus no migraine was 0.3% (95% CI [0.2%, 0.4%]; p < 0.001) for women and 0.5% (95% CI [0.1%, 0.8%]; p < 0.001) for men. The adjusted HR was 1.21 (95% CI [1.13, 1.30]; p < 0.001) for women and 1.23 (95% CI [1.10, 1.38]; p < 0.001) for men. The RD of premature hemorrhagic stroke for migraine versus no migraine was 0.1% (95% CI [0.0%, 0.2%]; p = 0.011) for women and -0.1% (95% CI [-0.3%, 0.0%]; p = 0.176) for men. The adjusted HR was 1.13 (95% CI [1.02, 1.24]; p = 0.014) for women and 0.85 (95% CI [0.69, 1.05]; p = 0.131) for men. The main limitation of this study was the risk of misclassification of migraine, which could lead to underestimation of the impact of migraine on each outcome.ConclusionsIn this study, we observed that migraine was associated with similarly increased risk of premature ischemic stroke among men and women. For premature MI and hemorrhagic stroke, there may be an increased risk associated with migraine only among women.

Background Pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) are debilitating diseases with a high mortality. Despite emerging treatments, pulmonary vascular resistance frequently remains elevated. However, the ketone body 3‐hydroxybutyrate (3‐OHB) may reduce pulmonary vascular resistance in these patients. Hence, the aim was to assess the hemodynamic effects of 3‐OHB in patients with PAH or CTEPH. Methods and Results We enrolled patients with PAH (n=10) or CTEPH (n=10) and residual pulmonary hypertension. They received 3‐OHB infusion and placebo (saline) for 2 hours in a randomized crossover study. Invasive hemodynamic and echocardiography measurements were performed. Furthermore, we investigated the effects of 3‐OHB on the right ventricle of isolated hearts and isolated pulmonary arteries from Sprague–Dawley rats. Ketone body infusion increased circulating 3‐OHB levels from 0.5±0.5 to 3.4±0.7 mmol/L (P

BackgroundRemote ischaemic conditioning (RIC) applied to the arm by inflation and deflation of a pneumatic cuff has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (PPCI). However, the effect of RIC on left ventricular ejection fraction (LVEF) following infarct healing remains unknown.ObjectiveTo investigate whether RIC applied in the ambulance before PPCI can improve left ventricular (LV) function in STEMI patients 3 months following infarction.MethodsEchocardiography was performed in a total of 694 patients from the CONDI-2 study a median of 112 days (IQR 63) after the initial admission. LVEF and LV end-diastolic and end-systolic volumes were calculated using the modified Simpsons biplane method of disks. LV global longitudinal strain (GLS) was estimated using 2-dimensional cine-loops with a frame rate > 55 frames/second, measured in the three standard apical views.ResultsThere was no difference in the measured echocardiographic parameters in the RIC group as compared to the control group, including LV EF, LV GLS, tricuspid annular plane systolic excursion or left ventricular volumes. In the control group, 32% had an ejection fraction < 50% compared to 37% in the RIC group (p = 0.129).ConclusionIn this largest to date randomized imaging study of RIC, RIC as an adjunct to PPCI was not associated with a change in echocardiographic measures of cardiac function compared to standard PPCI alone.

Abstract The Sodium Glucose Co-Transporter-2 inhibitor, empagliflozin (EMPA), reduces mortality and hospitalisation for heart failure following myocardial infarction irrespective of diabetes status. While the findings suggest an inherent cardioprotective capacity, the mechanism remains unknown. We studied infarct size (IS) ex-vivo in isolated hearts exposed to global IR injury and in-vivo in rats subjected to regional myocardial ischemia reperfusion (IR) injury, in whom we followed left ventricular dysfunction for 28 days. We compared rats that were given EMPA orally for 7 days before, EMPA 1.5 h before IR injury and at onset of reperfusion and continued orally during the follow-up period. We used echocardiography, high resolution respirometry, microdialysis and plasma levels of β-hydroxybutyrate to assess myocardial performance, mitochondrial respiration and intermediary metabolism, respectively. Pretreatment with EMPA for 7 days reduced IS in-vivo (65 ± 7% vs. 46 ± 8%, p

Two α-isoforms of the Na+,K+-ATPase (α1 and α2) are expressed in the cardiovascular system, and it is unclear which isoform is the preferential regulator of contractility. Mice heterozygous for the familial hemiplegic migraine type 2 (FHM2) associated mutation in the α2-isoform (G301R; α2+/G301R mice) have decreased expression of cardiac α2-isoform but elevated expression of the α1-isoform. We aimed to investigate the contribution of the α2-isoform function to the cardiac phenotype of α2+/G301R hearts. We hypothesized that α2+/G301R hearts exhibit greater contractility due to reduced expression of cardiac α2-isoform. Variables for contractility and relaxation of isolated hearts were assessed in the Langendorff system without and in the presence of ouabain (1 µM). Atrial pacing was performed to investigate rate-dependent changes. The α2+/G301R hearts displayed greater contractility than WT hearts during sinus rhythm, which was rate-dependent. The inotropic effect of ouabain was more augmented in α2+/G301R hearts than in WT hearts during sinus rhythm and atrial pacing. In conclusion, cardiac contractility was greater in α2+/G301R hearts than in WT hearts under resting conditions. The inotropic effect of ouabain was rate-independent and enhanced in α2+/G301R hearts, which was associated with increased systolic work.

Abstract Mechanical unloading of the left ventricle reduces infarct size after acute myocardial infarction by reducing cardiac work. Left ventricular veno-occlusive unloading reduces cardiac work and may reduce ischemia and reperfusion injury. In a porcine model of myocardial ischemia–reperfusion injury we randomized 18 pigs to either control or veno-occlusive unloading using a balloon engaged from the femoral vein into the inferior caval vein and inflated at onset of ischemia. Evans blue and 2,3,5-triphenyltetrazolium chloride were used to determine the myocardial area at risk and infarct size, respectively. Pressure–volume loops were recorded to calculate cardiac work, left ventricular (LV) volumes and ejection fraction. Veno-occlusive unloading reduced infarct size compared with controls (Unloading 13.9 ± 8.2% versus Control 22.4 ± 6.6%; p = 0.04). Unloading increased myocardial salvage (54.8 ± 23.4% vs 28.5 ± 14.0%; p = 0.02), while the area at risk was similar (28.4 ± 6.7% vs 27.4 ± 5.8%; p = 0.74). LV ejection fraction was preserved in the unloaded group, while the control group showed a reduced LV ejection fraction. Veno-occlusive unloading reduced myocardial infarct size and preserved LV ejection fraction in an experimental acute ischemia–reperfusion model. This proof-of-concept study demonstrated the potential of veno-occlusive unloading as an adjunctive cardioprotective therapy in patients undergoing revascularization for acute myocardial infarction.

Abstract Background Diabetes patients without obstructive coronary artery disease as assessed by coronary angiography have a low risk of myocardial infarction, but their myocardial infarction risk may still be higher than the general population. We examined the 10-year risks of myocardial infarction, ischemic stroke, and death in diabetes patients without obstructive coronary artery disease according to coronary angiography, compared to risks in a matched general population cohort. Methods We included all diabetes patients without obstructive coronary artery disease examined by coronary angiography from 2003 to 2016 in Western Denmark. Patients were matched by age and sex with a cohort from the Western Denmark general population without a previous myocardial infarction or coronary revascularization. Outcomes were myocardial infarction, ischemic stroke, and death. Ten-year cumulative incidences were computed. Adjusted hazard ratios (HR) then were computed using stratified Cox regression with the general population as reference. Results We identified 5734 diabetes patients without obstructive coronary artery disease and 28,670 matched individuals from the general population. Median follow-up was 7 years. Diabetes patients without obstructive coronary artery disease had an almost similar 10-year risk of myocardial infarction (3.2% vs 2.9%, adjusted HR 0.93, 95% CI 0.72–1.20) compared to the general population, but had an increased risk of ischemic stroke (5.2% vs 2.2%, adjusted HR 1.87, 95% CI 1.47-2.38) and death (29.6% vs 17.8%, adjusted HR 1.24, 95% CI 1.13–1.36). Conclusions Patients with diabetes and no obstructive coronary artery disease have a 10-year risk of myocardial infarction that is similar to that found in the general population. However, they still remain at increased risk of ischemic stroke and death.

Abstract A multitargeted strategy to treat the consequences of ischemia and reperfusion (IR) injury in acute myocardial infarction may add cardioprotection beyond reperfusion therapy alone. We investigated the cardioprotective effect of mild hypothermia combined with local ischemic preconditioning (IPC) or remote ischemic conditioning (RIC) on IR injury in isolated rat hearts. Moreover, we aimed to define the optimum timing of initiating hypothermia and evaluate underlying cardioprotective mechanisms. Compared to infarct size in normothermic controls (56 ± 4%), mild hypothermia during the entire or final 20 min of the ischemic period reduced infarct size (34 ± 2%, p

AimsPersistent cardiac symptoms are an increasingly reported phenomenon following COVID-19. However, the underlying cause of cardiac symptoms is unknown. This study aimed to identify the underlying causes, if any, of these symptoms 1 year following acute COVID-19 infection.Methods and Results22 individuals with persistent cardiac symptoms were prospectively investigated using echocardiography, cardiovascular magnetic resonance (CMR), 6-min walking test, cardio-pulmonary exercise testing and electrocardiography. A median of 382 days (IQR 368, 442) passed between diagnosis of COVID-19 and investigation. As a cohort their echocardiography, CMR, 6-min walking test and exercise testing results were within the normal ranges. There were no differences in left ventricular ejection fraction (61.45 ± 6.59 %), global longitudinal strain (19.80 ± 3.12 %) or tricuspid annular plane systolic excursion (24.96 ± 5.55 mm) as measured by echocardiography compared to a healthy control group. VO2 max (2045.00 ± 658.40 ml/min), % expected VO2 max (114.80 ± 23.08 %) and 6-minute distance walked (608.90 ± 54.51 m) exceeded that expected for the patient cohort, whilst Troponin I (5.59 ± 6.59 ng/l) and Nt-proBNP (88.18 ± 54.27 ng/l) were normal.ConclusionAmong a cohort of 22 patients with self-reported persistent cardiac symptoms, we identified no underlying cardiac disease or reduced cardiopulmonary fitness 1 year following COVID-19.

Background Mutations in ATP1A2 gene encoding the Na,K‐ATPase α2 isoform are associated with familial hemiplegic migraine type 2. Migraine with aura is a known risk factor for heart disease. The Na,K‐ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that ATP1A2 is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism. Methods and Results Mice heterozygous for the familial hemiplegic migraine type 2–associated G301R mutation in the Atp1a2 gene (α2+/G301R mice) and matching wild‐type controls were compared. Reduced expression of the Na,K‐ATPase α2 isoform and increased expression of the α1 isoform were observed in hearts from α2+/G301R mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8‐month‐old α2+/G301R mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3‐month‐old α2+/G301R mice were similar to wild‐type mice. Amplified Na,K‐ATPase–dependent Src kinase/Ras/Erk1/2 (p44/42 mitogen‐activated protein kinase) signaling was observed in hearts from 8‐month‐old α2+/G301R mice, and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malondialdehyde measurements), and a heart failure–associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential (5,5´,6,6´‐tetrachloro‐1,1´,3,3´‐tetraethylbenzimidazolocarbocyanine iodide dye assay) and mitochondrial ultrastructure (transmission electron microscopy) were similar between the groups. Proteomics of heart tissue further suggested amplified Src/Ras/Erk1/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8‐month‐old α2+/G301R mice. Conclusions Our findings suggest that ATP1A2 mutation leads to disturbed cardiac metabolism and reduced cardiac function mediated via Na,K‐ATPase–dependent reactive oxygen species signaling through the Src/Ras/Erk1/2 pathway.

Abstract Ischemia reperfusion (IR) injury may be attenuated through succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). Whether SDH inhibition yields protection in diabetic individuals and translates into human cardiac tissue remain unknown. In isolated perfused hearts from 24 weeks old male Zucker diabetic fatty (ZDF) and age matched non-diabetic control rats and atrial trabeculae from patients with and without diabetes, we compared infarct size, contractile force recovery and mitochondrial function. The cardioprotective effect of a 10 minutes DiMAL administration prior to global ischemia and ischemic preconditioning (IPC) was evaluated. In non-diabetic hearts exposed to IR, DiMAL 0.1 mM reduced infarct size compared to IR (55 ± 7% vs. 69 ± 6%, p

Abstract Background Treatment with beta-blockers is currently recommended after myocardial infarction (MI). The evidence relies on trials conducted decades ago before implementation of revascularization and contemporary medical therapy or in trials enrolling patients with heart failure or reduced left ventricular ejection fraction (LVEF ≤ 40%). Accordingly, the impact of beta-blockers on mortality and morbidity following acute MI in patients without reduced LVEF or heart failure is unclear. Methods/design The Danish trial of beta-blocker treatment after myocardial infarction without reduced ejection fraction (DANBLOCK) is a prospective, randomized, controlled, open-label, non-blinded endpoint clinical trial designed to evaluate the efficacy of beta-blocker treatment in post-MI patients in the absence of reduced LVEF or heart failure. We will randomize 3570 patients will be randomized within 14 days of index MI to beta-blocker or control for a minimum of 2 years. The primary endpoint is a composite of all-cause mortality, recurrent MI, acute decompensated heart failure, unstable angina pectoris, or stroke. The primary composite endpoint will be assessed through locally reported and adjudicated endpoints supplemented by linkage to the Danish national registers. A number of secondary endpoints will be investigated including patient reported outcomes and cardiovascular mortality. Data from similar ongoing trials in Norway and Sweden will be pooled to perform an individual patient data meta-analysis. Discussion DANBLOCK is a randomized clinical trial investigating the effect of long-term beta-blocker therapy after myocardial infarction in patients without heart failure and reduced LVEF. Results from the trial will add important scientific evidence to inform future clinical guidelines. Trial registration Clinicaltrials.gov, NCT03778554 . Registered on 19 December 2018. European Clinical Trials Database, 2018-002699-42 , registered on 28 September 2018.

Heterozygous mice (α2+/G301R mice) for the migraine-associated mutation (G301R) in the Na+,K+-ATPase α2-isoform have decreased expression of cardiovascular α2-isoform. The α2+/G301R mice exhibit a pro-contractile vascular phenotype associated with decreased left ventricular ejection fraction. However, the integrated functional cardiovascular consequences of this phenotype remain to be addressed in vivo. We hypothesized that the vascular response to α2-isoform-specific inhibition of the Na+,K+-ATPase by ouabain is augmented in α2+/G301R mice leading to reduced cardiac efficiency. Thus, we aimed to assess the functional contribution of the α2-isoform to in vivo cardiovascular function of wild-type (WT) and α2+/G301R mice. Blood pressure, stroke volume, heart rate, total peripheral resistance, arterial dP/dt, and systolic time intervals were assessed in anesthetized WT and α2+/G301R mice. To address rate-dependent cardiac changes, cardiovascular variables were compared before and after intraperitoneal injection of ouabain (1.5 mg/kg) or vehicle during atrial pacing. The α2+/G301R mice showed an enhanced ouabain-induced increase in total peripheral resistance associated with reduced efficiency of systolic development compared to WT. When the hearts were paced, ouabain reduced stroke volume in α2+/G301R mice. In conclusion, the ouabain-induced vascular response was augmented in α2+/G301R mice with consequent suppression of cardiac function.

Introduction: The cardiac electrical conduction system is very sensitive to hypoglycemia and hypoxia, and the consequence may be brady-arrythmias. Weddell seals endure brady-arrythmias during their dives when desaturating to 3.2 kPa and elite breath-hold-divers (BHD), who share metabolic and cardiovascular adaptions including bradycardia with diving mammals, endure similar desaturation during maximum apnea. We hypothesized that hypoxia causes brady-arrythmias during maximum apnea in elite BHD. Hence, this study aimed to define the arterial blood glucose (Glu), peripheral saturation (SAT), heart rhythm (HR), and mean arterial blood pressure (MAP) of elite BHD during maximum apneas.Methods: HR was monitored with Direct-Current-Pads/ECG-lead-II and MAP and Glu from a radial arterial-catheter in nine BHD performing an immersed and head-down maximal static pool apnea after three warm-up apneas. SAT was monitored with a sensor on the neck of the subjects. On a separate day, a 12-lead-ECG-monitored maximum static apnea was repeated dry (n = 6).Results: During pool apnea of maximum duration (385 ± 70 s), SAT decreased from 99.6 ± 0.5 to 58.5 ± 5.5% (∼PaO2 4.8 ± 1.5 kPa, P < 0.001), while Glu increased from 5.8 ± 0.2 to 6.2 ± 0.2 mmol/l (P = 0.009). MAP increased from 103 ± 4 to 155 ± 6 mm Hg (P < 0.005). HR decreased to 46 ± 10 from 86 ± 14 beats/minute (P < 0.001). HR and MAP were unchanged after 3–4 min of apnea. During dry apnea (378 ± 31 s), HR decreased from 55 ± 4 to 40 ± 3 beats/minute (P = 0.031). Atrioventricular dissociation and junctional rhythm were observed both during pool and dry apneas.Conclusion: Our findings contrast with previous studies concluding that Glu decreases during apnea diving. We conclude during maximum apnea in elite BHD that (1) the diving reflex is maximized after 3–4 min, (2) increasing Glu may indicate lactate metabolism in accordance with our previous results, and (3) extreme hypoxia rather than hypoglycemia causes brady-arrythmias in elite BHD similar to diving mammals.

Abstract Objective To evaluate agreement between instantaneous wave free ratio (iFR) and fractional flow reserve (FFR) for the functional assessment of nonculprit coronary stenoses at staged follow-up after ST-segment elevation myocardial infarction (STEMI). Results We measured iFR and FFR at staged follow-up in 112 STEMI patients with 146 nonculprit stenoses. Median interval between STEMI and follow-up was 16 (interquartile range 5–32) days. Agreement between iFR and FFR was 77%

Abstract Background The mechanisms underlying increased mortality in patients with diabetes and admission hyperglycemia after an acute coronary syndrome may involve reduced capacity for cardioprotection. We investigated the impact of hyperglycemia on exogenously activated cardioprotection by ischemic preconditioning (IPC) in hearts from rats with type 2 diabetes mellitus (T2DM) that were endogenously cardioprotected by an inherent mechanism, and the involvement of myocardial glucose uptake (MGU) and myocardial O-linked β-N-acetylglucosamine (O-GlcNAc). Methods and results In isolated, perfused rat hearts subjected to ischemia–reperfusion, infarct size (IS) was overall larger during hyper- ([Glucose] = 22 mmol/L]) than normoglycemia ([Glucose] = 11 mmol/L]) (p

Abstract Background Local ischemic preconditioning (IPC) and remote ischemic conditioning (RIC) induced by brief periods of ischemia and reperfusion protect against ischemia‐reperfusion injury. Methods We studied the sensitivity to IR‐injury and the influence of strain, age, supplier, and anesthesia upon the efficacy of IPC and RIC in 7‐ and 16‐weeks‐old Sprague‐Dawley and Wistar rats from three different suppliers. The influence of sedation with a hypnorm and midazolam mixture (rodent mixture) and pentobarbiturate was compared. Results IPC attenuated infarct size in both 7‐weeks‐old Sprague–Dawley (48.4 ± 17.7% vs. 20.3 ± 6.9, p

Objective Rheumatoid arthritis (RA) is a known risk factor for developing coronary artery disease (CAD). The influence of RA on the prognosis after initial CAD diagnosis and treatment is however largely unknown. We examined the risk of major cardiovascular events among RA and non-RA patients with chest pain referred to cardiac CT.Methods This was a follow-up study, using data from the Western Denmark Heart Registry, containing data on CT angiography examinations (Cardiac CT). Information on RA diagnosis and covariates were identified through nationwide administrative registers. The primary outcome was a combined outcome including, myocardial infarction, ischaemic or unspecified stroke, coronary artery bypass grafting, percutaneous coronary intervention, and all-cause mortality. Median time until events or censoring was 3.5 years (min/max: 0.0: 9.2). Cox proportional hazard models were used to examine the association between RA/non-RA patients and outcomes.Results Among 42 257 patients, referred between 2008 and 2016, we identified 358 (0.8%) with RA. An increased risk was seen in RA compared with non-RA (adjusted HR 1.35, 95% CI 0.93 to 1.96). Among patients who had received flare treatment more than once prior to cardiac CT the adjusted HR 1.80 (95% CI 1.08 to 3.00), and among patients with seropositive RA the adjusted HR 1.42 (95% CI 0.93 to 2.16).Conclusion In patients referred to cardiac CT due to chest pain, we found a trend of an association between RA and the combined primary outcome, supporting that RA per se, but in particular seropositive and active RA, may increase the risk of CAD even after initial CAD diagnosis and treatment.

Background Polygenic risk scores (PRSs) based on risk variants from genome‐wide association studies predict coronary artery disease (CAD) risk. However, it is unknown whether the PRS is associated with specific CAD characteristics. Methods and Results We consecutively included 1645 patients with suspected stable CAD undergoing coronary computed tomography angiography. A multilocus PRS was calculated as the weighted sum of CAD risk variants. Plaques were evaluated using an 18‐segment model and characterized by stenosis severity and composition (soft [0%‐19% calcified], mixed‐soft [20%‐49% calcified], mixed‐calcified [50%‐79% calcified], or calcified [≥80% calcified]). Coronary artery calcium score and segment stenosis score were used to characterize plaque burden. For each standard deviation increase in the PRS, coronary artery calcium score increased by 78% (P=4.1e‐26) and segment stenosis score increased by 16% (P=2.4e‐29) in the fully adjusted model. The PRS was associated with a higher prevalence of obstructive plaques (odds ratio [OR]: 1.78, P=5.6e‐16), calcified (OR: 1.69, P=6.5e‐17), mixed‐calcified (OR: 1.67, P=7.3e‐9), mixed‐soft (OR: 1.45, P=1.6e‐6), and soft plaques (OR: 1.49, P=2.5e‐6), and a higher prevalence of plaque in each coronary vessel (all P0.05). Conclusions Our results suggest that polygenic risk based on large genome‐wide association studies increases CAD risk through an increased burden of coronary atherosclerosis rather than promoting specific plaque features. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02264717.

IntroductionAerobic capacity is a strong predictor of cardiovascular mortality. Whether aerobic capacity influences myocardial ischemia and reperfusion (IR) injury is unknown.PurposeTo investigate the impact of intrinsic differences in aerobic capacity and the cardioprotective potential on IR injury.MethodsWe studied hearts from rats developed by selective breeding for high (HCR) or low (LCR) capacity for treadmill running. The rats were randomized to: (1) control, (2) local ischemic preconditioning (IPC) or (3) remote ischemic preconditioning (RIC) followed by 30 minutes of ischemia and 120 minutes of reperfusion in an isolated perfused heart model. The primary endpoint was infarct size. Secondary endpoints included uptake of labelled glucose, content of selected mitochondrial proteins in skeletal and cardiac muscle, and activation of AMP-activated kinase (AMPK).ResultsAt baseline, running distance was 203±7 m in LCR vs 1905±51 m in HCR rats (p0.99; HCR: 69±6%, p>0.99, respectively). Phosphorylaion of AMPK did not differ between LCR and HCR controls. IPC did not modulate cardiac phosphorylation of AMPK. Glucose uptake during reperfusion was similar in LCR and HCR rats. IPC increased glucose uptake during reperfusion in LCR animals (p = 0.02). Mitochondrial protein content in skeletal muscle was lower in LCR than in HCR (0.77±0.10 arbitrary units (AU) vs 1.09±0.07 AU, p = 0.02), but not in cardiac muscle.ConclusionAerobic capacity is associated with altered myocardial sensitivity to IR injury, but the cardioprotective effect of IPC is not. Glucose uptake, AMPK activation immediately prior to ischemia and basal mitochondrial protein content in the heart seem to be of minor importance as underlying mechanisms for the cardioprotective effects.

Remote ischemic conditioning (RIC) is a procedure that can attenuate ischemic-reperfusion injury by conducting brief cycles of ischemia and reperfusion in the arm or leg. Extracellular vesicles (EVs) circulating in the bloodstream can release their content into recipient cells to confer protective function on ischemia-reperfusion injured (IRI) organs. Skeletal muscle cells are potential candidates to release EVs as a protective signal during RIC. In this study, we used C2C12 cells as a model system and performed cyclic hypoxia-reoxygenation (HR) to mimic RIC. EVs were collected and subjected to small RNA profiling and proteomics. HR induced a distinct shift in the miRNA profile and protein content in EVs. HR EV treatment restored cell viability, dampened inflammation, and enhanced tube formation in in vitro assays. In vivo, HR EVs showed increased accumulation in the ischemic brain compared to EVs secreted from normoxic culture (N EVs) in a mouse undergoing transient middle cerebral artery occlusion (tMCAO). We conclude that HR conditioning changes the miRNA and protein profile in EVs released by C2C12 cells and enhances the protective signal in the EVs to recipient cells in vitro.

Objectives: To investigate, whether renal denervation (RDN) improves arterial stiffness, central blood pressure (C-BP) and heart rate variability (HRV) in patients with treatment resistant hypertension. Methods: ReSET was a randomized, sham-controlled, double-blinded trial (NCT01459900). RDN was performed by a single experienced operator using the Medtronic unipolar Symplicity FlexTM catheter. C-BP, carotid-femoral pulse wave velocity (PWV), and HRV were obtained at baseline and after six months with the SphygmoCor®-device. Results: Fifty-three patients (77% of the ReSET-cohort) were included in this substudy. The groups were similar at baseline (SHAM/RDN): n = 27/n = 26; 78/65% males; age 59 ± 9/54 ± 8 years (mean ± SD); systolic brachial BP 158 ± 18/154 ± 17 mmHg; systolic 24-hour ambulatory BP 153 ± 14/151 ± 13 mmHg. Changes in PWV (0.1 ± 1.9 (SHAM) vs. −0.6 ± 1.3 (RDN) m/s), systolic C-BP (−2 ± 17 (SHAM) vs. −8 ± 16 (RDN) mmHg), diastolic C-BP (−2 ± 9 (SHAM) vs. −5 ± 9 (RDN) mmHg), and augmentation index (0.7 ± 7.0 (SHAM) vs. 1.0 ± 7.4 (RDN) %) were not significantly different after six months. Changes in HRV-parameters were also not significantly different. Baseline HRV or PWV did not predict BP-response after RDN. Conclusions: In a sham-controlled setting, there were no significant effects of RDN on arterial stiffness, C-BP and HRV. Thus, the idea of BP-independent effects of RDN on large arteries and cardiac autonomic activity is not supported.

Abstract Background Hypoglycemia is associated with increased mortality rate in patients with diabetes. The underlying mechanisms may involve reduced myocardial tolerance to ischemia and reperfusion (IR) or reduced capacity for ischemic preconditioning (IPC). As IPC is associated with increased myocardial glucose uptake (MGU) during reperfusion, cardioprotection is linked to glucose metabolism possibly by O-linked β-N-acetylglucosamine (O-GlcNAc). We aimed to investigate the impact of hypoglycemia in hearts from animals with diabetes on myocardial IR tolerance, on the efficacy of IPC and whether modulations of MGU and O-GlcNAc levels are involved in the underlying mechanisms. Methods In a Langendorff model using diabetic ZDF (fa/fa) and non-diabetic (fa/+) rats (n = 6–7 in each group) infarct size (IS) was evaluated after 40 min of global ischemia and 120 min reperfusion during hypoglycemia [(glucose) = 3 mmol/l] and normoglycemia [(glucose) = 11 mmol/l]. Myocardial glucose uptake and O-GlcNAc levels were evaluated during reperfusion. IPC was induced by 2 × 5 min of global ischemia prior to index ischemia. Results IS increased in hearts from animals with (p

Background Early triage is essential to improve outcomes in patients with suspected acute myocardial infarction (AMI). This study investigated whether cMyC (cardiac myosin‐binding protein), a novel biomarker of myocardial necrosis, can aid early diagnosis of AMI and risk stratification. Methods and Results cMyC and high‐sensitivity cardiac troponin T were retrospectively quantified in blood samples obtained by ambulance‐based paramedics in a prospective, diagnostic cohort study. Patients with ongoing or prolonged periods of chest discomfort, acute dyspnoea in the absence of known pulmonary disease, or clinical suspicion of AMI were recruited. Discrimination power was evaluated by calculating the area under the receiver operating characteristics curve; diagnostic performance was assessed at predefined thresholds. Diagnostic nomograms were derived and validated using bootstrap resampling in logistic regression models. Seven hundred seventy‐six patients with median age 68 [58;78] were recruited. AMI was the final adjudicated diagnosis in 22%. Median symptom to sampling time was 70 minutes. cMyC concentration in patients with AMI was significantly higher than with other diagnoses: 98 [43;855] versus 17 [9;42] ng/L. Discrimination power for AMI was better with cMyC than with high‐sensitivity cardiac troponin T (area under the curve, 0.839 versus 0.813; P=0.005). At a previously published rule‐out threshold (10 ng/L), cMyC reaches 100% sensitivity and negative predictive value in patients after 2 hours of symptoms. In logistic regression analysis, cMyC is superior to high‐sensitivity cardiac troponin T and was used to derive diagnostic and prognostic nomograms to evaluate risk of AMI and death. Conclusions In patients undergoing blood draws very early after symptom onset, cMyC demonstrates improved diagnostic discrimination of AMI and could significantly improve the early triage of patients with suspected AMI.

Background Peripheral artery disease is a major socioeconomic challenge in the diabetes mellitus community and non‐surgical treatment options are limited. As remote ischemic conditioning (RIC) improves vascular function and attenuates ischemia‐induced tissue damage, we investigated the efficacy of RIC on vascular and neuronal function in type 2 diabetes mellitus patients with peripheral artery disease. Methods and Results We enrolled 36 type 2 diabetes mellitus patients with moderately reduced toe pressure (40–70 mm Hg) in a randomized sham‐controlled double‐masked trial. Patients were allocated to 12 weeks once daily upper arm cuff‐based treatment of either RIC treatment (4 cycles of 5‐minute ischemia followed by 5‐minute reperfusion) or similar sham‐device treatment. Primary outcome was transcutaneous tissue oxygen tension of the instep of the feet. Secondary outcomes were aortic pulse wave velocity, toe pressure and toe‐brachial index. Tertiary outcomes were markers of peripheral and autonomic nerve function. We enrolled 36 patients (83% men). Patients had a mean (SD) age of 70.7 years (6.8), diabetes mellitus duration of 18.4 years (8.3), HbA1c (gycated hemoglobin) of 59.7 mmol/mol (11.2). Eighty percent had peripheral symmetrical neuropathy. The mean difference in change of transcutaneous tissue oxygen tension from baseline between the RIC and sham‐treated groups was −0.03 mm Hg ([95% CI −0.1; 0.04], P=0.438). RIC did not elicit any change in additional outcomes. Three patients experienced transient skin petechiae in the treated arm. Conclusions Long‐term repeated remote ischemic conditioning treatment have no effect on tissue oxygenation, vascular or neuronal function in patients with type 2 diabetes mellitus and moderate peripheral artery disease. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT02749942.

Purpose: It is well established that high-load resistance exercise (HLRE) can stimulate myofibrillar accretion. Additionally, recent studies suggest that HLRE can also stimulate mitochondrial biogenesis and respiratory function. However, in several clinical situations, the use of resistance exercise with high loading may not constitute a viable approach. Low-load blood flow restricted resistance exercise (BFRRE) has emerged as a time-effective low-load alternative to stimulate myofibrillar accretion. It is unknown if BFRRE can also stimulate mitochondrial biogenesis and respiratory function. If so, BFRRE could provide a feasible strategy to stimulate muscle metabolic health.Methods: To study this, 34 healthy previously untrained individuals (24 ± 3 years) participated in BFRRE, HLRE, or non-exercise control intervention (CON) 3 times per week for 6 weeks. Skeletal muscle biopsies were collected; (1) before and after the 6-week intervention period to assess mitochondrial biogenesis and respiratory function and; (2) during recovery from single-bout exercise to assess myocellular signaling events involved in transcriptional regulation of mitochondrial biogenesis. During the 6-week intervention period, deuterium oxide (D2O) was continuously administered to the participants to label newly synthesized skeletal muscle mitochondrial proteins. Mitochondrial respiratory function was assessed in permeabilized muscle fibers with high-resolution respirometry. Mitochondrial content was assessed with a citrate synthase activity assay. Myocellular signaling was assessed with immunoblotting.Results: Mitochondrial protein synthesis rate was higher with BFRRE (1.19%/day) and HLRE (1.15%/day) compared to CON (0.92%/day) (P < 0.05) but similar between exercise groups. Mitochondrial respiratory function increased to similar degree with both exercise regimens and did not change with CON. For instance, coupled respiration supported by convergent electron flow from complex I and II increased 38% with BFRRE and 24% with HLRE (P < 0.01). Training did not alter citrate synthase activity compared to CON. BFRRE and HLRE elicited similar myocellular signaling responses.Conclusion: These results support recent findings that resistance exercise can stimulate mitochondrial biogenesis and respiratory function to support healthy skeletal muscle and whole-body metabolism. Intriquingly, BFRRE produces similar mitochondrial adaptations at a markedly lower load, which entail great clinical perspective for populations in whom exercise with high loading is untenable.

Remote ischemic pre-conditioning (rIPC) has emerged as a potential mechanism to reduce ischemia-reperfusion injury. Clinical data, however, have been mixed, and its physiological basis remains unclear, although it appears to involve release of circulating factor(s) and/or neural pathways. Here, the authors demonstrate that adenosine receptor activation is an important step in initiating human pre-conditioning; that pre-conditioning liberates circulating cardioprotective factor(s); and that exogenous adenosine infusion is able to recapitulate release of this factor. However, blockade of adenosine receptors in ischemic tissue does not block the protection afforded by pre-conditioning. These data have important implications for defining the physiology of human pre-conditioning and its translation to future clinical trials.

Mitochondrial dysfunction has been implicated as a central mechanism in the metabolic myopathy accompanying critical limb ischemia (CLI). However, whether mitochondrial dysfunction is directly related to lower extremity ischemia and the structural and molecular mechanisms underpinning mitochondrial dysfunction in CLI patients is not understood. Here, we aimed to study whether mitochondrial dysfunction is a distinctive characteristic of CLI myopathy by assessing mitochondrial respiration in gastrocnemius muscle from 14 CLI patients (65.3 ± 7.8 y) and 15 matched control patients (CON) with a similar comorbidity risk profile and medication regimen but without peripheral ischemia (67.4 ± 7.4 y). Furthermore, we studied potential structural and molecular mechanisms of mitochondrial dysfunction by measuring total, sub-population, and fiber-type-specific mitochondrial volumetric content and cristae density with transmission electron microscopy and by assessing mitophagy and fission/fusion-related protein expression. Finally, we asked whether commonly used biomarkers of mitochondrial content are valid in patients with cardiovascular disease. CLI patients exhibited inferior mitochondrial respiration compared to CON. This respiratory deficit was not related to lower whole-muscle mitochondrial content or cristae density. However, stratification for fiber types revealed ultrastructural mitochondrial alterations in CLI patients compared to CON. CLI patients exhibited an altered expression of mitophagy-related proteins but not fission/fusion-related proteins compared to CON. Citrate synthase, cytochrome c oxidase subunit IV (COXIV), and 3-hydroxyacyl-CoA dehydrogenase (β-HAD) could not predict mitochondrial content. Mitochondrial dysfunction is a distinctive characteristic of CLI myopathy and is not related to altered organelle content or cristae density. Our results link this intrinsic mitochondrial deficit to dysregulation of the mitochondrial quality control system, which has implications for the development of therapeutic strategies.

Background Quantitative flow ratio (QFR) is a novel modality for physiological lesion assessment based on 3‐dimensional vessel reconstructions and contrast flow velocity estimates. We evaluated the value of online QFR during routine invasive coronary angiography for procedural feasibility, diagnostic performance, and agreement with pressure‐wire–derived fractional flow reserve (FFR) as a gold standard in an international multicenter study. Methods and Results FAVOR II E‐J (Functional Assessment by Various Flow Reconstructions II Europe‐Japan) was a prospective, observational, investigator‐initiated study. Patients with stable angina pectoris were enrolled in 11 international centers. FFR and online QFR computation were performed in all eligible lesions. An independent core lab performed 2‐dimensional quantitative coronary angiography (2D‐QCA) analysis of all lesions assessed with QFR and FFR. The primary comparison was sensitivity and specificity of QFR compared with 2D‐QCA using FFR as a reference standard. A total of 329 patients were enrolled. Paired assessment of FFR, QFR, and 2D‐QCA was available for 317 lesions. Mean FFR, QFR, and percent diameter stenosis were 0.83±0.09, 0.82±10, and 45±10%, respectively. FFR was ≤0.80 in 104 (33%) lesions. Sensitivity and specificity by QFR was significantly higher than by 2D‐QCA (sensitivity, 86.5% (78.4–92.4) versus 44.2% (34.5–54.3); P

Augmented mortality and morbidity following an acute myocardial infarction in patients with diabetes mellitus Type 2 (T2DM) may be caused by increased sensitivity to ischemia reperfusion (IR) injury or altered activation of endogenous cardioprotective pathways modified by T2DM per se or ischemic preconditioning (IPC). We aimed to investigate, whether the duration of T2DM influences sensitivity against IR injury and the efficacy of IPC, and how myocardial glucose oxidation rate was involved. Male Zucker diabetic fatty rats (homozygote (fa/fa)) at ages 6-(prediabetic), 12- (onset diabetes) and 24-weeks of age (late diabetes) and their age-matched non-diabetic controls (heterozygote (fa/+) were subjected to IR injury in the Langendorff model and randomised to IPC stimulus or control. T2DM rats were endogenously protected at onset of diabetes, as infarct size was lower in 12-weeks T2DM animals than in 6- (35±2% vs 53±4%; P = 0.006) and 24-weeks animals (35±2% vs 72±4%; P

BackgroundData on the clinical utility of coronary computed tomography angiography–derived fractional flow reserve (FFRCT) are sparse. In patients with intermediate (40–70%) coronary stenosis determined by coronary computed tomography angiography, we investigated the association of replacing standard myocardial perfusion imaging with FFRCT testing with downstream utilization of invasive coronary angiography (ICA) and the diagnostic yield of ICA (rate of no obstructive disease, and rate of revascularization). Methods and ResultsThis was a single‐center observational study of symptomatic patients with suspected coronary artery disease referred to coronary computed tomography angiography between 2013 and 2015. Patients were divided into 3 historical groups based on the adjunctive functional testing approach: myocardial perfusion imaging (n=1332) or FFRCT “implementation” (n=800) or “clinical use” (n=1391). Propensity score matching was used to estimate the average period effect on outcomes. Patients in the FFRCT clinical use group versus the myocardial perfusion imaging group were older and had higher pretest probability of obstructive disease. After adjusting for baseline risk characteristics, there was a reduction in downstream ICA utilization (absolute risk difference: −4.2; 95% CI, −6.9 to −1.6; P=0.002). In patients referred to ICA, findings of no obstructive coronary artery disease decreased (−12.8%; 95% CI, −22.2 to −3.4; P=0.008) and rate of coronary revascularization increased (14.1%; 95% CI, 3.3–24.9; P=0.01), as did availability of functional information for guidance of revascularization (27.8%; 95% CI, 11.3–44.4; P

Background High levels of ketone bodies are associated with improved survival as observed with regular exercise, caloric restriction, and—most recently—treatment with sodium–glucose linked transporter 2 inhibitor antidiabetic drugs. In heart failure, indices of ketone body metabolism are upregulated, which may improve energy efficiency and increase blood flow in skeletal muscle and the kidneys. Nevertheless, it is uncertain how ketone bodies affect myocardial glucose uptake and blood flow in humans. Our study was therefore designed to test whether ketone body administration in humans reduces myocardial glucose uptake (MGU) and increases myocardial blood flow. Methods and Results Eight healthy subjects, median aged 60 were randomly studied twice: (1) During 390 minutes infusion of Na‐3‐hydroxybutyrate (KETONE) or (2) during 390 minutes infusion of saline (SALINE), together with a concomitant low‐dose hyperinsulinemic–euglycemic clamp to inhibit endogenous ketogenesis. Myocardial blood flow was measured by 15O‐H2O positron emission tomography/computed tomography, myocardial fatty acid metabolism by 11C‐palmitate positron emission tomography/computed tomography and MGU by 18F‐fluorodeoxyglucose positron emission tomography/computed tomography. Similar euglycemia, hyperinsulinemia, and suppressed free fatty acids levels were recorded on both study days; Na‐3‐hydroxybutyrate infusion increased circulating Na‐3‐hydroxybutyrate levels from zero to 3.8±0.5 mmol/L. MGU was halved by hyperketonemia (MGU [nmol/g per minute]: 304±97 [SALINE] versus 156±62 [KETONE], P

Background: The Arteriograph is a cuff-based oscillometric device for non-invasive assessment of central systolic blood pressure (cSBP), aortic augmentation index (Aix) and aortic pulse wave velocity (PWV). Reproducibility of Arteriograph measurements and the agreement with SphygmoCor in diabetic patients has never been assessed. Methods: We compared Arteriograph reproducibility and agreement with SphygmoCor with data from two study populations: Study 1 (n = 17) was conducted in a research laboratory and Study 2 (n = 19) in a catheter lab. SphygmoCor PWV data was only available in study 1. Results: Reproducibility: Mean differences (±Standard deviation of the difference (SDD)) between duplicate cSBP, Aix and PWV Arteriograph measurements were −0.6 ± 6.6 mmHg, −1.1 ± 3.3% and 0.1 ± 0.5 m/s in study 1 and −0.01 ± 4.3 mmHg, 1.5 ± 3.2% and −0.2 ± 0.6 m/s in study 2, all differences non-significant. Agreement: Mean differences between SphygmoCor and Arteriograph were −14 ± 10 mmHg, −8 ± 7% and 2.4 ± 1.8 m/s, (p < 0.001 for all) in Study 1 and −5 ± 10 mmHg, p = 0.04 and −10 ± 8%, p =

Background The prevalence of depression is 4‐ to 5‐fold higher in heart failure patients than in the general population. We examined the influence of depression on all‐cause mortality in patients with heart failure. Methods and Results Using Danish medical registries, this nationwide population‐based cohort study included all patients with a first‐time hospitalization for heart failure (1995–2014). All‐cause mortality risks and 19‐year mortality rate ratios were estimated based on Cox regression analysis, adjusting for age, sex, time period, comorbidity, and socioeconomic status. The analysis included 9636 patients with and 194 887 patients without a diagnosis of depression. Compared with patients without a history of depression, those with depression had higher 1‐year (36% versus 33%) and 5‐year (68% versus 63%) mortality risks. Overall, the adjusted mortality rate ratio was 1.03 (95% CI 1.01–1.06). Compared with no depression, the adjusted mortality rate ratios for mild, moderate, and severe depression, as defined by diagnostic codes, were 1.06 (95% CI 1.00–1.13), 1.03 (95% CI 0.99–1.08), and 1.02 (95% CI 0.96–1.09), respectively. In a subcohort of patients, the mortality rate ratios were modified by left ventricular ejection fraction, with adjusted mortality rate ratios of 1.17 (95% CI, 1.05–1.31) for ≤35%, 0.98 (95% CI 0.81–1.18) for 36% to 49%, and 0.96 (95% CI 0.74–1.25) for ≥50%. Results were consistent after adjustment for alcohol abuse and smoking. Conclusions A history of depression was an adverse prognostic factor for all‐cause mortality in heart failure patients with left ventricular ejection fraction ≤35% but not for other heart failure patients.

Background and study aims: Dual antiplatelet therapy (DAPT) is recommended following percutaneous coronary intervention (PCI) with drug-eluting stent (DES). DAPT is a risk factor for gastrointestinal bleeding. We aimed to quantify (1) the rate of gastroscopy within 12 months after PCI, (2) the rate of adverse cardiac events and gastroscopy-related bleeding complications within 30 days of gastroscopy, and (3) the association between antiplatelet therapy and these events. Patients and methods: Patients receiving gastroscopy within 12 months of PCI were identified and two nested case-control analyses were performed within the PCI cohort by linking Danish medical registries. Cases were patients with adverse cardiac events (cardiac death, myocardial infarction, or stent thrombosis) or hemostatic intervention. In both studies, controls were patients with gastroscopy including biopsy without adverse cardiac events and hemostatic intervention, respectively. Medical records were reviewed to obtain information on exposure to DAPT. Results: We identified 22 654 PCI patients of whom 1497 patients (6.6 %) underwent gastroscopy. Twenty-two patients (1.5 %) suffered an adverse cardiac event, 93 patients (6.2 %) received hemostatic intervention during or within 30 days of the index gastroscopy. Interrupting DAPT was associated with a 3.46 times higher risk of adverse cardiac events (95 %CI 0.49 – 24.7). Discontinuation of one antiplatelet agent did not increase the risk (OR 0.65, 95 %CI 0.17 – 2.47). No hemostatic interventions were caused by endoscopic complications. Conclusion: Gastroscopy can be safely performed in PCI patients treated with DES and single antiplatelet therapy while interruption of DAPT may be associated with an increased risk of adverse cardiac events.

Glucagon-like peptide-1 (GLP-1) may provide beneficial cardiovascular effects, possibly due to enhanced myocardial energetic efficiency by increasing myocardial glucose uptake (MGU). We assessed the effects of GLP-1 on MGU in healthy subjects during normo- and hypoglycemia.We included eighteen healthy men in two randomized, double-blinded, placebo-controlled cross-over studies. MGU was assessed with GLP-1 or saline infusion during pituitary-pancreatic normo- (plasma glucose (PG): 4.5 mM, n = 10) and hypoglycemic clamps (PG: 3.0 mM, n = 8) by positron emission tomography with (18)fluoro-deoxy-glucose ((18)F-FDG) as tracer.In the normoglycemia study mean (± SD) age was 25±3 years, and BMI was 22.6±0.6 kg/m(2) and in the hypoglycemia study the mean age was 23±2 years with a mean body mass index of 23±2 kg/m(2). GLP-1 did not change MGU during normoglycemia (mean (+/- SD) 0.15+/-0.04 and 0.16+/-0.03 µmol/g/min, P = 0.46) or during hypoglycemia (0.16+/-0.03 and 0.13+/-0.04 µmol/g/min, P = 0.14). However, the effect of GLP-1 on MGU was negatively correlated to baseline MGU both during normo- and hypoglycemia, (P = 0.006, r(2) = 0.64 and P = 0.018, r(2) = 0.64, respectively) and changes in MGU correlated positively with the level of insulin resistance (HOMA 2IR) during hypoglycemia, P = 0.04, r(2) = 0.54. GLP-1 mediated an increase in circulating glucagon levels at PG levels below 3.5 mM and increased glucose infusion rates during the hypoglycemia study. No differences in other circulating hormones or metabolites were found.While GLP-1 does not affect overall MGU, GLP-1 induces changes in MGU dependent on baseline MGU such that GLP-1 increases MGU in subjects with low baseline MGU and decreases MGU in subjects with high baseline MGU. GLP-1 preserves MGU during hypoglycemia in insulin resistant subjects. ClinicalTrials.gov registration numbers: NCT00418288: (hypoglycemia) and NCT00256256: (normoglycemia).

Inhibition of glucose oxidation during initial reperfusion confers protection against ischemia-reperfusion (IR) injury in the heart. Mitochondrial metabolism is altered with progression of type 2 diabetes (T2DM). We hypothesized that the metabolic alterations present at onset of T2DM induce cardioprotection by metabolic shutdown during IR, and that chronic alterations seen in late T2DM cause increased IR injury.Isolated perfused hearts from 6 (prediabetic), 12 (onset of T2DM) and 24 (late T2DM) weeks old male Zucker diabetic fatty rats (ZDF) and their age-matched heterozygote controls were subjected to 40 min ischemia/120 min reperfusion. IR injury was assessed by TTC-staining. Myocardial glucose metabolism was evaluated by glucose tracer kinetics (glucose uptake-, glycolysis- and glucose oxidation rates), myocardial microdialysis (metabolomics) and tissue glycogen measurements.T2DM altered the development in sensitivity towards IR injury compared to controls. At late diabetes ZDF hearts suffered increased damage, while injury was decreased at onset of T2DM. Coincident with cardioprotection, oxidation of exogenous glucose was decreased during the initial and normalized after 5 minutes of reperfusion. Metabolomic analysis of citric acid cycle intermediates demonstrated that cardioprotection was associated with a reversible shutdown of mitochondrial glucose metabolism during ischemia and early reperfusion at onset of but not at late type 2 diabetes.The metabolic alterations of type 2 diabetes are associated with protection against IR injury at onset but detrimental effects in late diabetes mellitus consistent with progressive dysfunction of glucose oxidation. These findings may explain the variable efficacy of cardioprotective interventions in individuals with type 2 diabetes.

It is unknown whether changes in circulating glucose levels due to short-term insulin discontinuation affect left ventricular contractile function in type 2 diabetic patients with (T2D-HF) and without (T2D-nonHF) heart failure.In two randomized cross-over-designed trials, 18 insulin-treated type 2 diabetic patients with (Ejection Fraction (EF) 36 ± 6%, n = 10) (trial 2) and without systolic heart failure (EF 60 ± 3%, n = 8) (trial 1) were subjected to hyper- and normoglycemia for 9-12 hours on two different occasions. Advanced echocardiography, bicycle exercise tests and 6-minute hall walk distance were applied.Plasma glucose levels differed between study arms (6.5 ± 0.8 mM vs 14.1 ± 2.6 mM (T2D-HF), 5.8 ± 0.4 mM vs 9.9 ± 2.1 mM (T2D-nonHF), p