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Background and Aims: Previous studies showed that troponin blood levels may increase after exercise. In this study, we assessed whether, among patients with suspected of having stable angina, the increase in troponin I (TnI) levels after exercise stress test (EST) might help identify those with obstructive coronary artery disease (CAD) and myocardial ischemia., Methods: We performed maximal treadmill EST in 50 patients (age 64 ± 9 years; 38 men) admitted to our Cardiology Department to undergo elective coronary angiography because of a suspicion of stable angina. TnI was measured before and 12 h after EST., Results: TnI increased after EST compared with baseline in the whole population (from 0.44 ± 0.76 to 0.84 ± 1.12 ng/dl, P < 0.001). No difference in TnI increase was observed between patients with obstructive CAD (n = 29; 0.61 ± 0.90-1.13 ± 1.33 ng/dl) and no obstructive CAD (NO-CAD; n = 21; 0.21 ± 0.46-0.44 ± 0.54 ng/dl; P = 0.51). There was also no significant difference in post-EST TnI increase between patients with positive EST (n = 34; 0.56 ± 0.89-1.05 ± 1.28 ng/dl) or negative EST (n = 16; 0.19 ± 0.26-0.39 ± 0.43 ng/dl; P = 0.16). Moreover, no significant difference was observed in the post-EST TnI increase among groups of patients with positive EST and obstructive CAD, positive EST and NO-CAD, negative EST and obstructive CAD and negative EST and NO-CAD (P = 0.12). No clinical or EST variable was associated with post-EST TnI increase, although there was a tendency for a greater increase in those achieving a heart rate more than 85 vs. less than 85% of maximal predicted heart rate during EST (P = 0.075)., Conclusion: TnI increase after EST in patients with suspected stable angina is largely independent of the results of coronary angiography and EST., (Copyright © 2020 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Arachidonic acid (AA), a major long-chain omega-6 polyunsaturated fatty acid, is associated with ischemic heart disease (IHD) and stroke. We assessed bi-directional associations of AA synthesis reflected by plasma phospholipid AA with CVD risk factors, and identified mediators of associations of AA with IHD and stroke using Mendelian randomization (MR). We used two-sample MR to assess bi-directional associations of AA synthesis with lipids, blood pressure, adiposity, and markers of inflammation and coagulation. We used multivariable MR to assess mediators of associations of AA with IHD and stroke. Genetically predicted AA (% of total fatty acids increase) was positively associated with apolipoprotein B (ApoB, 0.022 standard deviations (SD), 95% confidence interval (CI) 0.010, 0.034), high-density (0.030 SD, 95% CI 0.012, 0.049) and low-density lipoprotein cholesterol (LDL-C, 0.016 SD, 95% CI 0.004, 0.027) and lower triglycerides (-0.031 SD, 95% CI -0.049, -0.012) but not with other traits. Genetically predicted these traits gave no association with AA. The association of AA with IHD was attenuated adjusting for ApoB or LDL-C. Genetically predicted AA was associated with lipids but not other traits. Given ApoB is thought to be the key lipid in IHD, the association of AA with IHD is likely mediated by ApoB.

A low intake of selenium is associated with increased cardiovascular mortality. This could be reduced by supplementation with selenium and coenzyme Q 10 . D-dimer, a fragment of fibrin mirroring fibrinolysis, is a biomarker of thromboembolism, increased inflammation, endothelial dysfunction and is associated with cardiovascular mortality in ischemic heart disease. The objective was to examine the impact of selenium and coenzyme Q 10 on the level of D-dimer, and its relationship to cardiovascular mortality. D-dimer was measured in 213 individuals at the start and after 48 months of a randomised double-blind placebo-controlled trial with selenium yeast (200 µg/day) and coenzyme Q 10 (200 mg/day) ( n = 106) or placebo ( n = 107). The follow-up time was 4.9 years. All included individuals were low in selenium (mean 67 μg/L, SD 16.8). The differences in D-dimer concentration were evaluated by the use of T-tests, repeated measures of variance and ANCOVA analyses. At the end, a significantly lower D-dimer concentration was observed in the active treatment group in comparison with those on placebo ( p = 0.006). Although D-dimer values at baseline were weakly associated with high-sensitive CRP, while being more strongly associated with soluble tumour necrosis factor receptor 1 and sP-selectin, controlling for these in the analysis there was an independent effect on D-dimer. In participants with a D-dimer level above median at baseline, the supplementation resulted in significantly lower cardiovascular mortality compared to those on placebo ( p = 0.014). All results were validated with a persisting significant difference between the two groups. Therefore, supplementation with selenium and coenzyme Q 10 in a group of elderly low in selenium and coenzyme Q 10 prevented an increase in D-dimer and reduced the risk of cardiovascular mortality in comparison with the placebo group. The obtained results also illustrate important associations between inflammation, endothelial function and cardiovascular risk.

Background: A distorted blood lipid profile is an important risk factor for ischemic heart disease (IHD) but the predictive ability of the different lipid measures has rarely been studied. Our aim was to examine and compare, in a large sample of women, the predictive ability of total cholesterol/HDL cholesterol ratio (TC/HDL-C) and non-HDL-C in relation to IHD, adjusted for age, exercise, smoking, waist-hip ratio, blood pressure, and diabetes mellitus., Methods: Between 1995 and 2000, a total of 6537 women aged 50-59 years from the Women's Health in Lund area (WHILA) study in southern Sweden were included and underwent a baseline examination. The women were followed through national registers for incidence of IHD during a mean follow-up of 17 years. The prediction accuracy was estimated through Harrell's C and Akaike Information Criterion (AIC)., Results: Increasing TC/HDL-C as well as non-HDL-C showed strong associations with IHD, with the highest risk in the 5th quintile, where the HR was 2.30 (95% CI: 1.70-3.11) for TC/HDL-C and 1.67 (95% CI: 1.25-2.24) for non-HDL-C, after adjustments. Comparisons using Harrell's C and AIC indicated that TC/HDL-C has a slightly higher predictive ability than that of non-HDL-C (Harrell's C 0.62 and 0.59 respectively, p = 0.003 for difference, age-adjusted model; AIC for TC/HDL-C < AIC for non-HDL-C)., Conclusions: TC/HDL-C ratio and non-HDL-C are both clinical predictors for IHD in middle-aged women. The results indicate that the predictive ability of TC/HDL-C was higher than that of non-HDL-C; however, non-HDL-C was linearly related to IHD (p = 0.58) and may be easier to calculate and interpret in clinical practice, for early identification of future IHD in women.

Background: CODE-MI is a pan-Canadian, multicentre, stepped-wedge, cluster randomized trial that evaluates the impact of using the female-specific 99th percentile threshold for high-sensitivity cardiac troponin (hs-cTn) on the diagnosis, treatment and outcomes of women presenting to the emergency department (ED) with symptoms suggestive for myocardial ischemia. A feasibility study was conducted to estimate the number of eligible patients, the rate of the study's primary outcome under control conditions, and the statistical power to detect a clinically important difference in the primary outcome., Methods: Using linked administrative data from 11 hospitals in Ontario, Canada, from October 2014 to September 2017, the following estimates were obtained: number of women presenting to the ED with symptoms suggestive of myocardial ischemia and a 24-hour peak hs-cTn value within the female-specific and overall thresholds (ie, primary cohort); the rate of the 1-year composite outcome of all-cause mortality, re-admission for nonfatal myocardial infarction, incident heart failure, or emergent/urgent coronary revascularization. Study power was evaluated via simulations., Results: Overall, 2,073,849 ED visits were assessed. Among women, chest pain (with or without cardiac features) and shortness of breath were the most common complaints associated with a diagnosis of acute coronary syndrome. An estimated 7.7% of women with these complaints are eligible for inclusion in the primary cohort. The rate of the 1-year outcome in the primary cohort varied significantly across hospitals with a median rate of 12.2% (95%CI: 7.9%-17.7%). With 30 hospitals, randomized at 5-month intervals in 5 steps, approximately 19,600 women are expected to be included in CODE-MI, resulting in >82% power to detect a 20% decrease in the odds of the primary outcome at a 0.05 significance level., Conclusions: This feasibility study greatly enhanced the design of CODE-MI, allowed accurate evaluation of the study power, and demonstrated the strength of using linked administrative health data to guide the design of pragmatic clinical trials., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Ischemia-modified albumin (IMA) is an oxidative stress marker used to assess the presence and severity of oxidative stress. This marker was first used for early diagnosis of myocardial ischemia. Materials & methods: A variety of IMA studies were carried out to show the effect of oxidative stress on gynecological disorders. Conclusion: This analysis summarizes the literature by conducting electronic research on the relationship between IMA and gynecological disorders.

Prasugrel and ticagrelor are potent oral platelet P2Y 12 inhibitors and are recommended over clopidogrel in patients with acute coronary syndrome (ACS). Oral platelet P2Y 12 inhibitors are characterized by varying degrees of pharmacodynamic response profiles as assessed by a variety of commercially available assays. Because of its ease of use, rapid turnaround times and ability to provide results specific to P2Y 12 inhibitory effects, VerifyNow has emerged as one of the most commonly utilized platelet function assays. However, reference ranges with VerifyNow have been reported mainly for clopidogrel and there has not yet been any study specifically conducted to provide the expected on treatment reference ranges following administration of prasugrel and ticagrelor. This was a prospective single center investigation conducted in 120 patients with ACS who were treated with prasugrel or ticagrelor as per standard of care. Patients who underwent percutaneous coronary interventions (PCI) were treated with a loading dose of prasugrel (60 mg) or ticagrelor (180 mg), and patients who were on maintenance therapy were taking prasugrel (10 mg qd or 5 mg qd) or ticagrelor (90 mg bid). Platelet function testing was performed using the VerifyNow™ PRUTest™. The overall range of PRUTest values was lower than that observed in studies of patients treated with clopidogrel. The use of a maintenance dose regimen had a wider range of PRUTest values compared to the use of a loading dose for both prasugrel (1-179 vs. 2-128) and ticagrelor (1-196 vs. 1-177). The average PRUTest values in patients on prasugrel and ticagrelor maintenance dosing were 20% and 9% higher those observed in patients treated with a loading dose. PRUTest results following loading dose administration were very similar between drugs, but were 20% higher with prasugrel compared with ticagrelor during maintenance dosing. This study establishes expected PRUTest ranges for patients taking loading and maintenance doses of prasugrel and ticagrelor.Clinical Trial Registration http://www.clinicaltrials.gov Unique Identifier: NCT04492423, registered July 2020 retrospectively registered.

Purpose: Hepatic steatosis has been associated with some cardiovascular risks. Increased alanine aminotransferase (ALT) was suggested to be linked to endothelial dysfunction. We prospectively investigated the joint effect of hepatic steatosis and elevated ALT within the normal range on incident ischemic heart disease (IHD) risk as an extrahepatic complication., Patients and Methods: We assessed 16,541 participants without diabetes using data from a health risk assessment study (HERAS) and Korean Health Insurance Review and Assessment (HIRA) data. We defined elevated ALT within the normal range as 30-40 IU/L in men and 23-40 IU/L in women, according to previous Korean epidemiological data. We prospectively assessed hazard ratios (HRs) with 95% confidence intervals (CIs) for IHD using multivariate Cox proportional hazards regression models over a 50-month period after the baseline survey., Results: During the follow-up period, 368 (2.2%) participants developed IHD. Compared to the group with no hepatic steatosis and controlled ALT, the HRs for IHD were 1.68 (95% CI, 1.16-2.42) in the group with hepatic steatosis and elevated ALT after adjusting for confounding variables., Conclusion: Hepatic steatosis and elevated ALT levels within the normal range may jointly affect the development of IHD among nondiabetic adults. This indicates that lifestyle advice and vascular health management should be recommended among individuals with hepatic steatosis and elevated ALT, even if it falls within the normal range., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Jung et al.)

Background: Cardiac and inflammatory biomarkers have been associated with adverse outcome after major abdominal surgery. This study investigated the effect of remote ischaemic preconditioning (RIPC) on perioperative concentrations of high-sensitive cardiac troponin (hs-cTn) T and interleukin (IL) 6., Methods: Adult patients scheduled for elective pancreatic surgery between March 2017 and February 2019 were randomized to either three cycles of upper-limb ischaemia and reperfusion (each 5 min) or a sham procedure before surgery. The primary endpoint was the maximum postoperative hs-cTnT concentration within 48 h after surgery. Secondary endpoints were postoperative myocardial injury (PMI), defined as an absolute increase of hs-cTnT of at least 14 ng/l above baseline concentration, maximum concentration of IL-6 within 48 h after surgery and postoperative complications within 30 days of surgery., Results: Of 99 eligible patients, 46 underwent RIPC and 46 a sham procedure. RIPC did not reduce the maximum hs-cTnT concentration after surgery (12.6 ng/l RIPC, 16.6 ng/l controls, P = 0.225), nor did it lessen the incidence of PMI (15/45 RIPC, 18/45 controls, P = 0.375). The maximum postoperative IL-6 concentration was 265 pg/ml after RIPC versus 385 pg/ml in controls (P = 0.108). Postoperative complications occurred in 23 RIPC and 24 control patients respectively., Conclusions: Remote ischaemic preconditioning did not reduce the maximum postoperative hs-cTnT concentration. Postoperative myocardial injury, IL-6 concentrations and postoperative complications were similar between RIPC patients and controls., Trial Registration: Clinicaltrials.gov identifier NCT03460938., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

In recent decades, vibrational spectroscopic methods such as Raman and FT-IR spectroscopy are widely applied to investigate plasma and serum samples. These methods are combined with drop coating deposition techniques to pre-concentrate the biomolecules in the dried droplet to improve the detected vibrational signal. However, most often encountered challenge is the inhomogeneous redistribution of biomolecules due to the coffee-ring effect. In this study, the variation in biomolecule distribution within the dried-sample droplet has been investigated using Raman and FT-IR spectroscopy and fluorescence lifetime imaging method. The plasma-sample from healthy donors were investigated to show the spectral differences between the inner and outer-ring region of the dried-sample droplet. Further, the preferred location of deposition of the most abundant protein albumin in the blood during the drying process of the plasma has been illustrated by using deuterated albumin. Subsequently, two patients with different cardiac-related diseases were investigated exemplarily to illustrate the variation in the pattern of plasma and serum biomolecule distribution during the drying process and its impact on patient-stratification. The study shows that a uniform sampling position of the droplet, both at the inner and the outer ring, is necessary for thorough clinical characterization of the patient's plasma and serum sample using vibrational spectroscopy.

Background: Ischaemic heart disease (IHD) often develops after decades of preceding subclinical coronary atherosclerosis. Biomarkers are useful prognostic predictors of IHD, but their long-term predictive value in a general population has not been adequately studied., Purpose: To investigate the early predictive value of multi-modality biomarkers in addition to clinical risk factors in incident IHD in a random male general population sample followed from 50 to 71 years of age., Method: "The Study of Men Born in 1943" is a longitudinal cohort study during follow-up. All the men underwent a baseline examination in 1993, where a panel of biomarkers were analysed and incident IHD was registered during 21-year follow-ups., Results: Of 739 participants, 97 men (13.1%) developed an IHD event. For time to first occurrence of IHD, univariable analyses showed that elevated levels of high sensitivity troponin T (hs-TNT), high sensitivity-C reactive protein (hs-CRP) and interleukin-6 (IL-6) were significant predictors of IHD. In addition, a high number of biomarkers with elevated levels (hs-TNT > 10 ng/L, hs-CRP > 1 mg/L, IL-6 > 8 ng/L and N-terminal pro b-type natriuretic peptide (NT-proBNP) > 100 pg/mL) increased predictive ability. In univariable and multivariable analysis high-density lipoprotein-cholesterol (HDL-C) had the highest predictive ability. Hs-TNT provided better predictive ability than smoking, body mass index and glucose, and was an independent significant predictor when adjusted for HDL-C, total cholesterol and hypertension. Addition of biomarkers on top of clinical risk factors provided significantly better prediction as tested by likelihood ratio test (p = 0.033), but did not significantly enhance the model's discriminative ability However, it appeared contributing to higher sensitivity in the late phase of follow-up., Conclusion: In this random, middle-aged male population sample, the addition of biomarker hs-TNT was an independent significant predictor of IHD and significantly improved prediction, indicating the probability of a better prediction of long-term risk of IHD in a low-risk population., Trial Registration: The study is registered at Clinical Trials.gov Identifier number: NCT03138122.

Background White blood cell count, which is inexpensive and widely available in clinical practice, has been proposed to provide prognostic information in coronary artery disease (CAD). Elevated levels of white blood cell subtypes may play different roles in atherothrombosis and predict cardiovascular outcomes. Methods and Results The association between white blood cell counts and mortality was evaluated in 823 subjects with angiographically demonstrated and clinically stable CAD in an observational-longitudinal study. The correlation among white blood cell counts and factor II plasma coagulant activity was analyzed in 750 subjects (554 CAD and 196 CAD-free) not taking anticoagulant drugs. Subjects with overt leukocytosis or leukopenia were excluded. In the longitudinal study after a median follow-up of 61 months, 160 (19.4%) subjects died, 107 (13.0%) of whom from cardiovascular causes. High levels of neutrophils, monocytes, eosinophils, and basophils were associated with an increased mortality rate. In multiadjusted Cox regression models, only neutrophils and basophils remained predictors of total and cardiovascular mortality. The associations remained significant after adjustment for traditional cardiovascular risk factors and by including D-dimer and the chemokine CXCL12 in the regression models. Neutrophils and basophils were also significant predictors of factor II plasma coagulant activity variability after adjustment for blood cell counts, age, sex, inflammatory markers, CAD diagnosis, and prothrombin G20210A polymorphism. Factor II plasma coagulant activity was similarly increased in subjects with high neutrophil and basophil counts and in carriers of the prothrombin 20210A allele. Conclusions Both high neutrophil and basophil blood counts may predict mortality in patients with clinically stable CAD and are associated with enhanced factor II plasma coagulant activity, thereby suggesting underlying prothrombotic mechanisms.

Aims: The progression of myocardial infarction (MI) involves multiple metabolic disorders. Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate multiple cardiovascular functions. G protein-coupled bile acid receptor (TGR5) is one of the receptors sensing bile acids to mediate their biological functions. In this study, we aimed to elucidate the effects of bile acids-TGR5 signaling pathways in myocardial infarction (MI)., Methods and Results: Blood samples of AMI patients or control subjects were collected and plasma was used for bile acid metabolism analysis. We discovered that bile acid levels were altered and deoxycholic acid (DCA) was substantially reduced in the plasma of AMI patients. Mice underwent either the LAD ligation model of MI or sham operation. Both MI and sham mice were gavaged with 10 mg/kg/d DCA or vehicle control since 3-day before the operation. Cardiac function was assessed by ultrasound echocardiography, infarct area was evaluated by TTC staining and Masson trichrome staining. Administration of DCA improved cardiac function and reduced ischemic injury at the 7th-day post-MI. The effects of DCA were dependent on binding to its receptor TGR5. Tgr5 - / - mice underwent the same MI model. Cardiac function deteriorated and infarct size was increased at the 7th-day post-MI, which were not savaged by DCA administration. Moreover, DCA inhibited interleukin (IL)-1β expression in the infarcted hearts, and ameliorated IL-1β activation at 1-day post-MI. DCA inhibited NF-κB signaling and further IL-1β expression in cultured neonatal mouse cardiomyocytes under hypoxia as well as cardio-fibroblasts with the treatment of LPS., Conclusions: DCA-TGR5 signaling pathway activation decreases inflammation and ameliorates heart function post-infarction. Strategies that control bile acid metabolism and TGR5 signaling to ameliorate the inflammatory responses may provide beneficial effects in patients with myocardial infarction., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Carbon monoxide (CO), which is well known as silent killer, has many toxic effects on organs with high rate of metabolism such as heart and brain. CO-induced cardiotoxicity resulted in a wide range of disabilities including electrocardiogram (ECG) abnormalities, elevation in level of cardiac enzymes, arrhythmias, impairment of left ventricular and myocardial infarction (MI). Cardio-protective effects of Granulocyte colony-stimulating factor (G-CSF) on infarcted heart was proved previously in various reports., Objective: In this study, possible effect of G-CSF on cardiac function of patients with moderate to severe acute CO poisoning was investigated., Methods: Cardioprotective effects of G-CSF in CO-poisoned patients was evaluated through ECG, Holter monitoring, echocardiography, and biochemical studies. Continuous intravenous infusion of G-CSF (90 μg/kg) and normal saline were administered respectively to treatment and placebo groups., Results: The results demonstrated that in moderate to severe CO poisoning, myocardial injury is common. ECG changes (e.g., ST-segment and T-wave changes, QTC), cardiac arrhythmias (e.g., heart blocks and ventricular arrhythmias), serum level of Troponin I, left ventricular ejection fraction were determined after G-CSF administration. Frequencies of ST depression, inversion or flatting of T wave and QTC in ECG were significantly reduced after G-CSF treatment. In addition, incidence of cardiac arrhythmias due to CO poisoning were reduced after G-CSF treatment. However, G-CSF did not exert protective effects on TPI level and function of left ventricular in CO-poisoned patients., Conclusion: GCSF could probably reduce CO-induced cardiac ischemia in patients with acute CO poisoning., Clinical Trial Registration: The trial protocol was registered in the Iranian Registry of Clinical Trials (http://www.irct.ir) registry (Irct ID: IRCT201607232083N7)., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Aim of the Study: To investigate the effect of myocardial injury on the prognosis of patients with severe or critical coronavirus disease 2019 (COVID-19)., Methods: Between February 10, 2020 and March 31, 2020, data of severe and critical COVID-19 patients were collected and retrospectively analyzed. Admission data included age, heart rates, mean arterial pressure, and myocardial injury markers including creatine kinase isoenzyme-MB (CK-MB), myoglobin, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and interleukin-6. The endpoints included mortality, the incidence of malignant arrhythmia, and mechanical ventilation time. Univariate regression analysis, multivariate linear regression analysis, and binary logistic analysis were performed to develop the risk predictors in myocardial injury to the prognosis of severe and critical COVID-19 patients., Results: Seventy-four COVID-19 patients were included (mean age of 67.2 ± 14.6 years, male of 66.2%), including 42 severe and 32 critical cases. The mortality was 62.2% (n = 46). CK-MB (odds ratio = 5.895, p < .001, 95% confidence interval: 3.097-8.692) and interleukin-6 (odds ratio = 0.379; p = .005; 95% confidence interval: 1.051-1.769) were independent risk factors of increased mechanical ventilation time; myoglobin (odds ratio = 7.710; p = .045; 95% confidence interval: 1.051-56.571) were the independent predictor of incidence of malignant arrhythmia; age (odds ratio = 1.077; p = .009; 95% confidence interval: 1.019-1.139), myoglobin (odds ratio = 9.480; p = .032; 95% confidence interval: 1.211-78.188), and NT-proBNP (odds ratio = 4.852; p = .047; 95% confidence interval: 0.956-24.627) were the independent predictors of mortality., Conclusions: In severe and critical COVID-19 patients, the obvious myocardial injury was observed. Increases of CK-MB, myoglobin, NT-proBNP, interleukin-6, and age were independently associated with poor prognosis including increased ventilation duration, the incidence of malignant arrhythmia, and mortality., (© 2020 Wiley Periodicals LLC.)

Blood coagulation is central to myocardial ischemia and reperfusion (IR) injury. Studies on the light elicited circadian rhythm protein Period 2 (PER2) using whole body Per2-/- mice found deficient platelet function and reduced clotting which would be expected to protect from myocardial IR-injury. In contrast, intense light induction of PER2 protected from myocardial IR-injury while Per2 deficiency was detrimental. Based on these conflicting data, we sought to evaluate the role of platelet specific PER2 in coagulation and myocardial ischemia and reperfusion injury. We demonstrated that platelets from mice with tissue-specific deletion of Per2 in the megakaryocyte lineage (Per2loxP/loxP-PF4-CRE) significantly clot faster than platelets from control mice. We further found increases in infarct sizes or plasma troponin levels in Per2loxP/loxP-PF4-CRE mice when compared to controls. As intense light increases PER2 protein in human tissues, we also performed translational studies and tested the effects of intense light therapy on coagulation in healthy human subjects. Our human studies revealed that intense light therapy repressed procoagulant pathways in human plasma samples and significantly reduced the clot rate. Based on these results we conclude that intense light elicited PER2 has an inhibitory function on platelet aggregation in mice. Further, we suggest intense light as a novel therapy to prevent or treat clotting in a clinical setting., Competing Interests: The authors have declared that no competing interests exist.

Background: Ischemic heart disease (IHD) without diabetes is considered an important challenge to human health and is associated with a poor prognosis, as well as a lack of health awareness. We prospectively investigated the relationship between the triglyceride-glucose (TyG) index, a surrogate marker of early insulin resistance, and incident IHD risk in a large cohort of nondiabetic Korean adults using National Health Insurance Service data., Methods: We assessed 16,455 participants (8426 men and 8029 women) without diabetes using data from a health risk assessment study (HERAS) and Korea Health Insurance Review and Assessment (HIRA) data. The participants were divided into four groups according to TyG index quartiles, calculated as ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. We prospectively assessed hazard ratios (HRs) with 95% confidence intervals (CIs) for IHD using multivariate Cox proportional-hazards regression models over a 50-month period that followed the baseline survey., Results: During the follow-up period, 322 (2.0%) participants developed IHD. HRs of IHD for TyG index quartiles 2-4 were 1.61 (95% CI 1.05-2.48), 1.85 (95% CI 1.21-2.81), and 2.29 (95% CI 1.50-3.51), respectively, after adjusting for age, sex, body mass index, smoking status, alcohol intake, and physical activity., Conclusions: A higher TyG index precedes and significantly predicts future IHD among nondiabetic Koreans. Accordingly, the TyG index may be a useful measure in assessing cardiovascular risk for nondiabetic adults in the preclinical stage.

Soluble suppression of tumorigenesis-2 (sST2) has been introduced as a marker associated with heart failure (HF) pathophysiology and status. Endothelial dysfunction is a component underlying HF pathophysiology. Therefore, we examined the association of arterial wall properties with sST2 levels in patients with HF of ischemic etiology. We enrolled 143 patients with stable HF of ischemic etiology and reduced left ventricular ejection fraction (LVEF) and 77 control subjects. Flow-mediated dilation (FMD) was used to evaluate endothelial function and pulse wave velocity (PWV) to assess arterial stiffness. Although there was no significant difference in baseline demographic characteristics, levels of sST2 were increased in HF compared to the control (15.8 (11.0, 21.8) ng/mL vs. 12.5 (10.4, 16.3) ng/mL; p < 0.001). In the HF group, there was a positive correlation of sST2 levels with age (rho = 0.22; p = 0.007) while there was no association of LVEF with sST2 (rho = -0.119; p = 0.17) nor with PWV (rho = 0.1; p = 0.23). Interestingly, sST2 was increased in NYHA III [20.0 (12.3, 25.7) ng/mL] compared to patients with NYHA II (15.0 (10.4, 18.2) ng/mL; p = 0.003) and inversely associated with FMD (rho = -0.44; p < 0.001) even after adjustment for possible confounders. In patients with chronic HF of ischemic etiology, sST2 levels are increased and are associated with functional capacity. There is an inverse association between FMD and sST2 levels, highlighting the interplay between the dysfunctional endothelium and HF pathophysiologic mechanisms.

Background: Women with symptoms and signs of ischemia, preserved left ventricular ejection fraction (LVEF), and no obstructive coronary artery disease (CAD), often have coronary microvascular dysfunction (CMD), and are at risk of future heart failure with preserved ejection fraction (HFpEF). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used to evaluate HF and myocardial ischemia. Relationships between NT-proBNP and CMD are not well defined in this population., Methods: We evaluated resting NT-proBNP levels in 208 women with symptoms and signs of ischemic heart disease, preserved LVEF and no obstructive CAD undergoing clinically indicated invasive coronary flow reserve (CFR) as a measure of CMD-related ischemia and resting left ventricular end-diastolic pressure (LVEDP). Chi-square testing was used for categorical variables and ANOVA or Kruskal-Wallis tests were used for continuous variables., Results: Overall, 79% had an elevated resting LVEDP, and mean NT-proBNP was 115 ± 158 pg/mL. NT-proBNP levels correlated directly with age (r = 0.28, p = <0.0001), and indirectly with body mass index (r = -0.21, p = 0.0006), but did not independently associate with CFR. When stratified by NT-proBNP thresholds, higher NT-proBNP was initially associated with lower CFR, which did not persist with adjustment for multiple testing (p = 0.01 and 0.36, respectively)., Conclusion: Among women with symptoms and signs of ischemia, preserved LVEF, no obstructive CAD, and undergoing clinically indicated functional coronary angiography (FCA) for suspected CMD, while a majority had elevated resting LVEDP, we failed to find an independent association between CFR and NT-proBNP, although stratified clinical thresholds may relate to lower CFR. Further work is needed to investigate if these findings support the hypothesis that CMD-related ischemia may be a precursor to HFpEF., Competing Interests: Dr. Mehta has received research grants from Gilead and General Electric. Dr. Handberg receives research grants from Aastrom Biosciences, Amorcyte, Biocardia, Brigham and Women’s Hospital, Capricor, Cytori Therapeutics, Department of Defense, Direct Flow Medical, Duke Clinical Research Institute, East Carolina University, Everyfit Inc., Medtronic, Merck & Co., Mesoblast, National Institutes of Health (NIH), NIH through University of Rochester, NIH through Brigham and Women’s Health, NIH through University of Texas, PCORI, and Sanofi Aventis; Research grant and educational grant from Gilead Sciences; Unrestricted educational grants for the Vascular Biology Working Group from Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Ionis, and Relypsa; and Consultant fees from Bristol-Myers Squibb Company. Dr. Bairey Merz serves as Board of Director for iRhythm, receieves personal fees paid through CSMC from Abbott Diagnostics, Sanofi. Dr. Pepine receives support from the NIH NHLBI--HL087366 (UFRCC for the Cardiovascular Cell Therapy Research Network), HL132448 (Brain-Gut Microbiome-Immune Axis in Hypertension), HL033610 (Angiotensin and Neuroimmune Activation in Hypertension), and HL146158 (WISE HFpEF); the Gatorade Trust through funds distributed by the University of Florida, Department of Medicine; NIH NCATS—University of Florida Clinical and Translational Science UL1TR001427; PCORnet-OneFlorida Clinical Research Consortium CDRN-1501- 26692; and US Dept. of Defense PR161603 (WARRIOR). This does not affect our adherence to PLOS ONE policies on data and materials sharing. There are no patents, marketed products, or products in development to declare.

Objective: Women with symptoms or signs of myocardial ischemia but no obstructive coronary artery disease (INOCA) often have coronary vascular dysfunction and elevated risk for adverse cardiovascular events. We hypothesized that u-hscTnI (ultra-high-sensitivity cardiac troponin I), a sensitive indicator of ischemic cardiomyocyte injury, is associated with coronary vascular dysfunction in women with INOCA. Approach and Results: Women (N=263) with INOCA enrolled in the WISE-CVD study (Women's Ischemic Syndrome Evaluation-Coronary Vascular Dysfunction) underwent invasive coronary vascular function testing and u-hscTnI measurements (Simoa HD-1 Analyzer; Quanterix Corporation, Lexington, MA). Logistic regression models, adjusted for traditional cardiovascular risk factors were used to evaluate associations between u-hscTnI and coronary vascular function. Women with coronary vascular dysfunction (microvascular constriction and limited coronary epicardial dilation) had higher plasma u-hscTnI levels (both P =0.001). u-hscTnI levels were associated with microvascular constriction (odds ratio, 1.38 per doubling of u-hscTnI [95% CI, 1.03-1.84]; P =0.033) and limited coronary epicardial dilation (odds ratio, 1.37 per doubling of u-hscTnI [95% CI, 1.04-1.81]; P =0.026). u-hscTnI levels were not associated with microvascular dilation or coronary epicardial constriction., Conclusions: Our findings indicate that higher u-hscTnI is associated with coronary vascular dysfunction in women with INOCA. This suggests that ischemic cardiomyocyte injury in the setting of coronary vascular dysfunction has the potential to contribute to adverse cardiovascular outcomes observed in these women. Additional studies are needed to confirm and investigate mechanisms underlying these findings in INOCA. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00832702.

Aims: Growth hormone (GH) therapy in heart failure (HF) is controversial. We investigated the cardiovascular effects of GH in patients with chronic HF due to ischemic heart disease., Methods: In a double-blind, placebo-controlled trial, we randomly assigned 37 patients (mean age 66 years; 95% male) with ischemic HF (ejection fraction [EF] < 40%) to a 9-month treatment with either recombinant human GH (1.4 mg every other day) or placebo, with subsequent 3-month treatment-free follow-up. The primary outcome was change in left ventricular (LV) end-systolic volume measured by cardiac magnetic resonance (CMR). Secondary outcomes comprised changes in cardiac structure and EF. Prespecified tertiary outcomes included changes in New York Heat Association (NYHA) functional class and quality of life (QoL), as well as levels of insulin-like growth factor-1 (IGF-1) and N-terminal pro-brain natriuretic peptide (NT-proBNP)., Results: No changes in cardiac structure or systolic function were identified in either treatment group; nor did GH treatment affect QoL or functional class. In the GH group, circulating levels of IGF-1 doubled from baseline (+105%; p < 0.001) and NT-proBNP levels halved (-48%; p < 0.001) during the treatment period, with subsequently a partial return of both towards baseline levels. No changes in IGF-1 or NT-proBNP were observed in the placebo group at any time during the study., Conclusion: In patients with chronic ischemic HF, nine months of GH treatment was associated with significant increases in levels of IGF-1 and reductions in levels of NT-proBNP, but did not affect cardiac structure, systolic function or functional capacity., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Obstructive sleep apnea (OSA) is associated with multiple comorbid conditions including cardiovascular diseases and cancer. There is a growing interest in exploring biomarkers to understand the related mechanisms and improve the risk stratification of OSA. Circulating microRNAs (miRNAs) are single noncoding strands of nearly 22 nucleotides that posttranscriptionally regulate target gene expression. Our aim was to identify miRNA profiles associated with OSA., Methods: We studied 48 male subjects, mostly Caucasian (63%) and overweight, divided by polysomnography into the no OSA control group (n = 6), mild OSA group (n = 12), moderate OSA group (n = 15), and severe OSA group (n = 15). The study groups were matched for age, body mass index (BMI), and body fat composition. miRNA profiles were measured from peripheral whole blood using two steps: (1) microarray analysis comprising more than 2500 miRNAs in a subsample of 12 subjects (three from each group); and (2) validation phase using real-time quantitative polymerase chain reaction (RTqPCR)., Results: The microarray assessment identified 21 differentially expressed miRNAs among the groups. The RT-qPCR assessment showed that miR-1254 and miR-320e presented a gradual increase in expression parallel to OSA severity. Linear regression analysis showed that severe OSA was independently associated with miR-1254 (ß = 68.4; EP = 29.8; p = 0.02) and miR-320e (ß = 76.1; EP = 31.3; p = 0.02)., Conclusion: Severe OSA is independently associated with miRNAs that are involved in heart failure (miR-1254), myocardial ischemia/reperfusion (miR-320e), and cell proliferation in some cancer types (miR-1254 and miR-320e). Future investigations addressing whether these miRs may provide prognostic information in OSA are needed.

Background and Aims: Evidence on the association between aspartate aminotransferase (AST) activity and mortality of patients with ischemic heart disease (IHD) is limited. We investigated whether there is an association between AST activity and mortality in IHD patients., Methods and Results: The study included 6857 patients with coronary angiography-proven IHD and AST activity within the reference range. AST activity measurements were available in all patients. The primary outcome was 3-year cardiac mortality. Patients were categorized in groups according to the AST activity tertiles: a group with AST within the 1st tertile (AST < 17.0 U/L), a group with AST within the 2nd tertile (AST > 17-24.5 U/L) and a group with AST within the 3rd tertile (AST > 24.5 U/L). Cardiac death (n = 297) occurred in 109, 69 and 119 patients in the 1st to 3rd AST tertiles (Kaplan-Meier estimates of mortality: 5.3%, 3.6% and 5.9%; univariable hazard ratio [HR] = 1.75, 95% confidence interval [CI] 1.30-2.36, P < 0.001 for tertile 3 vs. 2; HR = 1.13 [0.87-1.46], P = 0.370 for tertile 3 vs. 1; and HR = 0.65 [0.48-0.87], P = 0.004 for tertile 2 vs. 1). The association between AST and cardiac mortality was U-shaped. AST values <15 U/L (HR = 1.118 [1.009-1.238]) and >23 U/L (HR = 1.029 [1.003-1.056]) were associated with higher cardiac mortality compared with the reference value (21 U/L). After adjustment, the association between AST and cardiac mortality was attenuated (P = 0.133) but remained non-linear (P = 0.047)., Conclusions: In patients with IHD, AST activity was associated with the risk of cardiac mortality with a U-shaped relationship. After adjustment, the association between AST and mortality was attenuated., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

An inadequate platelet response to aspirin (ASA) has been identified in some patients under chronic ASA treatment. The aim of this study was to analyze if ASA-sensitive and ASA-resistant platelets have differences in their apoptotic capability. Clinically stable ischemic coronary patients who had been taking ASA (100 mg/d) for at least 9 months before inclusion were divided into ASA-resistant (n = 11) and ASA-sensitive (n = 13) groups as defined by the PFA-100 test. Platelets from ASA-sensitive patients showed higher expression of the proapoptotic proteins Bak and Bax than those from ASA-resistant patients, although only Bak protein remained different when the results were adjusted by age. In resting platelets, neither caspase-3 activity nor cytosolic cytochrome C levels were different between both experimental groups. Stimulation of platelets with calcium ionophore (10 nmol/L, A23187) increased caspase-3 activity (1.91-fold higher; P < 0.05) and cytosolic cytochrome C levels (1.84-fold higher; P < 0.05) to a higher degree in ASA-sensitive than in ASA-resistant platelets. In conclusion, ASA-sensitive platelets seem to be better prepared to undergo apoptosis during robust platelet activation.

Background: Elevated plasma or serum troponin, indicating perioperative myocardial injury (PMI), is common after noncardiac surgery. However, underlying mechanisms remain unclear. Acute coronary syndrome (ACS) is associated with the early appearance of circulating microRNAs, which regulate post-translational gene expression. We hypothesised that if PMI and ACS share pathophysiological mechanisms, common microRNA signatures should be evident., Methods: We performed a nested case control study of samples obtained before and after noncardiac surgery from patients enrolled in two prospective observational studies of PMI (postoperative troponin I/T>99th centile). In cohort one, serum microRNAs were compared between patients with or without PMI, matched for age, gender, and comorbidity. Real-time polymerase chain reaction quantified (qRT-PCR) relative microRNA expression (cycle quantification [Cq] threshold <37) before and after surgery for microRNA signatures associated with ACS, blinded to PMI. In cohort two, we analysed (EdgeR) microRNA from plasma extracellular vesicles using next-generation sequencing (Illumina HiSeq 500). microRNA-messenger RNA-function pathway analysis was performed (DIANA miRPath v3.0/TopGO)., Results: MicroRNAs were detectable in all 59 patients (median age 67 yr [61-75]; 42% male), who had similar clinical characteristics independent of developing PMI. In cohort one, serum microRNA expression increased after surgery (mean fold-change) hsa-miR-1-3p: 3.99 (95% confidence interval [CI: 1.95-8.19]; hsa-miR-133-3p: 5.67 [95% CI: 2.94-10.91]; P<0.001). These changes were not associated with PMI. Bioinformatic analysis of differentially expressed microRNAs from cohorts one (n=48) and two (n=11) identified pathways associated with adrenergic stress and calcium dysregulation, rather than ischaemia., Conclusions: Circulating microRNAs associated with cardiac ischaemia were universally elevated in patients after surgery, independent of development of myocardial injury., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Background: There is a growing recognition of the inherent limitations of the use of the left ventricular ejection fraction (LVEF) to accurately phenotype patients with heart failure (HF)., Objectives: The authors sought to identify unique proteomic signatures for patients with HF with reduced ejection fraction (HFrEF), HF with a midrange LVEF (HFmrEF), and HF with preserved ejection fraction (HFpEF), as well as to identify molecular differences between patients with ischemic and nonischemic HF., Methods: We used high-content aptamer-based proteomics technology (SOMAscan) to interrogate the blood proteome of age- and sex-matched patients with HF within different LVEF groups., Results: Within the Washington University Heart Failure Registry, we identified age/sex-matched patients within 3 LVEF categories: HFrEF (LVEF <40%), HFmrEF (LVEF 40% to 50%), and HFpEF (LVEF >50%). We found that patients with HFrEF, HFmrEF, and HFpEF had unique variations in circulating proteins that reflected distinct biological pathophysiologies. Bioinformatics analysis revealed that there were biological themes that were unique to patients with HFrEF, HFpEF, or HFmrEF. Comparative analyses of patients with HFmrEF with improved LVEF and patients with HFmrEF with unchanged LVEF revealed marked differences between these 2 patient populations and indicated that patients with recovered LVEF are more similar to patients with HFpEF than to patients with HFrEF. Moreover, there were marked differences in the proteomic signatures of patients with ischemic and nonischemic HF., Conclusions: Viewed together, these findings suggest that it may be possible to use high-content multiplexed proteomics assays in combination with the clinical assessment of LVEF to more accurately identify clinical phenotypes of patients with HF., (Published by Elsevier Inc.)

Background: Infection is postulated as a possible risk factor for ischemic heart disease with a spiralling body of evidence. Hepatitis B is one of the most comprehensively investigated infection for its association with ischemic heart disease. This study aims at establishing an association between Hepatitis B core antibody status and ischemic heart disease using National Health and Nutrition Examination Survey (NHANES) database., Methods: NHANES data from 2007 to 2016 were used for the present analysis. To identify patients with self-reported coronary heart disease, angina/angina pectoris, myocardial infarction, we examined the answers to questions MCQ160c, MCQ160d, MCQ160e delineated in NHANES data. These questions as described in the NHANES dataset are as follows: MCQ160c-Has a doctor or other health professional ever told you that you had coronary heart disease?, MCQ160d-Has a doctor or other health professional ever told you that you had angina, also called angina pectoris?, MCQ160e- Has a doctor or other health professional ever told you that you had a heart attack also called myocardial infarction?. Next, to identify patients with positive Hepatitis B core antibody, we examined the variable LBXHBC of the NHANES dataset. Baseline characteristics, along with unadjusted and adjusted odds ratio using multivariable logistic regression analysis, of included patients were analyzed for Hepatitis B core antibody and its association with ischemic heart disease., Results: A total of 3,248 individuals with ischemic heart disease and 42,345 individuals with no ischemic heart disease were included in the final analysis. Hepatitis B core antibody positive status was associated with lower incidence of ischemic heart disease, adjusted odds ratio of 0.61 (95% confidence interval: 0.41-0.92, P value < 0.02)., Conclusions: In conclusion, the present analysis points toward a possible association between past Hepatitis B infection and ischemic heart disease. Hepatitis B infection was associated with a decreased incidence of ischemic heart disease. Further research with better design and possible molecular mechanism is warranted., (Copyright © 2020 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Objective: To describe the intraindividual changes of heart biomarker levels during and after pregnancy and to evaluate existing cut-off levels for heart failure or myocardial ischaemia in pregnant women., Method: A total of 196 healthy pregnant women were recruited from maternal outpatient clinics and included in the study. Blood samples were obtained on four occasions: at 10-12 gestational weeks (gw), 20-25 gw, after delivery and 6 months postpartum and analysed for N-terminal pro-brain natriuretic peptide (NTproBNP) and high sensitive cardiac troponin T (hs-cTNT). Echocardiography ruled out existing cardiac disease. Estimated glomerular filtration rate (eGFR) was calculated., Results: There were significant changes in NTproBNP between the measurements with the highest NTproBNP at 10-12 gw and the lowest value being at 20-25 gw, (with eGFR being the highest). Hs-cTNT was significantly higher at the peripartum measurement compared with the other measurements (p<0.05). Regardless, the 95th percentile for both biomarkers was below cut-off levels of 300 ng/L for NTproBNP and 14 ng/L for hs-cTNT. There was an association between NTproBNP above the upper limit of normal of 125 ng/L and eGFR (p=0.04) and between hs-cTNT >5.0 ng/L and time from delivery to blood sample (p=0.001) at the peripartum measurement. Both were associated with the use of oxytocin., Conclusion: Existing cut-off values for ruling out heart failure (NTproBNP <300 ng/L) and myocardial ischaemia (hs-cTNT <14 ng/L) are applicable during pregnancy and after delivery. Elevated levels mandate further attention on cardiac symptoms and renal function., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective To explore the therapeutic effects of trimetazidine (TMZ) on diabetic patients with coronary heart diseases.Methods We conducted a comprehensive electronic search of PubMed, EMBASE, and Cochrane databases between the inception dates of databases and May 2019 (last search conducted on 30 May 2019) to identify randomized controlled trials. The evaluation method recommended by Cochrane Collaboration for bias risk assessment was employed for quality assessment. Random or fixed models were used to investigate pooled mean differences in left ventricular function, serum glucose metabolism, serum lipid profile, myocardial ischemia episodes and exercise tolerance with effect size indicated by the 95% confidence interval ( CI ).Results Additional TMZ treatment contributed to considerable improvement of left ventricular ejection fraction ( WMD =4.39, 95% CI : 3.83, 4.95, P <0.00001), left ventricular end diastolic diameter ( WMD =-3.17, 95% CI : -4.90, -1.44, P =0.0003) and left ventricular end systolic diameter ( WMD =-4.69, 95% CI : -8.66, -0.72, P =0.02). TMZ administration also significantly decreased fasting blood glucose ( SMD =-0.43, 95% CI : -0.70, -0.17, P =0.001), glycosylated hemoglobin level ( WMD =-0.59, 95% CI : -0.95, -0.24, P =0.001), serum level of total cholesterol ( WMD =-20.36, 95% CI : -39.80, -0.92, P =0.04), low-density lipoprotein cholesterol ( WMD =-20.12, 95% CI : -32.95, -7.30, P =0.002) and incidence of myocardial ischemia episodes ( SMD =-0.84, 95% CI : -1.50, -0.18, P =0.01). However, there were no significant differences in serum triglyceride level, high-density lipoprotein cholesterol, exercise tolerance between the TMZ group and the control group. Conclusion TMZ treatment in diabetic patients with coronary heart disease is effective to improve cardiac function, serum glucose and lipid metabolism and clinical symptoms.

Imbalances of proatherogenic inflammatory and antiatherogenic inflammatory mediators were involved in the pathogenesis of atherosclerosis. This study sought to investigate the effects of proatherogenic inflammatory and antiatherogenic inflammatory mediators on the proximal, middle, and distal coronary artery reocclusions in elderly patients after coronary stent implantations. We measured the expression levels of proatherogenic inflammatory/antiatherogenic inflammatory cytokines. This included interleukin-1 β (IL-1 β ), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor- α (TNF- α ), high-sensitivity C-reactive protein (hs-CRP), interleukin-10 (IL-10), interleukin-17 (IL-17), interleukin-13 (IL-13), and interleukin-37 (IL-37) in the elderly patients with the proximal, middle, and distal coronary artery reocclusions after coronary stent implantations. Levels of IL-1 β , IL-6, IL-8, TNF- α , and hs-CRP were remarkably increased ( P < 0.001), and levels of IL-10, IL-17, IL-13, and IL-37 were remarkably lowered ( P < 0.001) in the elderly patients with the proximal, middle, and distal coronary artery reocclusions. Imbalances of proatherogenic inflammatory and antiatherogenic inflammatory mediators may be involved in the formation and progression of proximal, middle, and distal coronary artery reocclusions in elderly patients after coronary stent implantations., Competing Interests: The authors declare that they have no competing interests regarding the publication of this article., (Copyright © 2020 Xia Li et al.)

Background A vegetarian diet (VD) may reduce future cardiovascular risk in patients with ischemic heart disease. Methods and Results A randomized crossover study was conducted in subjects with ischemic heart disease, assigned to 4-week intervention periods of isocaloric VD and meat diet (MD) with individually designed diet plans, separated by a 4-week washout period. The primary outcome was difference in oxidized low-density lipoprotein cholesterol (LDL-C) between diets. Secondary outcomes were differences in cardiometabolic risk factors, quality of life, gut microbiota, fecal short-chain and branched-chain fatty acids, and plasma metabolome. Of 150 eligible patients, 31 (21%) agreed to participate, and 27 (87%) participants completed the study. Mean oxidized LDL-C (-2.73 U/L), total cholesterol (-5.03 mg/dL), LDL-C (-3.87 mg/dL), and body weight (-0.67 kg) were significantly lower with the VD than with the MD. Differences between VD and MD were observed in the relative abundance of several microbe genera within the families Ruminococcaceae, Lachnospiraceae, and Akkermansiaceae. Plasma metabolites, including l-carnitine, acylcarnitine metabolites, and phospholipids, differed in subjects consuming VD and MD. The effect on oxidized LDL-C in response to the VD was associated with a baseline gut microbiota composition dominated by several genera of Ruminococcaceae. Conclusions The VD in conjunction with optimal medical therapy reduced levels of oxidized LDL-C, improved cardiometabolic risk factors, and altered the relative abundance of gut microbes and plasma metabolites in patients with ischemic heart disease. Our results suggest that composition of the gut microbiota at baseline may be related to the reduction of oxidized LDL-C observed with the VD. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02942628.

Introduction: Elevated plasma levels of asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase, are associated with adverse outcome. There is no data available, whether ADMA levels are associated with arrhythmic death (AD) in patients with ischemic cardiomyopathy (ICM) or non-ischemic, dilated cardiomyopathy (DCM)., Methods and Results: A total of 110 ICM, 52 DCM and 30 control patients were included. Primary outcome parameter of this prospective study was arrhythmic death (AD) or resuscitated cardiac arrest (RCA). Plasma levels of ADMA were significantly higher in ICM (p < 0.001) and in DCM (p < 0.001) patients compared to controls. During a median follow-up of 7.0 years, 62 (32.3%) patients died. AD occurred in 26 patients and RCA was observed in 22 patients. Plasma levels of ADMA were not associated with a significantly increased risk of AD or RCA in ICM (hazard ratio (HR) = 1.37, p = 0.109) or in DCM (HR = 1.06, p = 0.848) patients. No significant association was found with overall mortality in ICM (HR = 1.39, p = 0.079) or DCM (HR = 1.10, p = 0.666) patients. Stratified Kaplan-Meier curves for ADMA levels in the upper tertile (>0.715 µmol/l) or the two lower tertiles (≤0.715 µmol/l) did not show a higher risk for AD or RCA (p = 0.221) or overall mortality (p = 0.548). In patients with left ventricular ejection fraction ≤ 35%, ADMA was not associated with AD or RCA (HR = 1.35, p = 0.084) or with overall mortality (HR = 1.24, p = 0.162)., Conclusions: Plasma levels of ADMA were elevated in patients with ICM or DCM as compared to controls, but were not significantly predictive for overall mortality or the risk for arrhythmic death., (Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Mortality from ischemic heart disease (IHD) is significantly lower in Japan than in Western countries. The purpose of this study was to investigate differences in circulating microRNA (miRNA) levels related to IHD in Austrians and Japanese. Participants were middle-aged healthy male Austrians (n = 20) and Japanese (n = 20). Total miRNAs in serum from each participant were analyzed using the 3D-Gene miRNA Oligo chip. Twenty-one miRNAs, previously reported as associated with IHD, were compared between Austrians and Japanese. The expression levels of miR-106a-5p, miR-135a-3p, miR-150-3p, miR-16-5p, miR-17-5p. miR-191-5p, miR-320b, miR-451a, miR-486-5p, miR-663b, and miR-92a-3p were significantly higher, while the miR-2861 expression level was significantly lower in Austrians as compared to Japanese. Both in Austrians and Japanese, there were significant positive correlations between serum expression levels of each pair of the above miRNAs except for miR-2861. The expression level of miR-2861 showed significant positive correlations with the expression levels of miR-106a-5p, miR-150-3p, miR-17-5p, miR-486-5p, miR-663b and miR-92a-3p in Austrians but not in Japanese. In pathway analysis, proinflammatory cytokine production in foam cells and collagen synthesis in vascular smooth muscle cells were associated with differentially expressed miRNAs. Difference in miRNA levels may contribute to lower cardiovascular risk in Japan than in Western countries.

Background: Thrombin, a key enzyme of the clotting system, is involved in thrombus formation, platelet activation, and atherosclerosis, thereby possessing a central role in the pathogenesis of ischemic heart disease. Studies have shown an association between thrombin generation (TG) and cardiovascular morbidity and mortality, but results have been equivocal. Our aim was to study the predictive ability of TG assay in evaluating coronary stenosis severity., Methods: In this prospective study we recruited patients with acute coronary syndrome (ACS) or acute chest pain (without evidence of myocardial injury) planned for coronary angiography. Thrombin generation was evaluated by Calibrated Automated Thrombogram (CAT) prior to angiography. Primary end points were significant coronary stenosis and the Syntax I score evaluated by coronary angiography., Results: From April 2018 through September 2019, we recruited 128 patients. In the primary analysis there was no significant association between TG and significant coronary stenosis nor between TG and syntax I score, however, there was a positive correlation between peak height and troponin peak (Spearman correlation coefficient 0.194, P-value = 0.035). In sub-group analysis, the chest pain group bare no association between TG and coronary stenosis. In unstable angina group there was an association between peak height and significant coronary stenosis (P-value = 0.029), and in non ST-elevation myocardial infarction group, TG values possessed a relatively good predictive ability of significant coronary stenosis (area under the receiver operating characteristic curve of ~65%) and a positive correlation between both lag time and ttpeak with the syntax I score was noticed (Spearman correlation coefficient 0.31, P-value = 0.099 and Spearman correlation coefficient 0.37, P-value = 0.045 respectively)., Conclusion: In patients with acute chest pain, TG values, evaluated by CAT, do not predict severity of coronary stenosis, nor do they possess prognostic value. Yet, in ACS patients, TG may have the ability to predict coronary disease severity., Competing Interests: The authors have declared that no competing interests exist.

Background: This study is aimed at investigating natriuretic peptide B ( NPPB ) coexpression genes and their pathways involved in heart failure (HF) among patients both with and without type 2 diabetes mellitus (T2DM)., Methods: The microarray dataset GSE26887, containing 19 postischemic HF patients' peripheral blood samples (7 with T2DM and 12 without T2DM), was examined to detect the genes coexpressed with NPPB using the corr.test function in the R packet. Furthermore, using online analytical tools, we determined the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, Gene Ontology (GO) annotation, and protein-protein interaction (PPI) network of the coexpression genes. The modules and hub genes of the PPI network were then identified using the Cytoscape software., Results: In patients with T2DM, a total of 41 biological processes (BP), 20 cellular components (CC), 13 molecular functions (MF), and 41 pathways were identified. Furthermore, a total of 61 BPs, 16 CCs, 13 MFs, and 22 pathways in patients without T2DM were identified. In both groups of patients, 17 BPs, 10 CCs, 6 MFs, and 13 pathways were enriched. We also identified 173 intersectional coexpression genes (63 positively, 106 negatively, and 4 differently coexpressed in patients with and without T2DM, respectively) in both types of patients, which were enriched in 16 BPs, 8 CCs, 3 MFs, and 8 KEGG pathways. Moreover, the PPI network (containing 237 edges and 170 nodes) with the top module significantly enriched in 4 BPs (tricarboxylic acid metabolic process, citrate metabolic process, tricarboxylic acid cycle, and aerobic respiration) and 3 pathways (citrate cycle, malaria parasite metabolic pathway, and AGE-RAGE signaling pathway in diabetic complications) was constructed. DECR1 , BGN , TIMP1 , VCAN , and CTCF are the top hub genes., Conclusions: Our findings may elucidate the functions and roles of the NPPB gene in patients with postischemic HF and facilitate HF management., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020 Yao-Zong Guan et al.)

Platelets aggregation leading to thrombosis plays a pivotal role in the pathophysiology of acute coronary syndrome (ACS) and of stent thrombosis. Antiplatelet therapy with aspirin plus an ADP-receptor inhibitor (ticagrerol, prasugrel or clopidogrel) is recommended to reduce the risk of other platelet-mediated events. Clopidogrel is recommended in patients with Chronic Coronary Syndromes (CCS) or in ACS patients at high bleeding risk. Unfortunately, up to 30% of patients are non-responders to clopidogrel and show residual high platelet reactivity (HPR). Colchicine (COLC) is a drug with cardiovascular effects. We have demonstrated that COLC might exert protective cardiovascular effects by interfering with cytoskeleton rearrangement, a phenomenon involved in platelet aggregation. Here, we investigate in vitro the effects of colchicine on platelet aggregation of patients on DAPT with clopidogrel. Platelets obtained from 35 CCS patients on therapy with clopidogrel were pre-incubated with COLC 10 µM before being stimulated with ADP (20 µM), or TRAP (25 µM) at 0, 30, 60 and 90 min to measure max aggregation by LTA. Platelets not COLC-preincubated served as controls. Seven patients were pre-selected as clopidogrel non-responders. COLC significantly reduced TRAP-induced platelet aggregation in clopidogrel responders and non-responders. Interestingly, COLC inhibited ADP-induced platelet aggregation in clopidogrel non-responders in which ADP still caused activation despite DAPT. We demonstrate that COLC inhibits platelet aggregation in clopidogrel non-responders with HPR despite DAPT with this ADP receptor-inhibitor. Further in vivo studies should be designed to evaluate the opportunity to prescribe colchicine after ACS/CCS to overcome the clopidogrel limitations in the DAPT therapy.

Objective: Underlying Coronary Artery Disease (CAD) complicated by Mental Stress-Induced Myocardial Ischemia (MSIMI) has been linked with an increased risk for adverse cardiovascular events and even sudden death. However, the underlying mechanisms of MSIMI remain unknown. In this study, we investigated cytokine levels at baseline inflammation status and during acute inflammatory responses to mental stress in patients with known CAD who presented with MSIMI., Method: 77 patients with known CAD were recruited and all underwent echocardiography before and during arithmetic stress task. MSIMI was diagnosed by new or worsening wall motion abnormalities greater than or equal to a 5% reduction of left ventricle ejection fraction. Inflammatory markers were measured both before and immediately after the Mental Stress (MS) by ELISA kits. Repeated measures models were used to report the responses and mixed linear regression models were used to report the differences between MSIMI negative and positive patients., Result: MS induced a significant increase in Stromal Cell-Derived Factor-1α (SDF-1α) and Monocyte Chemoattractant Protein-1 (MCP-1) in all subjects; 20.78% of the patients with known CAD developed MSIMI during the arithmetic task. MSIMI positive patients had significantly lower baseline levels of Interleukin-1β (IL-1β) and Tumor Necrosis Factor-α (TNF-α), but a higher response in levels of SDF-1α than MSIMI negative patients., Conclusion: MS can induce acute inflammatory responses. MSIMI is associated with lower levels of IL-1β and TNF-α at baseline and higher levels of SDF-1α in response to MS.

Context: Glucagon acts reciprocally with insulin to regular blood glucose. However, the effect of glucagon on cardiovascular disease has not been widely studied. It has been suggested that insulin may increase the risk of ischemic heart disease., Objective: To investigate whether glucagon, the main counteracting hormone of insulin, plays a role in development of ischemic heart disease., Design, Setting, and Participants: In this 2-sample Mendelian randomization study, we estimated the causal effect of glucagon on ischemic heart disease and its risk factors using the inverse-variance weighted method with multiplicative random effects and multiple sensitivity analyses. Genetic associations with glucagon and ischemic heart disease and its risk factors, including type 2 diabetes and fasting insulin, were obtained from publicly available genome-wide association studies., Main Outcome Measure: Odds ratio for ischemic heart disease and its risk factors per 1 standard deviation change in genetically predicted glucagon., Results: Twenty-four single-nucleotide polymorphisms strongly (P < 5 × 10-6) and independently (r2 < 0.05) predicting glucagon were obtained. Genetically predicted higher glucagon was associated with an increased risk of ischemic heart disease (inverse-variance weighted odds ratio, 1.03; 95% confidence interval, 1.0003-1.05) but not with type 2 diabetes (inverse-variance weighted odds ratio, 0.998, 95% confidence interval, 0.97-1.03), log-transformed fasting insulin (inverse-variance weighted beta, 0.002, 95% confidence interval, -0.01 to 0.01), other glycemic traits, blood pressure, reticulocyte, or lipids., Conclusion: Glucagon might have an adverse impact on ischemic heart disease. Relevance of the underlying pathway to existing and potential interventions should be investigated., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study was designed to investigate the effects of leukocyte Rho kinase activity and serum Cystatin C (Cys C) on cardiovascular events in patients with acute coronary syndrome (ACS)., Methods: A total of 48 patients with ST-segment elevation myocardial infarction (STEMI), 23 patients with non-ST-segment elevation myocardial infarction (NSTEMI), 25 patients with unstable angina (UA) and 20 patients with no-acute coronary syndrome as control from January 2017 to June 2018 in Tianyou Hospital affiliated to Wuhan University of Science and Technology were selected in this study. Western blot was used to detect the leukocyte Rho kinase activity and Elisa kit was used to measure serum Cys C. Univariate and multivariate analysis were used to analyze the influencing factors of cardiovascular events in ACS patients., Results: The activity of leukocyte Rho kinase and serum Cys C were gradually reduced in the STEMI, NSTEMI and UA patients, but all significantly higher than that in No-ASC patients, and there was a positive correlation between leukocyte Rho kinase activity and serum Cys C in ACS patients (r = 0.516, P < .001). The activity of leukocyte Rho kinase was positively correlated with the levels of serum TNF-α (r = 0.634, P < .001), IL-6 (r = 0.578, P < .001), IL-8 (r = 0.582, P < .001) in ACS patients, and the level of Cys C was positively correlated with the levels of serum TNF-α (r = 0.634, P < .001), IL-6 (r = 0.578, P < .001), IL-8 (r = 0.582, P < .001) in ACS patients. Univariate and multivariate analysis showed that the leukocyte Rho kinase activity (HR = 2.994, 95%CI = 1.328-6.054, P < .0001) and the levels of serum Cys C (HR = 1.692, 95%CI = 1.028-2.124, P < .0001) were independent influencing factors of cardiovascular events in ACS patients., Conclusion: The leukocyte Rho kinase activity and serum Cystatin C are high in acute coronary syndrome patients, and are the independent influencing factors of cardiovascular events in ACS patients.

Myocardial injury after noncardiac surgery (MINS) differs from myocardial infarction in being defined by troponin elevation apparently from cardiac ischemia with or without signs and symptoms. Such myocardial injury is common, silent, and strongly associated with mortality. MINS is usually asymptomatic and only detected by routine troponin monitoring. There is currently no known safe and effective prophylaxis for perioperative myocardial injury. However, appropriate preoperative screening may help guide proactive postoperative preventative actions. Intraoperative hypotension is associated with myocardial injury, acute kidney injury, and death. Hypotension is common and largely undetected in the postoperative general care floor setting, and independently associated with myocardial injury and mortality. Critical care patients are especially sensitive to hypotension, and the risk appears to be present at blood pressures previously regarded as normal. Tachycardia appears to be less important. Available information suggests that clinicians would be prudent to avoid perioperative hypotension.

Clusterin exerts anti-inflammatory, cytoprotective and anti-apoptotic effects. Both an increase and decrease of clusterin in acute myocardial infarction (AMI) has been reported. We aimed to clarify the role of clusterin as a systemic biomarker in AMI. AMI was induced by percutaneous left anterior artery (LAD) occlusion for 90 min followed by reperfusion in 24 pigs. Contrast ventriculography was performed after reperfusion to assess left ventricular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV) and left ventricular end systolic volume (LVESV) and additional cMRI + late enhancement to measure infarct size and LV functions at day 3 and week 6 post-MI. Blood samples were collected at prespecified timepoints. Plasma clusterin and other biomarkers (cTnT, NT-proBNP, neprilysin, NGAL, ET-1, osteopontin, miR21, miR29) were measured by ELISA and qPCR. Gene expression profiles of infarcted and remote region 3 h ( n = 5) and 3 days ( n = 5) after AMI onset were analysed by RNA-sequencing. AMI led to an increase in LVEDV and LVESV during 6-week, with concomitant elevation of NT-proBNP 3-weeks after AMI. Plasma clusterin levels were increased immediately after AMI and returned to normal levels until 3-weeks. Plasma NGAL, ET-1 and miR29 was significantly elevated at 3 weeks follow-up, miR21 increased after reperfusion and at 3 weeks post-AMI, while circulating neprilysin levels did not change. Elevated plasma clusterin levels 120 min after AMI onset suggest that clusterin might be an additional early biomarker of myocardial ischemia., Competing Interests: The authors declare no conflict of interest.

Background: Ischemic heart disease is common in COPD and associated with worse prognosis. This study aimed to investigate the presence and prognostic impact of biomarkers of myocardial injury and ischemia among individuals with COPD and normal lung function, respectively., Methods: In 2002-04, all individuals with airway obstruction (FEV 1 /VC < 0.70, n = 993) were identified from population-based cohorts, together with age and sex-matched non-obstructive referents. At re-examination in 2005, spirometry, Minnesota-coded ECG and analyses of high-sensitivity cardiac troponin I (hs-cTnI) were performed in individuals with COPD (n = 601) and those with normal lung function (n = 755). Deaths were recorded until December 31st, 2010., Results: Hs-cTnI concentrations were above the risk stratification threshold of ≥5 ng/L in 31.1 and 24.9% of those with COPD and normal lung function, respectively. Ischemic ECG abnormalities were present in 14.8 and 13.4%, while 7.7 and 6.6% had both elevated hs-cTnI concentrations and ischemic ECG abnormalities. The 5-year cumulative mortality was higher in those with COPD than those with normal lung function (13.6% vs. 7.7%, p < 0.001). Among individuals with COPD, elevated hs-cTnI both independently and in combination with ischemic ECG abnormalities were associated with an increased risk for death (adjusted hazard ratio [HR]; 95% confidence interval [CI] 2.72; 1.46-5.07 and 4.54; 2.25-9.13, respectively). Similar associations were observed also among individuals with COPD without reported ischemic heart disease., Conclusions: In this study, elevated hs-cTnI concentrations in combination with myocardial ischemia on the electrocardiogram were associated with a more than four-fold increased risk for death in a population-based COPD-cohort, independent of disease severity.

Purpose of Review: For over 20 years, the Women's Ischemia Syndrome Evaluation (WISE), a program sponsored by the National Heart, Lung, and Blood Institute, has explored diverse and important aspects of ischemic heart disease in women., Recent Findings: Women with symptoms and signs of ischemia but no significant epicardial obstructive coronary artery disease (INOCA) were documented to be at elevated risk for recurrent angina hospitalization, major adverse cardiac events, death, and health resource consumption rivaling those with obstructive coronary disease. WISE investigators have advanced our understanding of cardiovascular outcomes, systemic manifestations, psychological variables, socioeconomic factors, genetic contributions, hormonal status, advanced imaging, coronary functional findings, biomarkers, patient-reported outcomes, and treatments pertaining to women with this disease entity. This review delves into the WISE findings subsequent to a prior review1, postulates directions for future research, and asks are we "Even 'WISE-R?'".

Background FGF21 (fibroblast growth factor 21), a novel hepatokine regulating lipid metabolism, has been linked to atherosclerotic disease. However, whether this relationship exists in patients without nonalcoholic fatty liver disease is unclear. We assessed the association between serum FGF21 levels and atherosclerosis in patients without nonalcoholic fatty liver disease, and investigated whether baseline FGF21 could predict incident atherosclerotic cardiovascular disease in a 7-year prospective cohort. Methods and Results Baseline serum FGF21 was measured in a cross-sectional cohort of 371 patients with type 2 diabetes mellitus without nonalcoholic fatty liver disease (determined by hepatic magnetic resonance spectroscopy), and in a population-based prospective cohort of 705 patients from the Shanghai Diabetes Study. In the cross-sectional study, FGF21 was significantly higher in patients with than in those without subclinical carotid atherosclerosis ( P <0.01). The association remained significant after adjusting for demographic and traditional cardiovascular risk factors. In the prospective cohort, 80 patients developed atherosclerotic cardiovascular disease during follow-up. Baseline FGF21 was significantly higher in those who developed ischemic heart disease or cerebral infarction than in those who did not. Using a cutoff serum concentration of 232.0 pg/mL, elevated baseline FGF21 independently predicted incident total atherosclerotic cardiovascular disease events, ischemic heart disease, and cerebral infarction in a nondiabetic population (all P <0.05), and significantly improved the discriminatory and reclassifying abilities of our prediction model after adjustment for established cardiovascular risk factors. Conclusions This study provides the first evidence that FGF21 levels are elevated in patients without nonalcoholic fatty liver disease with subclinical atherosclerosis. Baseline FGF21 is an independent predictor of atherosclerotic cardiovascular disease and represents a novel biomarker for primary prevention in the general population.

Background Patients with ischemic cardiomyopathy (ICM) have worse outcomes than those with coronary artery disease alone and those with non-ICM. N8-acetylspermidine (N8AS) is a polyamine that regulates ischemic cardiac apoptosis and resultant cardiac dysfunction. We hypothesized that N8AS is a mechanistic biomarker of adverse outcomes in patients with ICM. Methods and Results High-resolution plasma metabolomics profiling and mass spectrometry were used to quantitate N8AS levels in a discovery cohort of 474 patients with coronary artery disease (age: 68±11 years, 12% black, 26% women): 154 with ICM, and 320 without ICM; and in an external validation cohort of 85 patients with ICM (age: 60±12 years, 37% black, 19% women). Patients without heart failure (HF) at baseline were followed for incident HF. The association between N8AS (log 2 -transformed, standardized) and outcomes of all-cause mortality and incident HF were examined using Cox regression. N8AS was higher (10.39 [interquartile range, 7.21-17.75] versus 8.29 nmol/L [interquartile range, 5.91-11.42]; P <0.001) in patients with ICM compared with patients who had coronary artery disease without ICM. Higher N8AS levels were associated with higher mortality in patients with ICM (hazard ratio [HR], 1.48; 95% CI, 1.19-1.85 per SD increase [ P =0.001]), independent of B-type natriuretic peptide, high-sensitivity troponin I, and high-sensitivity C-reactive protein. Findings were validated in the independent cohort. Moreover, higher N8AS level was associated with incident HF in patients without HF at baseline (HR, 4.16; 95% CI, 1.41-12.25 per SD increase [ P =0.01]). Conclusions Independent of traditional HF measures, higher N8AS levels are associated with higher mortality in patients with ICM and incident HF in those who have coronary artery disease without HF. N8AS is a novel mechanistic biomarker in ICM.

Purpose: The Fourth Universal Definition of Myocardial Infarction (MI) has highlighted the different pathophysiological mechanisms that may lead to ischaemic and non-ischaemic myocardial injury and has emphasised that the diagnosis of myocardial infarction requires the presence of acute myocardial ischaemia in the setting of acute myocardial injury. This case based review intends to illustrate basic principles on how to apply this new, revised definition in clinical practice. Methods and Results: The distinction between different types of MIs (type 1 or type 2) and the delineation of MI from acute non-ischaemic myocardial injury may be challenging in individual patients, which is illustrated by presenting and discussing real-life routine cases. Conclusions: Type 1 MI is a consequence of coronary plaque rupture or erosion with intracoronary thrombus formation that is usually apparent on coronary angiography. Plausible triggering mechanisms causing myocardial oxygen supply/demand mismatch must be identified for the diagnosis of type 2 MI and its treatment should focus initially on management of the underlying disease attributable to acute myocardial ischaemia.

High blood cholesterol is typically considered a feature of wealthy western countries 1,2 . However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world 3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health 4,5 . However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular risk-changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.