Effect of Metformin Treatment on Lipoprotein Subfractions in Non-Diabetic Patients with Acute Myocardial Infarction: A Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) Trial.
ABSTRACT: OBJECTIVE:Metformin affects low density lipoprotein (LDL) and high density (HDL) subfractions in the context of impaired glucose tolerance, but its effects in the setting of acute myocardial infarction (MI) are unknown. We determined whether metformin administration affects lipoprotein subfractions 4 months after ST-segment elevation MI (STEMI). Second, we assessed associations of lipoprotein subfractions with left ventricular ejection fraction (LVEF) and infarct size 4 months after STEMI. METHODS:371 participants without known diabetes participating in the GIPS-III trial, a placebo controlled, double-blind randomized trial studying the effect of metformin (500 mg bid) during 4 months after primary percutaneous coronary intervention for STEMI were included of whom 317 completed follow-up (clinicaltrial.gov Identifier: NCT01217307). Lipoprotein subfractions were measured using nuclear magnetic resonance spectroscopy at presentation, 24 hours and 4 months after STEMI. (Apo)lipoprotein measures were obtained during acute STEMI and 4 months post-STEMI. LVEF and infarct size were measured by cardiac magnetic resonance imaging. RESULTS:Metformin treatment slightly decreased LDL cholesterol levels (adjusted P = 0.01), whereas apoB remained unchanged. Large LDL particles and LDL size were also decreased after metformin treatment (adjusted P<0.001). After adjustment for covariates, increased small HDL particles at 24 hours after STEMI predicted higher LVEF (P = 0.005). In addition, increased medium-sized VLDL particles at the same time point predicted a smaller infarct size (P<0.001). CONCLUSION:LDL cholesterol and large LDL particles were decreased during 4 months treatment with metformin started early after MI. Higher small HDL and medium VLDL particle concentrations are associated with favorable LVEF and infarct size.
Project description:Plasma concentrations of many cardiovascular and inflammatory proteins are altered after ST-elevation myocardial infarction (STEMI) and may provide prognostic information. We conducted a large-scale proteomic analysis in patients with STEMI, correlating protein levels to infarct size and left ventricular ejection fraction (LVEF) determined with cardiac magnetic resonance imaging. We analysed 131 cardiovascular and inflammatory proteins using a multiplex proximity extension assay and blood samples obtained at baseline, 6, 24, and 96 h from the randomised clinical trial CHILL-MI. Cardiac magnetic resonance imaging data at 4?±?2 days and 6 months were available as per trial protocol. Using a linear regression model with bootstrap resampling and false discovery rate adjustment we identified five proteins (ST2, interleukin-6, pentraxin-3, interleukin-10, renin, and myoglobin) with elevated values corresponding to larger infarct size or worse LVEF and four proteins (TNF-related apoptosis-inducing ligand, TNF-related activation induced cytokine, interleukin-16, and cystatin B) with values inversely related to LVEF and infarct size, concluding that among 131 circulating inflammatory and cardiovascular proteins in the acute and sub-acute phase of STEMI, nine showed a relationship with infarct size and LVEF post-STEMI, with IL-6 and ST2 exhibiting the strongest association.
Project description:BACKGROUND: Although echocardiography is used as a first line imaging modality, its accuracy to detect acute and chronic myocardial infarction (MI) in relation to infarct characteristics as assessed with late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) is not well described. METHODS: One-hundred-forty-one echocardiograms performed in 88 first acute ST-elevation MI (STEMI) patients, 2 (IQR1-4) days (n = 61) and 102 (IQR92-112) days post-MI (n = 80), were pooled with echocardiograms of 36 healthy controls. 61 acute and 80 chronic echocardiograms were available for analysis (53 patients had both acute and chronic echocardiograms). Two experienced echocardiographers, blinded to clinical and CMR data, randomly evaluated all 177 echocardiograms for segmental wall motion abnormalities (SWMA). This was compared with LGE-CMR determined infarct characteristics, performed 104 ± 11 days post-MI. Enhancement on LGE-CMR matched the infarct-related artery territory in all patients (LAD 31%, LCx 12% and RCA 57%). RESULTS: The sensitivity of echocardiography to detect acute MI was 78.7% and 61.3% for chronic MI; specificity was 80.6%. Undetected MI were smaller, less transmural, and less extensive (6% [IQR3-12] vs. 15% [IQR9-24], 50 ± 14% vs. 61 ± 15%, 7 ± 3 vs. 9 ± 3 segments, p < 0.001 for all) and associated with higher left ventricular ejection fraction (LVEF) and non-anterior location as compared to detected MI (58 ± 5% vs. 46 ± 7%, p < 0.001 and 82% vs. 63%, p = 0.03). After multivariate analysis, LVEF and infarct size were the strongest independent predictors of detecting chronic MI (OR 0.78 [95%CI 0.68-0.88], p < 0.001 and OR 1.22 [95%CI0.99-1.51], p = 0.06, respectively). Increasing infarct transmurality was associated with increasing SWMA (p < 0.001). CONCLUSIONS: In patients presenting with STEMI, and thus a high likelihood of SWMA, the sensitivity of echocardiography to detect SWMA was higher in the acute than the chronic phase. Undetected MI were smaller, less extensive and less transmural, and associated with non-anterior localization and higher LVEF. Further work is needed to assess the diagnostic accuracy in patients with non-STEMI.
Project description:INTRODUCTION:Hypercholesterolemia is a well-known risk factor for developing atherosclerosis and subsequently for the risk of a myocardial infarction (MI). Moreover, it might also be related to the extent of damaged myocardium in the event of a MI. The aim of this study was to evaluate the association of baseline low density lipoprotein-cholesterol (LDL-c) level with infarct size in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneously coronary intervention (pPCI). METHODS:Baseline blood samples were obtained from all patients admitted between 2004 and 2014 with STEMI who underwent pPCI. Patients were excluded in case of out of hospital cardiac arrest, treatment delay of at least 10 h or no complete reperfusion after pPCI in the culprit vessel. Peak creatine kinase (CK) level was used for infarct size estimation, defined as the maximal value during admission. RESULTS:A total of 2248 patients were included in this study (mean age 61.8?±?12.2 years; 25.0% female). Mean LDL-c level was 3.6?±?1.1 mmol/L and median peak CK level was 1275 U/L (IQR 564-2590 U/L). Baseline LDL-c level [??=?0.041; (95% CI 0.019-0.062); p?<?0.001] was independently associated with peak CK level. Furthermore, left anterior descending artery as culprit vessel, initial TIMI 0-1 flow in the culprit vessel, male gender, and treatment delay were also correlated with high peak CK level (p?<?0.05). Prior aspirin therapy was associated with lower peak CK level [??=?-?0.073 (95% CI -?0.146 to 0.000), p?=?0.050]. CONCLUSION:This study demonstrates that besides the more established predictors of infarct size, elevated LDL-c is associated with augmented infarct size in patients with STEMI treated with pPCI.
Project description:BACKGROUND:Mineralocorticoid receptor antagonist (MRA) therapy has been shown to prevent adverse left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) patients with heart failure. Whether initiating MRA therapy prior to primary percutaneous coronary intervention (PPCI) accrues additional benefit of reducing myocardial infarct size and preventing adverse LV remodeling is not known. We aimed to investigate whether MRA therapy initiated prior to reperfusion reduces myocardial infarct (MI) size and prevents adverse LV remodeling in STEMI patients. METHODS:STEMI patients presenting within 12 hours and with a proximal coronary artery occlusion with Thrombolysis In Myocardial Infarction flow grade 0 were consented and randomized to either an intravenous bolus of potassium canrenoate, followed by oral spironolactone for 3 months or matching placebo. The primary endpoint was MI size by cardiovascular magnetic resonance at 3 months. RESULTS:Sixty-seven patients completed the study. There was no significant difference in the final MI size at 3 months between the 2 groups (placebo: 17 ± 11%, MRA: 16 ± 10%, P = .574). There was also no difference in acute MI size (26 ± 16% versus 23 ± 14%, P = .425) or myocardial salvage (26 ± 12% versus 24 ± 8%, P = .456). At follow-up, there was a trend towards an improvement in LVEF (placebo: 49 ± 8%, MRA: 54 ± 11%, P = .053), and the MRA group had significantly greater percentage decrease in LVEDV (mean difference: -12.2 (95% CI -20.3 to -4.4)%, P = .003) and LVESV (mean difference: -18.2 (95% CI -30.1 to -6.3)%, P = .003). CONCLUSION:This pilot study showed no benefit of MRA therapy in reducing MI size in STEMI patients when initiated prior to reperfusion, but there was an improvement in LV remodeling at 3 months. Adequately powered studies are warranted to confirm these findings.
Project description:Although intensive lifestyle change (ILS) and metformin reduce diabetes incidence in subjects with impaired glucose tolerance (IGT), their effects on lipoprotein subfractions have not been studied.The objective of the study was to characterize the effects of ILS and metformin vs placebo interventions on lipoprotein subfractions in the Diabetes Prevention Program.This was a randomized clinical trial, testing the effects of ILS, metformin, and placebo on diabetes development in subjects with IGT.Selected individuals with IGT randomized in the Diabetes Prevention Program participated in the study.Interventions included randomization to metformin 850 mg or placebo twice daily or ILS aimed at a 7% weight loss using a low-fat diet with increased physical activity.Lipoprotein subfraction size, density, and concentration measured by magnetic resonance and density gradient ultracentrifugation at baseline and 1 year were measured.ILS decreased large and buoyant very low-density lipoprotein, small and dense low-density lipoprotein (LDL), and small high-density lipoprotein (HDL) and raised large HDL. Metformin modestly reduced small and dense LDL and raised small and large HDL. Change in insulin resistance largely accounted for the intervention-associated decreases in large very low-density lipoprotein, whereas changes in body mass index (BMI) and adiponectin were strongly associated with changes in LDL. Baseline and a change in adiponectin were related to change in large HDL, and BMI change associated with small HDL change. The effect of metformin to increase small HDL was independent of adiponectin, BMI, and insulin resistance.ILS and metformin treatment have favorable effects on lipoprotein subfractions that are primarily mediated by intervention-related changes in insulin resistance, BMI, and adiponectin. Interventions that slow the development of diabetes may also retard the progression of atherosclerosis.
Project description:Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo.In 11?186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) participants, we tested whether lipids, apolipoproteins, and ion mobility-measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522). In placebo-allocated participants, baseline LDL-C was not associated with CVD (adjusted hazard ratio [HR] per SD, 1.03; 95% confidence interval [CI], 0.88-1.21). In contrast, associations with CVD events were observed for baseline non-high-density lipoprotein (HDL) cholesterol (HR, 1.18; 95% CI, 1.01-1.38), apolipoprotein B (HR, 1.28; 95% CI, 1.11-1.48), and ion mobility-measured non-HDL particles (HR, 1.19; 95% CI, 1.05-1.35) and LDL particles (HR, 1.21; 95% CI, 1.07-1.37). Association with CVD events was also observed for several LDL and very-low-density lipoprotein subfractions but not for ion mobility-measured HDL subfractions. In statin-allocated participants, CVD events were associated with on-treatment LDL-C, non-HDL cholesterol, and apolipoprotein B; these were also associated with CVD/all-cause death, as were several LDL and very-low-density lipoprotein subfractions, albeit with a pattern of association that differed from the baseline risk.In JUPITER, baseline LDL-C was not associated with CVD events, in contrast with significant associations for non-HDL cholesterol and atherogenic particles: apolipoprotein B and ion mobility-measured non-HDL particles, LDL particles, and select subfractions of very-low-density lipoprotein particles and LDL particles. During high-intensity statin therapy, on-treatment levels of LDL-C and atherogenic particles were associated with residual risk of CVD/all-cause death.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.
Project description:BACKGROUND:Left ventricular ejection fraction (LVEF) is a major determinant of long-term prognosis after ST-segment elevation myocardial infarction (STEMI). STEMI patients with reduced LVEF have a poor prognosis, despite successful reperfusion and the use of renin-angiotensin-aldosterone inhibitors. HYPOTHESIS:Intracoronary infusion of bone marrow-derived mononuclear cells (BMMC) may improve LVEF in STEMI patients successfully reperfused. METHODS:The main inclusion criteria for this double-blind, randomized, multicenter study were patient age 30 to 80?years, LVEF ?50%, successful angioplasty of infarct-related artery, and regional dysfunction in the infarct-related area analyzed before cell injection. Cardiac magnetic resonance imaging was used to assess LVEF, left ventricular volumes, and infarct size at 7 to 9?days and 6?months post-myocardial infarction. RESULTS:One hundred and twenty-one patients were included (66 patients in the BMMC group and 55 patients in the placebo group). The primary endpoint, mean LVEF, was similar between both groups at baseline (44.63%?±?10.74% vs 42.23%?±?10.33%; P?=?0.21) and at 6?months (44.74%?±?12.95 % vs 43.50?±?12.43%; P?=?0.59). The groups were also similar regarding the difference between baseline and 6?months (0.11%?±?8.5% vs 1.27%?±?8.93%; P?=?0.46). Other parameters of left ventricular remodeling, such as systolic and diastolic volumes, as well as infarct size, were also similar between groups. CONCLUSIONS:In this randomized, multicenter, double-blind trial, BMMC intracoronary infusion did not improve left ventricular remodeling or decrease infarct size.
Project description:BACKGROUND:Left ventricular systolic dysfunction (LVSD) occurs frequently after acute ST-segment elevation myocardial infarction (STEMI). The predisposing factors and underlying mechanism of post-infarct LVSD are not fully understood. The present study mainly investigated the correlation between glycaemic gap, a novel index of stress-induced hyperglycaemia (SIH), and post-infarct LVSD. METHODS:A total of 274 first STEMI patients were enrolled in this cross-sectional study. Transthoracic echocardiography was performed within 48 h after admission and at 6 months after discharge to obtain left ventricular ejection fraction (LVEF). The change in LVEF was calculated as LVEF at 6 months after discharge minus baseline LVEF. Additionally, post-infarct LVSD was defined as LVEF ? 50%. Most importantly, glycaemic gap was calculated as admission blood glucose (ABG) minus the estimated average glucose over the previous 3 months. RESULTS:In patients without diabetes mellitus (DM), multivariate linear regression analysis revealed that both glycaemic gap (Beta?=?- 1.214, 95% CI - 1.886 to - 0.541, p?<?0.001) and ABG (Beta?=?- 1.124, 95% CI - 1.795 to - 0.453, p?=?0.001) were associated with change in LVEF. In DM patients, only glycaemic gap was still associated with change in LVEF, although this association was not observed in univariate linear regression analysis. Regarding the association between SIH and post-infarct LVSD, multivariate logistic regression analysis revealed that both glycaemic gap (OR?=?1.490, 95% CI 1.043 to 2.129, p?=?0.028) and ABG (OR?=?1.600, 95% CI 1.148 to 2.229, p?=?0.005) were associated with an increased risk of having post-infarct LVSD in non-DM patients. However, after multivariate adjustment in DM patients, only glycaemic gap (OR?=?1.399, 95% CI 1.021 to 1.919, p?=?0.037) remained associated with an increased risk of having post-infarct LVSD. Furthermore, the predictive value of glycaemic gap for post-infarct LVSD was not inferior to ABG in non-DM patients (p?=?0.499), and only glycaemic gap, instead of ABG, could significantly predict post-infarct LVSD in DM patients (AUC?=?0.688, 95% CI 0.591 to 0.774, p?=?0.002). CONCLUSIONS:Glycaemic gap was strongly associated with a change in LVEF and an increased risk of having post-infarct LVSD in patients following STEMI. In STEMI patients with DM, glycaemic gap could provide more valuable information than ABG in identifying patients at high risk of developing post-infarct LVSD.
Project description:<h4>Aims</h4>Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma low-density lipoprotein cholesterol. Beyond lipid control, recent findings suggest a deleterious effect of this protein in the pathogenesis of postmyocardial infarction left ventricle remodelling and heart failure-related complications. The aim of this study was to assess the relationship between circulating PCSK9 and 6 month cardiac magnetic resonance imaging-derived left ventricular ejection fraction (LVEF) after a first ST-segment elevation myocardial infarction (STEMI).<h4>Methods and results</h4>We prospectively evaluated 40 patients with a first STEMI, LVEF < 50% and treated with primary percutaneous coronary intervention in which PCSK9 was measured 24 h postreperfusion. All patients underwent cardiac magnetic resonance imaging 1 week and 6 months after STEMI. Baseline characteristics were compared across median values of PCSK9. The association between PCSK9 levels and LVEF at 6 months was evaluated by analysis of covariance. The mean age of the sample was 60 ± 12 years and 33 (82.5%) were male patients. The infarct location was anterior in 27 patients (67.5%), and 9 patients (22.5%) were Killip class ? II. The mean 1 week and 6 month LVEF were 41 ± 7% and 48 ± 10%, respectively. The mean PCSK9 was 1.93 ± 0.38 U/mL. Testing the association between serum PCSK9 and 6 month LVEF with analysis of covariance revealed an inverse relationship (r = -0.35, P = 0.028). After multivariate adjustment, circulating PCSK9 remained significant and inversely associated with 6 month LVEF (P = 0.002).<h4>Conclusions</h4>In patients with a first STEMI with reduced ejection fraction at index admission and treated with primary percutaneous coronary intervention, circulating PCSK9 was associated with lower LVEF at 6 months.
Project description:BACKGROUND:Complex multimarker approaches to predict outcome after ST-elevation myocardial infarction (STEMI) have only considered a single baseline sample, while neglecting easily obtainable peak creatine kinase and creatine kinase-MB (CK-MB) values during hospitalization. METHODS:We studied 476 patients undergoing primary percutaneous coronary intervention for STEMI and cardiac magnetic resonance imaging (CMRI) at 4-6 months after STEMI. We determined the association with cardiac biomarkers (peak CK-MB, peak troponin T, N-terminal pro-brain natriuretic peptide), clinical and angiographic characteristics with infarct size, and LVEF, followed by association with mortality in 1120 STEMI patients. RESULTS:Peak CK-MB was the strongest predictor for infarct size (P<0.001, R 2 =0.60) and LVEF (P<0.001, R 2 =0.40). The additional value of clinical and angiographic characteristics was limited. The optimal peak CK-MB cutpoints, for differentiation among small (<10% of the left ventricle), moderate (≥10%-<30%), and large infarct size (≥30%), were 210 U/L and 380 U/L, respectively. These cutpoints were associated with 90-day mortality; the hazard ratio for moderate infarct was 2.99 (95% confidence interval [CI]: 1.51-5.93, P=0.002) and for large infarct 6.53 (95% CI: 3.63-11.76, P<0.001). CONCLUSIONS:Classical peak CK-MB measured during hospitalization for STEMI was superior to other clinical and angiographic characteristics in predicting CMRI-defined infarct size and LVEF, and should be included and validated in future multimarker studies. Peak CK-MB cutpoints differentiated among infarct size categories and were associated with increased 90-day mortality risk.