Erik Lipsic

Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study

AimsBiomarkers are increasingly being used in the management of patients with chronic heart failure (HF). Galectin-3 is a recently developed biomarker associated with fibrosis and inflammation, and it may play a role in cardiac remodeling in HF. We determined its prognostic value in patients with chronic HF.Methods and resultsPatients with chronic HF (New York Heart Association functional class III or IV) who participated in the Deventer–Alkmaar heart failure study were studied. Galectin-3 levels were determined at baseline using a novel optimized enzyme-linked immunosorbent assay. Univariate and multivariate analyses were used to determine the prognostic value of this biomarker. We studied 232 patients; their mean age was 71xa0±xa010xa0years, 72% were male, and 96% were in NYHA class III. During a follow-up period of 6.5xa0years, 98 patients died. Galectin-3 was a significant predictor of mortality risk after adjustment for age and sex, and severity of HF and renal dysfunction, as assessed by NT-proBNP and estimated glomerular filtration rate, respectively (hazard ratio per standard deviation 1.24, 95% CI 1.03–1.50, Pxa0=xa00.026).ConclusionPlasma galectin-3 is a novel prognostic marker in patients with chronic HF. Its prognostic value is independent of severity of HF, as assessed by NT-proBNP levels, and it may potentially be used in the management of such patients.

Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial

IMPORTANCEnMetformin treatment is associated with improved outcome after myocardial infarction in patients with diabetes. In animal experimental studies metformin preserves left ventricular function.nnnOBJECTIVEnTo evaluate the effect of metformin treatment on preservation of left ventricular function in patients without diabetes presenting with ST-segment elevation myocardial infarction (STEMI).nnnDESIGN, SETTING, AND PARTICIPANTSnDouble-blind, placebo-controlled study conducted among 380 patients who underwent primary percutaneous coronary intervention (PCI) for STEMI at the University Medical Center Groningen, The Netherlands, between January 1, 2011, and May 26, 2013.nnnINTERVENTIONSnMetformin hydrochloride (500 mg) (nu2009=u2009191) or placebo (nu2009=u2009189) twice daily for 4 months.nnnMAIN OUTCOMES AND MEASURESnThe primary efficacy measure was left ventricular ejection fraction (LVEF) after 4 months, assessed by magnetic resonance imaging. A secondary efficacy measure was the N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration after 4 months. The incidence of major adverse cardiac events (MACE; the combined end point of death, reinfarction, or target-lesion revascularization) was recorded until 4 months as a secondary efficacy measure.nnnRESULTSnAt 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% (95% CI, 51.6%-54.6%) in the metformin group (nu2009=u2009135), compared with 54.8% (95% CI, 53.5%-56.1%) (Pu2009=u2009.10) in the placebo group (nu2009=u2009136). NT-proBNP concentration was 167 ng/L in the metformin group (interquartile range [IQR], 65-393 ng/L) and 167 ng/L in the placebo group (IQR, 74-383 ng/L) (Pu2009=u2009.66). MACE were observed in 6 patients (3.1%) in the metformin group and in 2 patients (1.1%) in the placebo group (Pu2009=u2009.16). Creatinine concentration (79 µmol/L [IQR, 70-87 µmol/L] vs 79 µmol/L [IQR, 72-89 µmol/L], Pu2009=u2009.61) and glycated hemoglobin (5.9% [IQR, 5.6%-6.1%] vs 5.9% [IQR, 5.7%-6.1%], Pu2009=u2009.15) were not significantly different between both groups. No cases of lactic acidosis were observed.nnnCONCLUSIONS AND RELEVANCEnAmong patients without diabetes presenting with STEMI and undergoing primary PCI, the use of metformin compared with placebo did not result in improved LVEF after 4 months. The present findings do not support the use of metformin in this setting.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT01217307.

Metformin in non-Diabetic Patients Presenting with ST Elevation Myocardial Infarction: Rationale and Design of the Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction (GIPS)-III Trial

BackgroundLeft ventricular dysfunction and the development of heart failure is a frequent and serious complication of myocardial infarction. Recent animal experimental studies suggested that metformin treatment reduces myocardial injury and preserves cardiac function in non-diabetic rats after experimental myocardial infarction. We will study the efficacy of metformin with the aim to preserve left ventricular ejection fraction in non-diabetic patients presenting with ST elevation myocardial infarction (STEMI).MethodsThe Glycometabolic Intervention as adjunct to Primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial is a prospective, single center, double blind, randomized, placebo-controlled trial. Three-hundred-and-fifty patients, without diabetes, requiring primary percutaneous coronary intervention (PCI) for STEMI will be randomized to metformin 500xa0mg twice daily or placebo treatment and will undergo magnetic resonance imaging (MRI) after 4xa0months. Major exclusion criteria were prior myocardial infarction and severe renal dysfunction. The primary efficacy parameter is left ventricular ejection fraction 4xa0months after randomization. Secondary and tertiary efficacy parameters include major adverse cardiac events, new onset diabetes and glycometabolic parameters, and echocardiographic diastolic function. Safety parameters include renal function deterioration and lactic acidosis.ConclusionsThe GIPS-III trial will evaluate the efficacy of metformin treatment to preserve left ventricular ejection fraction in STEMI patients without diabetes.

The effect of metformin on cardiovascular risk profile in patients without diabetes presenting with acute myocardial infarction: data from the Glycometabolic Intervention as adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) trial

Objective In patients with diabetes mellitus, metformin treatment is associated with reduced mortality and attenuation of cardiovascular risk. As a subanalysis of the Glycometabolic Intervention as adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) study, we evaluated whether metformin treatment in patients with ST-segment elevation myocardial infarction (STEMI) without diabetes improves the cardiovascular risk profile. Methods A total of 379 patients, without known diabetes, presenting with STEMI were randomly allocated to receive metformin 500u2005mg twice daily or placebo for 4u2005months. Results After 4u2005months, the cardiovascular risk profile of patients receiving metformin (n=172) was improved compared with placebo (n=174); glycated hemoglobin (5.83% (95% CI 5.79% to 5.87%) vs 5.89% (95% CI 5.85% to 5.92%); 40.2u2005mmol/mol (95% CI 39.8 to 40.6) vs 40.9u2005mmol/mol (40.4 to 41.2), p=0.049); total cholesterol (3.85u2005mmol/L (95% CI 3.73 to 3.97) vs 4.02u2005mmol/L (95% CI 3.90 to 4.14), p=0.045); low-density lipoprotein cholesterol (2.10u2005mmol/L (95% CI 1.99 to 2.20) vs 2.3u2005mmol/L (95% CI 2.20 to 2.40), p=0.007); body weight (83.8u2005kg (95% CI 83.0 to 84.7) vs 85.2u2005kg (95% CI 84.4 to 86.1), p=0.024); body mass index (26.8u2005kg/m2 (95% CI 26.5 to 27.0) vs 27.2u2005kg/m2 (95% CI 27.0 to 27.5), p=0.014). Levels of fasting glucose, postchallenge glucose, insulin, high-density lipoprotein cholesterol, and blood pressure were similar in both groups. Conclusions Among patients with STEMI without diabetes, treatment with metformin for 4u2005months resulted in a modest improvement of the cardiovascular risk profile compared with placebo. Trial register number NCT01217307.

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

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.

Chronic ischemic mitral regurgitation and papillary muscle infarction detected by late gadolinium-enhanced cardiac magnetic resonance imaging in patients with ST-segment elevation myocardial infarction

BackgroundBoth papillary muscle infarction (PMI) and chronic ischemic mitral regurgitation (CIMR) are associated with reduced survival after myocardial infarction. The influence of PMI on CIMR and factors influencing both entities are incompletely understood.ObjectivesWe sought to determine the influence of PMI on CIMR after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) and to define independent predictors of PMI and CIMR.MethodsBetween January 2011 and May 2013, 263 patients (mean age 57.8xa0±xa011.5xa0years) underwent late gadolinium-enhanced cardiac magnetic resonance imaging and transthoracic echocardiography 4xa0months after PCI for STEMI. Infarct size, PMI, and mitral valve and left ventricular geometric and functional parameters were assessed. Univariate and multivariate analyses were performed to identify predictors of PMI and CIMR (≥grade 2+).ResultsPMI was present in 61 patients (23xa0%) and CIMR was present in 86 patients (33xa0%). In patients with PMI, 52xa0% had CIMR, and in patients without PMI, 27xa0% had CIMR (Pxa0<xa00.001). In multivariate analyses, infarct size [odds ratio (OR) 1.09 (95xa0% confidence interval 1.04–1.13), Pxa0<xa00.001], inferior MI [OR 4.64 (1.04–20.62), Pxa0=xa00.044], and circumflex infarct-related artery [OR 8.21 (3.80–17.74), Pxa0<xa00.001] were independent predictors of PMI. Age [OR 1.08 (1.04–1.11), Pxa0<xa00.001], infarct size [OR 1.09 (1.03-1.16), Pxa0=xa00.003], tethering height [OR 19.30 (3.28–113.61), Pxa0=xa00.001], and interpapillary muscle distance [OR 3.32 (1.31–8.42), Pxa0=xa00.011] were independent predictors of CIMR.ConclusionsThe risk of PMI is mainly associated with inferior infarction and infarction in the circumflex coronary artery. Although the prevalence of CIMR is almost doubled in the presence of PMI, PMI is not an independent predictor of CIMR. Tethering height and interpapillary muscle distance are the strongest independent predictors of CIMR.

Leukocyte telomere length and left ventricular function after acute ST-elevation myocardial infarction: data from the glycometabolic intervention as adjunct to primary coronary intervention in ST elevation myocardial infarction (GIPS-III) trial

AbstractBackgroundTelomere length has been associated with coronary artery disease and heart failure. We studied whether leukocyte telomere length is associated with left ventricular ejection fraction (LVEF) after ST-elevation myocardial infarction (STEMI).Methods and resultsLeukocyte telomere length (LTL) was determined using the monochrome multiplex quantitative PCR method in 353 patients participating in the glycometabolic intervention as adjunct to primary percutaneous coronary intervention in STEMI III trial. LVEF was assessed by magnetic resonance imaging. The mean age of patients was 58.9xa0±xa011.6xa0years, 75xa0% were male. In age- and gender-adjusted models, LTL at baseline was significantly associated with age (betaxa0±xa0standard error; −0.33xa0±xa00.01; Pxa0<xa00.01), gender (0.15xa0±xa00.03; Pxa0<xa00.01), TIMI flow pre-PCI (0.05xa0±xa00.03; Pxa0<xa00.01), TIMI flow post-PCI (0.03xa0±xa00.04; Pxa0<xa00.01), myocardial blush grade (−0.05xa0±xa00.07; Pxa0<xa00.01), serum glucose levels (−0.11xa0±xa00.01; Pxa0=xa00.03), and total leukocyte count (−0.11xa0±xa00.01; Pxa0=xa00.04). At 4xa0months after STEMI, LVEF was well preserved (54.1xa0±xa08.4xa0%) and was not associated with baseline LTL (Pxa0=xa00.95). Baseline LTL was associated with nn-terminal pro-brain natriuretic peptide (NT-proBNP) at 4xa0months (−0.14xa0±xa00.01; Pxa0=xa00.02), albeit not independent for age and gender.ConclusionOur study does not support a role for LTL as a causal factor related to left ventricular ejection fraction after STEMI.

Effect of Metformin on Renal Function After Primary Percutaneous Coronary Intervention in Patients Without Diabetes Presenting with ST-elevation Myocardial Infarction: Data from the GIPS-III Trial

Purpose The association between metformin use and renal function needs further to be elucidated since data are insufficient whether metformin affects renal function in higher risk populations such as after ST-elevation myocardial infarction (STEMI). Methods We studied 379 patients included in the GIPS-III trial in which patients without diabetes or renal dysfunction, who underwent primary percutaneous coronary interventions (PCI) for STEMI, were randomized to metformin 500 mg or placebo twice daily for four months. At baseline and at seven scheduled visits up to four months after PCI, estimated glomerular filtration rate (eGFR) was determined (2582 values). Contrast-induced acute kidney injury (CI-AKI) was defined as an increase in serum creatinine of ≥0.3 mg/dl or 25 % rise within 48 h after PCI. Results At all visits, the mean eGFR was similar in patients randomized to metformin or placebo. Over the four month period, mixed-effect repeated-measures model analysis showed a least-squares mean ± standard error change in eGFR of -5.9u2009±u20090.8 ml/min/1.73 m2 in the metformin group and −7.1u2009±u20090.8 ml/min/1.73 m2 in the control group (Pu2009=u20090.27 for overall interaction). The incidence of CI-AKI was 14.8 %; 29 (15.2 %) patients in the metformin group versus 27 (14.4 %) controls (Pu2009=u20090.89). After adjustment for covariates, metformin treatment was not associated with CI-AKI (odds ratio: 0.96, 95%CI 0.52u2009−u20091.75, Pu2009=u20090.88). Conclusion We conclude that initiation of metformin shortly after primary PCI has no adverse effect on renal function in patients without diabetes or prior renal impairment, further providing evidence of the safety of metformin use after myocardial infarction and subsequent contrast exposure. Electronic supplementary material The online version of this article (doi:10.1007/s10557-015-6618-1) contains supplementary material, which is available to authorized users.PurposeThe association between metformin use and renal function needs further to be elucidated since data are insufficient whether metformin affects renal function in higher risk populations such as after ST-elevation myocardial infarction (STEMI).MethodsWe studied 379 patients included in the GIPS-III trial in which patients without diabetes or renal dysfunction, who underwent primary percutaneous coronary interventions (PCI) for STEMI, were randomized to metformin 500xa0mg or placebo twice daily for four months. At baseline and at seven scheduled visits up to four months after PCI, estimated glomerular filtration rate (eGFR) was determined (2582 values). Contrast-induced acute kidney injury (CI-AKI) was defined as an increase in serum creatinine of ≥0.3xa0mg/dl or 25xa0% rise within 48xa0h after PCI.ResultsAt all visits, the mean eGFR was similar in patients randomized to metformin or placebo. Over the four month period, mixed-effect repeated-measures model analysis showed a least-squares mean ± standard error change in eGFR of -5.9u2009±u20090.8xa0ml/min/1.73xa0m2 in the metformin group and −7.1u2009±u20090.8xa0ml/min/1.73xa0m2 in the control group (Pu2009=u20090.27 for overall interaction). The incidence of CI-AKI was 14.8xa0%; 29 (15.2xa0%) patients in the metformin group versus 27 (14.4xa0%) controls (Pu2009=u20090.89). After adjustment for covariates, metformin treatment was not associated with CI-AKI (odds ratio: 0.96, 95%CI 0.52u2009−u20091.75, Pu2009=u20090.88).ConclusionWe conclude that initiation of metformin shortly after primary PCI has no adverse effect on renal function in patients without diabetes or prior renal impairment, further providing evidence of the safety of metformin use after myocardial infarction and subsequent contrast exposure.

Predictors of left ventricular remodeling after ST-elevation myocardial infarction

Adverse left ventricular (LV) remodeling after acute ST-elevation myocardial infarction (STEMI) is associated with morbidity and mortality. We studied clinical, biochemical and angiographic determinants of LV end diastolic volume index (LVEDVi), end systolic volume index (LVESVi) and mass index (LVMi) as global LV remodeling parameters 4 months after STEMI, as well as end diastolic wall thickness (EDWT) and end systolic wall thickness (ESWT) of the non-infarcted myocardium, as compensatory remote LV remodeling parameters. Data was collected in 271 patients participating in the GIPS-III trial, presenting with a first STEMI. Laboratory measures were collected at baseline, 2 weeks, and 6–8 weeks. Cardiovascular magnetic resonance imaging (CMR) was performed 4 months after STEMI. Linear regression analyses were performed to determine predictors. At baseline, patients were 21% female, median age was 58 years. At 4 months, mean LV ejection fraction (LVEF) was 54u2009±u20099%, mean infarct size was 9.0u2009±u20097.9% of LVM. Strongest univariate predictors (all pu2009<u20090.001) were peak Troponin T for LVEDVi (R2u2009=u20090.26), peak CK-MB for LVESVi (R2u2009=u20090.41), NT-proBNP at 2 weeks for LVMi (R2u2009=u20090.24), body surface area for EDWT (R2u2009=u20090.32), and weight for ESWT (R2u2009=u20090.29). After multivariable analysis, cardiac biomarkers remained the strongest predictors of LVMi, LVEDVi and LVESVi. NT-proBNP but none of the acute cardiac injury biomarkers were associated with remote LV wall thickness. Our analyses illustrate the value of cardiac specific biochemical biomarkers in predicting global LV remodeling after STEMI. We found no evidence for a hypertrophic response of the non-infarcted myocardium.

Effect of Metformin on Metabolites and Relation With Myocardial Infarct Size and Left Ventricular Ejection Fraction After Myocardial Infarction

Background— Left ventricular ejection fraction (LVEF) and infarct size (ISZ) are key predictors of long-term survival after myocardial infarction (MI). However, little is known about the biochemical pathways driving LV dysfunction after MI. To identify novel biomarkers predicting post-MI LVEF and ISZ, we performed metabolic profiling in the GIPS-III randomized clinical trial (Glycometabolic Intervention as Adjunct to Primary Percutaneous Intervention in ST Elevation Myocardial Infarction). We also investigated the metabolic footprint of metformin, a drug associated with improved post-MI LV function in experimental studies. Methods and Results— Participants were patients with ST-segment–elevated MI who were randomly assigned to receive metformin or placebo for 4 months. Blood samples were obtained on admission, 24 hours post-MI, and 4 months post-MI. A total of 233 metabolite measures were quantified using nuclear magnetic resonance spectrometry. LVEF and ISZ were assessed 4 months post-MI. Twenty-four hours post-MI measurements of high-density lipoprotein (HDL) triglycerides (HDL-TG) predicted LVEF (&bgr;=1.90 [95% confidence interval (CI), 0.82 to 2.98]; P=6.4×10−4) and ISZ (&bgr;=−0.41 [95% CI, −0.60 to −0.21]; P=3.2×10−5). In addition, 24 hours post-MI measurements of medium HDL-TG (&bgr;=−0.40 [95% CI, −0.60 to −0.20]; P=6.4×2×10−5), small HDL-TG (&bgr;=−0.34 [95% CI, −0.53 to −0.14]; P=7.3×10−4), and the triglyceride content of very large HDL (&bgr;=−0.38 [95% CI, −0.58 to −0.18]; P=2.7×10−4) were associated with ISZ. After the 4-month treatment, the phospholipid content of very large HDL was lower in metformin than in placebo-treated patients (28.89% versus 38.79%; P=7.5×10−5); alanine levels were higher in the metformin group (0.46 versus 0.44 mmol/L; P=2.4×10−4). Conclusions— HDL triglyceride concentrations predict post-MI LVEF and ISZ. Metformin increases alanine levels and reduces the phospholipid content in very large HDL particles. Clinical Trial Registration— URL: https://clinicaltrials.gov/ct2/show/NCT01217307. Unique Identifier: NCT01217307.