Publications by authors named "Christian M Matter"

156 Publications

Prognostic value of inflammatory biomarkers and GRACE score for cardiac death and acute kidney injury after acute coronary syndromes.

Eur Heart J Acute Cardiovasc Care 2021 Feb 24. Epub 2021 Feb 24.

Department of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.

Aims : The aim of this study was to analyse the role of inflammation and established clinical scores in predicting acute kidney injury (AKI) after acute coronary syndromes (ACS).

Methods And Results : In a prospective multicentre cohort including 2034 patients with ACS undergoing percutaneous coronary intervention, high-sensitivity C-reactive protein (hsCRP), neutrophil count, neutrophil-to-lymphocyte ratio (NL-ratio), and creatinine were measured at the index procedure. AKI (n = 39, defined according to RIFLE criteria) and major cardiovascular and cerebrovascular events were adjudicated after 1 year. Associations between inflammation, AKI, and cardiac death (CD) were assessed by C-statistics and Cox proportional hazard models with log-rank test to compare survival. Patients with ACS with elevated neutrophil count >7.8 × 109/L, NL-ratio >5, combined neutrophil-count/creatinine, or NL-ratio/creatinine at baseline showed a higher incidence of AKI (all P < 0.05) and CD (all P < 0.001). The risk of AKI, CD, and their combination was increased in patients with higher neutrophil count/creatinine (heart rate (HR) = 3.7, 95% cardiac index (CI) 1.9-7.1; HR = 2.7, 95% CI 1.6-4.6; HR = 3.2, 95% CI 2.1-4.9); NL-ratio/creatinine (HR = 2.1, 95% CI 1.6-4.1; HR = 2.2, 95% CI 1.3-3.8; HR = 2.3, 95% CI 1.5-3.5); and hsCRP (HR = 1.8, 95% CI 0.9-3.5; HR = 2.2, 95% CI 1.3-3.6; HR = 1.9, 95% CI 1.2-2.8) after adjustment for age, diabetes, hypertension, previous heart failure, kidney function, haemodynamic instability at admission, statin, and renin-angiotensin-aldosterone antagonists use. Subjects with higher GRACE score 1.0/NL-ratio had higher rate of AKI, CD, and both (HR = 1.4, 95% CI 0.5-4.2; HR = 2.7, 95% CI 1.3-5.9; HR = 2.1, 95% CI 1-4.3).

Conclusions : Inflammation markers may predict AKI after correction for renal function at the index procedure. hsCRP performed better than the NL-ratio. However, the integration of inflammation markers to traditional risk factors or scores does not add prognostic information.

Trial Registration : ClinicalTrials.gov, NCT01000701.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ehjacc/zuab003DOI Listing
February 2021

Residual inflammatory risk at 12 months after acute coronary syndromes is frequent and associated with combined adverse events.

Atherosclerosis 2021 Jan 18;320:31-37. Epub 2021 Jan 18.

Department of Cardiology, University Heart Center, University Hospital Zurich, Switzerland; Center for Molecular Cardiology, University of Zurich, Switzerland.

Background And Aims: Residual inflammatory risk (RIR) after acute coronary syndromes (ACS) may identify patients likely to benefit from anti-inflammatory therapies.

Methods: Patients from the Special Program University Medicine ACS cohort were divided into four groups according to level of hsCRP at baseline and after 12 months: persistently high RIR, increased RIR (first low, then high hsCRP), attenuated RIR (first high, then low hsCRP), or persistently low RIR. High RIR was defined as hsCRP ≥ 2 mg/L. An independently adjudicated incident of combined adverse events was defined as the composite of myocardial infarction, clinically indicated coronary revascularization or cerebrovascular events.

Results: Among 1209 patients with available hsCRP, clinical and demographic data, 295 (24.4%) patients had persistently high RIR (delta hsCRP median (IQR): 2.3 (-9.9; 0.3) (mg/L) and 72 (5.96%) patients had increased RIR (delta hsCRP median (IQR): +2.45 (1.2; 8.35) (mg/L). A total of 390 (32.26%) patients had attenuated RIR (delta hsCRP median (IQR): 3.55 (-10; -2) (mg/L) and 452 (37.38%) patients had persistently low RIR (delta hsCRP median (IQR): 0.2 (-0.6; 0.1) (mg/L). Of 90 combined adverse events, 31 (10.5%) occurred in the persistently high (multivariable adjusted OR: 1.71, (95% CI 1.08-2.7), p = 0.022) compared with the three other groups combined (increased RIR: 3 (4.2%), attenuated RIR 30 (7.7%), persistently low RIR 26 (5.8%).

Conclusions: Persistently elevated hsCRP after ACS is found in a quarter of patients with the highest risk of combined adverse events. This underlines the need to perform anti-inflammatory intervention trials in RIR patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2021.01.012DOI Listing
January 2021

Impact of malignancy on clinical outcomes in patients with acute coronary syndromes.

Int J Cardiol 2021 Apr 13;328:8-13. Epub 2020 Dec 13.

Department of Cardiology, University Heart Centre, Zurich, Switzerland.

Background: The impact of cancer on survival in patients with coronary artery disease has not been well defined. We designed the present study to explore the prevalence and prognostic influence of cancer in patients with acute coronary syndrome (ACS).

Methods: 2'132 patients with ACS were enrolled in the prospective, multicenter Special Program University Medicine ACS (SPUM-ACS) cohort. The primary endpoints of major cardiovascular and cerebrovascular events (MACCE) and death were independently adjudicated at 30-day and at one-year follow-up.

Results: Of the 2'132 ACS patients 7.74% (n = 165) had cancer. At 30-day, except for net adverse clinical events (NACE defined as MACCE plus major bleeding), outcomes did not differ significantly between the two groups. At one year, MACCE rate was higher in cancer than in non-cancer patients (21.8 vs. 12.2%, p < 0.001). Even after adjusting for covariates, one-year all-cause mortality was higher in cancer patients than in those without (30.3% vs. 11.9%; p < 0.0001) as was cardiovascular mortality (15.7% vs. 5.9%; p < 0.001) and revascularization (12.7% vs. 5.5%, p < 0.001). Net adverse clinical events were also higher in patients with cancer at one-year follow-up (33.9% vs. 19.8%, p < 0.001). A sub-analysis revealed that those with solid tumors, but not hematological malignancies were more likely to experience MACCE (p = 0.001) as well as a higher cardiovascular and all cause mortality (both p = 0.001) at one-year follow-up.

Conclusions: ACS patients with cancer, specifically those with solid tumors, have a higher MACCE as well as cardiovascular and total mortality rate than non-cancer patients independent of cardiovascular risk factors. Thus, cancer is an independent risk factor for a poor outcome in ACS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2020.12.010DOI Listing
April 2021

Prognostic role of plasma galectin-3 levels in acute coronary syndrome.

Eur Heart J Acute Cardiovasc Care 2020 Dec;9(8):869-878

Royal Brompton and Harefield Hospitals and Imperial College, UK.

Aim: Cystatin C, neutrophil gelatinase-associated lipocalin and galectin-3 have emerged as biomarker candidates to predict cardiovascular outcomes and mortality in the general population as well as in patients with coronary artery or renal disease. However, their predictive role and clinical utility in patients with acute coronary syndromes alone or in combination beyond currently used risk scores remains to be determined.

Methods And Results: Cystatin C, neutrophil gelatinase-associated lipocalin, and galectin-3 were measured in plasmas of 1832 patients at the time of presentation with acute coronary syndromes requiring percutaneous coronary intervention or coronary artery bypass grafting. The primary outcomes were major adverse cardiac and cerebrovascular events (defined as the composite of all-cause mortality, cerebrovascular events, any repeat revascularization or myocardial infarction) and all-cause mortality after 1 year and occurred in 192 (10.5%) and 78 (4.3%) of patients, respectively. All three biomarkers were increased in those with major adverse cardiac and cerebrovascular events compared with those without (<0.001). However, only galectin-3 (all-cause mortality: hazard ratio=1.027 (95% confidence interval (1.011-1.043); =0.001), major adverse cardiac and cerebrovascular events: hazard ratio=1.025 (95% confidence interval (1.012-1.037); <0.001)) but not cystatin C nor neutrophil gelatinase-associated lipocalin emerged as independent predictors of both major adverse cardiac and cerebrovascular events and death. The risks were particularly high in the highest quartile of galectin-3. The integration of galectin-3 into the global registry of acute coronary events (GRACE) score improved the prediction of major adverse cardiac and cerebrovascular events and all-cause mortality significantly. The areas under the receiver operator characteristics curves increased from 0.6701 to 0.6932 for major adverse cardiac and cerebrovascular events (=0.0474) and from 0.804 to 0.8199 for all-cause mortality (=0.0197). Finally, we applied net reclassification improvement index using different cut-offs for major adverse cardiac and cerebrovascular events which showed negative results (for the cut-offs of 5% and 15%, net reclassification improvement index 0.028, =0.586, for the cut-offs of 10% and 20%, net reclassification improvement index 0.072, =0.1132 and for the cut-offs of 10% and 30% the net reclassification improvement index is 0.0843, =0.077).

Conclusion: In acute coronary syndromes patients, galectin-3 has moderate prognostic accuracy, provides statistically significant incremental value in some, but not all models, and that the magnitude of any improvement would seem of questionable clinical value.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2048872620974612DOI Listing
December 2020

Role of the Nuclear Receptor Corepressor 1 (NCOR1) in Atherosclerosis and Associated Immunometabolic Diseases.

Front Immunol 2020 8;11:569358. Epub 2020 Oct 8.

Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.

Atherosclerotic cardiovascular disease is part of chronic immunometabolic disorders such as type 2 diabetes and nonalcoholic fatty liver disease. Their common risk factors comprise hypertension, insulin resistance, visceral obesity, and dyslipidemias, such as hypercholesterolemia and hypertriglyceridemia, which are part of the metabolic syndrome. Immunometabolic diseases include chronic pathologies that are affected by both metabolic and inflammatory triggers and mediators. Important and challenging questions in this context are to reveal how metabolic triggers and their downstream signaling affect inflammatory processes and vice-versa. Along these lines, specific nuclear receptors sense changes in lipid metabolism and in turn induce downstream inflammatory and metabolic processes. The transcriptional activity of these nuclear receptors is regulated by the nuclear receptor corepressors (NCORs), including NCOR1. In this review we describe the function of NCOR1 as a central immunometabolic regulator and focus on its role in atherosclerosis and associated immunometabolic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.569358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578257PMC
October 2020

Eligibility for PCSK9 inhibitors based on the 2019 ESC/EAS and 2018 ACC/AHA guidelines.

Eur J Prev Cardiol 2020 Jul 20:2047487320940102. Epub 2020 Jul 20.

Department of Cardiology, University Hospital Bern, Switzerland.

Aims: The 2018 American College of Cardiology (ACC)/American Heart Association (AHA) and 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) lipid guidelines recently updated their recommendations regarding proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i). We assessed the potential eligibility for PCSK9i according to the new guidelines in patients with acute coronary syndromes.

Methods And Results: We analysed a contemporary, prospective Swiss cohort of patients hospitalised for acute coronary syndromes. We modelled a statin intensification effect and an incremental ezetimibe effect on low-density lipoprotein-cholesterol levels among patients who were not on high-intensity statins or ezetimibe. One year after the index acute coronary syndrome event, treatment eligibility for PCSK9i was defined as low-density lipoprotein-cholesterol of 1.4 mmol/l or greater according to ESC/EAS guidelines. For ACC/AHA guidelines, treatment eligibility was defined as low-density lipoprotein-cholesterol of 1.8 mmol/l or greater in the presence of very high-risk atherosclerotic cardiovascular disease, defined by multiple major atherosclerotic cardiovascular disease events and/or high-risk conditions. Of 2521 patients, 93.2% were treated with statins (53% high-intensity statins) and 7.3% with ezetimibe at 1 year, and 54.9% had very high-risk atherosclerotic cardiovascular disease. Low-density lipoprotein-cholesterol levels less than 1.8 mmol/l and less than 1.4 mmol/l at 1 year were observed in 37.5% and 15.7% of patients, respectively. After modelling the statin intensification and ezetimibe effects, these numbers increased to 76.1% and 49%, respectively. The proportion of patients eligible for PCSK9i was 51% according to ESC/EAS criteria versus 14% according to ACC/AHA criteria.

Conclusions: In this analysis, the 2019 ESC/EAS guidelines rendered half of all post-acute coronary syndrome patients potentially eligible for PCSK9i treatment, as compared to a three-fold lower eligibility rate based on the 2018 ACC/AHA guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2047487320940102DOI Listing
July 2020

Deletion of fibroblast activation protein provides atheroprotection.

Cardiovasc Res 2020 May 13. Epub 2020 May 13.

Center for Molecular Cardiology, University of Zurich, CH-8952 Schlieren, Switzerland.

Aims: Fibroblast activation protein (FAP) is upregulated at sites of tissue remodelling including chronic arthritis, solid tumours, and fibrotic hearts. It has also been associated with human coronary atherosclerotic plaques. Yet, the causal role of FAP in atherosclerosis remains unknown. To investigate the cause-effect relationship of endogenous FAP in atherogenesis, we assessed the effects of constitutive Fap deletion on plaque formation in atherosclerosis-prone apolipoprotein E (Apoe) or low-density lipoprotein receptor (Ldlr) knockout mice.

Methods And Results: Using en face analyses of thoraco-abdominal aortae and aortic sinus cross-sections, we demonstrate that Fap deficiency decreased plaque formation in two atherosclerotic mouse models (-46% in Apoe and -34% in Ldlr knockout mice). As a surrogate of plaque vulnerability fibrous cap thickness was used; it was increased in Fap-deficient mice, whereas Sirius red staining demonstrated that total collagen content remained unchanged. Using polarized light, atherosclerotic lesions from Fap-deficient mice displayed increased FAP targets in terms of enhanced collagen birefringence in plaques and increased pre-COL3A1 expression in aortic lysates. Analyses of the Stockholm Atherosclerosis Gene Expression (STAGE) data revealed that FAP expression was increased in human atherosclerotic compared to non-atherosclerotic arteries.

Conclusions: Our data provide causal evidence that constitutive Fap deletion decreases progression of experimental atherosclerosis and increases features of plaque stability with decreased collagen breakdown. Thus, inhibition of FAP expression or activity may not only represent a promising therapeutic target in atherosclerosis but appears safe at the experimental level for FAP-targeted cancer therapies.

Translational Perspective: Fibroblast activation protein (FAP) is upregulated at sites of chronic tissue remodelling including rheumatoid arthritis and solid tumours. Indeed, depletion of FAP-positive cells inhibits tumour growth by increasing antitumour immunity. FAP has also been correlated with human coronary plaques, whereby its causal role remains unknown. Our data provide causal evidence that constitutive Fap deletion decreases progression of experimental atherosclerosis and increases features of plaque stability. Thus, inhibition of FAP expression or activity may not only represent a novel therapeutic target for atherosclerosis but appears safe - at the experimental level - for FAP-targeted cancer therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvaa142DOI Listing
May 2020

Optimal Timing of Invasive Coronary Angiography following NSTEMI.

J Interv Cardiol 2020 3;2020:8513257. Epub 2020 Mar 3.

Department of Cardiology, Lausanne University Center Hospital, Lausanne, Switzerland.

Objective: To obtain a real-world perspective of the optimal timing of angiography performed within 24 hours of admission with non-ST elevation myocardial infarction (NSTEMI).

Background: Current guidelines recommend angiography within 24 hours of hospitalisation with NSTEMI. The recent VERDICT trial found that angiography within 12 hours of admission with NSTEMI was associated with improved cardiovascular outcomes among high-risk patients. We compared the outcomes of real-world NSTEMI patients undergoing angiography within 12 hours of admission with those of patients undergoing angiography 12 to 24 hours after admission.

Methods: NSTEMI patients without life-threatening features who received angiography within 24 hours of admission were obtained from the SPUM-ACS registry, a cohort of consecutive patients admitted with acute coronary syndromes to four university hospitals in Switzerland. Cox models assessed for an association between door-to-catheter time and one-year major adverse cardiovascular events (MACE: cardiovascular mortality, myocardial infarction, and stroke).

Results: Of 2672 NSTEMI patients, 1832 met the inclusion criteria. Among them, 1464 patients underwent angiography within 12 hours (12 h group) compared with 368 patients between 12 and 24 hours (12-24 h group). Multiple logistic regression identified out-of-hours admission as the only factor associated with delayed angiography. After 2 : 1 propensity score matching, 736 patients from the 12 h group and 368 patients from the 12-24 h group demonstrated no significant difference in rates of one-year MACE (7.7% vs. 7.3%, HR: 1.050, 95% CI 0.637-1.733, =0.847). Stratification by GRACE score (>140 vs. ≤140) found no significant reduction in MACE among high-risk patients in the 12 h group (=0.847). Stratification by GRACE score (>140 vs. ≤140) found no significant reduction in MACE among high-risk patients in the 12 h group (.

Conclusions: In an unselected real-world cohort of NSTEMI patients, angiography within 12 hours of admission was not associated with improved one-year cardiovascular outcomes when compared with angiography 12 and 24 hours after admission, even among high-risk patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8513257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073472PMC
September 2020

Clinical predictors of left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

Am Heart J 2020 05 7;223:34-43. Epub 2020 Feb 7.

Department of Cardiology, University Heart Center Zurich, Switzerland; Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Electronic address:

Aim: The impact of clinical characteristics for predicting patterns of ventricular involvement in arrhythmogenic right ventricular cardiomyopathy (ARVC) are not well defined. The aims of this study were to characterize different patterns of ventricular involvement in patients with ARVC and to stratify them based on clinical characteristics exercise and underlying genetic mutations.

Methods: Sixty-four patients with definite ARVC from the Swiss ARVC Registry were enrolled. Right and left ventricular functions were assessed at baseline and most recent follow-up. All patients received genetic testing. Serum high-sensitivity cardiac Troponin T (hs-cTNT) and N-terminal of pro-brain natriuretic peptide (NT-proBNP) were determined at baseline.

Results: Thirty-five patients (55%) had isolated right ventricular (RV) involvement, 12 patients (19%) had biventricular (BiV) involvement at baseline and 17 patients (26%) had no left ventricular (LV) involvement at baseline, but revealed new onset LV involvement at mean follow-up of 7.5 years. Patients with BiV involvement at baseline harbored significantly more desmoplakin and multiple mutations and patients with new-onset LV involvement at follow-up frequently showed non-desmosomal mutations. Patients engaging in competitive sports more often showed LV involvement during follow-up. Baseline hs-cTNT and NT-proBNP levels were higher in patients developing BiV involvement.

Conclusion: Multiple mutations are more common in ARVC patients with BiV involvement. Competitive exercise is associated with disease progression resulting in BiV involvement. Hs-cTNT and NT-proBNP are elevated in patients with BiV involvement and may help to identify ARVC patients at risk for developing BiV disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ahj.2020.01.019DOI Listing
May 2020

Elevated HbA1c is not associated with recurrent venous thromboembolism in the elderly, but with all-cause mortality- the SWEETCO 65+ study.

Sci Rep 2020 02 12;10(1):2495. Epub 2020 Feb 12.

Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland.

The association of glycated hemoglobin (HbA1c) with venous thromboembolism (VTE) and death in the elderly is unknown. In the SWEETCO 65+ study we analyzed prospectively a Swiss Cohort of Elderly Patients with Venous Thromboembolism (SWITCO 65+). 888 patients were enrolled for the SWEETCO 65+ analysis. HbA1c was determined at baseline and divided into three categories (HbA1c < 5.7%, normal range; 5.7-6.49%, pre-diabetic range; and >6.5%, diabetic range). Median follow-up was 2.5 years. The primary endpoint was recurrent VTE. Secondary endpoints included all-cause mortality and major bleeds. The total prevalence of diabetes was 22.1%. The risk of recurrent VTE was similar in patients with HbA1c with pre-diabetes (adjusted subhazard ratio (aSHR) 1.07 [0.70 to 1.63]) and diabetes (aSHR 0.73 [0.39 to 1.37]) as compared to those with a HbA1c in the normal range. However, a HbA1c ≥ 6.5% (median IQ range 7.0 [6.70;7.60]) was significantly associated with a higher risk of all-cause mortality (adjusted hazard ratio [aHR] 1.83 [1.21 to 2.75]). In summary we found no association between HbA1c and major bleeding. Elevated HbA1c levels are not associated with recurrent VTE but with increased all-cause mortality in an elderly population with acute VTE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-59173-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016100PMC
February 2020

Sirt6 deletion in bone marrow-derived cells increases atherosclerosis - Central role of macrophage scavenger receptor 1.

J Mol Cell Cardiol 2020 02 21;139:24-32. Epub 2020 Jan 21.

Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland; Department of Cardiology, University Heart Center, Zurich University Hospital, Zurich, Switzerland. Electronic address:

Aims: Sirtuin 6 (Sirt6) is a NAD-dependent deacetylase that plays a key role in DNA repair, inflammation and lipid regulation. Sirt6-null mice show severe metabolic defects and accelerated aging. Macrophage-foam cell formation via scavenger receptors is a key step in atherogenesis. We determined the effects of bone marrow-restricted Sirt6 deletion on foam cell formation and atherogenesis using a mouse model.

Methods And Results: Sirt6 deletion in bone marrow-derived cells increased aortic plaques, lipid content and macrophage numbers in recipient Apoe mice fed a high-cholesterol diet for 12 weeks (n = 12-14, p < .001). In RAW macrophages, Sirt6 overexpression reduced oxidized low-density lipoprotein (oxLDL) uptake, Sirt6 knockdown enhanced it and increased mRNA and protein levels of macrophage scavenger receptor 1 (Msr1), whereas levels of other oxLDL uptake and efflux transporters remained unchanged. Similarly, in human primary macrophages, Sirt6 knockdown increased MSR1 protein levels and oxLDL uptake. Double knockdown of Sirt6 and Msr1 abolished the increase in oxLDL uptake observed upon Sirt6 single knockdown. FACS analyses of macrophages from aortic plaques of Sirt6-deficient bone marrow-transplanted mice showed increased MSR1 protein expression. Double knockdown of Sirt6 and the transcription factor c-Myc in RAW cells abolished the increase in Msr1 mRNA and protein levels; c-Myc overexpression increased Msr1 mRNA and protein levels.

Conclusions: Loss of Sirt6 in bone marrow-derived cells is proatherogenic; hereby macrophages play an important role given a c-Myc-dependent increase in MSR1 protein expression and an enhanced oxLDL uptake in human and murine macrophages. These findings assign endogenous SIRT6 in macrophages an important atheroprotective role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2020.01.002DOI Listing
February 2020

Comparison of P2Y12 receptor inhibitors in patients with ST-elevation myocardial infarction in clinical practice: a propensity score analysis of 5 contemporary European registries.

Eur Heart J Cardiovasc Pharmacother 2020 Jan 22. Epub 2020 Jan 22.

Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: Among acute coronary syndromes (ACS), ST-segment elevation myocardial infarction (STEMI) has the most severe early clinical course. Recent randomized clinical trials have demonstrated that novel antithrombotic therapies improve in-hospital outcomes in STEMI patients. We aimed to describe the effectiveness and safety of P2Y12 receptor inhibitors in clinical practice in patients with STEMI based on data from contemporary European ACS registries.

Methods And Results: Five registries from the PIRAEUS initiative (AAPCI/ADPAT, ALKK-PIC, AMIS Plus, Belgium STEMI, EYESHOT) provided data for the assessment of P2Y12 receptor inhibitor-based dual antiplatelet therapy. Registries were heterogeneous in terms of setting, patient characteristics and treatment selection. Matched pair analysis and propensity score matching were used to assess all-cause in-hospital death rates based on data from 25'250 patients (8'577 patients on prasugrel, 5'995 on ticagrelor, and 10'678 on clopidogrel). The odds ratio for death of any cause when compared to clopidogrel were 0.72 (CI 0.62 - 0.84, p < 0.001) in favor of the new P2Y12 receptor inhibitors (prasugrel and ticagrelor combined). In the comparison between prasugrel and ticagrelor, there were no relevant differences (OR 0.97; CI 0.77 -1.23, p = 0.81). Event rates of cardiovascular death and stroke were also substantially lower for the new P2Y12 receptor inhibitors. The differences between clopidogrel and prasugrel or ticagrelor on major bleeding were numerically in the same order as for death of any cause, but were not statistically significant. No differences in ischemic and bleeding outcomes were observed between prasugrel and ticagrelor.

Conclusion: This analysis suggests that the prasugrel or ticagrelor compared to clopidogrel have favorable outcomes in clinical practice while not being inferior in terms of safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ehjcvp/pvaa002DOI Listing
January 2020

Intensified lipid lowering using ezetimibe after publication of the IMPROVE-IT trial: A contemporary analysis from the SPUM-ACS cohort.

Int J Cardiol 2020 03 10;303:8-13. Epub 2019 Dec 10.

Cardiology Division, Geneva University Hospitals, Switzerland.

Background: The relevance of the IMPROVE-IT trial on real-life practice has not been explored in patients with ACS.

Methods: A prospective Swiss cohort of 6266 patients hospitalized for ACS between 2009 and 2017 with a one-year follow-up. The primary endpoints were the ezetimibe use overall or in combination with high-intensity statin at discharge and at one year after ACS. Secondary endpoint was LDL-C target achievement at one year in a subsample of 2984 patients. Relative Ratios (RR) were used to assess changes in primary endpoints before and after the publication of IMPROVE-IT, adjusting for age, sex, diabetes, prior myocardial infarction, LDL-C and attendance to cardiac rehabilitation.

Results: The period following the publication of the IMPROVE-IT trial was associated with a steady increase in the use of ezetimibe at discharge (from 1.8% to 3.8%, P < 0.001, adjusted RR 2.85, 95% CI 1.90-4.25) and at one year (from 5.0% to 13.8%, P < 0.001, adjusted RR 3.00, 95% CI 2.40-3.75). The combination of high-intensity statin and ezetimibe rose from 0.9% to 2.1% at discharge (P < 0.001, adjusted RR 3.35, 95% CI 1.90-5.89) and from 2.1% to 7.8% at one year (P < 0.001, adjusted RR 3.98, 95% CI 2.90-5.47). The period following the publication of the IMPROVE-IT trial was associated with an improvement of LDL-C target <1.8 mmol/L (adjusted RR 1.37, 95% CI 1.12-1.68).

Conclusions: After the publication of the IMPROVE-IT trial, the use of ezetimibe was increased by three-fold in a large contemporary cohort of ACS patients, concomitant with an improved LDL-C target achievement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2019.12.011DOI Listing
March 2020

Cardiomyocyte-Specific JunD Overexpression Increases Infarct Size following Ischemia/Reperfusion Cardiac Injury by Downregulating Sirt3.

Thromb Haemost 2020 Jan 13;120(1):168-180. Epub 2019 Dec 13.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Zurich, Switzerland.

Ischemia/reperfusion (I/R) injury in acute myocardial infarction activates several deleterious molecular mechanisms. The transcription factor JunD regulates pathways involved in oxidative stress as well as in cellular proliferation, differentiation, and death. The present study investigated the potential role of JunD as a modulator of myocardial injury pathways in a mouse model of cardiac I/R injury. Infarct size, systemic and local inflammation, and production of reactive oxygen species, as well as cytosolic and mitochondrial apoptotic pathways were investigated in adult males after myocardial I/R. In wild-type (WT) mice, 30 minutes after ischemia and up to 24 hours following reperfusion, cardiac messenger ribonucleic acid expression was reduced while increased. Cardiac-specific JunD overexpressing mice ( ) displayed larger infarcts compared with WT. However, postischemic inflammatory or oxidative responses did not differ. JunD overexpression reduced Sirt3 transcription by binding to its promoter, thus leading to mitochondrial dysfunction, myocardial cell death, and increased infarct size. On the other hand, JunD silencing reduced, while Sirt3 silencing increased infarct size. In human myocardial autopsy specimens, JunD-positive areas within the infarcted left ventricle staining corresponded to undetectable Sirt3 areas in consecutive sections of the same heart. Cardiac-specific JunD overexpression increases myocardial infarct size following I/R. These effects are mediated via Sirt3 transcriptional repression, mitochondrial swelling, and increased apoptosis, suggesting that JunD is a key regulator of myocardial I/R injury. The present data set the stage for further investigation of the potential role of Sirt3 activation as a novel target for the treatment of acute myocardial infarction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-3400299DOI Listing
January 2020

Interleukin-1β Mediates Arterial Thrombus Formation via NET-Associated Tissue Factor.

J Clin Med 2019 Nov 26;8(12). Epub 2019 Nov 26.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, 8952 Schlieren, Switzerland.

CANTOS reported reduced secondary atherothrombotic events in patients with residual inflammatory risk treated with the inhibitory anti-IL-1β antibody, Canakinumab. Yet, mechanisms that underlie this benefit remain elusive. Recent work has implicated formation of neutrophil extracellular traps (NETosis) in arterial thrombosis. Hence, the present study explored the potential link between IL-1β, NETs, and tissue factor (TF)-the key trigger of the coagulation cascade-in atherothrombosis. To this end, ST-elevation myocardial infarction (STEMI) patients from the Swiss multicenter trial SPUM-ACS were retrospectively and randomly selected based on their CRP levels. In particular, 33 patients with STEMI and high C-reactive protein (CRP) levels (≥ 10 mg/L) and, 33 with STEMI and low CRP levels (≤ 4 mg/L) were investigated. High CRP patients displayed elevated circulating IL-1β, NETosis, and NET-associated TF plasma levels compared with low CRP ones. Additionally, analysis of patients stratified by circulating IL-1β levels yielded similar results. Moreover, NETosis and NET-associated TF plasma levels correlated positively in the whole population. In addition to the above, translational research experiments provided mechanistic confirmation for the clinical data identifying IL-1β as the initial trigger for the release of the pro-coagulant, NET-associated TF. In conclusion, blunted TF presentation by activated neutrophils undergoing NETosis may provide a mechanistic explanation to reduced secondary atherothrombotic events as observed in canakinumab-treated patients in CANTOS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm8122072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947515PMC
November 2019

Prognosis of Patients with Chronic and Hospital-Acquired Anaemia After Acute Coronary Syndromes.

J Cardiovasc Transl Res 2020 08 25;13(4):618-628. Epub 2019 Nov 25.

Department of Cardiology, Lausanne University Center Hospital, Rue du Bugnon 46, CH-1011, Lausanne, Switzerland.

Discharge anaemia is common following acute coronary syndromes (ACS). However, it is unknown if chronic anaemia (CA) and hospital-acquired anaemia (HAA) are associated with similar outcomes. In this retrospective analysis of 4083 ACS admissions treated with percutaneous coronary intervention in Switzerland (SPUM-ACS registry), 1896 patients (46.4%) had discharge anaemia (CA: n = 643 (15.7%) vs. HAA: n = 1253 (30.7%)). Landmark analysis that matched patients with CA (n = 504) and HAA (n = 866) with non-anaemic patients found increased 1-year major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, stroke) among patients with CA (6.9% vs. 3.0%, HR 2.073, 95% CI 1.039-4.134, p = 0.039) and HAA (3.8% vs. 2.3%, HR 1.772, 95% CI 1.002-3.232, p = 0.049). Only CA was associated with increased 1-year all-cause mortality (7.9% vs. 1.6%, HR 4.255, 95% CI 1.950-9.284, p < 0.001). CA and HAA were associated with poor 1-year cardiovascular outcomes. Only CA was associated with increased all-cause mortality suggesting that HAA and CA represent distinct subclinical entities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12265-019-09934-wDOI Listing
August 2020

Diabetes and baseline glucose are associated with inflammation, left ventricular function and short- and long-term outcome in acute coronary syndromes: role of the novel biomarker Cyr 61.

Cardiovasc Diabetol 2019 10 31;18(1):142. Epub 2019 Oct 31.

Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland.

Background: Hyperglycemia in the setting of an acute coronary syndrome (ACS) impacts short term outcomes, but little is known about longer term effects. We therefore designed this study to firstly determine the association between hyperglycemia and short term and longer term outcomes in patients presenting with ACS and secondly evaluate the prognostic role of diabetes, body mass index (BMI) and the novel biomarker Cyr61 on outcomes.

Methods: The prospective Special Program University Medicine-Acute Coronary Syndrome (SPUM-ACS) cohort enrolled 2168 patients with ACS between December 2009 and October 2012, of which 2034 underwent PCI (93.8%). Patients were followed up for 12 months. Events were independently adjudicated by three experienced cardiologists. Participants were recruited from four tertiary hospitals in Switzerland: Zurich, Geneva, Lausanne and Bern. Participants presenting with acute coronary syndromes and who underwent coronary angiography were included in the analysis. Patients were grouped according to history of diabetes (or HbA1c greater than 6%), baseline blood sugar level (BSL; < 6, 6-11.1 and > 11.1 mmol/L) and body mass index (BMI). The primary outcome was major adverse cardiac events (MACE) which was a composite of myocardial infarction, stroke and all-cause death. Secondary outcomes included the individual components of the primary endpoint, revascularisations, bleeding events (BARC classification) and cerebrovascular events (ischaemic or haemorrhagic stroke or TIA).

Results: Patients with hyperglycemia, i.e. BSL ≥ 11.1 mmol/L, had higher levels of C-reactive protein (CRP), white blood cell count (WBC), creatinine kinase (CK), higher heart rates and lower left ventricular ejection fraction (LVEF) and increased N-terminal pro-brain natriuretic peptide. At 30 days and 12 months, those with BSL ≥ 11.1 mmol/L had more MACE and death compared to those with BSL < 6.0 mmol/L or 6.0-11.1 mmol/L (HR-ratio 4.78 and 6.6; p < 0.001). The novel biomarker Cyr61 strongly associated with high BSL and STEMI and was independently associated with 1 year outcomes (HR 2.22; 95% CI 1.33-3.72; Tertile 3 vs. Tertile 1).

Conclusions And Relevance: In this large, prospective, independently adjudicated cohort of in all comers ACS patients undergoing PCI, both a history of diabetes and elevated entry glucose was associated with inflammation and increased risk of MACE both at short and long-term. The mediators might involve increased sympathetic activation, inflammation and ischemia as reflected by elevated Cyr61 levels leading to larger levels of troponin and lower LVEF. Trial registration Clinical Trial Registration Number: NCT01000701. Registered October 23, 2009.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12933-019-0946-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824030PMC
October 2019

Control of cardiovascular risk factors and health behaviors in patients post acute coronary syndromes eligible for protein convertase subtilisin/kexin-9 inhibitors.

Int J Cardiol 2020 01 9;299:289-295. Epub 2019 Oct 9.

Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland.

Background: We aimed to examine cardiovascular risk factors and health behaviors in patients with acute coronary syndromes (ACS) according to potential extension of eligibility criteria for protein convertase subtilisin/kexin-9 inhibitors (PCSK9i) to all patients with low-density lipoprotein cholesterol (LDL-c) equal or above 1.8 mmol/l.

Methods: In this prospective cross-sectional study, patients with ACS between 2009 and 2016 and with available LDL-c at one year were considered. We defined three mutually exclusive groups of patients according to eligibility for PCSK9i: "not eligible", "currently eligible", and "newly eligible". We explored the control of cardiovascular risk factors and health behaviors.

Results: Out of 3025 patients who had an ACS one year ago, 1071 (35.4%) were not eligible for PCSK9i, 415 (13.7%) were currently eligible, and 1539 (50.9%) were newly eligible. The proportion of patients with uncontrolled hypertension in the not eligible group was lower than in the group currently eligible (27.6% vs 33.6%, p = 0.02), but similar to the group newly eligible (27.6% vs 28.2%, p = 0.73). The proportion of smokers in the not eligible group was lower than in the group currently eligible (21.2% vs 28.0%, p = 0.02), but similar to the group newly eligible (21.2% vs 22.5%, p = 0.51).

Conclusions: More than half of patients with ACS would be additionally eligible for PCSK9i if prescription is extended from current guidelines to all patients with LDL-c equal or above 1.8 mmol/l. Patients currently eligible for PCSK9i one year after an ACS had a worst control of cardiovascular risk factors than patients potentially newly eligible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2019.10.012DOI Listing
January 2020

Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood-brain barrier integrity: a translational study.

Eur Heart J 2020 04;41(16):1575-1587

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, Schlieren 8952, Switzerland.

Aims: Aging is an established risk factor for stroke; genes regulating longevity are implicated in the pathogenesis of ischaemic stroke where to date, therapeutic options remain limited. The blood-brain barrier (BBB) is crucially involved in ischaemia/reperfusion (I/R) brain injury thus representing an attractive target for developing novel therapeutic agents. Given the role of endothelial cells in the BBB, we hypothesized that the endothelial-specific expression of the recently described longevity gene SIRT6 may exhibit protective properties in stroke.

Methods And Results: SIRT6 endothelial expression was reduced following stroke. Endothelial-specific Sirt6 knockout (eSirt6-/-) mice, as well as animals in which Sirt6 overexpression was post-ischaemically induced, underwent transient middle cerebral artery occlusion (tMCAO). eSirt6-/- animals displayed increased infarct volumes, mortality, and neurological deficit after tMCAO, as compared to control littermates. Conversely, post-ischaemic Sirt6 overexpression decreased infarct size and neurological deficit. Analysis of ischaemic brain sections revealed increased BBB damage and endothelial expression of cleaved caspase-3 in eSIRT6-/- mice as compared to controls. In primary human brain microvascular endothelial cells (HBMVECs), hypoxia/reoxygenation (H/R) reduced SIRT6 expression and SIRT6 silencing impaired the barrier function (transendothelial resistance) similar to what was observed in mice exposed to I/R. Further, SIRT6-silenced HBMVECs exposed to H/R showed reduced viability, increased cleaved caspase-3 expression and reduced activation of the survival pathway Akt. In ischaemic stroke patients, SIRT6 expression was higher in those with short-term neurological improvement as assessed by NIHSS scale and correlated with stroke outcome.

Conclusion: Endothelial SIRT6 exerts a protective role in ischaemic stroke by blunting I/R-mediated BBB damage and thus, it may represent an interesting novel therapeutic target to be explored in future clinical investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehz712DOI Listing
April 2020

Evolocumab for Early Reduction of LDL Cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS).

J Am Coll Cardiol 2019 11 31;74(20):2452-2462. Epub 2019 Aug 31.

Department of Cardiology, Geneva University Hospital, Geneva, Switzerland.

Background: Although guidelines recommend in-hospital initiation of high-intensity statin therapy in patients with acute coronary syndromes (ACS), low-density lipoprotein cholesterol (LDL-C) target levels are frequently not attained. Evolocumab, a rapidly acting, potent LDL-C-lowering drug, has not been studied in the acute phase of ACS.

Objectives: The purpose of this study was to assess the feasibility, safety, and LDL-C-lowering efficacy of evolocumab initiated during the in-hospital phase of ACS.

Methods: The authors conducted an investigator-initiated, randomized, double-blind, placebo-controlled trial involving 308 patients hospitalized for ACS with elevated LDL-C levels (≥1.8 mmol/l on high-intensity statin for at least 4 weeks; ≥2.3 mmol/l on low- or moderate-intensity statin; or ≥3.2 mmol/l on no stable dose of statin). Patients were randomly assigned 1:1 to receive subcutaneous evolocumab 420 mg or matching placebo, administered in-hospital and after 4 weeks, on top of atorvastatin 40 mg. The primary endpoint was percentage change in calculated LDL-C from baseline to 8 weeks.

Results: Most patients (78.2%) had not been on previous statin treatment. Mean LDL-C levels decreased from 3.61 to 0.79 mmol/l at week 8 in the evolocumab group, and from 3.42 to 2.06 mmol/l in the placebo group; the difference in mean percentage change from baseline was -40.7% (95% confidence interval: -45.2 to -36.2; p < 0.001). LDL-C levels <1.8 mmol/l were achieved at week 8 by 95.7% of patients in the evolocumab group versus 37.6% in the placebo group. Adverse events and centrally adjudicated cardiovascular events were similar in both groups.

Conclusions: In this first randomized trial assessing a PCSK9 antibody in the very high-risk setting of ACS, evolocumab added to high-intensity statin therapy was well tolerated and resulted in substantial reduction in LDL-C levels, rendering >95% of patients within currently recommended target levels. (EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients With Acute Coronary Syndromes [EVOPACS]; NCT03287609).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2019.08.010DOI Listing
November 2019

Non-Linear Relationship between Anti-Apolipoprotein A-1 IgGs and Cardiovascular Outcomes in Patients with Acute Coronary Syndromes.

J Clin Med 2019 Jul 9;8(7). Epub 2019 Jul 9.

Division of Cardiology, Cardiology Center, Geneva University Hospital, 1205 Geneva Switzerland.

Autoantibodies against apolipoprotein A-I (anti-apoA-I IgGs) are prevalent in atherosclerosis-related conditions. It remains elusive whether they improve the prognostic accuracy of the Global Registry of Acute Coronary Events (GRACE) score 2.0 (GS) in acute coronary syndromes (ACS). In this prospective multicenter registry, 1713 ACS patients were included and followed for 1 year. The primary endpoint (major adverse cardiovascular events (MACE)) was defined as the composite of myocardial infarction, stroke (including transient ischemic attack), or cardiovascular (CV) death with individual events independently adjudicated. Plasma levels of anti-apoA-I IgGs upon study inclusion were assessed using ELISA. The association between anti-apoA-I IgGs and incident MACE was assessed using Cox models with splines and C-statistics. One-year MACE incidence was 8.4% (144/1713). Anti-apoA-I IgG levels were associated with MACE with a non-linear relationship ( = 0.01), which remained unchanged after adjusting for the GS ( = 0.04). The hazard increased progressively across the two first anti-apoA-I IgG quartiles before decreasing thereafter. Anti-apoA-I IgGs marginally improved the prognostic accuracy of the GS (c-statistics increased from 0.68 to 0.70). In this multicenter study, anti-apoA-I IgGs were predictive of incident MACE in ACS independently of the GS but in a nonlinear manner. The practical implications of these findings remain to be defined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm8071002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679072PMC
July 2019

Risk stratification of elderly patients with acute pulmonary embolism.

Eur J Clin Invest 2019 Sep 16;49(9):e13154. Epub 2019 Jul 16.

Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: Combining high-sensitivity cardiac Troponin T (hs-cTnT), NT-pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) may improve risk stratification of patients with pulmonary embolism (PE) beyond the PESI risk score.

Methods: In the prospective multicentre SWITCO65+ study, we analysed 214 patients ≥ 65 years with a new submassive PE. Biomarkers and clinical information for the PESI risk score were ascertained within 1 day after diagnosis. Associations of hs-TnT, NT-proBNP, hs-CRP and the PESI risk score with the primary endpoint defined as 6-month mortality were assessed. The discriminative power of the PESI risk score and its combination with hs-cTnT, NT-proBNP and hs-CRP for 6-month mortality was compared using integrated discrimination improvement (IDI) index and net reclassification improvement (NRI).

Results: Compared with the lowest quartile, patients in the highest quartile had a higher risk of death during the first 6 months for hs-cTnT (adjusted HR 10.22; 95% CI 1.79-58.34; P = 0.009) and a trend for NT-proBNP (adjusted HR 4.3; 95% CI 0.9-20.41; P = 0.067) unlike hs-CRP (adjusted HR 1.97; 95% CI 0.48-8.05; P = 0.344). The PESI risk score (c-statistic 0.77 (95% CI 0.69-0.84) had the highest prognostic accuracy for 6-month mortality, outperforming hs-cTnT, NT-proBNP and hs-CRP (c-statistics of 0.72, 0.72, and 0.54), respectively. Combining all three biomarkers had no clinically relevant impact on risk stratification when added to the PESI risk score (IDI = 0.067; 95% CI 0.012-0.123; P = 0.018; NRI = 0.101 95% CI -0.099-0.302; P = 0.321).

Conclusions: In elderly patients with PE, 6-month mortality can adequately be predicted by the PESI risk score alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/eci.13154DOI Listing
September 2019

Prognostic value of total testosterone levels in patients with acute coronary syndromes.

Eur J Prev Cardiol 2019 Jun 1:2047487319853343. Epub 2019 Jun 1.

1 Cardiology Division, Geneva University Hospitals, Switzerland.

Background: Endogenous testosterone levels decrease in men with aging. Controversies persist regarding the screening and treatment of low testosterone levels in patients with acute coronary syndromes (ACS).

Methods And Results: Total serum testosterone levels were measured in 1054 men hospitalized for ACS that were part of a Swiss prospective cohort. Total testosterone levels were classified first in tertiles and using the cut-off of 300 ng/dL. Primary endpoint was all-cause mortality at one year. Cox regression models adjusting for the GRACE score (composite of age, heart rate systolic blood pressure, creatinine, cardiac arrest at admission, ST segment deviation, abnormal troponin enzyme and Killip classification), preexisting diabetes and inflammation (high-sensitivity C-reactive protein). A total of 430 men (40.8%) had total testosterone levels ≤300 ng/dL. Low total testosterone levels were correlated with lower high-density lipoprotein cholesterol and higher triglycerides, high-sensitivity C-reactive protein, high-sensitivity troponin T, N-terminal-pro B-type natriuretic peptide and glucose levels (all p < 0.01). Patients in the lowest testosterone tertile had a mortality rate at one-year of 5.4% compared with 2.9% in the highest tertile with an unadjusted hazard ratio of 1.92 (95% confidence interval 0.96-1.90, p = 0.095) and adjusted hazard ratio of 1.26 (95% confidence interval 0.57-2.78, p = 0.565). In an exploratory analysis, the highest mortality rate (10.3%) was observed in men aged >65 years old belonging to the lowest testosterone tertile.

Conclusion: In this large population of men with ACS, we found a prevalence of low total endogenous testosterone levels of almost 40%. However, low testosterone levels were not significantly associated with mortality after adjustment for high-risk confounders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2047487319853343DOI Listing
June 2019

Trimethyllysine, a trimethylamine N-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes.

Eur Heart J 2019 08;40(32):2700-2709

Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

Aims: Trimethyllysine (TML) serves as a nutrient precursor of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) and is associated with incident cardiovascular (CV) events in stable subjects. We examined the relationship between plasma TML levels and incident CV events in patients presenting with acute coronary syndromes (ACS).

Methods And Results: Plasma levels of TML were quantified in two independent cohorts using mass spectrometry, and its relationship with CV events was investigated. In a Cleveland Cohort (N = 530), comprised of patients presenting to the emergency department with chest pain and suspected ACS, TML was associated with major adverse cardiac events (MACE, myocardial infarction, stroke, need for revascularization, or all-cause mortality) over both 30 days [3rd tertile (T3), adjusted odds ratio (OR) 1.77, 95% confidence interval (CI) 1.04-3.01; P < 0.05] and 6 months (T3, adjusted OR 1.95, 95% CI 1.15-3.32; P < 0.05) of follow-up independent of traditional CV risk factors and indices of renal function. Elevated TML levels were also associated with incident long-term (7-year) all-cause mortality [T3, adjusted hazard ratio (HR) 2.52, 95% CI 1.50-4.24; P < 0.001], and MACE even amongst patients persistently negative for cardiac Troponin T at presentation (e.g. 30-day MACE, T3, adjusted OR 4.49, 95% CI 2.06-9.79; P < 0.001). Trimethyllysine in combination with TMAO showed additive significance for near- and long-term CV events, including patients with 'negative' high-sensitivity Troponin T levels. In a multicentre Swiss Cohort (N = 1683) comprised of ACS patients, similar associations between TML and incident 1-year adverse cardiac risks were observed (e.g. mortality, adjusted T3 HR 2.74, 95% CI 1.28-5.85; P < 0.05; and MACE, adjusted T3 HR 1.55, 95% CI 1.04-2.31; P < 0.05).

Conclusion: Plasma TML levels, alone and together with TMAO, are associated with both near- and long-term CV events in patients with chest pain and ACS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehz259DOI Listing
August 2019

Inflammation during acute coronary syndromes - Risk of cardiovascular events and bleeding.

Int J Cardiol 2019 07 27;287:13-18. Epub 2019 Mar 27.

Department of Cardiology, University Heart Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Background: Many parameters can affect the level of inflammation during acute coronary syndromes (ACS). We aimed to assess the one-year risk of major adverse cardiovascular events (MACE) and bleeding associated with elevated hsCRP levels during ACS, taking into account the severity of myocardial infarction, the timing of blood sampling and established long-term prognostic factors.

Methods: We studied 1864 consecutive patients with ACS enrolled in a contemporary multicenter prospective cohort study in Switzerland. HsCRP levels were determined at hospital admission. One year after discharge MACE and bleeding events were assessed. Multivariable adjusted Cox proportional hazards were computed with age, sex, time from symptom onset to blood draw, body mass index, current smoking, hypertension, diabetes mellitus, pre-existing cardiovascular disease, history of inflammatory disease, LDL-cholesterol levels, type of ACS, left ventricular ejection fraction and GRACE 1.0 risk score.

Results: At one-year follow-up, 151 (8.1%) patients suffered MACE. Compared to patients with hsCRP below 2 mg/l, the risk of MACE was higher in patients with hsCRP levels between 2 and 5 mg/l, with a multivariate adjusted hazard ratio (HR) of 1.63 (95% confidence interval (CI) 0.93-2.84), in those with levels between 5 and 10 mg/l, with a HR of 2.80 (95% CI 1.58-4.96), and in those with levels above 10 mg/l, with a HR of 2.23 (95% CI 1.28-3.88). There was no difference in bleeding risk between the four groups.

Conclusions: Systemic inflammation in the acute phase of myocardial infarction is an independent predictor for cardiovascular events, but not for bleeding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2019.03.049DOI Listing
July 2019

Association between income and control of cardiovascular risk factors after acute coronary syndromes: an observational study.

Swiss Med Wkly 2019 Apr 17;149:w20049. Epub 2019 Apr 17.

Department of Ambulatory Care and Community Medicine, University of Lausanne, Switzerland.

Background: The role of income in cardiovascular disease prevention after an acute coronary syndrome (ACS) remains unclear. We aimed to assess the association between income and control of cardiovascular risk factors one year after an ACS in a country with universal health insurance.

Methods: Between 2013 and 2014, we studied 255 consecutive patients with ACS in an observational study in a university hospital in Switzerland in which self-reported household income was assessed. We classified patients into two categories based on the median income in Switzerland: higher than CHF 6000 (€ 5300) or less than or equal to CHF 6000 (€ 5300) per month. One year after discharge, patients were evaluated for the achievement of lipid and blood pressure targets, smoking cessation and drug adherence. Multivariate odds ratios (OR) were adjusted for age, sex, education, living status and working status.

Results: Overall, 52.2% (n = 133) of patients with ACS were in the low-income category and 47.8% (n = 122) were in the high-income category. One year after discharge, high-income patients had higher rates of smoking cessation (64.2 vs 30.1%, multivariate-adjusted odds ratio (OR) 3.82, 95% confidence interval (CI) 1.58–9.24) and blood pressure target achievement (78.6 vs 60.2%, multivariate-adjusted OR 2.19, 95% CI 1.09–4.41) compared to those in the low-income category. There were no differences regarding adherence to drugs or lipid control between the two income groups.

Conclusion: A high household income was associated with a higher rate of smoking cessation and better control of blood pressure one year after ACS, independently of education, living status and working status.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4414/smw.2019.20049DOI Listing
April 2019

Prognostic value of elevated lipoprotein(a) in patients with acute coronary syndromes.

Eur J Clin Invest 2019 Jul 7;49(7):e13117. Epub 2019 May 7.

Cardiology Division, Geneva University Hospitals, Geneva, Switzerland.

Background: Minimal lipoprotein(a) [Lp(a)] target values are advocated for high-risk cardiovascular patients. We investigated the prognostic value of Lp(a) in the acute setting of patients with acute coronary syndromes (ACS).

Materials And Methods: Plasma levels of Lp(a) were collected at time of angiography from 1711 patients hospitalized for ACS in a multicentre Swiss prospective cohort. Associations between elevated Lp(a) ≥30 mg/dL (cut-off corresponding to the 75th percentile of the assay) or Lp(a) tertiles at baseline, and major adverse cardiovascular events (MACE) at 1 year, defined as a composite of cardiac death, myocardial infarction or stroke, were assessed using hazard ratios (HR) and 95% confidence intervals (CI) adjusting for traditional cardiovascular risk factors (age, sex, smoking, diabetes, hypertension, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides.

Results: Lp(a) levels range between 2.5 and 132 mg/dL with a median value of 6 mg/dL and a mean value of 14.2 mg/dL. A total of 276 patients (23.0%) had Lp(a) plasma levels ≥30 mg/dL. Patients with elevated Lp(a) were more likely to be of female gender and to have higher levels of total cholesterol, LDL-C, HDL-C and triglycerides. Higher Lp(a) was associated with failure to reach the LDL-C target <1.8 mmol/L at 1 year (HR 1.71, 95% CI 1.13-2.58, P = 0.01). No association was found between elevated Lp(a) and MACE at 1 year (HR 1.05, 95% CI 0.64-1.73), nor for Lp(a) tertiles (HR 0.82, 95% CI 0.52-1.28, P > 0.20) or standardized continuous variables (0.98, 95% CI 0.82-1.19 for each increase of standard deviation).

Conclusions: Our real-world data suggest high Lp(a) levels at time of angiography are not predictive for cardiovascular outcomes in patients otherwise medically well controlled, but might be useful to identify patients who would not be on LDL-C targets 1 year after ACS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/eci.13117DOI Listing
July 2019

Clinical impact of a structured secondary cardiovascular prevention program following acute coronary syndromes: A prospective multicenter healthcare intervention.

PLoS One 2019 21;14(2):e0211464. Epub 2019 Feb 21.

Cardiology Division, Geneva University Hospitals, Geneva, Switzerland.

Background: Structured secondary cardiovascular prevention programs (SSCP) following acute coronary syndromes (ACS) may reduce major adverse cardiovascular events (MACE) through better adherence to post-ACS recommendations.

Methods: Through a prospective multicenter cohort study, we compared the outcomes of two sequential post-ACS patient cohorts, the initial one receiving standard care (SC) followed by one receiving additional interventions (SSCP) aimed at improving patient education as well as healthcare provider and hospital systems. The primary endpoint was MACE at one year. Secondary endpoints included adherence to recommended therapies, attendance to cardiac rehabilitation (CR) and successful achievement of cardiovascular risk factor (CVRF) targets.

Results: In total, 2498 post-ACS patients from 4 Swiss university hospitals were included: 1210 vs 1288 in the SC and SSCP groups, respectively. The SSCP group demonstrated a significant increase in attendance to CR programs (RR 1.08, 95%CI 1.02-1.14, P = 0.006), despite not achieving the primary MACE endpoint (HR 0.97, 95%CI 0.77-1.22, P = 0.79). After age-stratification, significant reductions in cardiac death, MI and stroke events (HR 0.53, 95%CI 0.30-0.93, P for interaction = 0.016) were observed for SSCP patients ≤ 65 years old. The SSCP group also scored significantly better for the LDL cholesterol target (RR 1.07, 95%CI 1.02-1.13, P = 0.012), systolic blood pressure target (RR 1.06, 95%CI 1.01-1.13, P = 0.029) and physical activity (RR 1.10, 95%CI 1.01-1.20, P = 0.021).

Conclusions: The implementation of an SSCP post ACS was associated with an improvement in the control of CVRF and attendance to CR programs, and was also associated with significant reductions in cardiac death, MI and stroke at one year for patients ≤65years old.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211464PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383891PMC
November 2019

Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy.

Eur Heart J 2019 03;40(12):997-1008

Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, Schlieren, Switzerland.

Aims: Metabolic cardiomyopathy (MC)-characterized by intra-myocardial triglyceride (TG) accumulation and lipotoxic damage-is an emerging cause of heart failure in obese patients. Yet, its mechanisms remain poorly understood. The Activator Protein 1 (AP-1) member JunD was recently identified as a key modulator of hepatic lipid metabolism in obese mice. The present study investigates the role of JunD in obesity-induced MC.

Methods And Results: JunD transcriptional activity was increased in hearts from diet-induced obese (DIO) mice and was associated with myocardial TG accumulation and left ventricular (LV) dysfunction. Obese mice lacking JunD were protected against MC. In DIO hearts, JunD directly binds PPARγ promoter thus enabling transcription of genes involved in TG synthesis, uptake, hydrolysis, and storage (i.e. Fas, Cd36, Lpl, Plin5). Cardiac-specific overexpression of JunD in lean mice led to PPARγ activation, cardiac steatosis, and dysfunction, thereby mimicking the MC phenotype. In DIO hearts as well as in neonatal rat ventricular myocytes exposed to palmitic acid, Ago2 immunoprecipitation, and luciferase assays revealed JunD as a direct target of miR-494-3p. Indeed, miR-494-3p was down-regulated in hearts from obese mice, while its overexpression prevented lipotoxic damage by suppressing JunD/PPARγ signalling. JunD and miR-494-3p were also dysregulated in myocardial specimens from obese patients as compared with non-obese controls, and correlated with myocardial TG content, expression of PPARγ-dependent genes, and echocardiographic indices of LV dysfunction.

Conclusion: miR-494-3p/JunD is a novel molecular axis involved in obesity-related MC. These results pave the way for approaches to prevent or treat LV dysfunction in obese patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehy903DOI Listing
March 2019

A high Gas6 level in plasma predicts venous thromboembolism recurrence, major bleeding and mortality in the elderly: a prospective multicenter cohort study.

J Thromb Haemost 2019 02;17(2):306-318

Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Essentials Predictive ability of pro-hemostatic Gas6 for recurrent venous thromboembolism (VTE) is unknown. We measured Gas6 levels in 864 patients with VTE over 3 years. High Gas6 (> 157%) at diagnosis is associated with VTE recurrence, major bleeding and mortality. Gas6 plasma levels measured 12 months after the index VTE are discriminatory for VTE recurrence. SUMMARY: Background Growth arrest-specific gene 6 (Gas6) is a prohemostatic protein with an unknown predictive ability for recurrent venous thromboembolism (VTE). In the elderly, VTE results in higher mortality but does not have a higher rate of recurrence than in younger patients. Consequently, anticoagulation management in the elderly is challenging. Objective To prospectively investigate the performance of Gas6 in predicting VTE recurrence, major bleeding and mortality in the elderly. Methods Consecutive patients aged ≥ 65 years with acute VTE were followed for a period of 3 years. Primary outcomes were symptomatic VTE recurrence, major bleeding, and mortality. Plasma Gas6 was measured with ELISA. Results Gas6 levels were measured in 864 patients at the time of the index VTE (T1) and, in 70% of them, also 12 months later (T2). The Gas6 level at T1 was discriminatory for VTE recurrence (C-statistic, 0.56; 95% confidence interval [CI] 0.51-0.62), major bleeding (0.60, 95% CI 0.55-0.65) and mortality (0.69, 95% CI 0.65-0.73) up to 36 months. VTE recurrence up to 24 months after T2 was discriminated by the Gas6 level at T2 (0.62, 95% CI 0.54-0.71). High Gas6 levels (> 157%) and continuous Gas6 levels at T1 were associated with VTE recurrence up to 6 months and 12 months, respectively. Conclusions In elderly patients, a high Gas6 level is associated with higher risks of VTE recurrence, major bleeding, and death. These findings support further studies to assess the performance of Gas6 in adjusting the length of anticoagulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.14365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850608PMC
February 2019