Publications by authors named "François Mach"

409 Publications

Long-term effects of systematic smoking cessation counselling during acute coronary syndrome, a multicentre before-after study.

Swiss Med Wkly 2022 Jul 18;152:w30209. Epub 2022 Jul 18.

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

Trial Design: In the Special Program University Medicine-Acute Coronary Syndromes (SPUM-ACS) observational study (clinical trial registration: NCT01000701), a multicentre before-after clinical trial, we assessed 5-year outcome after acute coronary syndrome, comparing a systematic with an opportunistic smoking cessation counselling phase.

Methods: We studied smokers who were hospitalised for acute coronary syndromes (ACS), and we assessed self-reported smoking cessation, incidence of cardiovascular events and mortality 5 years after hospital discharge. In the observational phase, from August 2009 to October 2010, only smokers who requested smoking cessation counselling received it during hospitalisation. In the interventional phase, from November 2010 to February 2012, hospitalised smokers with ACS were systematically offered intensive smoking cessation counselling including four telephone calls within 2 months of discharge. Because of the before-after design, the care givers were aware of study phase. The objective was to assess whether systematic counselling to every smoker with ACS has an impact on the long-term smoking cessation rate, incidence of cardiovascular events and mortality. Missing data on smoking cessation were analysed with multiple imputation. The study was not powered to assess differences in 5-year smoking cessation rates or cardiovascular outcomes.

Results: Overall, 458 smokers with ACS were included at baseline (225 during the intervention phase and 233 during the observation phase). At 5 years, 286 (62.4%) reported their smoking status (140 for the intervention phase and 146 for the observation phase) and 51 (11.1%) had died. There was no statistically significant difference in the abstinence rate between the interventional phase (75/140, 54%), and the observational phase (68/146, 47%), with a risk ratio with multiple imputation adjusted for age, sex, education and ACS type of 1.13 (95% confidence interval [CI] 0.84-1.51, p = 0.4). The 5-year risk of major acute cardiovascular event was similar in the intervention phase as compared with the observational phase. The multivariate adjusted hazard ratio for all-cause mortality was 0.84 (95% CI 0.45-1.60, p = 0.6).

Conclusions: In this controlled long-term interventional study, systematic intensive smoking cessation counselling in all hospitalised smokers with ACS did not increase 5-year smoking cessation rates, nor decrease cardiovascular event recurrence, as compared with opportunistic smoking cessation counselling during hospitalization.
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http://dx.doi.org/10.4414/smw.2022.w30209DOI Listing
July 2022

Optimized Treatment of Refractory Hypercholesterolemia in Patients With Atherosclerotic Cardiovascular Disease or Heterozygous Familial Hypercholesterolemia With Alirocumab (OPTIMIZE).

Front Cardiovasc Med 2022 15;9:953040. Epub 2022 Jul 15.

Medical Department, Sanofi, Vernier, Switzerland.

Background: Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). In confirmatory trials, proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab substantially lowered LDL-C and reduced cardiovascular morbidity and mortality. However, the routine clinical use of alirocumab in Switzerland has not yet been studied.

Methods: In this prospective nation-wide cohort study, we aimed to investigate the patient profile and routine clinical efficacy and safety of alirocumab in 207 patients with ASCVD or heterozygous familial hypercholesterolemia and increased LDL-C despite maximally tolerated statin therapy. LDL-C was measured at baseline and after 3-months follow-up.

Results: Overall, mean age was 63 ± 11 years, 138 (67%) were men, and 168 (81%) had statin intolerance (SI). Patients with SI had a higher baseline LDL-C (4.3 ± 1.4 vs. 3.3 ± 1.4 mmol/l; < 0.001) and less frequently ASCVD (71% vs. 95%; = 0.002). After 3 months of treatment with alirocumab, LDL-C was reduced from 4.1 ± 1.5 to 2.0 ± 1.2 mmol/l (50.5%; < 0.001). Mean absolute and relative reductions in LDL-C were similar in patients with vs. without SI (2.2 ± 1.2 vs. 1.9 ± 1.3 mmol/l; = 0.24 and 49.0 vs. 56.6%; = 0.11, respectively). In total, adverse events were recorded in 25 (12%) patients, with no new safety signals.

Conclusions: In routine clinical practice, alirocumab was predominantly used in patients with SI suggesting that the great majority of patients with insufficient LDL-C control who would be candidates for alirocumab are not receiving this therapeutic option in Switzerland. LDL-C lowering was potent and similar in patients with and without SI, replicating the favorable efficacy-safety profile of alirocumab from randomized trials.
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http://dx.doi.org/10.3389/fcvm.2022.953040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9335009PMC
July 2022

Smoking cessation and depression after acute coronary syndrome.

Prev Med 2022 Jul 25:107177. Epub 2022 Jul 25.

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

Smoking and depression are risk factors for acute coronary syndrome (ACS) that often co-exist. We investigated the evolution of depression according to smoking cessation one-year after ACS. Data from 1822 ACS patients of the Swiss multicenter SPUM-ACS cohort study were analyzed over a one-year follow-up. Participants were classified in three groups based on smoking status one-year post-ACS - continuous smokers, smokers who quit within the year, and non-smokers. Depression status at baseline and one-year was assessed with the Center for Epidemiologic Studies Depression scale (CES-D) and antidepressant drug use. A CES-D score ≥ 16 defined depression. A multivariate-adjusted logistic regression model was used to calculate odds ratios (OR) between groups. The study sample mean age was 62.4 years and females represented 20.8%. At baseline, 22.6% were depressed, 40.9% were smokers, and 47.5% of these quit smoking over the year post-ACS. In comparison to depressed continuous smokers, depressed smokers who quit had an adjusted OR 2.59 (95% confidence interval (CI) 1.27-5.25) of going below a CES-D score of 16 or not using antidepressants. New depression at one-year was found in 24.4% of non-depressed smokers who quit, and in 27.1% of non-depressed continuous smokers, with an adjusted OR 0.85 (95% CI 0.55-1.29) of moving to a CES-D score of ≥16 or using antidepressants. In conclusion, smokers with depression at time of ACS who quit smoking improved their depression more frequently compared to continuous smokers. The incidence of new depression among smokers who quit after ACS was similar compared to continuous smokers.
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http://dx.doi.org/10.1016/j.ypmed.2022.107177DOI Listing
July 2022

Smoking cessation in people with and without diabetes after acute coronary syndrome.

Nicotine Tob Res 2022 Jul 5. Epub 2022 Jul 5.

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

Introduction: People with diabetes smoke at similar rates as those without diabetes, with cardiovascular consequences. Smoking cessation rates were compared between people with and without diabetes one year after an acute coronary syndrome (ACS).

Methods: People with ACS who smoked and were part of an observational prospective multicenter study in Switzerland were included from 2007 to 2017 and followed for 12 months. Seven-day point prevalence abstinence was assessed at 12-months follow-up. Association between diabetes and smoking cessation was assessed using multivariable-adjusted logistical regression model.

Results: 2'457 people with ACS who smoked were included, mean age 57 years old, 81.9% were men and 13.3% had diabetes. At one year, smoking cessation was 35.1% for people with diabetes and 42.6% for people without diabetes (p-value 0.01). After adjustment for age, sex and educational level, people with diabetes who smoked were less likely to quit smoking compared with people without diabetes who smoked (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.59-0.98, p-value=0.037). The multivariable-adjusted model, with further adjustments for personal history of previous cardiovascular disease and cardiac rehabilitation attendance, attenuated this association (OR 0.85, 95% CI 0.65-1.12, p-value=0.255). Among people with diabetes, cardiac rehabilitation attendance was a positive predictor of smoking cessation, and personal history of cardiovascular disease was a negative predictor of smoking cessation.

Conclusions: People with diabetes who smoke are less likely to quit smoking after an ACS and need tailored secondary prevention programs. In this population, cardiac rehabilitation is associated with increased smoking cessation.

Implication Section: This study provides new information on smoking cessation following acute coronary syndromes comparing people with and without diabetes. After an ACS, people with diabetes who smoked were less likely to quit smoking than people without diabetes. Our findings highlight the importance of tailoring secondary prevention to people with diabetes.
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http://dx.doi.org/10.1093/ntr/ntac161DOI Listing
July 2022

Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, phase 3 trial.

Lancet Haematol 2022 Aug 30;9(8):e585-e593. Epub 2022 Jun 30.

Department of Angiology, University Hospital Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland.

Background: COVID-19 is a viral prothrombotic respiratory infection. Heparins exert antithrombotic and anti-inflammatory effects, and might have antiviral properties. We aimed to investigate whether thromboprophylaxis with enoxaparin would prevent untoward hospitalisation and death in symptomatic, but clinically stable outpatients with COVID-19.

Methods: OVID was a randomised, open-label, parallel-group, investigator-initiated, phase 3 trial and was done at eight centres in Switzerland and Germany. Outpatients aged 50 years or older with acute COVID-19 were eligible if they presented with respiratory symptoms or body temperature higher than 37·5°C. Eligible participants underwent block-stratified randomisation (by age group 50-70 vs >70 years and by study centre) in a 1:1 ratio to receive either subcutaneous enoxaparin 40 mg once daily for 14 days versus standard of care (no thromboprophylaxis). The primary outcome was a composite of any untoward hospitalisation and all-cause death within 30 days of randomisation. Analysis of the efficacy outcomes was done in the intention-to-treat population. The primary safety outcome was major bleeding. The study was registered in ClinicalTrials.gov (NCT04400799) and has been completed.

Findings: At the predefined formal interim analysis for efficacy (50% of total study population), the independent Data Safety Monitoring Board recommended early termination of the trial on the basis of predefined statistical criteria having considered the very low probability of showing superiority of thromboprophylaxis with enoxaparin for the primary outcome under the initial study design assumptions. Between Aug 15, 2020, and Jan 14, 2022, from 3319 participants prescreened, 472 were included in the intention-to-treat population and randomly assigned to receive enoxaparin (n=234) or standard of care (n=238). The median age was 57 years (IQR 53-62) and 217 (46%) were women. The 30-day risk of the primary outcome was similar in participants allocated to receive enoxaparin and in controls (8 [3%] of 234 vs 8 [3%] of 238; adjusted relative risk 0·98; 95% CI 0·37-2·56; p=0·96). All hospitalisations were related to COVID-19. No deaths were reported during the study. No major bleeding events were recorded. Eight serious adverse events were recorded in the enoxaparin group versus nine in the control group.

Interpretation: These findings suggest thromboprophylaxis with enoxaparin does not reduce early hospitalisations and deaths among outpatients with symptomatic COVID-19. Futility of the treatment under the initial study design assumptions could not be conclusively assessed owing to under-representation of older patients and consequent low event rates.

Funding: SNSF (National Research Programme COVID-19 NRP78: 198352), University Hospital Zurich, University of Zurich, Dr-Ing Georg Pollert (Berlin), Johanna Dürmüller-Bol Foundation.
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http://dx.doi.org/10.1016/S2352-3026(22)00175-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243568PMC
August 2022

[A He(art) museum for an existential rebirth after a myocardial infarction].

Rev Med Suisse 2022 May;18(783):1065-1069

Service de cardiologie, Département de médecine, Hôpitaux universitaires de Genève, 1211 Genève 14.

Rebuilding one's life after a myocardial infarction requires mobilizing each and every resource available during a difficult period. Medical treatments, physical training and patient education (PE) help to initiate this process. Associating healthcare with art and culture is known to favour an existential « rebirth » and positive biological effects. Since 2019, we propose an initiation to museotherapy (museum in health) to patients in our cardiac rehabilitation program. This article summarizes the evidence about museotherapy benefits in cardiovascular diseases and describes the experience gathered by the cardiology service of the HUG since museotherapy was initiated in 2019.
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http://dx.doi.org/10.53738/REVMED.2022.18.783.1065DOI Listing
May 2022

A Short Intervention and an Interactive e-Learning Module to Motivate Medical and Dental Students to Enlist as First Responders: Implementation Study.

J Med Internet Res 2022 05 18;24(5):e38508. Epub 2022 May 18.

Division of Emergency Medicine, Department of Anesthesiology, Clinical Pharmacology, Intensive Care and Emergency Medicine, University of Geneva Hospitals and Faculty of Medicine, Geneva, Switzerland.

Background: Prompt and proficient basic life support (BLS) maneuvers are essential to increasing the odds of survival after out-of-hospital cardiac arrest. However, significant time can elapse before the arrival of professional rescuers. To decrease these delays, many countries have developed first responder networks. These networks are composed of BLS-certified lay or professional rescuers who can be dispatched by emergency medical communication centers to take care of those who experience out-of-hospital cardiac arrest. Many systems are, however, limited by a relatively low number of active first responders, and first-year medical and dental students may represent an almost untapped pool of potential rescuers. On top of providing an enhanced BLS coverage to the population, this could also help medical students be better prepared to their future role as certified health care providers and address societal expectations regarding health care students.

Objective: Our objective was to describe the impact of a short motivational intervention followed by a blended BLS course (e-learning and practice session) designed to motivate first-year medical and dental students to enlist as first responders.

Methods: A short, web-based, motivational intervention presenting this project took place, and first-year University of Geneva, Faculty of Medicine students were provided with a link to the study platform. Those who agreed to participate were redirected to a demographic questionnaire before registering on the platform. The participants were then asked to answer a second questionnaire designed to determine their baseline knowledge prior to following an interactive e-learning module. Upon completion, a web-based booking form enabling them to register for a 1-hour practice session was displayed. These sessions were held by senior medical students who had been trained and certified as BLS instructors. The participants who attended these practice sessions were asked to answer a postcourse questionnaire before receiving the certificate enabling them to register as first responders.

Results: Out of the 529 first-year students registered at University of Geneva, Faculty of Medicine on January 14, 2021, 190 (35.9%) initially agreed to participate. Moreover, 102 (19.3%) attended the practice sessions, and 48 (9.1%) had completed all training and enlisted as first responders on the dedicated platform, Save a Life, at 6 months (July 14, 2021). Postcourse confidence in resuscitation skills was associated with a higher likelihood of registering as first responder (P=.03). No association was found between prior BLS knowledge and the probability of registering to a practice session (P=.59), of obtaining a course completion certificate (P=.29), or of enlisting as first responder (P=.56).

Conclusions: This study shows that a motivational intervention associated with a short BLS course can convince medical students to enlist as first responders. Further studies are needed to understand the rather low proportion of medical students finally registering as first responders.

International Registered Report Identifier (irrid): RR2-10.2196/24664.
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http://dx.doi.org/10.2196/38508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9161047PMC
May 2022

Soluble lectin-like oxidized low-density lipoprotein receptor-1 predicts premature death in acute coronary syndromes.

Eur Heart J 2022 05;43(19):1849-1860

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

Aims: The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its shedding product [soluble LOX-1 (sLOX-1)] are implicated in atherosclerotic cardiovascular disease (ASCVD) pathogenesis. Herein, we examined the relationship of sLOX-1 with both fatal events and plaque progression in patients with acute coronary syndromes (ACS).

Methods And Results: Plasma sLOX-1 was assessed at baseline in ACS and chronic coronary syndrome (CCS) patients prospectively recruited in the multicentre SPUM-ACS study, with sex- and age-matched healthy subjects serving as additional controls (n = 2924). Compared with both CCS and controls, ACS patients showed markedly elevated sLOX-1 levels (median, 2.00 and 2.00 vs. 35.08 pg/mL; P < 0.0001) which were independently associated with increased mortality risk over 30-day [tertile (T)3: adjusted hazard ratio (HR), 3.11; 95% confidence interval (CI), 1.44-10.61; P = 0.0055] and 1-year intervals (T3: adjusted HR, 2.04; 95% CI, 1.19-3.92; P = 0.0098). Results remained consistent after adjustment for GRACE 2.0 (T3: adjusted HR, 1.86; 95% CI, 1.04-3.74; P = 0.0391) and were primarily driven by the pronounced relationship of sLOX-1 with cardiovascular mortality at 30 days (T3: adjusted HR, 3.81; 95% CI, 1.62-19.62; P = 0.0036) and at 1 year (T3: adjusted HR, 2.29; 95% CI, 1.19-5.34; P = 0.0148). In ACS patients undergoing serial intracoronary imaging and statin therapy, sLOX-1 dropped significantly in those with coronary plaque regression at 1 year (ΔsLOX-1: -4.64 ± 1.80; P = 0.0057), and showed a good discrimination for predicting plaque progression (area under the curve = 0.74; 95% CI, 0.59-0.86; P = 0.0031).

Conclusion: Plasma sLOX-1 levels are increased during ACS and predict fatal events beyond traditional and emerging risk factors. Persistently high sLOX-1 associates with coronary plaque progression in patients with established ASCVD.

Clinical Trial Registration: NCT01000701.
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http://dx.doi.org/10.1093/eurheartj/ehac143DOI Listing
May 2022

No association between APOE genotype and lipid lowering with cognitive function in a randomized controlled trial of evolocumab.

PLoS One 2022 11;17(4):e0266615. Epub 2022 Apr 11.

Alpert Medical School of Brown University, Providence, RI, United States of America.

APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher circulating cholesterol levels, ß-amyloid burden, and risk of Alzheimer's disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. There is some evidence that cholesterol-lowering medications may confer greater cognitive benefits in APOE ε4 carriers. Thus, the purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab use and cognitive function. APOE-genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of evolocumab added to statin therapy in patients with stable atherosclerotic cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm (p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the evolocumab arm (p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant (p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB, APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, (p's>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol-lowering medications in people at genetic risk for Alzheimer's disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0266615PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9000128PMC
April 2022

Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial.

JAMA 2022 05;327(18):1771-1781

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

Importance: Coronary plaques that are prone to rupture and cause adverse cardiac events are characterized by large plaque burden, large lipid content, and thin fibrous caps. Statins can halt the progression of coronary atherosclerosis; however, the effect of the proprotein convertase subtilisin kexin type 9 inhibitor alirocumab added to statin therapy on plaque burden and composition remains largely unknown.

Objective: To determine the effects of alirocumab on coronary atherosclerosis using serial multimodality intracoronary imaging in patients with acute myocardial infarction.

Design, Setting, And Participants: The PACMAN-AMI double-blind, placebo-controlled, randomized clinical trial (enrollment: May 9, 2017, through October 7, 2020; final follow-up: October 13, 2021) enrolled 300 patients undergoing percutaneous coronary intervention for acute myocardial infarction at 9 academic European hospitals.

Interventions: Patients were randomized to receive biweekly subcutaneous alirocumab (150 mg; n = 148) or placebo (n = 152), initiated less than 24 hours after urgent percutaneous coronary intervention of the culprit lesion, for 52 weeks in addition to high-intensity statin therapy (rosuvastatin, 20 mg).

Main Outcomes And Measures: Intravascular ultrasonography (IVUS), near-infrared spectroscopy, and optical coherence tomography were serially performed in the 2 non-infarct-related coronary arteries at baseline and after 52 weeks. The primary efficacy end point was the change in IVUS-derived percent atheroma volume from baseline to week 52. Two powered secondary end points were changes in near-infrared spectroscopy-derived maximum lipid core burden index within 4 mm (higher values indicating greater lipid content) and optical coherence tomography-derived minimal fibrous cap thickness (smaller values indicating thin-capped, vulnerable plaques) from baseline to week 52.

Results: Among 300 randomized patients (mean [SD] age, 58.5 [9.7] years; 56 [18.7%] women; mean [SD] low-density lipoprotein cholesterol level, 152.4 [33.8] mg/dL), 265 (88.3%) underwent serial IVUS imaging in 537 arteries. At 52 weeks, mean change in percent atheroma volume was -2.13% with alirocumab vs -0.92% with placebo (difference, -1.21% [95% CI, -1.78% to -0.65%], P < .001). Mean change in maximum lipid core burden index within 4 mm was -79.42 with alirocumab vs -37.60 with placebo (difference, -41.24 [95% CI, -70.71 to -11.77]; P = .006). Mean change in minimal fibrous cap thickness was 62.67 μm with alirocumab vs 33.19 μm with placebo (difference, 29.65 μm [95% CI, 11.75-47.55]; P = .001). Adverse events occurred in 70.7% of patients treated with alirocumab vs 72.8% of patients receiving placebo.

Conclusions And Relevance: Among patients with acute myocardial infarction, the addition of subcutaneous biweekly alirocumab, compared with placebo, to high-intensity statin therapy resulted in significantly greater coronary plaque regression in non-infarct-related arteries after 52 weeks. Further research is needed to understand whether alirocumab improves clinical outcomes in this population.

Trial Registration: ClinicalTrials.gov Identifier: NCT03067844.
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http://dx.doi.org/10.1001/jama.2022.5218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8978048PMC
May 2022

Soluble lectin-like oxidized low-density lipoprotein receptor-1 predicts premature death in acute coronary syndromes.

Eur Heart J 2022 Mar 24. Epub 2022 Mar 24.

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

Aims: The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its shedding product [soluble LOX-1 (sLOX-1)] are implicated in atherosclerotic cardiovascular disease (ASCVD) pathogenesis. Herein, we examined the relationship of sLOX-1 with both fatal events and plaque progression in patients with acute coronary syndromes (ACS).

Methods And Results: Plasma sLOX-1 was assessed at baseline in ACS and chronic coronary syndrome (CCS) patients prospectively recruited in the multicentre SPUM-ACS study, with sex- and age-matched healthy subjects serving as additional controls (n = 2924). Compared with both CCS and controls, ACS patients showed markedly elevated sLOX-1 levels (median, 2.00 and 2.00 vs. 35.08 pg/mL; P < 0.0001) which were independently associated with increased mortality risk over 30-day [tertile (T)3: adjusted hazard ratio (HR), 3.11; 95% confidence interval (CI), 1.44-10.61; P = 0.0055] and 1-year intervals (T3: adjusted HR, 2.04; 95% CI, 1.19-3.92; P = 0.0098). Results remained consistent after adjustment for GRACE 2.0 (T3: adjusted HR, 1.86; 95% CI, 1.04-3.74; P = 0.0391) and were primarily driven by the pronounced relationship of sLOX-1 with cardiovascular mortality at 30 days (T3: adjusted HR, 3.81; 95% CI, 1.62-19.62; P = 0.0036) and at 1 year (T3: adjusted HR, 2.29; 95% CI, 1.19-5.34; P = 0.0148). In ACS patients undergoing serial intracoronary imaging and statin therapy, sLOX-1 dropped significantly in those with coronary plaque regression at 1 year (ΔsLOX-1: -4.64 ± 1.80; P = 0.0057), and showed a good discrimination for predicting plaque progression (area under the curve = 0.74; 95% CI, 0.59-0.86; P = 0.0031).

Conclusion: Plasma sLOX-1 levels are increased during ACS and predict fatal events beyond traditional and emerging risk factors. Persistently high sLOX-1 associates with coronary plaque progression in patients with established ASCVD.

Clinical Trial Registration: NCT01000701.

Key Question: Experimental evidence has implicated the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its shedding product [soluble LOX-1 (sLOX-1)] in atherosclerosis. The aim was to study the relationship of sLOX-1 with mortality and plaque progression in patients with acute coronary syndromes (ACS).

Key Finding: Acute coronary syndrome patients displayed elevated sLOX-1 levels, with those in the highest tertile being at increased multivariable-adjusted risk of death from any [hazard ratio (HR) 2.04; P = 0.0098] and cardiovascular causes (HR, 2.29; P = 0.0148). Dynamics of sLOX-1 showed good discrimination for predicting plaque progression.

Take-home Message: Plasma levels of sLOX-1 are increased during ACS and predict fatal events beyond established risk factors. Trajectories of sLOX-1 mirror coronary plaque progression after the index ACS. Soluble LOX-1 is a novel biomarker of coronary plaque vulnerability and progression.
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http://dx.doi.org/10.1093/eurheartj/ehac143DOI Listing
March 2022

Single-Cell Analysis Uncovers Osteoblast Factor Growth Differentiation Factor 10 as Mediator of Vascular Smooth Muscle Cell Phenotypic Modulation Associated with Plaque Rupture in Human Carotid Artery Disease.

Int J Mol Sci 2022 Feb 4;23(3). Epub 2022 Feb 4.

Division of Cardiology, Foundation for Medical Research, Department of Medicine Specialized Medicine, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, CH-1211 Geneva 4, Switzerland.

(1) Background: Vascular smooth muscle cells (VSMCs) undergo a complex phenotypic switch in response to atherosclerosis environmental triggers, contributing to atherosclerosis disease progression. However, the complex heterogeneity of VSMCs and how VSMC dedifferentiation affects human carotid artery disease (CAD) risk has not been clearly established. (2) Method: A single-cell RNA sequencing analysis of CD45 cells derived from the atherosclerotic aorta of Apolipoprotein E-deficient (Apoe) mice on a normal cholesterol diet (NCD) or a high cholesterol diet (HCD), respecting the site-specific predisposition to atherosclerosis was performed. Growth Differentiation Factor 10 (GDF10) role in VSMCs phenotypic switch was investigated via flow cytometry, immunofluorescence in human atherosclerotic plaques. (3) Results: scRNAseq analysis revealed the transcriptomic profile of seven clusters, five of which showed disease-relevant gene signature of VSMC macrophagic calcific phenotype, VSMC mesenchymal chondrogenic phenotype, VSMC inflammatory and fibro-phenotype and VSMC inflammatory phenotype. Osteoblast factor GDF10 involved in ossification and osteoblast differentiation emerged as a hallmark of VSMCs undergoing phenotypic switch. Under hypercholesteremia, GDF10 triggered VSMC osteogenic switch in vitro. The abundance of GDF10 expressing osteogenic-like VSMCs cells was linked to the occurrence of carotid artery disease (CAD) events. (4) Conclusions: Taken together, these results provide evidence about GDF10-mediated VSMC osteogenic switch, with a likely detrimental role in atherosclerotic plaque stability.
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http://dx.doi.org/10.3390/ijms23031796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8836240PMC
February 2022

Single-Cell RNA-Seq Reveals a Crosstalk between Hyaluronan Receptor LYVE-1-Expressing Macrophages and Vascular Smooth Muscle Cells.

Cells 2022 01 25;11(3). Epub 2022 Jan 25.

Division of Cardiology, Foundation for Medical Research, Department of Medicine Specialized Medicine, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, 1206 Geneva, Switzerland.

: Atherosclerosis is a chronic inflammatory disease where macrophages participate in the progression of the disease. However, the role of resident-like macrophages (res-like) in the atherosclerotic aorta is not completely understood. A single-cell RNA sequencing analysis of CD45 leukocytes in the atherosclerotic aorta of apolipoprotein E-deficient () mice on a normal cholesterol diet (NCD) or a high cholesterol diet (HCD), respecting the side-to-specific predisposition to atherosclerosis, was performed. A population of res-like macrophages expressing hyaluronan receptor LYVE-1 was investigated via flow cytometry, co-culture experiments, and immunofluorescence in human atherosclerotic plaques from carotid artery disease patients (CAD). We identified 12 principal leukocyte clusters with distinct atherosclerosis disease-relevant gene expression signatures. LYVE-1 res-like macrophages, expressing a high level of CC motif chemokine ligand 24 (CCL24, eotaxin-2), expanded under hypercholesteremia in mice and promoted VSMC phenotypic modulation to osteoblast/chondrocyte-like cells, ex vivo, in a CCL24-dependent manner. Moreover, the abundance of LYVE-1CCL24 macrophages and elevated systemic levels of CCL24 were associated with vascular calcification and CAD events. LYVE-1 res-like macrophages, via the secretion of CCL24, promote the transdifferentiation of VSMC to osteogenic-like cells with a possible role in vascular calcification and likely a detrimental role in atherosclerotic plaque destabilization.
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http://dx.doi.org/10.3390/cells11030411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8834524PMC
January 2022

Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS) - A phase II, randomized, double-blind, multi-center, placebo-controlled trial.

Am Heart J 2022 05 28;247:33-41. Epub 2022 Jan 28.

Department of Cardiology, Bern University Hospital, Inselspital, Bern, Switzerland; Imperial College, National Heart and Lung Institute and Royal Brompton and Harefield Hospitals, Heart Division London, U.K.. Electronic address:

Background: Activation of inflammatory pathways during acute myocardial infarction contributes to infarct size and left ventricular (LV) remodeling. The present prospective randomized clinical trial was designed to test the efficacy and safety of broad-spectrum anti-inflammatory therapy with a mammalian target of rapamycin (mTOR) inhibitor to reduce infarct size.

Design: Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS, clinicaltrials.gov NCT01529554) is a phase II randomized, double-blind, multi-center, placebo-controlled trial on the effects of a 5-day course of oral everolimus on infarct size, LV remodeling, and inflammation in patients with acute ST-elevation myocardial infarction (STEMI). Within 5 days of successful primary percutaneous coronary intervention (pPCI), patients are randomly assigned to everolimus (first 3 days: 7.5 mg every day; days 4 and 5: 5.0 mg every day) or placebo, respectively. The primary efficacy outcome is the change from baseline (defined as 12 hours to 5 days after pPCI) to 30-day follow-up in myocardial infarct size as measured by cardiac magnetic resonance imaging (CMRI). Secondary endpoints comprise corresponding changes in cardiac and inflammatory biomarkers as well as microvascular obstruction and LV volumes assessed by CMRI. Clinical events, laboratory parameters, and blood cell counts are reported as safety endpoints at 30 days.

Conclusion: The CLEVER-ACS trial tests the hypothesis whether mTOR inhibition using everolimus at the time of an acute STEMI affects LV infarct size following successful pPCI.
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http://dx.doi.org/10.1016/j.ahj.2022.01.010DOI Listing
May 2022

The 'ten commandments' for the 2021 ESC Guidelines on CVD prevention.

Eur Heart J 2022 01;43(3):174-176

Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, Netherlands.

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http://dx.doi.org/10.1093/eurheartj/ehab742DOI Listing
January 2022

NLRP3 Inflammasome Activation Controls Vascular Smooth Muscle Cells Phenotypic Switch in Atherosclerosis.

Int J Mol Sci 2021 Dec 29;23(1). Epub 2021 Dec 29.

Division of Cardiology, Foundation for Medical Research, Department of Medicine, Specialized Medicine, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, 1211 Geneva, Switzerland.

(1) Background: Monocytes and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome orchestrate lipid-driven amplification of vascular inflammation promoting the disruption of the fibrous cap. The components of the NLRP3 inflammasome are expressed in macrophages and foam cells within human carotid atherosclerotic plaques and VSMCs in hypertension. Whether monocytes and NLRP3 inflammasome activation are direct triggers of VSMC phenotypic switch and plaque disruption need to be investigated. (2) Methods: The direct effect of oxLDL-activated monocytes in VSMCs co-cultured system was demonstrated via flow cytometry, qPCR, ELISA, caspase 1, and pyroptosis assay. Aortic roots of VSMCs lineage tracing mice fed normal or high cholesterol diet and human atherosclerotic plaques were used for immunofluorescence quantification of NLRP3 inflammasome activation/VSMCs phenotypic switch. (3) Results: OxLDL-activated monocytes reduced α-SMA, SM22α, , and upregulation of and macrophage markers MAC2, F4/80 and CD68 expression as well as caspase 1 activation, IL-1β secretion, and pyroptosis in VSMCs. Increased caspase 1 and IL-1β in phenotypically modified VSMCs was detected in the aortic roots of VSMCs lineage tracing mice fed high cholesterol diet and in human atherosclerotic plaques from carotid artery disease patients who experienced a stroke. (4) Conclusions: Taken together, these results provide evidence that monocyte promote VSMC phenotypic switch through VSMC NLRP3 inflammasome activation with a likely detrimental role in atherosclerotic plaque stability in human atherosclerosis.
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http://dx.doi.org/10.3390/ijms23010340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745068PMC
December 2021

Association between self-reported motivation to quit smoking with effectiveness of smoking cessation intervention among patients hospitalized for acute coronary syndromes in Switzerland.

Prev Med Rep 2021 Dec 7;24:101583. Epub 2021 Oct 7.

Institute of Primary Health Care (BIHAM), University of Bern, Switzerland.

Guidelines recommend brief smoking cessation interventions for hospitalized smokers reporting low motivation-to-quit. However, an intensive smoking cessation intervention may improve smoking cessation for these smokers. We conducted a secondary analysis of a pre-post interventional study that tested the efficacy of a approach systematically offering intensive smoking cessation intervention to all hospitalized smokers with acute coronary syndrome (ACS) compared to a approach offering it only to smokers willing to quit. We analyzed data from one study site in Switzerland, which recorded motivation-to-quit smoking at study inclusion between 08.2009 and 02.2012. The primary outcome was smoking cessation at 1- and 5-year. We tested for interaction by participant's motivation-to-quit score (low vs. high motivation), and calculated multivariable adjusted risk ratios (RR), stratified by motivation score. We obtained motivation scores for 230 smokers. Follow-up was 94% (217/230) at 1-year and 68% (156/230) at 5-year. Among participants with low motivation to quit, 19% of smokers in the reactive phase had quit at 1 year compared to 50% of smokers in the proactive phase (multivariable adjusted RR = 2.85, 95%CI:0.91-8.91). Among highly motivated smokers, rates did not differ between phases: 48% vs. 49% (multivariable adjusted RR = 1.02, 95%CI:0.75-1.39, p-value for interaction between motivation-to-quit categories = 0.10). At 5-year follow-up, the point estimates were similar. While our study has limitations inherent to the study design and sample size, we found that a proactive approach to offer systematic smoking cessation counseling for smokers with ACS reporting low motivation to quit was associated with higher smoking cessation rates at 1 year.
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http://dx.doi.org/10.1016/j.pmedr.2021.101583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683949PMC
December 2021

Symptoms and quality of life at 1-year follow up of patients discharged after an acute COVID-19 episode.

Swiss Med Wkly 2021 12 13;151:w30093. Epub 2021 Dec 13.

Department of Internal Medicine, Division of Cardiology, University Hospitals of Geneva, Switzerland.

Aim Of The Study: Patients surviving COVID-19 have been described as being at risk of developing sequelae. We aimed to investigate and elicit persistent symptoms, emotional status and quality-of-life in patients discharged after an acute COVID-19 episode.

Methods: Patient-reported outcome measures were collected during a telephone interview 30 days and 1 year after discharge. Patients' general health status was evaluated using questions based on their symptoms, emotional status was assessed using the items 9 to 12 of the HeartQoL questionnaire and quality of life was assessed at 1 year through the EQ-5D-5L. In patients with a history of cardiovascular disease, all 14 items of the HeartQoL questionnaire were completed to derive the HeartQoL global score.

Results: Among 687 patients who survived after being hospitalised for COVID-19 at the University Hospitals of Geneva between 26 February and 26 April 2020, 184 (27%) and 165 (24%), respectively, participated in the follow-up at 30 days and 1 year. Of these 184 participants, 62% were male, median age was 58 years and 21% had a past medical history of cardiovascular disease. At one month after discharge, 61% (113/184) of patients presented fatigue and 28% (52/184) dyspnoea. One year after discharge, the main complaints were persistent fatigue in 27% (45/165) of patients, neurological problems in 17% (28/165) and dyspnoea in 14% (23/165). Eight percent (14/184) of patients declared being significantly worried 1 month after discharge and 5% (9/184) feeling depressed. The number of patients reporting being significantly worried or depressed at 1 year was lower. Regarding the quality of life at 1 year, the median EQ-5D-5L visual analogue scale score was 80 (interquartile range 70-90).

Conclusions: Approximately half of patients reported some symptoms 1 year after discharge following an acute episode of COVID-19. The predominant symptom was persistent fatigue both at 1-month and at 1-year follow-up. Emotional status and quality of life appeared satisfactory.
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http://dx.doi.org/10.4414/smw.2021.w30093DOI Listing
December 2021

Effectiveness, Adherence, and Safety of Evolocumab in a Swiss Multicenter Prospective Observational Study.

Adv Ther 2022 01 18;39(1):504-517. Epub 2021 Nov 18.

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

Introduction: The aims of this study were to describe patient characteristics, lipid parameters, lipid-lowering drug use, and safety of patients receiving evolocumab in a real-world clinical setting.

Methods: We conducted a 1-year multicenter observational study of adults using evolocumab with confirmed atherosclerotic cardiovascular disease (CVD) or at high cardiovascular risk, and elevated LDL-C despite maximally tolerated statin doses. An e-health application optionally supported patient management. The primary outcome was change in lipid parameters over time. The secondary outcomes included evolocumab safety.

Results: Of 100 participants, 81% had pre-existing CVD, 71% self-reported statin-related muscle symptoms, 44% received statins. All patients received evolocumab, 65% were PCSK9i pre-treated at baseline. PCSK9i-naïve patients achieved a mean LDL-C reduction of 60% within 3 months of evolocumab treatment, which was maintained thereafter; 74% achieved LDL-C < 1.8 mmol/L at least once during observation, 69% attained < 1.4 mmol/L. In PCSK9i pre-treated patients, LDL-C remained stable throughout; 79% and 74% attained < 1.8 mmol/L and < 1.4 mmol/L, respectively, at least once. Goal attainment was higher with any combination of evolocumab, statin, and/or ezetimibe. Overall, 89% self-reported full evolocumab adherence. Treatment-emergent adverse events (TEAE) were reported in 30% of patients, two serious TEAEs occurred in one patient; three patients discontinued evolocumab because of TEAEs.

Conclusion: In real-world clinical practice, evolocumab was mainly used in patients with statin intolerance and pre-existing CVD. In this population, adherence to evolocumab and low LDL-C levels were maintained over 1 year, with better LDL-C goal achievement in patients using evolocumab in combination with other lipid-lowering drugs. Safety of evolocumab was similar to that documented in randomized controlled trials.
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http://dx.doi.org/10.1007/s12325-021-01962-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8799585PMC
January 2022

Changes of lipoprotein(a) levels with endogenous steroid hormones.

Eur J Clin Invest 2022 Feb 8;52(2):e13699. Epub 2021 Nov 8.

Cardiology, Geneva University Hospitals, Geneva, Switzerland.

Background: Lipoprotein(a) [Lp(a)] is an LDL-like molecule that is likely causal for cardiovascular events and Lp(a) variability has been shown to be mostly of genetic origin. Exogenous hormones (hormone replacement therapy) seem to influence Lp(a) levels, but the impact of endogenous hormone levels on Lp(a) is still unknown. The aim of the study was to assess the effect of endogenous steroid hormone metabolites on Lp(a).

Methods: Lipoprotein(a) levels were measured in 1,021 participants from the Swiss Kidney Project on Genes in Hypertension, a family-based, multicentre, population-based prospective cohort study. Endogenous levels of 28 steroid hormone precursors were measured in 24-h urine collections from 883 individuals. Of the participants with Lp(a) data, 1,011 participants had also genotypes available.

Results: The participants had an average age of 51 years and 53% were female. Median Lp(a) levels were 62 mg/L, and the 90 percentile was 616 mg/L. The prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. Forty-three per cent of Lp(a) variability was explained respectively by: age (2%, p < .001), LDL-C (1%, p = .001), and two SNPs (39%, p value<2⋅10 ). Of the 28 endogenous steroid hormones assessed, androstenetriol, androsterone, 16α-OH-DHEA and estriol were nominatively associated with serum Lp(a) levels in univariable analyses and explained 0.4%-1% of Lp(a) variability, but none of them reached significance in multivariable models.

Conclusions: In this contemporary population-based study, the prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. The effect of endogenous steroid hormone levels of Lp(a) variability was small at best, suggesting a negligible impact on the wide range of Lp(a) variability.
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http://dx.doi.org/10.1111/eci.13699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9286445PMC
February 2022

European Society of Cardiology Quality Indicators for Cardiovascular Disease Prevention: developed by the Working Group for Cardiovascular Disease Prevention Quality Indicators in collaboration with the European Association for Preventive Cardiology of the European Society of Cardiology.

Eur J Prev Cardiol 2022 05;29(7):1060-1071

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9LU, UK.

Aims: To develop a set of quality indicators (QIs) for the evaluation of the care and outcomes for atherosclerotic cardiovascular disease (ASCVD) prevention.

Methods And Results: The Quality Indicator Committee of the European Society of Cardiology (ESC) formed the Working Group for Cardiovascular Disease Prevention Quality Indicators in collaboration with Task Force members of the 2021 ESC Guidelines on Cardiovascular Disease Prevention in Clinical Practice and the European Association of Preventive Cardiology (EAPC). We followed the ESC methodology for QI development, which involved (i) the identification of the key domains of care for ASCVD prevention by constructing a conceptual framework of care, (ii) the development of candidate QIs by conducting a systematic review of the literature, (iii) the selection of the final set of QIs using a modified Delphi method, and (iv) the evaluation of the feasibility of the developed QIs. In total, 17 main and 14 secondary QIs were selected across six domains of care for ASCVD prevention: (i) structural framework, (ii) risk assessment, (iii) care for people at risk for ASCVD, (iv) care for patients with established ASCVD, (v) patient education and experience, and (vi) outcomes.

Conclusion: We present the 2021 ESC QIs for Cardiovascular Disease Prevention, which have been co-constructed with EAPC using the ESC methodology for QI development. These indicators are supported by evidence from the literature, underpinned by expert consensus and aligned with the 2021 ESC Guidelines on Cardiovascular Disease Prevention in Clinical Practice to offer a mechanism for the evaluation of ASCVD prevention care and outcomes.
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http://dx.doi.org/10.1093/eurjpc/zwab160DOI Listing
May 2022

Prognosis of Laboratory-Confirmed Influenza and Respiratory Syncytial Virus in Acute Heart Failure.

J Clin Med 2021 Sep 30;10(19). Epub 2021 Sep 30.

Service of General Internal Medicine, Department of Medicine, Geneva University Hospitals, 1211 Geneva, Switzerland.

Concomitant respiratory viral infections may influence clinical outcomes of acute decompensated heart failure (ADHF) but this association is based on indirect observation. The aim of this study was to evaluate the prevalence and impact of laboratory-confirmed influenza or respiratory syncytial virus (RSV) infection on outcomes in patients hospitalised for ADHF. Prospective cohort of patients hospitalised for ADHF with systematic influenza and RSV screening using real-time PCR on nasopharyngeal swabs. The primary outcome was all-cause mortality or readmission at 90 days. Among 803 patients with ADHF, 196 (24.5%) patients had concomitant flu-like symptoms of influenza. PCR was positive in 45 patients (27 for influenza, 19 for RSV). At 90 days, PCR positive patients had lower rates of all-cause mortality or readmission as compared to patients without flu-like symptoms (HR 0.40, 95% CI 0.18-0.91, = 0.03), and non-significantly less all-cause mortality (HR 0.30, 95% CI 0.04-2.20, = 0.24), or HF-related death or readmission (HR 0.36, 95% CI 0.13-0.99, = 0.05). The prevalence of influenza or RSV infection in patients admitted for ADHF was low and associated with less all-cause mortality and readmission. Concomitant viral infection with ADHF may not in itself be a predictor of poor outcomes. (ClinicalTrials.gov NCT02444416).
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http://dx.doi.org/10.3390/jcm10194546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509592PMC
September 2021

Combination lipid-lowering therapy as first-line strategy in very high-risk patients.

Eur Heart J 2022 02;43(8):830-833

Department of Vascular Medicine, Amsterdam University Medical Centers, location AMC, University of Amsterdam, Meibergdreef 9, Amsterdam 1105AZ, the Netherlands.

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http://dx.doi.org/10.1093/eurheartj/ehab718DOI Listing
February 2022

Cysteine-Rich Angiogenic Inducer 61 Improves Prognostic Accuracy of GRACE (Global Registry of Acute Coronary Events) 2.0 Risk Score in Patients With Acute Coronary Syndromes.

J Am Heart Assoc 2021 10 8;10(20):e020488. Epub 2021 Oct 8.

Department of Cardiology University Heart CenterUniversity Hospital Zurich Zurich Switzerland.

Background It remains unclear whether the novel biomarker cysteine-rich angiogenic inducer 61 (CCN1) adds incremental prognostic value to the GRACE 2.0 (Global Registry of Acute Coronary Events) risk score and biomarkers high-sensitivity Troponin T, hsCRP (high-sensitivity C-reactive protein), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in patients with acute coronary syndromes. Methods and Results Patients referred for coronary angiography with a primary diagnosis of acute coronary syndromes were enrolled in the Special Program University Medicine - Acute Coronary Syndromes and Inflammation cohort. The primary/secondary end points were 30-day/1-year all-cause mortality and the composite of all-cause mortality or myocardial infarction as used in the GRACE risk score. Associations between biomarkers and outcome were assessed using log-transformed biomarker values and the GRACE risk score (versions 1.0 and 2.0). The incremental value of CCN1 beyond a reference model was assessed using Harrell's C-statistics calculated from a Cox proportional-hazard model. The value of the C-statistics was derived from a likelihood ratio test. Among 2168 patients recruited, 1732 could be analyzed. CCN1 was the strongest single predictor of all-cause mortality at 30 days (hazard ratio [HR], 1.77 [1.31, 2.40]) and 1 year (HR, 1.81 [1.47, 2.22]). Adding CCN1 alone to the GRACE 2.0 risk score improved C-statistics for prognostic accuracy of all-cause mortality at 30 days (0.87-0.88) and 1 year (0.81-0.82) and when combined with high-sensitivity Troponin T, hsCRP, NT-proBNP for 30 days (0.87-0.91), and for 1-year follow-up (0.81-0.84). CCN1 also increased the prognostic value for the composite of all-cause mortality or myocardial infarction. Conclusions CCN1 predicts adverse outcomes in patients with acute coronary syndromes adding incremental information to the GRACE risk score, suggesting distinct underlying molecular mechanisms. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01000701.
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http://dx.doi.org/10.1161/JAHA.120.020488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751861PMC
October 2021

CCN family member 1 (CCN1) is an early marker of infarct size and left ventricular dysfunction in STEMI patients.

Atherosclerosis 2021 10 17;335:77-83. Epub 2021 Sep 17.

Department of Cardiology, Lausanne University Center Hospital, Lausanne, Switzerland. Electronic address:

Background And Aims: CCN family member 1 (CCN1) has recently been proposed as a novel biomarker of myocardial injury, improving prediction of 30-day and one-year mortality following acute coronary syndromes. Among ST-elevation myocardial infarction (STEMI) patients, we evaluated the utility of CCN1 measured immediately before primary percutaneous coronary intervention (PPCI) as a predictor of two earlier endpoints: final myocardial infarct size and post-infarction left ventricular ejection fraction (LVEF). Furthermore, we evaluated the impact of CCN1 on the discriminatory power of the CADILLAC score.

Methods: STEMI patients were obtained from the SPUM-ACS cohort. Serum CCN1 was measured prior to PPCI. Linear regression assessed the association between CCN1, peak creatinine kinase (CK), and post-infarction LVEF. Cox models assessed an association between CCN1 and 30-day all-cause mortality.

Results: CCN1 was measured in 989 patients with a median value of 706.2 ng/l (IQR 434.3-1319.6). A significant correlation between CCN1, myocardial infarct size (peak CK) and LVEF was observed in univariate and multivariate analysis (both p < 0.001). Even among patients with normal classical cardiac biomarker levels at the time of PPCI, CCN1 correlated significantly with final infarct size. CCN1 significantly improved prediction of 30-day all-cause mortality by the CADILLAC score (C-index 0.864, likelihood-ratio chi-square test statistic 6.331, p = 0.012; IDI 0.026, p= 0.050).

Conclusions: Compared with classical cardiac biomarkers, CCN1 is potentially the earliest predictor of final myocardial infarct size and post-infarction LVEF. CCN1 improved the discriminatory capacity of the CADILLAC score suggesting a potential role in the very-early risk stratification of STEMI patients.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.09.019DOI Listing
October 2021

Vascular endothelial tissue factor contributes to trimethylamine N-oxide-enhanced arterial thrombosis.

Cardiovasc Res 2022 Jul;118(10):2367-2384

Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, 9500 Euclid Ave, Cleveland, OH 44195, USA.

Aims: Gut microbiota and their generated metabolites impact the host vascular phenotype. The metaorganismal metabolite trimethylamine N-oxide (TMAO) is both associated with adverse clinical thromboembolic events, and enhances platelet responsiveness in subjects. The impact of TMAO on vascular Tissue Factor (TF) in vivo is unknown. Here, we explore whether TMAO-enhanced thrombosis potential extends beyond TMAO effects on platelets, and is linked to TF. We also further explore the links between gut microbiota and vascular endothelial TF expression in vivo.

Methods And Results: In initial exploratory clinical studies, we observed that among sequential stable subjects (n = 2989) on anti-platelet therapy undergoing elective diagnostic cardiovascular evaluation at a single-site referral centre, TMAO levels were associated with an increased incident (3 years) risk for major adverse cardiovascular events (MACE) (myocardial infarction, stroke, or death) [4th quartile (Q4) vs. Q1 adjusted hazard ratio (HR) 95% confidence interval (95% CI), 1.73 (1.25-2.38)]. Similar results were observed within subjects on aspirin mono-therapy during follow-up [adjusted HR (95% CI) 1.75 (1.25-2.44), n = 2793]. Leveraging access to a second higher risk cohort with previously reported TMAO data and monitoring of anti-platelet medication use, we also observed a strong association between TMAO and incident (1 year) MACE risk in the multi-site Swiss Acute Coronary Syndromes Cohort, focusing on the subset (n = 1469) on chronic dual anti-platelet therapy during follow-up [adjusted HR (95% CI) 1.70 (1.08-2.69)]. These collective clinical data suggest that the thrombosis-associated effects of TMAO may be mediated by cells/factors that are not inhibited by anti-platelet therapy. To test this, we first observed in human microvascular endothelial cells that TMAO dose-dependently induced expression of TF and vascular cell adhesion molecule (VCAM)1. In mouse studies, we observed that TMAO-enhanced aortic TF and VCAM1 mRNA and protein expression, which upon immunolocalization studies, was shown to co-localize with vascular endothelial cells. Finally, in arterial injury mouse models, TMAO-dependent enhancement of in vivo TF expression and thrombogenicity were abrogated by either a TF-inhibitory antibody or a mechanism-based microbial choline TMA-lyase inhibitor (fluoromethylcholine).

Conclusion: Endothelial TF contributes to TMAO-related arterial thrombosis potential, and can be specifically blocked by targeted non-lethal inhibition of gut microbial choline TMA-lyase.
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http://dx.doi.org/10.1093/cvr/cvab263DOI Listing
July 2022
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