Publications by authors named "Baris Gencer"

110 Publications

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

Eur J Prev Cardiol 2021 Apr;28(2):235-242

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.
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http://dx.doi.org/10.1177/2047487319853343DOI Listing
April 2021

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

Eur J Prev Cardiol 2021 Mar;28(1):59-65

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.
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http://dx.doi.org/10.1177/2047487320940102DOI Listing
March 2021

Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation: A Randomized Clinical Trial.

JAMA 2021 03;325(11):1061-1073

Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Atrial fibrillation (AF) is the most common heart rhythm disturbance, continues to increase in incidence, and results in significant morbidity and mortality. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D have been reported to have both benefits and risks with respect to incident AF, but large-scale, long-term randomized trial data are lacking.

Objective: To test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF.

Design, Setting, And Participants: An ancillary study of a 2 × 2 factorial randomized clinical trial involving 25 119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017.

Interventions: Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D3 (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D3 and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed).

Main Outcomes And Measures: The primary outcome was incident AF confirmed by medical record review.

Results: Among the 25 119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24 127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D3 vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39).

Conclusions And Relevance: Among adults aged 50 years or older, treatment with EPA-DHA or vitamin D3, compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF.

Trial Registration: ClinicalTrials.gov Identifiers: NCT02178410; NCT01169259.
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http://dx.doi.org/10.1001/jama.2021.1489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967086PMC
March 2021

Plasma ceramide and phospholipid-based risk score and the risk of cardiovascular death in patients after acute coronary syndrome.

Eur J Prev Cardiol 2020 Dec 29. Epub 2020 Dec 29.

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Aims: Ceramide (Cer) and phosphatidylcholine (PC) lipids are associated with pathophysiological processes in cardiovascular (CV) diseases. A previously derived and validated plasma Cer-PC risk score (CERT2) was associated with CV death risk in patients with stable disease, but its prognostic value has not been evaluated in patients early post-acute coronary syndrome (ACS).

Methods And Results: Prespecified plasma Cer and PC species of CERT2 risk score were measured in 4871 subjects from SOLID-TIMI 52, which enrolled patients ≤30 days after ACS (median follow-up 2.5 years). The CERT2 score (scale 0-12 points) was calculated as previously defined. The primary outcome was CV death; CV death or heart failure (HF) hospitalization (HF), myocardial infarction (MI), stroke, and all-cause death were also analysed. Poisson models included baseline characteristics and established biomarkers. Patients with higher CERT2 risk scores were more likely to be older, female, current smokers, presenting with STEMI, and to have impaired renal function and higher LDL-C. After multivariable adjustment, patients in the highest risk score category remained at a nearly two-fold higher risk of CV death (adj relative risk [RR] 1.92, 95% CI 1.01-3.66, P = 0.047). Patients in the highest risk score category were also at higher risk of all-cause death (adj RR 2.01, 95% CI 1.21-3.35, P = 0.007), whereas the relationships with HF, MI, and stroke were attenuated with multivariable adjustment.

Conclusions: A plasma ceramide and phospholipid-based risk score are associated with the risk of CV death independent of established clinical risk factors and biomarkers in patients after ACS.
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http://dx.doi.org/10.1093/eurjpc/zwaa143DOI Listing
December 2020

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

Cardiovascular risk and testosterone - from subclinical atherosclerosis to lipoprotein function to heart failure.

Rev Endocr Metab Disord 2021 Feb 22. Epub 2021 Feb 22.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.

The cardiovascular (CV) benefit and safety of treating low testosterone conditions is a matter of debate. Although testosterone deficiency has been linked to a rise in major adverse CV events, most of the studies on testosterone replacement therapy were not designed to assess CV risk and thus excluded men with advanced heart failure or recent history of myocardial infarction or stroke. Besides considering observational, interventional and prospective studies, this review article evaluates the impact of testosterone on atherosclerosis process, including lipoprotein functionality, progression of carotid intima media thickness, inflammation, coagulation and thromboembolism, quantification of plaque volume and vascular calcification. Until adequately powered studies evaluating testosterone effects in hypogonadal men at increased CV risk are available (TRAVERSE trial), clinicians should ponder the use of testosterone in men with atherosclerotic cardiovascular disease and discuss benefit and harms with the patients.
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http://dx.doi.org/10.1007/s11154-021-09628-2DOI Listing
February 2021

Air pollution triggers inflammation and cardiovascular events: now is the time to act.

Eur Heart J 2021 Feb 14. Epub 2021 Feb 14.

Cardiology Division, Geneva University Hospitals, Switzerland.

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http://dx.doi.org/10.1093/eurheartj/ehaa1020DOI Listing
February 2021

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

Atherosclerosis 2021 03 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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.01.012DOI Listing
March 2021

The Reply.

Am J Med 2021 01;134(1):e71

Institute of Primary Health Care (BIHAM), University of Bern, Switzerland; Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2020.09.008DOI 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.
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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.
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http://dx.doi.org/10.1177/2048872620974612DOI Listing
December 2020

Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials.

Lancet 2020 11 10;396(10263):1637-1643. Epub 2020 Nov 10.

TIMI Study Group, Division of Cardiovascular Medicine, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: The clinical benefit of LDL cholesterol lowering treatment in older patients remains debated. We aimed to summarise the evidence of LDL cholesterol lowering therapies in older patients.

Methods: In this systematic review and meta-analysis, we searched MEDLINE and Embase for articles published between March 1, 2015, and Aug 14, 2020, without any language restrictions. We included randomised controlled trials of cardiovascular outcomes of an LDL cholesterol-lowering drug recommended by the 2018 American College of Cardiology and American Heart Association guidelines, with a median follow-up of at least 2 years and data on older patients (aged ≥75 years). We excluded trials that exclusively enrolled participants with heart failure or on dialysis because guidelines do not recommend lipid-lowering therapy in such patients who do not have another indication. We extracted data for older patients using a standardised data form for aggregated study-level data. We meta-analysed the risk ratio (RR) for major vascular events (a composite of cardiovascular death, myocardial infarction or other acute coronary syndrome, stroke, or coronary revascularisation) per 1 mmol/L reduction in LDL cholesterol.

Findings: Data from six articles were included in the systematic review and meta-analysis, which included 24 trials from the Cholesterol Treatment Trialists' Collaboration meta-analysis plus five individual trials. Among 244 090 patients from 29 trials, 21 492 (8·8%) were aged at least 75 years, of whom 11 750 (54·7%) were from statin trials, 6209 (28·9%) from ezetimibe trials, and 3533 (16·4%) from PCSK9 inhibitor trials. Median follow-up ranged from 2·2 years to 6·0 years. LDL cholesterol lowering significantly reduced the risk of major vascular events (n=3519) in older patients by 26% per 1 mmol/L reduction in LDL cholesterol (RR 0·74 [95% CI 0·61-0·89]; p=0·0019), with no statistically significant difference with the risk reduction in patients younger than 75 years (0·85 [0·78-0·92]; p=0·37). Among older patients, RRs were not statistically different for statin (0·82 [0·73-0·91]) and non-statin treatment (0·67 [0·47-0·95]; p=0·64). The benefit of LDL cholesterol lowering in older patients was observed for each component of the composite, including cardiovascular death (0·85 [0·74-0·98]), myocardial infarction (0·80 [0·71-0·90]), stroke (0·73 [0·61-0·87]), and coronary revascularisation (0·80 [0·66-0·96]).

Interpretation: In patients aged 75 years and older, lipid lowering was as effective in reducing cardiovascular events as it was in patients younger than 75 years. These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin treatment, in older patients.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(20)32332-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015314PMC
November 2020

Management of LDL-cholesterol after an acute coronary syndrome: Key comparisons of the American and European clinical guidelines to the attention of the healthcare providers.

Clin Cardiol 2020 Jul 29;43(7):684-690. Epub 2020 Jun 29.

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Guidelines for the management of blood cholesterol were updated in the past year in the United States and Europe, reflecting a more intensive approach to lowering low-density lipoprotein cholesterol (LDL-C). The American College of Cardiology/American Heart Association task force on practice guideline released the 2018 guideline on the management of blood cholesterol on behalf of several American societies. Approximately 9 months later, the European Society of Cardiology/European Atherosclerosis Society published their 2019 guideline for the management of dyslipidemias. Both guidelines have similarities for the management of patients with acute coronary syndromes. Both emphasize risk assessment of patients as a main approach to guide therapy; those at higher risk of cardiovascular disease have a greater clinical benefit of LDL-C reduction by at least 50%. Both guidelines reinforce the indication to lower LDL-C as an important modifiable risk factor and consider the addition of nonstatin agents, such as ezetimibe and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, in addition to lifestyle counseling and high-intensity statin for further reduction of LDL-C levels. However, the guidelines have differences in the concepts of treatment thresholds (≥70 mg/dL in the United States) vs treatment goals (< 55 mg/dL in Europe), in the definition of very high-risk category and in the classes for recommendation for the use of PCSK9 inhibitors.
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http://dx.doi.org/10.1002/clc.23410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368309PMC
July 2020

Emerging Concepts and Applied Machine Learning Research in Patients with Drug-Induced Repolarization Disorders.

Stud Health Technol Inform 2020 Jun;270:198-202

Division of Clinical Pharmacology and Toxicology; Medical Direction, University Hospitals of Geneva and University of Geneva, Geneva, Switzerland.

The paper presents a review of current research to develop predictive models for automated detection of drug-induced repolarization disorders and shows a feasibility study for developing machine learning tools trained on massive multimodal datasets of narrative, textual and electrocardiographic records. The goal is to reduce drug-induced long QT and associated complications (Torsades-de-Pointes, sudden cardiac death), by identifying prescription patterns with pro-arrhythmic propensity using a validated electronic application for the detection of adverse drug events with data mining and natural language processing; and to compute individual-based predictive scores in order to further identify clinical conditions, concomitant diseases, or other variables that correlate with higher risk of pro-arrhythmic situations.
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http://dx.doi.org/10.3233/SHTI200150DOI Listing
June 2020

Efficacy of Evolocumab on Cardiovascular Outcomes in Patients With Recent Myocardial Infarction: A Prespecified Secondary Analysis From the FOURIER Trial.

JAMA Cardiol 2020 May 20. Epub 2020 May 20.

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: The 2018 American Heart Association/American College of Cardiology Multisociety Guideline on the Management of Blood Cholesterol identified patients with recent (past 12 months) myocardial infarction (MI) as very high risk, in whom a PCSK9 inhibitor is reasonable to add to maximally tolerated statin combined with ezetimibe if their low-density lipoprotein cholesterol level is 70 mg/dL or greater or non-high-density lipoprotein cholesterol level is 100 mg/dL or greater.

Objective: To examine the clinical efficacy of evolocumab in patients with recent MI.

Design, Setting, And Participants: This was a prespecified secondary analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, in which 27 564 patients with atherosclerotic cardiovascular disease treated with a statin were randomized to evolocumab vs placebo. Patients with prior MI with a known date (n = 22 320) were stratified as having a recent MI (within 12 months of randomization) or a remote MI (more than 12 months prior to randomization). Per protocol, patients with MI within 4 weeks prior to randomization were excluded from the FOURIER trial. Data were collected from February 2013 to November 2016, and data were analyzed from May 2019 to February 2020.

Main Outcomes And Measures: The primary composite end point was cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary composite end point was cardiovascular death, MI, or stroke.

Results: Of 22 320 included patients, 17 516 (78.5%) were male, and the mean (SD) age was 62.2 (9.0) years. Compared with 16 609 patients with a remote MI, 5711 patients with a recent MI were younger and more likely to be treated with high-intensity statin (77.3% [4415] vs 69.3% [11 506]). In the placebo arm, the 3-year Kaplan-Meier rate for the primary end point was 17.2% in patients with recent MI compared with 14.4% in those with remote MI (adjusted HR, 1.45; 95% CI, 1.29-1.64; P < .001). Similarly, the 3-year Kaplan-Meier rates for the key secondary end point was also higher in those with recent MI (10.9% vs 9.5%; adjusted HR, 1.45; 95% CI, 1.24-1.69; P < .001). In patients with a recent MI, evolocumab reduced the risk of the primary and key secondary end points by 19% (hazard ratio [HR], 0.81; 95% CI, 0.70-0.93) and 25% (HR, 0.75; 95% CI, 0.62-0.91), respectively. In patients with a remote MI, evolocumab reduced the risk of the primary and key secondary end points by 8% (HR, 0.92; 95% CI, 0.84-1.01; P for interaction = .13) and 15% (HR, 0.85; 95% CI, 0.76-0.96; P for interaction = .24), respectively. Given the higher event rates in patients with a recent MI, the absolute risk reductions over 3 years with evolocumab were 3.7% in those with recent MI vs 1.1% in those with remote MI for the primary end point and 3.2% vs 1.3%, respectively, for the key secondary end point.

Conclusions And Relevance: Patients with a recent MI were at higher risk of cardiovascular events and tended to experience greater absolute risk reductions with evolocumab than those with remote MIs. These findings support the concept in US and European guidelines to aggressively lower low-density lipoprotein cholesterol levels in very high-risk patients, such as those with a recent MI.

Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.
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http://dx.doi.org/10.1001/jamacardio.2020.0882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240652PMC
May 2020

Cognition After Lowering LDL-Cholesterol With Evolocumab.

J Am Coll Cardiol 2020 05;75(18):2283-2293

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trial demonstrated that evolocumab added to a background statin did not affect cognitive performance in a subset of 1,204 patients enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects With Elevated Risk).

Objectives: The authors describe patient-reported cognition in the entire FOURIER trial using a self-survey.

Methods: FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dl or non-high-density cholesterol ≥100 mg/dl despite statin therapy. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition (ECog) scale. Patients compared their levels of everyday function at the end of the trial with their levels at the beginning and scored as 1 (no change or improvement), 2 (occasionally worse), 3 (consistently little worse), or 4 (consistently much worse). ECog scores were compared by the 2 randomized treatment arms and by achieved LDL-C at 4 weeks.

Results: A total of 22,655 patients completed ECog after a median duration of 2.2 years. The proportions of patients reporting cognitive decline (ECog score ≥2) at the end of the study were similar for placebo versus evolocumab, both for total score 3.6% versus 3.7% (p = 0.62) and for subdomains (memory, 5.8% vs. 6.0%; total executive, 3.6% vs. 3.7%). The proportion of patients reporting a decline in total cognitive score was similar among the 2,338 patients who achieved very low LDL-C levels (<20 mg/dl) compared to the 3,613 patients with LDL-C ≥100 mg/dl (3.8% vs. 4.5%, p = 0.57).

Conclusions: The addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C <20 mg/dl.
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http://dx.doi.org/10.1016/j.jacc.2020.03.039DOI Listing
May 2020

Gut Microbiota-Dependent Trimethylamine N-oxide and Cardiovascular Outcomes in Patients With Prior Myocardial Infarction: A Nested Case Control Study From the PEGASUS-TIMI 54 Trial.

J Am Heart Assoc 2020 05 5;9(10):e015331. Epub 2020 May 5.

TIMI Study Group Division of Cardiovascular Medicine Brigham and Women's Hospital Harvard Medical School Boston MA.

Background Trimethylamine N-oxide (TMAO) may have prothrombotic properties. We examined the association of TMAO quartiles with major adverse cardiovascular events (MACE) and the effect of TMAO on the efficacy of ticagrelor. Methods and Results PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin - Thrombolysis in Myocardial Infarction 54) randomized patients with prior myocardial infarction to ticagrelor or placebo (median follow-up 33 months). Baseline plasma concentrations of TMAO were measured in a nested case-control study of 597 cases with cardiovascular death, myocardial infarction, or stroke (MACE) and 1206 controls matched for age, sex, and estimated glomerular filtration rate [eGFR]. Odds ratios (OR) were used for the association between TMAO quartiles and MACE, adjusting for baseline clinical characteristics (age, sex, eGFR, region, body mass index, hypertension, hypercholesterolemia, diabetes mellitus, smoking, peripheral artery disease, index event, aspirin dosage and treatment arm), and cardiovascular biomarkers (hs-TnT [high-sensitivity troponin T], hs-CRP [high-sensitivity C-reactive protein], NT-proBNP [N-terminal-pro-B-type natriuretic peptide]). Higher TMAO quartiles were associated with risk of MACE (OR for quartile 4 versus quartile 1, 1.43, 95% CI, 1.06-1.93, trend=0.015). The association was driven by cardiovascular death (OR 2.25, 95% CI, 1.28-3.96, trend=0.003) and stroke (OR 2.68, 95% CI, 1.39-5.17, trend<0.001). After adjustment for clinical factors, the association persisted for cardiovascular death (OR 1.89, 95% CI, 1.03-3.45, trend=0.027) and stroke (OR 2.01, 95% CI, 1.01-4.01, trend=0.022), but was slightly attenuated after adjustment for cardiovascular biomarkers (cardiovascular death: OR 1.74, 95% CI, 0.88-3.45, trend=0.079; and stroke: OR 1.82, 95% CI, 0.88-3.78, trend=0.056). The reduction in MACE with ticagrelor was consistent across TMAO quartiles ( interaction=0.92). Conclusions Among patients with prior myocardial infarction, higher TMAO levels were associated with cardiovascular death and stroke but not with recurrent myocardial infarction. The efficacy of ticagrelor was consistent regardless of TMAO levels. Registration URL: https://www.clini​caltr​ials.gov; Unique identifiers: PEGASUS-TIMI 54, NCT01225562.
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http://dx.doi.org/10.1161/JAHA.119.015331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660879PMC
May 2020

Dynamical System Modeling of Self-Regulated Systems Undergoing Multiple Excitations: First Order Differential Equation Approach.

Multivariate Behav Res 2020 May 2:1-20. Epub 2020 May 2.

Quality of Care Division, Geneva University Hospitals.

This article proposes a dynamical system modeling approach for the analysis of longitudinal data of self-regulated homeostatic systems experiencing multiple excitations. It focuses on the evolution of a signal (e.g., heart rate) before, during, and after excitations taking the system out of its equilibrium (e.g., physical effort during cardiac stress testing). Such approach can be applied to a broad range of outcomes such as physiological processes in medicine and psychosocial processes in social sciences, and it allows to extract simple characteristics of the signal studied. The model is based on a first order linear differential equation with constant coefficients defined by three main parameters corresponding to the initial equilibrium value, the dynamic characteristic time, and the reaction to the excitation. Assuming the presence of interindividual variability (random effects) on these three parameters, we propose a two-step procedure to estimate them. We then compare the results of this analysis to several other estimation procedures in a simulation study that clarifies under which conditions parameters are accurately estimated. Finally, applications of this model are illustrated using cardiology data recorded during effort tests.
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http://dx.doi.org/10.1080/00273171.2020.1754155DOI Listing
May 2020

The Effect of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition on the Risk of Venous Thromboembolism.

Circulation 2020 May 29;141(20):1600-1607. Epub 2020 Mar 29.

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (N.A.M., Y.G., G.E.M.M., B.G., M.L.O., R.P.G., C.T.R., M.S.S.).

Background: The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in subgroups with clinically and genetically defined risk.

Methods: We performed a post hoc analysis of the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) testing whether evolocumab reduces the risk of VTE events (deep venous thrombosis or pulmonary embolism). Data from FOURIER and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) were then combined in a meta-analysis to assess the class effect of PCSK9 inhibition on the risk of VTE. We also analyzed baseline lipids in FOURIER to investigate potential mechanisms explaining the reduction in VTE with evolocumab. Last, an exploratory genetic analysis was performed in FOURIER to determine whether a VTE polygenic risk score could identify high-risk patients who would derive the greatest VTE reduction from evolocumab.

Results: In FOURIER, the hazard ratio (HR) for VTE with evolocumab was 0.71 (95% CI, 0.50-1.00; =0.05), with no effect in the 1st year (HR, 0.96 [95% CI, 0.57-1.62]) but a 46% reduction (HR, 0.54 [95% CI, 0.33-0.88]; =0.014) beyond 1 year. A meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative risk reduction in VTE with PCSK9 inhibition (HR, 0.69 [95% CI, 0.53-0.90]; =0.007). There was no relation between baseline low-density lipoprotein cholesterol levels and magnitude of VTE risk reduction. In contrast, in patients with higher baseline lipoprotein(a) (Lp[a]) levels, evolocumab reduced Lp(a) by 33 nmol/L and risk of VTE by 48% (HR, 0.52 [95% CI, 0.30-0.89]; =0.017), whereas, in patients with lower baseline Lp(a) levels, evolocumab reduced Lp(a) by only 7 nmol/L and had no effect on VTE risk ( 0.087 for HR; 0.037 for absolute risk reduction). Modeled as a continuous variable, there was a significant interaction between baseline Lp(a) concentration and magnitude of VTE risk reduction (=0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative (=0.04) and absolute VTE reduction (=0.009) in comparison with those without high genetic risk.

Conclusions: PCSK9 inhibition significantly reduces the risk of VTE. Lp(a) reduction may be an important mediator of this effect, a finding of particular interest given the ongoing development of potent Lp(a) inhibitors.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469753PMC
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.
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http://dx.doi.org/10.1155/2020/8513257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073472PMC
September 2020

The Impact of Levothyroxine on Cardiac Function in Older Adults With Mild Subclinical Hypothyroidism: A Randomized Clinical Trial.

Am J Med 2020 07 12;133(7):848-856.e5. Epub 2020 Mar 12.

Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland; Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland. Electronic address:

Background: Subclinical hypothyroidism has been associated with heart failure, but only small trials assessed whether treatment with levothyroxine has an impact on cardiac function.

Methods: In a randomized, double-blind, placebo-controlled, trial nested within the TRUST trial, Swiss participants ages ≥65 years with subclinical hypothyroidism (thyroid-stimulating hormone [TSH] 4.60-19.99 mIU/L; free thyroxine level within reference range) were randomized to levothyroxine (starting dose of 50 µg daily) to achieve TSH normalization or placebo. The primary outcomes were the left ventricular ejection fraction for systolic function and the ratio between mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e' ratio) for diastolic function. Secondary outcomes included e' lateral/septal, left atrial volume index, and systolic pulmonary artery pressure.

Results: A total of 185 participants (mean age 74.1 years, 47% women) underwent echocardiography at the end of the trial. After a median treatment duration of 18.4 months, the mean TSH decreased from 6.35 mIU/L to 3.55 mIU/L with levothyroxine (n = 96), and it remained elevated at 5.29 mIU/L with placebo (n = 89). The adjusted between-group difference was not significant for the mean left ventricular ejection fraction (62.7% vs 62.5%, difference = 0.4%, 95% confidence interval -1.8% to 2.5%, P = 0.72) and the E/e' ratio (10.6 vs 10.1, difference 0.4, 95% confidence interval -0.7 to 1.4, P = 0.47). No differences were found for the secondary diastolic function parameters or for interaction according to sex, baseline TSH, preexisting heart failure, and treatment duration (P value >0.05).

Conclusion: Systolic and diastolic heart function did not differ after treatment with levothyroxine compared with placebo in older adults with mild subclinical hypothyroidism.
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http://dx.doi.org/10.1016/j.amjmed.2020.01.018DOI Listing
July 2020

Potential of Lipoprotein(a)-Lowering Strategies in Treating Coronary Artery Disease.

Drugs 2020 Feb;80(3):229-239

Cardiology Division, Department of Specialties in Medicine, Geneva University Hospitals, Rue Gabrielle-Perret Gentil 4, 1211, Geneva 14, Switzerland.

High levels of lipoprotein(a) [Lp(a)] are considered causal risk factor of cardiovascular disease (CVD), including aortic stenosis. The 2019 ESC/EAC guidelines for the management of dyslipidaemias recommend to measure Lp(a) at least once in each adult person's lifetime to identify those with inherited Lp(a) levels > 180 mg/dL (> 430 nmol/L) who may have a cardiovascular risk similar to heterozygous familial hypercholesterolaemia or in selected patients with a family history of premature CVD and for reclassification in people who are borderline between moderate- and high-risk. Some lipid-lowering agents not specific for Lp(a) have shown to reduce Lp(a) levels (niacin, PCSK9 inhibitors and CETP inhibitors). Prespecified analyses from the FOURIER trial have shown that participants who had reduction in Lp(a) levels with PCSK9 levels had a decreased risk of cardiovascular events. To lower Lp(a), two antisense oligonucleotides are under development targeting apolipoprotein B and apolipoprotein (a). Mipomersen is an oligonucleotide that targets apolipoprotein B, with a potential benefit in reducing Lp(a) by 20-50%. AKCEA-APO(a)-L is another antisense oligonucleotide targeting Lp(a) and reducing Lp(a) by 50-80%. A Phase III study with AKCEA-APO(a)-L will start in order to evaluate the effect on cardiovascular outcomes.
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http://dx.doi.org/10.1007/s40265-019-01243-5DOI Listing
February 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.
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http://dx.doi.org/10.1016/j.ijcard.2019.12.011DOI Listing
March 2020

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

Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation.

J Clin Med 2019 Nov 21;8(12). Epub 2019 Nov 21.

Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospital, 4 rue Gabrielle-Perret-Gentil, 1205 Geneva, Switzerland.

Aims: Anti-Apolipoprotein A-1 autoantibodies (anti-ApoA-1 IgG) promote atherogenesis via innate immune receptors, and may impair cellular cholesterol homeostasis (CH). We explored the presence of anti-ApoA-1 IgG in children (5-15 years old) with or without familial hypercholesterolemia (FH), analyzing their association with lipid profiles, and studied their in vitro effects on foam cell formation, gene regulation, and their functional impact on cholesterol passive diffusion (PD).

Methods: Anti-ApoA-1 IgG and lipid profiles were measured on 29 FH and 25 healthy children. The impact of anti-ApoA-1 IgG on key CH regulators (SREBP2, HMGCR, LDL-R, ABCA1, and miR-33a) and foam cell formation detected by Oil Red O staining were assessed using human monocyte-derived macrophages. PD experiments were performed using a validated THP-1 macrophage model.

Results: Prevalence of high anti-ApoA-1 IgG levels (seropositivity) was about 38% in both study groups. FH children seropositive for anti-ApoA-1 IgG had significant lower total cholesterol LDL and miR-33a levels than those who were seronegative. On macrophages, anti-ApoA-1 IgG induced foam cell formation in a toll-like receptor (TLR) 2/4-dependent manner, accompanied by NF-kB- and AP1-dependent increases of SREBP-2, LDL-R, and HMGCR. Despite increased ABCA1 and decreased mature miR-33a expression, the increased ACAT activity decreased membrane free cholesterol, functionally culminating to PD inhibition.

Conclusions: Anti-ApoA-1 IgG seropositivity is frequent in children, unrelated to FH, and paradoxically associated with a favorable lipid profile. In vitro, anti-ApoA-1 IgG induced foam cell formation through a complex interplay between innate immune receptors and key cholesterol homeostasis regulators, functionally impairing the PD cholesterol efflux capacity of macrophages.
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http://dx.doi.org/10.3390/jcm8122035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947407PMC
November 2019

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

Right ventricle and outcome in left ventricular non-compaction cardiomyopathy.

J Cardiol 2020 01 4;75(1):20-26. Epub 2019 Oct 4.

Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland. Electronic address:

Background: The risk of adverse events in patients with left ventricular non-compaction cardiomyopathy (LVNC) is substantial. Information on prognostic factors, however, is limited. This study was designed to assess the prognostic value of right ventricular (RV) size and function in LVNC patients.

Methods: Cox regression analyses were used to determine the association of indexed RV end-diastolic area (RV-EDAI), indexed end-diastolic diameter (RV-EDDI), fractional area change (FAC), and tricuspid annular systolic excursion (TAPSE) with the occurrence of death or heart transplantation (composite endpoint).

Results: Out of 127 patients (53.2 ± 17.8 years; 61% males, median follow-up time was 7.7 years), 17 patients reached the endpoint. In a univariate analysis, RV-EDAI was the strongest predictor of outcome [HR 1.48 (1.24-1.77) per cm/m; p < 0.0001]. FAC was predictive as well [HR 1.44 (1.16-1.83) per 5% decrease; p = 0.0009], while TAPSE was not (p=ns). RV-EDAI remained an independent predictor in a bivariable analysis with indexed left ventricular ED volume [HR 1.41 (1.18-1.70) per cm/m; p = 0.0002], while analysis of FAC and left ventricular ejection fraction demonstrated that FAC was not independent [HR 1.20 (0.98-1.52); per 5% decrease; p = 0.0721]. RV-EDAI 11.5 cm/m was the best cut-off value for separating patients in terms of outcome. Patients with RV-EDAI >11.5 cm/m had a survival rate of 18.5% over 12 years as compared to 93.8% in patients with RV-EDAI <11.5 cm/m (p < 0.0001).

Conclusion: Increased end-diastolic RV size and decreased systolic RV function are predictors of adverse outcome in patients with LVNC. Patients with RV-EDAI >11.5 cm/m exhibit a significantly lower survival than those <11.5 cm/m.
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http://dx.doi.org/10.1016/j.jjcc.2019.09.003DOI Listing
January 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).
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http://dx.doi.org/10.1016/j.jacc.2019.08.010DOI Listing
November 2019

Gender Specificity and Interpretation of Functional Cardiac Imaging: Let's Talk about Sex.

Thromb Haemost 2019 Sep 1;119(9):1379-1381. Epub 2019 Sep 1.

Cardiology Division, Geneva University Hospitals, Geneva, Switzerland.

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http://dx.doi.org/10.1055/s-0039-1695010DOI Listing
September 2019