Publications by authors named "François Mach"

373 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

Mortality and high risk of major adverse events in patients with COVID-19 and history of cardiovascular disease.

Open Heart 2021 Apr;8(1)

Department of Cardiology, University Hospitals of Geneva Department of Medical Specializations, Geneva, Switzerland

Objective: History of cardiovascular diseases (CVDs) may influence the prognosis of patients hospitalised for COVID-19. We investigated whether patients with previous CVD have increased risk of death and major adverse cardiovascular event (MACE) when hospitalised for COVID-19.

Methods: We included 839 patients with COVID-19 hospitalised at the University Hospitals of Geneva. Demographic characteristics, medical history, laboratory values, ECG at admission and medications at admission were collected based on electronic medical records. The primary outcome was a composite of in-hospital mortality or MACE.

Results: Median age was 67 years, 453 (54%) were males and 277 (33%) had history of CVD. In total, 152 (18%) died and 687 (82%) were discharged, including 72 (9%) who survived a MACE. Patients with previous CVD were more at risk of composite outcomes 141/277 (51%) compared with those without CVD 83/562 (15%) (OR=6.0 (95% CI 4.3 to 8.4), p<0.001). Multivariate analyses showed that history of CVD remained an independent risk factor of in-hospital death or MACE (OR=2.4; (95% CI 1.6 to 3.5)), as did age (OR for a 10-year increase=2.2 (95% CI 1.9 to 2.6)), male gender (OR=1.6 (95% CI 1.1 to 2.3)), chronic obstructive pulmonary disease (OR=2.1 (95% CI 1.0 to 4.2)) and lung infiltration associated with COVID-19 at CT scan (OR=1.9 (95% CI 1.2 to 3.0)). History of CVD (OR=2.9 (95% CI 1.7 to 5)), age (OR=2.5 (95% CI 2.0 to 3.2)), male gender (OR=1.6 (95% CI 0.98 to 2.6)) and elevated C reactive protein (CRP) levels on admission (OR for a 10 mg/L increase=1.1 (95% CI 1.1 to 1.2)) were independent risk factors for mortality.

Conclusion: History of CVD is associated with higher in-hospital mortality and MACE in hospitalised patients with COVID-19. Other factors associated with higher in-hospital mortality are older age, male sex and elevated CRP on admission.
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http://dx.doi.org/10.1136/openhrt-2020-001526DOI Listing
April 2021

Novel Blood Biomarkers for a Diagnostic Workup of Acute Aortic Dissection.

Diagnostics (Basel) 2021 Mar 30;11(4). Epub 2021 Mar 30.

Institute of Clinical Chemistry, University Hospital of Zurich, University of Zurich, 8091 Zurich, Switzerland.

Acute aortic dissection (AAD) is a rare condition, but together with acute myocardial infarction (AMI) and pulmonary embolism (PE) it belongs to the most relevant and life-threatening causes of acute chest pain. Until now, there has been no specific blood test in the diagnostic workup of AAD. To identify clinically relevant biomarkers for AAD, we applied Proseek Multiplex assays to plasma samples from patients with AAD, AMI, PE, thoracic aortic aneurysm (TAA), and non-cardiovascular chest pain (nonCVD). Subsequently, we validated top hits using conventional immunoassays and examined their expression in the aortic tissue. Interleukin 10 (IL-10) alone showed the best performance with a sensitivity of 55% and a specificity of 98% for AAD diagnosis. The combination of D-dimers, high-sensitive troponin T (hs-TnT), interleukin 6 (IL-6), and plasminogen activator inhibitor 1 (PAI1) correctly classified 75% of AAD cases, delivering a sensitivity of 83% and specificity of 95% for its diagnosis. Moreover, this model provided the correct classification of 77% of all analyzed cases. Our data suggest that IL-10 shows potential to be a rule-in biomarker for AAD. Moreover, the addition of PAI1 and IL-6 to hs-TnT and D-dimers may improve the discrimination of suspected AAD, AMI, and PE in patients presenting with acute chest pain.
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http://dx.doi.org/10.3390/diagnostics11040615DOI Listing
March 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

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

Lipid-lowering therapy and low-density lipoprotein cholesterol goal achievement in patients with acute coronary syndromes: The ACS patient pathway project.

Atheroscler Suppl 2020 Dec;42:e49-e58

Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy. Electronic address:

Background And Aims: Post-acute coronary syndrome (ACS) patients are at very high risk for recurrent events and mortality, despite the availability of effective pharmacological approaches. Aim of this survey was to evaluate the compliance to ESC/EAS guidelines during the management of ACS patients and the effectiveness of secondary prevention in seven European countries.

Methods: By means of an online questionnaire, data on 2775 ACS patients (either acute case or follow-up patients) were collected, including data on lipid profile, medications, follow-up visit planning, screening for familial hypercholesterolemia.

Results: Lipid profiles were obtained for 91% of ACS patients in the acute phase, mostly within the first day of hospitalization (73%). During hospitalization, 93% of the patients received a lipid-lowering treatment; at discharge, only 66% of the patients received a high intensity statin therapy. At the first follow-up, most of the patients (77.6%) had LDL-C >70 mg/dL; among them, 41% had no change in their lipid-lowering therapies. Similar data were obtained during the second follow-up visit. The analysis of a subgroup of patients with at least 2 follow-up visits and known LDL-C levels showed that the percentage of patients at goal increased from 9% to 32%, and patients with LDL-C <100 mg/dL raised from 23% to 72%. Among acute cases, 44 were admitted with a diagnosis of familial hypercholesterolemia (FH); only 18% of the remaining patients were screened for FH.

Conclusions: Contemporary lipid management of very high CV risk patients is sub-optimal despite available treatments. Greater efforts are warranted to optimize cardiovascular prevention.
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http://dx.doi.org/10.1016/j.atherosclerosissup.2021.01.009DOI Listing
December 2020

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

Current perceptions and practices in lipid management: results of a European Society of Cardiology/European Atherosclerosis Society Survey.

Eur J Prev Cardiol 2021 Jan 18. Epub 2021 Jan 18.

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

Aims: We sought to evaluate physicians' opinions and practices in lipid management.

Methods And Results: A web-based survey by the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) was distributed to 70 696 individuals at two time points, before and after publication of the 2019 ESC/EAS dyslipidaemia guidelines. Respondents (1271 in the first and 1056 in the second part) were most commonly cardiologists in Europe. More than 90% of participants reported that they regularly measure lipid levels and discuss lipid-lowering treatment with patients. More than 87% found the use of LDL-C goals useful or potentially useful, although it was acknowledged that recommended goals are frequently not achieved. Regarding the LDL-C goal according to the 2019 guidelines (<1.4 mmol/L for very high-risk patients), more than 70% of respondents felt that it is based on solid scientific evidence, but 31% noted that implementation should also consider available local resources and patient preferences. Statin intolerance was perceived as infrequent, affecting 1-5% of patients according to most respondents but was the main reason for not prescribing a statin to secondary-prevention patients, followed by patient non-adherence. Although most respondents reported that 11-20% of secondary-prevention patients have an indication to add a non-statin medication, fewer patients (<10% according to most respondents) receive these medications.

Conclusions: This survey shows a high level of acceptance of the LDL-C treatment goals recommended by current ESC/EAS guidelines. Although patient-related factors were the main reported reasons for suboptimal lipid-lowering therapy, physician inertia to intensify treatment cannot be excluded as an additional contributing factor.
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http://dx.doi.org/10.1093/eurjpc/zwaa156DOI Listing
January 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

It's never too early to beat your low-density lipoprotein cholesterol.

Arch Cardiovasc Dis 2021 Jan 25;114(1):1-3. Epub 2021 Jan 25.

Cardiology Division, Department of Specialties in Medicine, Geneva University Hospitals, 1211 Geneva 14, Switzerland.

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http://dx.doi.org/10.1016/j.acvd.2021.01.001DOI Listing
January 2021

New cardiovascular prevention guidelines: How to optimally manage dyslipidaemia and cardiovascular risk in 2021 in patients needing secondary prevention?

Atherosclerosis 2021 02 18;319:51-61. Epub 2021 Jan 18.

UCHealth University of Colorado Hospital, Aurora, CO, USA.

Elevated low-density lipoprotein cholesterol (LDL-C) is a principally modifiable cause of atherosclerotic cardiovascular disease; accordingly, recent European and US multisociety dyslipidaemia guidelines emphasise the importance of lowering LDL-C to reduce cardiovascular risk. This review provides perspectives on established and emerging agents that reduce LDL-C to help providers synthesize the abundance of new evidence related to prevention of cardiovascular disease. We provide hypothetical cases of patients with different cardiovascular risk factors and medical histories to illustrate application of current lipid-lowering guidelines in various clinical settings. As a core focus of preventive therapy, both European and US lipid management guidelines emphasise the importance of identifying patients at very high cardiovascular risk and treating to achieve LDL-C levels as low as possible, with European guidelines setting a goal of <1.4 mmol/L (<55 mg/dL) in patients with very high-risk cardiovascular disease. The proprotein convertase subtilisin/kexin type 9 inhibitors are now included in the guidelines and may fulfil an important unmet need for very high-risk patients who are not able to achieve LDL-C goals with conventional agents. The recently approved bempedoic acid and other promising agents under development will add to the armamentarium of lipid-lowering drugs available for clinicians to help patients meet their treatment goals.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.12.013DOI Listing
February 2021

Impact of the COVID-19 pandemic on acute coronary syndromes.

Swiss Med Wkly 2020 12 31;150:w20448. Epub 2020 Dec 31.

Cardiology division, Geneva University Hospitals, Geneva, Switzerland.

Aim: To assess the impact of the first wave of the COVID-19 pandemic on acute coronary syndromes and on the delay from symptom onset to first medical contact among patients presenting with ST-segment elevation myocardial infarction (STEMI), as well as to investigate whether there were patient-related reasons related to COVID-19 for delaying first medical contact.

Methods And Results: All patients undergoing percutaneous coronary intervention (PCI) at the Geneva University Hospitals for acute coronary syndromes (ACS) during the first COVID-19 wave were compared with a control group consisting of all ACS patients who underwent PCI during the same period in 2019 and those treated in the period immediately preceding the pandemic. The primary outcome measure was the difference in the delay from symptom onset to first medical contact in the setting of STEMI between the COVID-19 period and the control period. Secondary outcome measures were the difference in ACS incidence and the impact of the COVID-19 pandemic on patients’ decisions to call the emergency services, assessed using a questionnaire. Delay from symptom onset to first medical contact was longer among patients suffering from STEMI in the COVID-19 period compared with the control period (112 min vs 60 min, p = 0.049). The incidence rate of ACS was lower during the COVID-19 period (incidence rate ratio 0.6, 95% confidence interval [CI] 0.449–0.905). ACS patients delayed their call to the emergency services mainly because of fear of contracting or spreading COVID-19 following hospital admission, as well as of adding burden to the healthcare system.

Conclusion: We observed prolonged delays from symptom onset to first medical contact and a decline in overall ACS incidence during the first wave of the COVID-19 pandemic, with a higher threshold to call for help among ACS patients.
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http://dx.doi.org/10.4414/smw.2020.20448DOI Listing
December 2020

Prognostic and therapeutic considerations of antibodies against c-ter apolipoprotein A-1 in the general population.

Clin Transl Immunology 2020 14;9(12):e1220. Epub 2020 Dec 14.

Department of Internal Medicine Lausanne University Hospital Lausanne Switzerland.

Objectives: Autoantibodies against apolipoprotein A1 (anti-apoA1 IgGs) and its C-terminal region (cter apoA1) have emerged as an independent biomarker for cardiovascular disease. Cter apoA1 mimetic peptides were shown to reverse the deleterious anti-apoA1 IgG effects . We evaluated the association of anti-cter apoA1 IgGs with overall mortality in the general population and tested the ability of a cter apoA1 mimetic peptide to reverse the anti-apoA1 IgG-induced inflammatory response and mortality and , respectively.

Methods: Anti-cter apoA1 IgGs were measured in serum samples of 6386 participants of the CoLaus study of which 5220 were followed for a median duration of 5.6 years. The primary outcome was overall mortality. The peptide inhibitory concentration 50% (IC) was determined on HEK-Blue-4 and RAW cells. ApoE mice were exposed to 16 weeks of anti-apoA1IgG passive immunisation with and without peptide co-incubation.

Results: Anti-cter apoA1 IgGs were associated with higher interleukin 6 levels and independently predicted overall mortality; an increase of one standard deviation of anti-cter apoA1 IgG level was associated with an 18% increase in mortality risk (hazard ratio: 1.18, 95% confidence interval: 1.04-1.33;  = 0.009). The cterApoA1 analogue reversed the antibody-mediated inflammatory response with an IC of 1 µm but did not rescue the significant anti-apoA1 IgG-induced mortality rate (69% vs. 23%, LogRank  = 0.02).

Conclusion: Anti-cter apoA1 IgG independently predicts overall mortality in the general population. Despite being effective , our cter apoA1 analogue did not reverse the anti-apoA1 IgG-induced mortality in mice. Our data suggest that these autoantibodies are not readily treatable through cognate peptide immunomodulation.
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http://dx.doi.org/10.1002/cti2.1220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734471PMC
December 2020

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

A Short Intervention Followed by an Interactive E-Learning Module to Motivate Medical Students to Enlist as First Responders: Protocol for a Prospective Implementation Study.

JMIR Res Protoc 2020 Nov 6;9(11):e24664. Epub 2020 Nov 6.

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

Background: In Geneva, Switzerland, basic life support (BLS) maneuvers are provided in only 40% of out-of-hospital cardiac arrests (OHCAs) cases. As OHCA outcomes are markedly improved when BLS maneuvers are swiftly applied, a "first-responder" system was introduced in 2019. When emergency dispatchers identify a possible OHCA, first responders receive an alert message on a specific app (Save-a-Life) installed on their smartphones. Those nearest to the victim and immediately available are sent the exact location of the intervention. First-year medical students only have limited knowledge regarding BLS procedures but might nevertheless need to take care of OHCA victims. Medical students responding to out-of-hospital emergencies are off-duty in half of these situations, and offering junior medical students the opportunity to enlist as first responders might therefore not only improve OHCA outcomes but also foster a greater recognition of the role medical students can hold in our society.

Objective: Our aim is to determine whether providing first-year medical students with a short intervention followed by an interactive e-learning module can motivate them to enlist as first responders.

Methods: After obtaining the approval of the regional ethics committee and of the vice-dean for undergraduate education of the University of Geneva Faculty of Medicine (UGFM), 2 senior medical students will present the project to their first-year colleagues at the beginning of a lecture. First-year students will then be provided with a link to an interactive e-learning module which has been designed according to the Swiss Resuscitation Council's first aid guidelines. After answering a first questionnaire and completing the module, students will be able to register for practice sessions. Those attending and successfully completing these sessions will receive a training certificate which will enable them to enlist as first responders. The primary outcome will be the proportion of first-year medical students enlisting as first responders at the end of the study period. Secondary outcomes will be the proportion of first-year medical students electing to register on the platform, to begin the e-learning module, to complete the e-learning module, to register for practice sessions, to attend the practice sessions, and to obtain a certificate. The reasons given by medical students for refusing to participate will be analyzed. We will also assess how comfortable junior medical students would feel to be integrated into the first responders system at the end of the training program and whether it affects the registration rate.

Results: The regional ethics committee (Req-2020-01143) and the UGFM vice-dean for undergraduate education have given their approval to the realization of this study, which is scheduled to begin in January 2021.

Conclusions: This study should determine whether a short intervention followed by an interactive e-learning module can motivate first-year medical students to enlist as first responders.

International Registered Report Identifier (irrid): PRR1-10.2196/24664.
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http://dx.doi.org/10.2196/24664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679213PMC
November 2020

Atherosclerotic plaque vulnerability is increased in mouse model of lupus.

Sci Rep 2020 10 27;10(1):18324. Epub 2020 Oct 27.

Division of Cardiology, Foundation for Medical Researches, Department of Medicine Specialties, Faculty of Medicine, University of Geneva, Av. de la Roseraie 64, 1211, Geneva 4, Switzerland.

Anti-apolipoprotein A-1 (anti-apoA-1 IgG) and anti-double stranded DNA (anti-dsDNA IgG) autoantibodies have been described as mediators of atherogenesis in mice and humans. In the present study, we aim to investigate the association between atherosclerotic parameters, autoantibodies and plaque vulnerability in the context of systemic lupus erythematosus (SLE). We therefore bred a lupus prone-mouse model (Nba2.Yaa mice) with Apoe mice resulting in ApoeNba2.Yaa mice spontaneously producing anti-apoA-1 IgG antibodies. Although ApoeNba2.Yaa and Apoe mice subject to a high cholesterol diet displayed similar atherosclerosis lesions size in aortic roots and abdominal aorta, the levels of macrophage and neutrophil infiltration, collagen, MMP-8 and MMP-9 and pro-MMP-9 expression in ApoeNba2.Yaa mice indicated features of atherosclerotic plaque vulnerability. Even though ApoeNba2.Yaa mice and Apoe mice had similar lipid levels, ApoeNba2.Yaa mice showed higher anti-apoA-1 and anti-dsDNA IgG levels. ApoeNba2.Yaa mice displayed a reduction of the size of the kidney, splenomegaly and lymph nodes (LN) hypertrophy. In addition, anti-apoA-1 and anti-dsDNA IgG increased also in relation with mRNA levels of GATA3, IL-4, Bcl-6 and CD20 in the spleen and aortic arch of ApoeNba2.Yaa mice. Our data show that although atherosclerosis-lupus-prone ApoeNba2.Yaa mice did not exhibit exacerbated atherosclerotic lesion size, they did show features of atherosclerotic plaque destabilization in correlation with the increase of pro-atherogenic autoantibodies.
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http://dx.doi.org/10.1038/s41598-020-74579-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591560PMC
October 2020

Anti-Apolipoprotein A-1 IgG Influences Neutrophil Extracellular Trap Content at Distinct Regions of Human Carotid Plaques.

Int J Mol Sci 2020 10 19;21(20). Epub 2020 Oct 19.

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

Background: Neutrophils accumulate in atherosclerotic plaques. Neutrophil extracellular traps (NET) were recently identified in experimental atherosclerosis and in complex human lesions. However, not much is known about the NET marker citrullinated histone-3 (H3Cit) expression and functionality in human carotid plaques. Moreover, the association between the proatherosclerotic autoantibody anti-apolipoprotein A-1 (anti-ApoA-1 IgG) and NET has never been investigated.

Methods: Atherosclerotic plaques have been obtained from 36 patients with severe carotid stenosis that underwent carotid endarterectomy for severe carotid stenosis. Samples were sectioned into upstream and downstream regions from the same artery segment. Plaque composition and expression of NET markers neutrophil elastase (NE) and H3Cit were quantified by immunohistochemistry. H3Cit expression and function was evaluated by immunofluorescence and confocal analysis in a subset of patients.

Results: Pathological features of vulnerable phenotypes were exacerbated in plaques developed at downstream regions, including higher accumulation of neutrophils and enhanced expression of NE and H3Cit, as compared to plaques from upstream regions. The H3Cit signal was also more intense in downstream regions, with significant extracellular distribution in spaces outside of neutrophils. The percentage of H3Cit colocalization with CD66b (neutrophils) was markedly lower in downstream portions of carotid plaques, confirming the extrusion of NET in this region. In agreement, the maximum distance of the H3Cit signal from neutrophils, extrapolated from vortex distance calculation in all possible directions, was also higher in downstream plaques. The serum anti-ApoA-1index positively correlated with the expression of H3Cit in downstream segments of plaques. Expression of the H3Cit signal outside of neutrophils and H3Cit maximal distance from CD66b-positive cells increased in plaques from serum positive anti-ApoA-1 patients compared with serum negative patients.

Conclusion: NET elements are differentially expressed in upstream versus downstream regions of human carotid plaques and may be influenced by circulating levels of anti-ApoA-1 IgG. These findings could warrant the investigation of NET elements as potential markers of vulnerability.
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http://dx.doi.org/10.3390/ijms21207721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588926PMC
October 2020

Enoxaparin for primary thromboprophylaxis in ambulatory patients with coronavirus disease-2019 (the OVID study): a structured summary of a study protocol for a randomized controlled trial.

Trials 2020 Sep 9;21(1):770. Epub 2020 Sep 9.

Clinic of Angiology, University Hospital Zurich, Zurich, Switzerland.

Objectives: The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival and reduces hospitalizations in symptomatic ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation.

Trial Design: The OVID study is conducted as a multicentre open-label superiority randomised controlled trial.

Participants: Inclusion Criteria 1. Signed patient informed consent after being fully informed about the study's background. 2. Patients aged 50 years or older with a positive test for SARS-CoV2 in the past 5 days and eligible for ambulatory treatment. 3. Presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature >37.5° C. 4. Ability of the patient to travel to the study centre by private transportation, performed either by an accompanying person from the same household or by the patient themselves 5. Ability to comply with standard hygiene requirements at the time of in-hospital visit, including a face mask and hand disinfectant. 6. Ability to walk from car to study centre or reach it by wheelchair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements. 7. Ability to self-administer prefilled enoxaparin injections after instructions received at the study centre or availability of a person living with the patient to administer enoxaparin. Exclusion Criteria 1. Any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior venous thromboembolism (VTE), acute confirmed symptomatic VTE, acute coronary syndrome. 2. Anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity or predisposing strong risk factors for thrombosis:  a. Any of the following events occurring in the prior 30 days: fracture of lower limb, hospitalization for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke,  b. previous VTE,  c. histologically confirmed malignancy, which was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past 6 months, or recurrent, or metastatic, or inoperable. 3. Any clinically relevant bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 30 days prior to randomization or sign of acute bleeding. 4. Intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial haemorrhage. 5. Haemoglobin <8 g/dL and platelet count <50 x 10 cells/L confirmed by recent laboratory test (<90 days). 6. Subjects with any known coagulopathy or bleeding diathesis, including known significant liver disease associated with coagulopathy. 7. Severe renal insufficiency (baseline creatinine clearance <30 mL/min calculated using the Cockcroft-Gault formula) confirmed by recent laboratory test (<90 days). 8. Contraindications to enoxaparin therapy, including prior heparin-induced thrombocytopenia and known hypersensitivity. 9. Current use of dual antiplatelet therapy. 10. Participation in other interventional studies over the past 30 days. 11. Non-compliance or inability to adhere to treatment or lack of a family environment or support system for home treatment. 12. Cognitive impairment and/or inability to understand information provided in the study information. Patient enrolment will take place at seven Swiss centres, including five university hospitals and two large cantonal hospitals.

Intervention And Comparator: Patients randomized to the intervention group will receive subcutaneous enoxaparin at the recommended dose of 4,000 IU anti-Xa activity (40 mg/0.4 ml) once daily for 14 days. Patients randomized to the comparator group will receive no anticoagulation.

Main Outcomes: Primary outcome: a composite of any hospitalization or all-cause death occurring within 30 days of randomization.

Secondary Outcomes: (i) a composite of cardiovascular events, including deep vein thrombosis (including catheter-associated), pulmonary embolism, myocardial infarction/myocarditis, arterial ischemia including mesenteric and extremities, acute splanchnic vein thrombosis, or ischemic stroke within 14 days, 30 days, and 90 days of randomization; (ii) each component of the primary efficacy outcome, within 14 days, 30 days, and 90 days of randomization; (iii) net clinical benefit (accounting for the primary efficacy outcome, composite cardiovascular events, and major bleeding), within 14 days, 30 days, and 90 days of enrolment; (iv) primary efficacy outcome, within 14 days, and 90 days of enrolment; (v) disseminated intravascular coagulation (ISTH criteria, in-hospital diagnosis) within 14 days, 30 days, and 90 days of enrolment.

Randomisation: Patients will undergo block stratified randomization (by age: 50-70 vs. >70 years; and by study centre) with a randomization ratio of 1:1 with block sizes varying between 4 and 8. Randomization will be performed after the signature of the informed consent for participation and the verification of the eligibility criteria using the electronic data capture software (REDCAP, Vanderbilt University, v9.1.24).

Blinding (masking): In this open-label study, no blinding procedures will be used.

Numbers To Be Randomised (sample Size): The sample size calculation is based on the parameters α = 0.05 (2-sided), power: 1-β = 0.8, event rate in experimental group, pexp = 0.09 and event rate in control group, pcon = 0.15. The resulting total sample size is 920. To account for potential dropouts, the total sample size was fixed to 1000 with 500 patients in the intervention group and 500 in the control group.

Trial Status: Protocol version 1.0, 14 April 2020. Protocol version 3.0, 18 May 2020 Recruiting start date: June 2020. Last Patient Last Visit: March 2021.

Trial Registration: ClinicalTrials.gov Identifier: NCT04400799 First Posted: May 26, 2020 Last Update Posted: July 16, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-020-04678-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479300PMC
September 2020

Evolocumab in Pediatric Heterozygous Familial Hypercholesterolemia.

N Engl J Med 2020 10 29;383(14):1317-1327. Epub 2020 Aug 29.

From the Lipid Clinic Heart Institute, University of São Paulo Medical School Hospital and Hospital Israelita Albert Einstein, São Paulo (R.D.S.); Amgen, Thousand Oaks, CA (A.R., C.E.K, A.H.); the Departments of Vascular Medicine (G.K.H., J.J.P.K.) and Pediatrics (A.W., I.L.), Amsterdam UMC, Amsterdam; the Cardiology Department, Geneva University Hospital, Geneva (F.M.); the Biostatistics Department, Amgen, Cambridge (I.B.), and the Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital, Birmingham (S.S.) - both in the United Kingdom; the Rare Diseases and Clinical Genetics Unit, Academic Pediatric Department, Bambino Gesù Children's Hospital (A.B.), and the Department of Molecular Medicine, Umberto I Hospital, Sapienza University of Rome (C.S.), Rome; the Lipid Clinic, Department of Medicine, Centre Hospitalier Universitaire de Québec-Université Laval, Quebec (J.B.), and the Clinical Lipidology and Rare Lipid Disorders Unit, Community Genomic Medicine Centre and ECOGENE-21, Department of Medicine, Université de Montréal, Chicoutimi, QC (D.G.) - both in Canada; the 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary (T.S.); the Department of Internal Medicine, Centres Hospitaliers Jolimont, La Louvière, Belgium (O.S.D.); and the Division of Pediatric Pulmonology, Allergology, and Endocrinology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna (S.G.-P.).

Background: Evolocumab, a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9, is widely used in adult patients to lower low-density lipoprotein (LDL) cholesterol levels. Its effects in pediatric patients with heterozygous familial hypercholesterolemia are not known.

Methods: We conducted a 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of evolocumab in pediatric patients with heterozygous familial hypercholesterolemia. Patients 10 to 17 years of age who had received stable lipid-lowering treatment for at least 4 weeks before screening and who had an LDL cholesterol level of 130 mg per deciliter (3.4 mmol per liter) or more and a triglyceride level of 400 mg per deciliter (4.5 mmol per liter) or less were randomly assigned in a 2:1 ratio to receive monthly subcutaneous injections of evolocumab (420 mg) or placebo. The primary end point was the percent change in LDL cholesterol level from baseline to week 24; key secondary end points were the mean percent change in LDL cholesterol level from baseline to weeks 22 and 24 and the absolute change in LDL cholesterol level from baseline to week 24.

Results: A total of 157 patients underwent randomization and received evolocumab (104 patients) or placebo (53 patients). At week 24, the mean percent change from baseline in LDL cholesterol level was -44.5% in the evolocumab group and -6.2% in the placebo group, for a difference of -38.3 percentage points (P<0.001). The absolute change in the LDL cholesterol level was -77.5 mg per deciliter (-2.0 mmol per liter) in the evolocumab group and -9.0 mg per deciliter (-0.2 mmol per liter) in the placebo group, for a difference of -68.6 mg per deciliter (-1.8 mmol per liter) (P<0.001). Results for all secondary lipid variables were significantly better with evolocumab than with placebo. The incidence of adverse events that occurred during the treatment period was similar in the evolocumab and placebo groups.

Conclusions: In this trial involving pediatric patients with familial hypercholesterolemia, evolocumab reduced the LDL cholesterol level and other lipid variables. (Funded by Amgen; HAUSER-RCT ClinicalTrials.gov number, NCT02392559.).
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http://dx.doi.org/10.1056/NEJMoa2019910DOI Listing
October 2020

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

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

Department of Cardiology, University Hospital Bern, Switzerland.

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

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

Conclusions: In this analysis, the 2019 ESC/EAS guidelines rendered half of all post-acute coronary syndrome patients potentially eligible for PCSK9i treatment, as compared to a three-fold lower eligibility rate based on the 2018 ACC/AHA guidelines.
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July 2020

[Spontaneous coronary artery dissection : primum nihil nocere].

Rev Med Suisse 2020 Jun;16(696):1153-1158

Service de cardiologie, HUG, 1211 Genève 14.

Spontaneous coronary artery dissection (SCAD) is an important cause of acute coronary syndrome, myocardial infarction and sudden cardiac death, among young patient with little/no traditional cardiovascular risk factors. Historically SCAD was considered as a rare pathology, associated primarily with pregnancy and the peripartum period. In recent years, SCAD diagnosis improved thanks to data derived from large registries, thanks to the increased use of diagnostic coronary angiography and the availability of intracoronary imaging. To date there are no randomized trials dedicated to SCAD. However, thanks to global efforts to build national SCAD registries, knowledge of SCAD has tremendously increased during the last years, demonstrating that SCAD is a distinct pathophysiological entity, and presents key differences in management and outcomes compared to ACS of atherosclerotic aetiology.
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June 2020

Au Cœur du Covid-19.

Rev Med Suisse 2020 06;16(696):1131

Chef du service de cardiologie, CHUV, Lausanne.

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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

An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial.

JAMA Cardiol 2020 06;5(6):709-713

TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab reduces circulating LDL-C concentrations by 50% to 60% and Lp(a) by 20% to 30%.

Objective: To determine whether evolocumab reduces the risk of AS events in patients with atherosclerotic cardiovascular disease.

Interventions: Patients were randomized 1:1 to evolocumab or placebo.

Design, Setting, And Participants: Exploratory analysis of the FOURIER trial, which enrolled 27 564 patients with stable atherosclerotic cardiovascular disease who were taking statin therapy at 1242 sites in 49 countries from February 2013 to November 2016. Patients were randomized to evolocumab or placebo and followed up for a median (interquartile range) of 2.2 (1.8-2.5) years. This post hoc analysis was performed from September 2019 to February 2020.

Main Outcomes And Measures: Site-reported adverse events of new or worsening AS or aortic valve replacement (termed AS events). The adjusted risk of AS events was calculated with a multivariable model including concentrations of Lp(a) and LDL-C corrected for Lp(a) content, plus age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. Evolocumab efficacy was tested using a Cox proportional hazards model.

Results: Aortic stenosis events occurred in 63 patients (48 men [76%]; mean [SD] age, 69 [9] years) over a median of 2.2 years. Elevated Lp(a) concentration was associated with higher rates of AS events (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.17-2.05] per SD; P = .002), including aortic valve replacement (aHR, 2.22 [95% CI, 1.38-3.58] per SD; P = .001), after multivariable adjustment. The corrected LDL-C concentration was not significantly associated with AS events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P = .14). The overall HR for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (HR, 1.09 [95% CI, 0.48-2.47]) but an HR of 0.48 (95% CI, 0.25-0.93) after the first year of treatment.

Conclusions And Relevance: In this exploratory analysis of the FOURIER trial, higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial.

Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.
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http://dx.doi.org/10.1001/jamacardio.2020.0728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301224PMC
June 2020

Cardiotrophin-1 Deficiency Abrogates Atherosclerosis Progression.

Sci Rep 2020 04 1;10(1):5791. Epub 2020 Apr 1.

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.

Cardiotrophin-1 (CT-1) is associated with cardiovascular (CV) diseases. We investigated the effect of CT-1 deficiency in the development and progression of atherosclerosis in double knockout Apoect-1 mice. Apoe C57Bl/6 or Apoect-1 C57Bl/6 mice were fed a normal chow diet (NCD) or a high-cholesterol diet (HCD). After sacrifice, serum triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), free fatty acids and systemic paracrine factors were measured. Intraplaque lipid and collagen content were quantified in the aortic sections. Immune cell populations in spleen, lymph nodes and aorta were analysis by flow cytometry. Apoect-1 mice in accelerated atherosclerosis exhibited a reduction of total cholesterol, LDL-C, atherosclerotic plaques size in the aortic root and in the abdominal aorta and improved plaque stability in comparison to Apoe mice. CT-1 deficiency in Apoe mice on (HCD) promoted atheroprotective immune cell responses, as demonstrated by a rise in plasma anti-inflammatory immune cell populations (regulatory T cells, Tregs; regulatory B cells, Bregs and B1a cells) and atheroprotective IgM antibodies. CT-1 deficiency in advanced atherosclerosis mediated regulation of paracrine factors, such as interleukin (IL)-3, IL-6, IL-9, IL-15, IL-27, CXCL5, MCP-3, MIP-1α and MIP-1β. In a model of advanced atherosclerosis, CT-1 deficiency induced anti-inflammatory and atheroprotective effects which resulted in abrogation of atheroprogression.
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http://dx.doi.org/10.1038/s41598-020-62596-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113288PMC
April 2020

Follicular regulatory helper T cells control the response of regulatory B cells to a high-cholesterol diet.

Cardiovasc Res 2021 Feb;117(3):743-755

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.

Aims: B cell functions in the process of atherogenesis have been investigated but several aspects remain to be clarified.

Methods And Results: In this study, we show that follicular regulatory helper T cells (TFR) control regulatory B cell (BREG) populations in Apoe-/- mice models on a high-cholesterol diet (HCD). Feeding mice with HCD resulted in up-regulation of TFR and BREG cell populations, causing the suppression of proatherogenic follicular helper T cell (TFH) response. TFH cell modulation is correlated with the growth of atherosclerotic plaque size in thoracoabdominal aortas and aortic root plaques, suggesting that TFR cells are atheroprotective. During adoptive transfer experiments, TFR cells transferred into HCD mice decreased TFH cell populations, atherosclerotic plaque size, while BREG cell population and lymphangiogenesis are significantly increased.

Conclusion: Our results demonstrate that, through different strategies, both TFR and TFH cells modulate anti- and pro-atherosclerotic immune processes in an Apoe-/- mice model since TFR cells are able to regulate both TFH and BREG cell populations as well as lymphangiogenesis and lipoprotein metabolism.
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http://dx.doi.org/10.1093/cvr/cvaa069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898950PMC
February 2021