Publications by authors named "Jean-Claude Tardif"

557 Publications

Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.

Lancet Respir Med 2021 May 27. Epub 2021 May 27.

Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.

Background: Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission.

Methods: The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants.

Findings: Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0-61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61-1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57-0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001).

Interpretation: In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended.

Funding: The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.
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http://dx.doi.org/10.1016/S2213-2600(21)00222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159193PMC
May 2021

Genetics of symptom remission in outpatients with COVID-19.

Sci Rep 2021 05 25;11(1):10847. Epub 2021 May 25.

Montreal Heart Institute, 5000 Belanger Street, Montreal, H1T 1C8, Canada.

We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 × 10) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 × 10) in interaction with colchicine (P = 1.19 × 10) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.
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http://dx.doi.org/10.1038/s41598-021-90365-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149390PMC
May 2021

Glucagon-Like Peptide 1 Receptor Agonists, Carotid Atherosclerosis, and Cardiovascular Outcomes.

Diabetes Care 2021 May 20. Epub 2021 May 20.

Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada

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http://dx.doi.org/10.2337/dci20-0076DOI Listing
May 2021

Prevalence, Incidence and Prognostic Implications of Left Bundle Branch Block in Patients with Chronic Coronary Syndromes (From the CLARIFY Registry).

Am J Cardiol 2021 Jul 16;150:40-46. Epub 2021 May 16.

Université de Paris, Assistance Publique - Hôpitaux de Paris; FACT, French Alliance for Cardiovascular Trials, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Paris, France; INSERM U-1148, Laboratory for Vascular Translationnal Science; National Heart and Lung Institute, Royal Brompton Hospital, Imperial College, London, United Kingdom.

Left Bundle Branch Block (LBBB) is a frequently encountered electrical abnormality in patients with chronic (more than 3 months after myocardial infarction, or evidence of coronary artery disease with ischemia) coronary syndromes (CCS), but its prognostic significance remains unclear. We aimed to describe the prevalence, incidence and five-year outcomes of LBBB in outpatients with CCS using the CLARIFY registry. Main outcome was a composite of CV death, MI or stroke. Secondary outcomes included all cause death, hospitalization for heart failure (HF) and permanent pacemaker implantation. Among 23.544 patients with available information regarding LBBB status at baseline, 1.041 (4.4%) had LBBB at baseline and 1.015 (4.5%) patients developed a new LBBB during 5-year follow-up. In multivariate analysis, LBBB at baseline was not associated with the composite outcome of CV death, MI or stroke (HR 1.06, 95% CI [0.86 - 1.31], p = 0.67) or the risk of all-cause death (HR 1.07, 95% CI [0.87 - 1.32], p = 0.52) but was significantly associated with a higher risk of hospitalization for HF (HR 1.50, 95% CI [1.21 - 1.88], p < 0.001) and permanent pacemaker implantation (HR 2.11, 95% CI [1.45 - 3.07], p < 0.001). The main factors associated with new-onset LBBB were male sex (HR 0.8 [0.66-0.98], p = 0.028) history of atrial fibrillation (HR 1.29, 95% CI [1.01 - 1.64], p = 0.04), CABG (HR 1.27, [1.08 - 1.51], p = 0.004) and MI (HR 1.19, 95% CI [1.01 - 1.40], p = 0.034). In conclusion, in a contemporary registry of outpatients with CCS, the prevalence of LBBB was 4.4% and the additional 5-years incidence 6.2%. LBBB, in itself, was not associated with a higher risk of major adverse cardiovascular events or all cause mortality. It was however an independent predictor of risk of hospitalization for heart failure and permanent pacemaker implantation.
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http://dx.doi.org/10.1016/j.amjcard.2021.03.047DOI Listing
July 2021

Vascular inflammation in moderate-to-severe atopic dermatitis is associated with enhanced Th2 response.

Allergy 2021 Apr 18. Epub 2021 Apr 18.

Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: In atopic dermatitis (AD), some studies have shown an association with increased cardiovascular disease in certain populations. However, other investigations found modest or no association. Despite conflicting results, molecular profiling studies in both AD skin and blood have demonstrated upregulation of atherosclerosis and cardiovascular risk-related markers. However, the underlying mechanisms connecting AD to vascular inflammation/atherosclerosis are unknown. In this study, we aim to determine factors associated with vascular inflammation/atherosclerosis in AD patients.

Methods: We used 18-FDG PET-CT to characterize vascular inflammation in AD patients and healthy subjects. In parallel, we assessed their skin and blood immune profiles to determine AD-related immune biomarkers associated with vascular inflammation. We also assessed levels of circulating microparticles, which are known to be associated with increased cardiovascular risk.

Results: We found significant correlations between vascular inflammation and Th2-related products in skin and blood of AD patients as well as atherosclerosis-related markers that were modulated by dupilumab. Circulating levels of endothelial microparticles were significantly higher in severe AD patients and tended to correlate with vascular inflammation assessed by PET-CT.

Conclusion: Vascular inflammation in AD is associated with enhanced Th2 response and clinical severity, which may explain cardiovascular comorbidities observed in select AD populations. Larger prospective studies are needed to further evaluate vascular inflammation and cardiovascular events and mortality in AD patients. Finally, as dupilumab treatment demonstrated significant modulation of atherosclerosis-related genes in AD patients compared to placebo, these data suggest that modulation of vascular inflammation with systemic treatment should be explored in patients with AD.
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http://dx.doi.org/10.1111/all.14859DOI Listing
April 2021

Long-Chain Acylcarnitines and Monounsaturated Fatty Acids Discriminate Heart Failure Patients According to Pulmonary Hypertension Status.

Metabolites 2021 Mar 26;11(4). Epub 2021 Mar 26.

Research Center, Montreal Heart Institute, Montréal, QC H1T1C8, Canada.

Defects in fatty acid (FA) utilization have been well described in group 1 pulmonary hypertension (PH) and in heart failure (HF), yet poorly studied in group 2 PH. This study was to assess whether the metabolomic profile of patients with pulmonary hypertension (PH) due HF, classified as group 2 PH, differs from those without PH. We conducted a proof-of-principle cross-sectional analysis of 60 patients with chronic HF with reduced ejection fraction and 72 healthy controls in which the circulating level of 71 energy-related metabolites was measured using various methods. Echocardiography was used to classify HF patients as noPH-HF ( = 27; mean pulmonary artery pressure [mPAP] 21 mmHg) and PH-HF ( = 33; mPAP 35 mmHg). The profile of circulating metabolites among groups was compared using principal component analysis (PCA), analysis of covariance (ANCOVA), and Pearson's correlation tests. Patients with noPH-HF and PH-HF were aged 64 ± 11 and 68 ± 10 years, respectively, with baseline left ventricular ejection fractions of 27 ± 7% and 26 ± 7%. Principal component analysis segregated groups, more markedly for PH-HF, with long-chain acylcarnitines, acetylcarnitine, and monounsaturated FA carrying the highest loading scores. After adjustment for age, sex, kidney function, insulin resistance, and N-terminal pro-brain natriuretic peptide (NT-proBNP), 5/15 and 8/15 lipid-related metabolite levels were significantly different from controls in noPH-HF and PH-HF subjects, respectively. All metabolites for which circulating levels interacted between group and NT-proBNP significantly correlated with NT-proBNP in HF-PH, but none with HF-noPH. FA-related metabolites were differently affected in HF with or without PH, and may convey adverse outcomes given their distinct correlation with NT-proBNP in the setting of PH.
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http://dx.doi.org/10.3390/metabo11040196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066759PMC
March 2021

Role of Adenylate Cyclase 9 in the Pharmacogenomic Response to Dalcetrapib: Clinical Paradigm and Molecular Mechanisms in Precision Cardiovascular Medicine.

Circ Genom Precis Med 2021 Apr 2;14(2):e003219. Epub 2021 Apr 2.

Montreal Heart Institute (D.R., M.R.B., M.-P.D., J.-C.T.).

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 () gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.
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http://dx.doi.org/10.1161/CIRCGEN.121.003219DOI Listing
April 2021

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

Eur Heart J 2021 05;42(18):1742-1756

Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA.

Aims: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown.

Methods And Results: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality.

Conclusion: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
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http://dx.doi.org/10.1093/eurheartj/ehab107DOI Listing
May 2021

Lessons learned from large Cardiovascular Outcome Trials targeting inflammation in cardiovascular disease (CANTOS, CIRT, COLCOT and LoDoCo2).

Future Cardiol 2021 May 9;17(3):411-414. Epub 2021 Mar 9.

Montreal Heart Institute, University of Montreal, Montreal H1T 1C8, Canada.

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http://dx.doi.org/10.2217/fca-2021-0027DOI Listing
May 2021

Genetic meta-analysis of cancer diagnosis following statin use identifies new associations and implicates human leukocyte antigen (HLA) in women.

Pharmacogenomics J 2021 Mar 1. Epub 2021 Mar 1.

Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Montreal, QC, Canada.

We sought to perform a genomic evaluation of the risk of incident cancer in statin users, free of cancer at study entry. Patients who previously participated in two phase IV trials (TNT and IDEAL) with genetic data were used (n = 11,196). A GWAS meta-analysis using Cox modeling for the prediction of incident cancer was conducted in the pooled cohort and sex-stratified. rs13210472 (near HLA-DOA gene) was associated with higher risk of incident cancer amongst women with prevalent coronary artery disease (CAD) taking statins (hazard ratio [HR]: 2.66, 95% confidence interval [CI]: 1.88-3.76, P = 3.5 × 10). Using the UK Biobank and focusing exclusively on women statin users with CAD (n= 2952), rs13210472 remained significantly associated with incident cancer (HR: 1.71, 95% CI: 1.14-2.56, P = 9.0 × 10). The association was not observed in non-statin users. In this genetic meta-analysis, we have identified a variant in women statin users with prevalent CAD that was associated with incident cancer, possibly implicating the human leukocyte antigen pathway.
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http://dx.doi.org/10.1038/s41397-021-00221-zDOI Listing
March 2021

Cardiovascular risk of chronic coronary syndrome patients according to vascular phenotype, diabetes, and smoking.

Eur J Prev Cardiol 2020 Dec 16. Epub 2020 Dec 16.

Department of Cardiology, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, French Alliance for Cardiovascular Trials, INSERM U1148, Laboratory for Vascular Translational Science, 46 rue Henri Huchard, 75018, Paris, France.

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http://dx.doi.org/10.1093/eurjpc/zwaa137DOI Listing
December 2020

Pharmacogenomics of the Efficacy and Safety of Colchicine in COLCOT.

Circ Genom Precis Med 2021 Apr 9;14(2):e003183. Epub 2021 Feb 9.

PhyMedExp (Physiologie et Médecine Expérimentale du Coeur et des Muscles), Université de Montpellier, INSERM, Centre National de la Recherche Scientifique, Cardiology Department, CHU de Montpellier, France (F.R.).

Background: The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine.

Methods: There were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients.

Results: None of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52-2.35], =7.41×10) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82-3.47]; =2.70×10), an intronic variant in gene . The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant.

Conclusions: We found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.
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http://dx.doi.org/10.1161/CIRCGEN.120.003183DOI Listing
April 2021

Comparative effectiveness and safety of high-dose rivaroxaban and apixaban for atrial fibrillation: A propensity score-matched cohort study.

Pharmacotherapy 2021 Apr 27;41(4):379-393. Epub 2021 Feb 27.

Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.

Study Objective: Observational studies assessing direct oral anticoagulant (DOACs) dosage in atrial fibrillation (AF) reported that a lower proportion of patients received high-dose DOACs compared to those in randomized controlled trials (RCTs). Effectiveness and safety of high-dose DOACs relative to apixaban in a real-world AF population need to be addressed. The aim is to assess comparative effectiveness and safety of high-dose rivaroxaban relative to apixaban.

Design: We conducted a cohort study. Setting We built a cohort of patients hospitalized and discharged in community with a primary or secondary AF diagnosis from 2011-2017 using Quebec administrative databases (Med-Echo and RAMQ). Patients Cohort entry was defined as the first OAC claim in new users of high-dose rivaroxaban and apixaban, with no OAC claims in the prior year. Intervention To compare effectiveness and safety of high-dose rivaroxaban to apixaban. Measurement We ascertained patient demographics, comorbidities, CHA2DS2-VASc and HASBLED scores and Charlson score within 3 years prior to cohort entry. Primary effectiveness and safety were a composite of ischemic stroke/systemic thrombosis, death, myocardial infarction, and of intracranial bleeding (ICH), extracranial major bleeding, in the first year following drug initiation. We conducted propensity score matching and estimated hazard ratios (HRs) for outcomes using Cox proportional hazard models. All the analyses were conducted to account for competing risks. Main results The cohort consisted of 4,632 and 6,771 patients received high-dose rivaroxaban and apixaban, respectively. High-dose rivaroxaban users were younger with a mean age of 73.2 years, presented less associated comorbidities and had lower CHA2DS2-VASc scores compared to apixaban. High-dose rivaroxaban at the intention to treat was associated with a higher risk of stroke/SE/death (HR 1.21, 95% CI 1.04-1.40) and worse composite effectiveness (HR 1.21: 1.05-1.40); under treatment exposure, those values were at HR (1.66: 1.21-2.29) and HR (1.58:1.19-2.10), respectively. And, rivaroxaban presented a less favorable safety profile relative to apixaban. Conclusion In this study, composite effectiveness and safety varied between rivaroxaban and apixaban. High-dose apixaban was observed to have a better effectiveness and safety.
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http://dx.doi.org/10.1002/phar.2509DOI Listing
April 2021

Initiation of low-dose colchicine early after myocardial infarction.

Eur Heart J 2021 Feb 4. Epub 2021 Feb 4.

Montreal Heart Institute, Montreal, Canada.

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http://dx.doi.org/10.1093/eurheartj/ehab038DOI Listing
February 2021

MK2-Deficient Mice Are Bradycardic and Display Delayed Hypertrophic Remodeling in Response to a Chronic Increase in Afterload.

J Am Heart Assoc 2021 Feb 3;10(4):e017791. Epub 2021 Feb 3.

Department of Medicine Université de Montréal Québec Canada.

Background Mitogen-activated protein kinase-activated protein kinase-2 (MK2) is a protein serine/threonine kinase activated by p38α/β. Herein, we examine the cardiac phenotype of pan MK2-null (MK2) mice. Methods and Results Survival curves for male MK2 and MK2 mice did not differ (Mantel-Cox test, =0.580). At 12 weeks of age, MK2 mice exhibited normal systolic function along with signs of possible early diastolic dysfunction; however, aging was not associated with an abnormal reduction in diastolic function. Both R-R interval and P-R segment durations were prolonged in MK2-deficient mice. However, heart rates normalized when isolated hearts were perfused ex vivo in working mode. Ca transients evoked by field stimulation or caffeine were similar in ventricular myocytes from MK2 and MK2 mice. MK2 mice had lower body temperature and an age-dependent reduction in body weight. mRNA levels of key metabolic genes, including , , , and were increased in hearts from MK2 mice. For equivalent respiration rates, mitochondria from MK2 hearts showed a significant decrease in Ca sensitivity to mitochondrial permeability transition pore opening. Eight weeks of pressure overload increased left ventricular mass in MK2 and MK2 mice; however, after 2 weeks the increase was significant in MK2 but not MK2 mice. Finally, the pressure overload-induced decrease in systolic function was attenuated in MK2 mice 2 weeks, but not 8 weeks, after constriction of the transverse aorta. Conclusions Collectively, these results implicate MK2 in (1) autonomic regulation of heart rate, (2) cardiac mitochondrial function, and (3) the early stages of myocardial remodeling in response to chronic pressure overload.
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http://dx.doi.org/10.1161/JAHA.120.017791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955338PMC
February 2021

Improved Segmentation of the Intracranial and Ventricular Volumes in Populations with Cerebrovascular Lesions and Atrophy Using 3D CNNs.

Neuroinformatics 2021 Feb 1. Epub 2021 Feb 1.

Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, Canada.

Successful segmentation of the total intracranial vault (ICV) and ventricles is of critical importance when studying neurodegeneration through neuroimaging. We present iCVMapper and VentMapper, robust algorithms that use a convolutional neural network (CNN) to segment the ICV and ventricles from both single and multi-contrast MRI data. Our models were trained on a large dataset from two multi-site studies (N = 528 subjects for ICV, N = 501 for ventricular segmentation) consisting of older adults with varying degrees of cerebrovascular lesions and atrophy, which pose significant challenges for most segmentation approaches. The models were tested on 238 participants, including subjects with vascular cognitive impairment and high white matter hyperintensity burden. Two of the three test sets came from studies not used in the training dataset. We assessed our algorithms relative to four state-of-the-art ICV extraction methods (MONSTR, BET, Deep Extraction, FreeSurfer, DeepMedic), as well as two ventricular segmentation tools (FreeSurfer, DeepMedic). Our multi-contrast models outperformed other methods across many of the evaluation metrics, with average Dice coefficients of 0.98 and 0.96 for ICV and ventricular segmentation respectively. Both models were also the most time efficient, segmenting the structures in orders of magnitude faster than some of the other available methods. Our networks showed an increased accuracy with the use of a conditional random field (CRF) as a post-processing step. We further validated both segmentation models, highlighting their robustness to images with lower resolution and signal-to-noise ratio, compared to tested techniques. The pipeline and models are available at: https://icvmapp3r.readthedocs.io and https://ventmapp3r.readthedocs.io to enable further investigation of the roles of ICV and ventricles in relation to normal aging and neurodegeneration in large multi-site studies.
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http://dx.doi.org/10.1007/s12021-021-09510-1DOI Listing
February 2021

Lessons from COLCOT and LoDoCo2: colchicine for secondary prevention in coronary artery disease.

Eur Heart J 2021 Jan 26. Epub 2021 Jan 26.

Montreal Heart Institute and the Montreal Health Innovations Coordinating Center (MHICC), 5000 Belanger Street, Montreal, QC H1T 1C8, Canada.

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http://dx.doi.org/10.1093/eurheartj/ehab020DOI Listing
January 2021

Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.

Nat Genet 2021 02 25;53(2):128-134. Epub 2021 Jan 25.

Department of Epidemiology and Biostatistics, Imperial College London, London, UK.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.
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http://dx.doi.org/10.1038/s41588-020-00762-2DOI Listing
February 2021

ApoA-I mimetic does not improve left ventricular diastolic dysfunction in rabbits without aortic valve stenosis.

Int J Cardiol 2021 05 6;331:199-205. Epub 2021 Jan 6.

Montreal Heart Institute, 5000 Belanger Street, Montreal H1T 1C8, Canada; Department of medicine, Université de Montréal, 2900 Edouard-Montpetit boulevard, Montreal H3T 1J4, Canada. Electronic address:

Background: We previously demonstrated that high-density lipoprotein (HDL) infusions may improve left ventricular diastolic dysfunction (LVDD) in an aortic valve stenosis (AVS) model. Whether the benefit was direct or mediated by the observed reduction in AVS severity is not clear. Here, we aimed to test the direct effect of an ApoA-I mimetic on LVDD in the absence of AVS.

Methods: Rabbits were exposed to three different protocols to develop LVDD. First, rabbits were exposed to 0.5% cholesterol-rich diet for an average of 17 weeks. Second, rabbits were subjected to surgical ascending aortic constriction (AAC), to mimic the effect of fixed reduced aortic valve area, and studied after 10 weeks. The third model combined both cholesterol-enriched diet (for 12 weeks) and surgical AAC. The control group consisted of age-matched rabbits under normal diet. After development of LVDD, rabbits were randomized to receive infusions of saline or apoA-I mimetic (25 mg/kg) 3 times per week for 4 weeks. Detailed cardiac structure and function measurements were assessed at baseline and weekly during treatment period. Histological and molecular analyses were performed on LV samples.

Results: In the three models, echocardiographic results showed development of LVDD over time, with preserved LV systolic and aortic valve functions versus controls. ApoA-I mimetic infusions did not significantly improve echocardiographic parameters nor molecular markers of cardiac inflammation, oxidative stress and fibrosis.

Conclusion: ApoA-I mimetic therapy did not directly improve LVDD. These results indicate that previously observed changes of LVDD were caused by AVS improvement induced by this treatment.
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http://dx.doi.org/10.1016/j.ijcard.2020.12.089DOI Listing
May 2021

Thermal tolerance and fish heart integrity: fatty acids profiles as predictors of species resilience.

Conserv Physiol 2020 26;8(1):coaa108. Epub 2020 Dec 26.

Département de Biologie, Université du Québec à Rimouski, Rimouski, Québec, G5L3A1, Canada.

The cardiovascular system is a major limiting system in thermal adaptation, but the exact physiological mechanisms underlying responses to thermal stress are still not completely understood. Recent studies have uncovered the possible role of reactive oxygen species production rates of heart mitochondria in determining species' upper thermal limits. The present study examines the relationship between individual response to a thermal challenge test (CT), susceptibility to peroxidation of membrane lipids, heart fatty acid profiles and cardiac antioxidant enzyme activities in two salmonid species from different thermal habitats (, ) and their hybrids. The susceptibility to peroxidation of membranes in the heart was negatively correlated with individual thermal tolerance. The same relationship was found for arachidonic and eicosapentaenoic acid. Total HO buffering activity of the heart muscle was higher for the group with high thermal resistance. These findings underline a potential general causative relationship between sensitivity to oxidative stress, specific fatty acids, antioxidant activity in the cardiac muscle and thermal tolerance in fish and likely other ectotherms. Heart fatty acid profile could be indicative of species resilience to global change, and more importantly the plasticity of this trait could predict the adaptability of fish species or populations to changes in environmental temperature.
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http://dx.doi.org/10.1093/conphys/coaa108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771578PMC
December 2020

The Canadian Alliance for Healthy Hearts and Minds: How Well Does It Reflect the Canadian Population?

CJC Open 2020 Nov 22;2(6):599-609. Epub 2020 Jul 22.

ICES, Toronto, Ontario, Canada.

Background: The intent of the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort is to understand the early determinants of subclinical cardiac and vascular disease and progression in adults selected from existing cohorts-the Canadian Partnership for Tomorrow's Health, the Prospective Urban and Rural Evaluation (PURE) cohort, and the Montreal Heart Institute Biobank. We evaluated how well the CAHHM-Health Services Research (CAHHM-HSR) subcohort reflects the Canadian population.

Methods: A cross-sectional design was used among a prospective cohort of community-dwelling adults aged 35-69 years who met the CAHHM inclusion criteria, and a cohort of adults aged 35-69 years who responded to the 2015 Canadian Community Health Survey-Rapid Response module. The INTERHEART risk score was calculated at the individual level with means and proportions reported at the overall and provincial level.

Results: There are modest differences between CAHHM-HSR study participants and the 2015 Canadian Community Health Survey-Rapid Response respondents in age (56.3 vs 51.7 mean years), proportion of men (44.9% vs 49.3%), and mean INTERHEART risk score (9.7 vs 10.1). Larger differences were observed in postsecondary education (86.8% vs 70.2%), Chinese ethnicity (11.0% vs 3.3%), obesity (23.2% vs 29.3%), current smoker status (6.1% vs 18.4%), and having no cardiac testing (30.4% vs 55.9%).

Conclusions: CAHHM-HSR participants are older, of higher socioeconomic status, and have a similar mean INTERHEART risk score, compared with participants in the Canadian Community Health Survey. Differing sampling strategies and missing data may explain some differences between the CAHHM-HSR cohort and Canadian community-dwelling adults and should be considered when using the CAHHM-HSR for scientific research.
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http://dx.doi.org/10.1016/j.cjco.2020.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711015PMC
November 2020

Anti-inflammatory therapy for COVID-19 infection: the case for colchicine.

Ann Rheum Dis 2020 Dec 8. Epub 2020 Dec 8.

Rheumatology/Medicine, New York University Grossman School of Medicine, New York, New York, USA

The search for effective COVID-19 management strategies continues to evolve. Current understanding of SARS-CoV-2 mechanisms suggests a central role for exaggerated activation of the innate immune system as an important contributor to COVID-19 adverse outcomes. The actions of colchicine, one of the oldest anti-inflammatory therapeutics, target multiple mechanisms associated with COVID-19 excessive inflammation. While many COVID-19 trials have sought to manipulate SARS-CoV-2 or dampen the inflammatory response once patients are hospitalised, few examine therapeutics to prevent the need for hospitalisation. Colchicine is easily administered, generally well tolerated and inexpensive, and holds particular promise to reduce the risk of hospitalisation and mortality due to COVID-19 in the outpatient setting. Successful outpatient treatment of COVID-19 could greatly reduce morbidity, mortality and the demand for rare or expensive care resources (front-line healthcare workers, hospital beds, ventilators, biological therapies), to the benefit of both resource-replete and resource-poor regions.
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http://dx.doi.org/10.1136/annrheumdis-2020-219174DOI Listing
December 2020

Use of risk scores to identify lower and higher risk subsets among COMPASS-eligible patients with chronic coronary syndromes. Insights from the CLARIFY registry.

Clin Cardiol 2021 Jan 4;44(1):58-65. Epub 2020 Dec 4.

Université de Paris, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: The COMPASS trial showed a reduction of ischemic events with low-dose rivaroxaban and aspirin in chronic coronary syndromes (CCS) compared with aspirin alone, at the expense of increased bleeding.

Hypothesis: The CHA DS VaSc Score, REACH Recurrent Ischemic (RIS), and REACH Bleeding Risk Score (BRS) could identify patients with a favorable trade-off between ischemic and bleeding events, among COMPASS-eligible patients.

Methods: We identified the COMPASS-eligible population within the CLARIFY registry (>30.000 patients with CCS). High-bleeding risk patients (REACH BRS > 10) were excluded, as in the COMPASS trial. Patients were categorized as low (0-1) or high (≥ 2) CHA DS VaSc; low (0-12) or intermediate (13-19) REACH RIS, and low (0-6) or intermediate (7-10) REACH BRS. Ischemic outcome was the composite of cardiovascular death, myocardial infarction or stroke. Bleeding was defined as serious bleeding (haemorrhagic stroke, hospitalization for bleeding, transfusion).

Results: The COMPASS-eligible population comprised 5.142 patients with ischemic and bleeding outcome of 2.3 (2.1-2.5) and 0.5 (0.4-0.6) per 100 patient-years, respectively. Patients with intermediate REACH RIS (n = 1934 [37.6%]) had the higher ischemic risk (3.0 [2.6-3.4]) with similar bleeding risk (0.5 [0.4-0.7]) as the overall population. Patients with low CHA DS VaSc (n = 229 [4.4%]) had a very low ischemic risk (0.6 [0.3-1.3]) with similar bleeding risk (0.5 [0.2-1.1]).

Conclusions: Intermediate REACH RIS identified potential optimal candidates for adjunction of low-dose rivaroxaban while patients with low CHA DS VaSc score .appears unlikely to benefit from the COMPASS regimen. None of the three risk scores predicted the occurrence of serious bleeding.
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http://dx.doi.org/10.1002/clc.23505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803362PMC
January 2021

Colchicine reduces lung injury in experimental acute respiratory distress syndrome.

PLoS One 2020 2;15(12):e0242318. Epub 2020 Dec 2.

Montreal Heart Institute Research Center, Montreal, Quebec, Canada.

The acute respiratory distress syndrome (ARDS) is characterized by intense dysregulated inflammation leading to acute lung injury (ALI) and respiratory failure. There are no effective pharmacologic therapies for ARDS. Colchicine is a low-cost, widely available drug, effective in the treatment of inflammatory conditions. We studied the effects of colchicine pre-treatment on oleic acid-induced ARDS in rats. Rats were treated with colchicine (1 mg/kg) or placebo for three days prior to intravenous oleic acid-induced ALI (150 mg/kg). Four hours later they were studied and compared to a sham group. Colchicine reduced the area of histological lung injury by 61%, reduced lung edema, and markedly improved oxygenation by increasing PaO2/FiO2 from 66 ± 13 mmHg (mean ± SEM) to 246 ± 45 mmHg compared to 380 ± 18 mmHg in sham animals. Colchicine also reduced PaCO2 and respiratory acidosis. Lung neutrophil recruitment, assessed by myeloperoxidase immunostaining, was greatly increased after injury from 1.16 ± 0.19% to 8.86 ± 0.66% and significantly reduced by colchicine to 5.95 ± 1.13%. Increased lung NETosis was also reduced by therapy. Circulating leukocytosis after ALI was not reduced by colchicine therapy, but neutrophils reactivity and CD4 and CD8 cell surface expression on lymphocyte populations were restored. Colchicine reduces ALI and respiratory failure in experimental ARDS in relation with reduced lung neutrophil recruitment and reduced circulating leukocyte activation. This study supports the clinical development of colchicine for the prevention of ARDS in conditions causing ALI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242318PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710059PMC
January 2021

Colchicine for Secondary Cardiovascular Prevention in Coronary Disease.

Circulation 2020 Nov 16;142(20):1901-1904. Epub 2020 Nov 16.

Montreal Heart Institute, Canada (J.-C.T.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051240DOI Listing
November 2020

Diabetes, Brain Infarcts, Cognition, and Small Vessels in the Canadian Alliance for Healthy Hearts and Minds Study.

J Clin Endocrinol Metab 2021 Jan;106(2):e891-e898

Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada.

Background: Diabetes is a risk factor for cerebrovascular disease and cognitive impairment. The anatomical basis for this is uncertain.

Methods: The Canadian Alliance for Healthy Hearts and Minds collected brain and carotid magnetic resonance imaging (MRI) and 2 cognitive tests (the Digit Symbol Substitution Test and the Montreal Cognitive Assessment test) in a cross-sectional sample of men and women. Brain MRIs identified brain infarcts (BI), lacunar BI, high white matter hyperintensity (WMH), vascular brain injury (VBI; BI or high WMH), and small vessel VBI (lacunar BI or high WMH). Carotid MRIs estimated carotid wall volume, a measure of subclinical atherosclerosis. Cognitive scores were standardized to each site's mean score, and cognitive impairment was identified by 1 or both test scores ≤1 standard deviation below the site's mean score on that test.

Results: The 7733 participants included 495 participants (6.4%) with diabetes, of whom 388 were taking diabetes drugs. After age and sex adjustment, diabetes was independently associated with BI (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.05, 2.24), VBI (OR 1.64, 95% CI 1.26, 2.13), small vessel VBI (OR 1.67, 95% CI 1.28, 2.19), and cognitive impairment (OR 1.47, 95% CI 1.20, 1.80). The association between diabetes and small vessel VBI persisted after adjustment for cerebrovascular disease risk factors and nonlacunar infarcts (OR 1.52, 95% CI 1.15, 2.01), and the association with cognitive impairment persisted after adjustment for small vessel VBI (OR 1.27, 95% CI 1.03, 1.56).

Conclusion: Small vessel disease characterizes much of the relationship between diabetes and VBI. However, additional factors are required to disentangle the relationship between diabetes and cognitive impairment.
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http://dx.doi.org/10.1210/clinem/dgaa815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823245PMC
January 2021

Pulmonary Vein Stenosis After Atrial Fibrillation Ablation: Insights From the ADVICE Trial.

Can J Cardiol 2020 12 3;36(12):1965-1974. Epub 2020 Nov 3.

Montreal Health Innovations Coordinating Center (MHICC), Montreal, Quebec, Canada.

Background: Pulmonary vein (PV) stenosis is a complication of atrial fibrillation (AF) ablation. The incidence of PV stenosis after routine post-ablation imaging remains unclear and is limited to single-centre studies. Our objective was to determine the incidence and predictors of PV stenosis following circumferential radiofrequency ablation in the multicentre Adenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination (ADVICE) trial.

Methods: Patients with symptomatic AF underwent circumferential radiofrequency ablation in one of 13 trial centres. Computed tomographic (CTA) or magnetic resonance (MRA) angiography was performed before ablation and 90 days after ablation. Two blinded reviewers measured PV diameters and areas. PVs with stenosis were classified as severe (> 70%), moderate (50%-70%), or mild (< 50%). Predictors of PV stenosis were identified by means of multivariable logistic regression.

Results: A total of 197 patients (median age 59.5 years, 29.4% women) were included in this substudy. PV stenosis was identified in 41 patients (20.8%) and 47 (8.2%) of 573 ablated PVs. PV stenosis was classified as mild in 42 PVs (7.3%) and moderate in 5 PVs (0.9%). No PVs had severe stenosis. Both cross-sectional area and diameter yielded similar classifications for severity of PV stenosis. Diabetes was associated with a statistically significant increased risk of PV stenosis (OR 4.91, 95% CI 1.45-16.66).

Conclusions: In the first systematic multicentre evaluation of post-ablation PV stenosis, no patient acquired severe PV stenosis. Although the results are encouraging for the safety of AF ablation, 20.8% of patients had mild or moderate PV stenosis, in which the long-term effects are unknown.
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http://dx.doi.org/10.1016/j.cjca.2020.10.013DOI Listing
December 2020

Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia.

Nature 2020 11 4;587(7834):460-465. Epub 2020 Nov 4.

Cardiothoracic Surgery, Oxford Heart Centre, John Radcliffe Hospital, Oxford, UK.

Atrial fibrillation, the most common cardiac arrhythmia, is an important contributor to mortality and morbidity, and particularly to the risk of stroke in humans. Atrial-tissue fibrosis is a central pathophysiological feature of atrial fibrillation that also hampers its treatment; the underlying molecular mechanisms are poorly understood and warrant investigation given the inadequacy of present therapies. Here we show that calcitonin, a hormone product of the thyroid gland involved in bone metabolism, is also produced by atrial cardiomyocytes in substantial quantities and acts as a paracrine signal that affects neighbouring collagen-producing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of calcitonin receptor signalling in mice causes atrial fibrosis and increases susceptibility to atrial fibrillation. In mice in which liver kinase B1 is knocked down specifically in the atria, atrial-specific knockdown of calcitonin promotes atrial fibrosis and increases and prolongs spontaneous episodes of atrial fibrillation, whereas atrial-specific overexpression of calcitonin prevents both atrial fibrosis and fibrillation. Human patients with persistent atrial fibrillation show sixfold lower levels of myocardial calcitonin compared to control individuals with normal heart rhythm, with loss of calcitonin receptors in the fibroblast membrane. Although transcriptome analysis of human atrial fibroblasts reveals little change after exposure to calcitonin, proteomic analysis shows extensive alterations in extracellular matrix proteins and pathways related to fibrogenesis, infection and immune responses, and transcriptional regulation. Strategies to restore disrupted myocardial calcitonin signalling thus may offer therapeutic avenues for patients with atrial fibrillation.
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http://dx.doi.org/10.1038/s41586-020-2890-8DOI Listing
November 2020

Reduction in Revascularization With Icosapent Ethyl: Insights From REDUCE-IT Revascularization Analyses.

Circulation 2021 Jan 5;143(1):33-44. Epub 2020 Nov 5.

Department of Medicine, Baylor College of Medicine, and Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX (C.M.B.).

Background: Patients with elevated triglycerides despite statin therapy have increased risk for ischemic events, including coronary revascularizations.

Methods: REDUCE-IT (The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL), controlled low-density lipoprotein (41-100 mg/dL), and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl 4 g/d or placebo. The primary and key secondary composite end points were significantly reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.

Results: A total of 8179 randomly assigned patients were followed for 4.9 years (median). First revascularizations were reduced to 9.2% (22.5/1000 patient-years) with icosapent ethyl versus 13.3% (33.7/1000 patient-years) with placebo (hazard ratio, 0.66 [95% CI, 0.58-0.76]; <0.0001; number needed to treat for 4.9 years=24); similar reductions were observed in total (first and subsequent) revascularizations (negative binomial rate ratio, 0.64 [95% CI, 0.56-0.74]; <0.0001), and across elective, urgent, and emergent revascularizations. Icosapent ethyl significantly reduced percutaneous coronary intervention (hazard ratio, 0.68 [95% CI, 0.59-0.79]; <0.0001) and coronary artery bypass grafting (hazard ratio, 0.61 [95% CI, 0.45-0.81]; =0.0005).

Conclusions: Icosapent ethyl reduced the need for first and subsequent coronary revascularizations in statin-treated patients with elevated triglycerides and increased cardiovascular risk. To our knowledge, icosapent ethyl is the first non-low-density lipoprotein-lowering treatment that has been shown to reduce coronary artery bypass grafting in a blinded, randomized trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752247PMC
January 2021