Autotaxin Inhibition Reduces Post-Ischemic Myocardial Inflammation via Epigenetic Gene Modifications.

Myocardial infarction (MI) triggers a complex inflammatory response that is essential for cardiac repair but can also lead to adverse outcomes if left uncontrolled. Recent studies have highlighted the importance of epigenetic modifications in regulating post-MI inflammation. This study investigated the role of the autotaxin (ATX)/lysophosphatidic acid (LPA) signaling axis in modulating myocardial inflammation through epigenetic pathways in a mouse model of MI. C57BL/6 J mice underwent left anterior descending coronary artery ligation to induce MI and were treated with the ATX inhibitor, PF-8380, or vehicle. Cardiac tissue from the border zone was collected at 6 h, 1, 3, and 7 days post-MI for epigenetic gene profiling using RT2 Profiler PCR Arrays. The results revealed distinct gene expression patterns across sham, MI + Vehicle, and MI + PF-8380 groups. PF-8380 treatment significantly altered the expression of genes involved in inflammation, stress response, and epigenetic regulation compared to the vehicle group. Notably, PF-8380 downregulated Hdac5, Prmt5, and Prmt6, which are linked to exacerbated inflammatory responses, as early as 6 h post-MI. Furthermore, PF-8380 attenuated the reduction of Smyd1, a gene important in myogenic differentiation, at 7 days post-MI. This study demonstrates that the ATX/LPA signaling axis plays a pivotal role in modulating post-MI inflammation via epigenetic pathways. Targeting ATX/LPA signaling may represent a novel therapeutic strategy to control inflammation and improve outcomes after MI. Further research is needed to validate these findings in preclinical and clinical settings and to elucidate the complex interplay between epigenetic mechanisms and ATX/LPA signaling in the context of MI.

Implementation of the Canadian syncope pathway: a pilot non-randomized stepped wedge trial.

BACKGROUND: We developed the Canadian Syncope Pathway (CSP) based on the Canadian Syncope Risk Score (CSRS) to aid emergency department (ED) syncope management. This pilot implementation study assessed patient inclusion, length of transition period, as well as process measures (engagement, reach, adoption, and fidelity) to prepare for multicenter implementation. METHODS: A non-randomized stepped wedge trial at two hospitals was conducted over a 7-month period. After 2-3 months in the control condition, the hospitals crossed over in a stepwise fashion to the intervention condition. Study participants were ED and non-ED physicians, or their delegates, and patients (aged ≥ 18 years) with syncope. We aimed to analyze patient characteristics, ED management including disposition decision, and CSRS recommendations application for all eligible patients during the intervention period. Our targets were 95% inclusion rate, 70% adoption (proportion of physicians who applied the pathway), 60% reach (intervention applied to eligible patients) and 70% fidelity (appropriate recommendations application) for all eligible patients. Clinical Trials registration NCT04790058. RESULTS: 1002 eligible patients (mean age 56.6 years; 51.0% males) were included: 349 patients during the control and 653 patients during the intervention period. Physician engagement varied from 39.7% to 97.1% for presentation at meetings. Process measures for the first month and the end of the intervention were: adoption 70.7% (58/82) and 84.4% (103/122), reach 67.5% (108/160) and 55.0% (359/653), fidelity among patients with physician data form completion 86.3% (88/102) and 88.3% (294/333), versus fidelity among all eligible patients 83.8% (134/160) and 83.3% (544/653) respectively with no significant differences in fidelity at one month and the end of the intervention period. CONCLUSION: In this pilot study, we achieved all prespecified benchmarks for proceeding to the multicenter CSP implementation except reach. Our results indicate a 1-month transition period will be adequate though regular reminders will be needed during full-scale implementation.

RéSUMé: CONTEXTE: Nous avons mis au point la Canadian Syncope Pathway (CSP) basée sur le Canadian Syncope Risk Score (CSRS) pour aider les services d'urgence à gérer la syncope. Cette étude pilote de mise en œuvre a évalué l'inclusion des patients, la durée de la période de transition, ainsi que les mesures de processus (engagement, portée, adoption et fidélité) pour se préparer à la mise en œuvre multicentrique MéTHODES: Un essai par étapes non randomisé dans deux hôpitaux a été mené sur une période de 7 mois. Après 2 à 3 mois dans l'état de contrôle, les hôpitaux sont passés progressivement à l'état d'intervention. Les participants à l'étude étaient des médecins du service de l'urgence et non du service de l'urgence, ou leurs délégués, et des patients (âgés de 18 ans) atteints de syncope. Nous avons cherché à analyser les caractéristiques des patients, la prise en charge des urgences, y compris la décision de disposition, et l'application des recommandations du CSRS pour tous les patients admissibles pendant la période d'intervention. Nos cibles étaient le taux d'inclusion de 95 %, l'adoption de 70 % (proportion de médecins qui ont appliqué la voie), la portée de 60 % (intervention appliquée aux patients admissibles) et la fidélité de 70 % (application des recommandations appropriées) pour tous les patients admissibles. Enregistrement des essais cliniques NCT04790058. RéSULTATS: 1002 patients éligibles (âge moyen 56,6 ans; 51,0% d'hommes) ont été inclus : 349 patients pendant le contrôle et 653 patients pendant la période d'intervention. La participation des médecins variait de 39,7 % à 97,1 % pour la présentation aux réunions. Les mesures du processus pour le premier mois et la fin de l'intervention étaient les suivantes : adoption 70,7 % (58/82) et 84,4 % (103/122), atteinte de 67,5 % (108/160) et 55,0 % (359/653), fidélité chez les patients ayant rempli le formulaire de données médicales 86,3 % (88/102) et 88,3 % (294/333), versus fidélité chez tous les patients admissibles 83,8 % (134/160) et 83,3 % (544/653) respectivement, sans différence significative de fidélité à un mois et à la fin de la période d'intervention. CONCLUSION: Dans cette étude pilote, nous avons atteint tous les points de repère prédéterminés pour procéder à la mise en œuvre du PSC multicentrique, sauf la portée. Nos résultats indiquent qu'une période de transition d'un mois sera adéquate, bien que des rappels réguliers seront nécessaires pendant la mise en œuvre à grande échelle.

Prognostic Significance of Activated Monocytes in Patients with ST-Elevation Myocardial Infarction.

Circulating monocytes have different subsets, including classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++), which play different roles in cardiovascular physiology and disease progression. The predictive value of each subset for adverse clinical outcomes in patients with coronary artery disease is not fully understood. We sought to evaluate the prognostic efficacy of each monocyte subset in patients with ST-elevation myocardial infarction (STEMI). We recruited 100 patients with STEMI who underwent primary percutaneous coronary intervention (PCI). Blood samples were collected at the time of presentation to the hospital (within 6 h from onset of symptoms, baseline (BL)) and then at 3, 6, 12, and 24 h after presentation. Monocytes were defined as CD45+/HLA-DR+ and then subdivided based on the expression of CD14, CD16, CCR2, CD11b, and CD42. The primary endpoint was a composite of all-cause death, hospitalization for heart failure, stent thrombosis, in-stent restenosis, and recurrent myocardial infarction. Univariate and multivariate Cox proportional hazards models, including baseline comorbidities, were performed. The mean age of our cohort was 58.9 years and 25% of our patients were females. Patients with high levels (above the median) of CD14+CD16++ monocytes showed an increased risk for the primary endpoint in comparison to patients with low levels; adjusted hazard ratio (aHR) for CD14+/CD16++ cells was 4.3 (95% confidence interval (95% CI) 1.2-14.8, p = 0.02), for CD14+/CD16++/CCR2+ cells was 3.82 (95% CI 1.06-13.7, p = 0.04), for CD14+/CD16++/CD42b+ cells was 3.37 (95% CI 1.07-10.6, p = 0.03), for CD14+/CD16++/CD11b+ was 5.17 (95% CI 1.4-18.0, p = 0.009), and for CD14+ HLA-DR+ was 7.5 (95% CI 2.0-28.5, p = 0.002). CD14++CD16-, CD14++CD16+, and their CD11b+, CCR2+, and CD42b+ aggregates were not significantly predictive for our composite endpoint. Our study shows that CD14+ CD16++ monocytes and their subsets expressing CCR2, CD42, and CD11b could be important predictors of clinical outcomes in patients with STEMI. Further studies with a larger sample size and different coronary artery disease phenotypes are needed to verify the findings.

C-Reactive Protein Levels and Risk of Cardiovascular Diseases: A Two-Sample Bidirectional Mendelian Randomization Study.

Elevated C-reactive protein (CRP) levels are an indicator of inflammation, a major risk factor for cardiovascular disease (CVD). However, this potential association in observational studies remains inconclusive. We performed a two-sample bidirectional Mendelian randomization (MR) study using publicly available GWAS summary statistics to evaluate the relationship between CRP and CVD. Instrumental variables (IVs) were carefully selected, and multiple approaches were used to make robust conclusions. Horizontal pleiotropy and heterogeneity were evaluated using the MR-Egger intercept and Cochran's Q-test. The strength of the IVs was determined using F-statistics. The causal effect of CRP on the risk of hypertensive heart disease (HHD) was statistically significant, but we did not observe a significant causal relationship between CRP and the risk of myocardial infarction, coronary artery disease, heart failure, or atherosclerosis. Our primary analyses, after performing outlier correction using MR-PRESSO and the Multivariable MR method, revealed that IVs that increased CRP levels also increased the HHD risk. However, after excluding outlier IVs identified using PhenoScanner, the initial MR results were altered, but the sensitivity analyses remained congruent with the results from the primary analyses. We found no evidence of reverse causation between CVD and CRP. Our findings warrant updated MR studies to confirm the role of CRP as a clinical biomarker for HHD.

Autologous CD133 + Cells and Laser Revascularization in patients with severe Ischemic Cardiomyopathy.

OBJECTIVE: We tested the hypothesis that targeted TMLR combined with intramyocardial injection of autologous CD 133+ progenitor cells is safe and feasible in patients with chronic ischemic cardiomyopathy (ICM) and no revascularization options. METHODS: Eight male patients (age 62 ± 2.4 years) with multivessel severe ischemic heart disease and no revascularization options were enrolled. Autologous CD 133 + endothelial progenitor cells were derived and purified from the bone marrow on the day of surgery using the clinical-grade closed CliniMACS system. Using a lateral thoracotomy approach, TMLR was performed, followed by transmyocardial transplantation of purified CD133 + cells (mean number of transplanted cells: 12.5 × 106) in the region surrounding the TMLR sites. These sites were selected based on ischemia on pre-procedure perfusion imaging. We performed clinical and myocardial perfusion imaging pre-procedure and then at 6- and 12-month follow-up. RESULTS: No major complications or death occurred during the procedure or during the peri-operative hospital stay. One patient died of cardiac cause 6 months post-procedure. There was a reported short-term improvement in anginal and heart failure symptoms and a modest reduction in the ischemic score as assessed by perfusion imaging. CONCLUSIONS: Our phase 1 clinical study examining the combination therapy of targeted transmyocardial laser revascularization therapy and autologous CD133 + endothelial progenitor cells in patients with chronic ICM and no revascularization options demonstrates the feasibility and short-term safety of this combined approach and warrants future larger phase 2 randomized clinical studies.

Combined Transplantation of Human MSCs and ECFCs Improves Cardiac Function and Decrease Cardiomyocyte Apoptosis After Acute Myocardial Infarction.

BACKGROUND: Ischemic heart disease, often caused by an acute myocardial infarction (AMI) is one of the leading causes of morbidity and mortality worldwide. Despite significant advances in medical and procedural therapies, millions of AMI patients progress to develop heart failure every year. METHODS: Here, we examine the combination therapy of human mesenchymal stromal cells (MSCs) and endothelial colony-forming cells (ECFCs) to reduce the early ischemic damage (MSCs) and enhance angiogenesis (ECFCs) in a pre-clinical model of acute myocardial infarction. NOD/SCID mice were subjected to AMI followed by transplantation of MSCs and ECFCs either alone or in combination. Cardiomyocyte apoptosis and cardiac functional recovery were assessed in short- and long-term follow-up studies. RESULTS: At 1 day after AMI, MSC- and ECFC-treated animals demonstrated significantly lower cardiomyocyte apoptosis compared to vehicle-treated animals. This phenomenon was associated with a significant reduction in infarct size, cardiac fibrosis, and improvement in functional cardiac recovery 4 weeks after AMI. CONCLUSIONS: The use of ECFCs, MSCs, and the combination of both cell types reduce cardiomyocyte apoptosis, scar size, and adverse cardiac remodeling, compared to vehicle, in a pre-clinical model of AMI. These results support the use of this combined cell therapy approach in future human studies during the acute phase of ischemic cardiac injury.

Medical Masks Versus N95 Respirators for Preventing COVID-19 Among Health Care Workers : A Randomized Trial.

BACKGROUND: It is uncertain if medical masks offer similar protection against COVID-19 compared with N95 respirators. OBJECTIVE: To determine whether medical masks are noninferior to N95 respirators to prevent COVID-19 in health care workers providing routine care. DESIGN: Multicenter, randomized, noninferiority trial. (ClinicalTrials.gov: NCT04296643). SETTING: 29 health care facilities in Canada, Israel, Pakistan, and Egypt from 4 May 2020 to 29 March 2022. PARTICIPANTS: 1009 health care workers who provided direct care to patients with suspected or confirmed COVID-19. INTERVENTION: Use of medical masks versus fit-tested N95 respirators for 10 weeks, plus universal masking, which was the policy implemented at each site. MEASUREMENTS: The primary outcome was confirmed COVID-19 on reverse transcriptase polymerase chain reaction (RT-PCR) test. RESULTS: In the intention-to-treat analysis, RT-PCR-confirmed COVID-19 occurred in 52 of 497 (10.46%) participants in the medical mask group versus 47 of 507 (9.27%) in the N95 respirator group (hazard ratio [HR], 1.14 [95% CI, 0.77 to 1.69]). An unplanned subgroup analysis by country found that in the medical mask group versus the N95 respirator group RT-PCR-confirmed COVID-19 occurred in 8 of 131 (6.11%) versus 3 of 135 (2.22%) in Canada (HR, 2.83 [CI, 0.75 to 10.72]), 6 of 17 (35.29%) versus 4 of 17 (23.53%) in Israel (HR, 1.54 [CI, 0.43 to 5.49]), 3 of 92 (3.26%) versus 2 of 94 (2.13%) in Pakistan (HR, 1.50 [CI, 0.25 to 8.98]), and 35 of 257 (13.62%) versus 38 of 261 (14.56%) in Egypt (HR, 0.95 [CI, 0.60 to 1.50]). There were 47 (10.8%) adverse events related to the intervention reported in the medical mask group and 59 (13.6%) in the N95 respirator group. LIMITATION: Potential acquisition of SARS-CoV-2 through household and community exposure, heterogeneity between countries, uncertainty in the estimates of effect, differences in self-reported adherence, differences in baseline antibodies, and between-country differences in circulating variants and vaccination. CONCLUSION: Among health care workers who provided routine care to patients with COVID-19, the overall estimates rule out a doubling in hazard of RT-PCR-confirmed COVID-19 for medical masks when compared with HRs of RT-PCR-confirmed COVID-19 for N95 respirators. The subgroup results varied by country, and the overall estimates may not be applicable to individual countries because of treatment effect heterogeneity. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research, World Health Organization, and Juravinski Research Institute.

Colchicine and aspirin in community patients with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial.

BACKGROUND: The large number of patients worldwide infected with the SARS-CoV-2 virus has overwhelmed health-care systems globally. The Anti-Coronavirus Therapies (ACT) outpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin for prevention of disease progression in community patients with COVID-19. METHODS: The ACT outpatient, open-label, 2 × 2 factorial, randomised, controlled trial, was done at 48 clinical sites in 11 countries. Patients in the community aged 30 years and older with symptomatic, laboratory confirmed COVID-19 who were within 7 days of diagnosis and at high risk of disease progression were randomly assigned (1:1) to receive colchicine 0·6 mg twice daily for 3 days and then 0·6 mg once daily for 25 days versus usual care, and in a second (1:1) randomisation to receive aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome was assessed at 45 days in the intention-to-treat population; for the colchicine randomisation it was hospitalisation or death, and for the aspirin randomisation it was major thrombosis, hospitalisation, or death. The ACT outpatient trial is registered at ClinicalTrials.gov, NCT04324463 and is ongoing. FINDINGS: Between Aug 27, 2020, and Feb 10, 2022, 3917 patients were randomly assigned to colchicine or control and to aspirin or control; after excluding 36 patients due to administrative reasons 3881 individuals were included in the analysis (n=1939 colchicine vs n=1942 control; n=1945 aspirin vs 1936 control). Follow-up was more than 99% complete. Overall event rates were 5 (0·1%) of 3881 for major thrombosis, 123 (3·2%) of 3881 for hospitalisation, and 23 (0·6%) of 3881 for death; 66 (3·4%) of 1939 patients allocated to colchicine and 65 (3·3%) of 1942 patients allocated to control experienced hospitalisation or death (hazard ratio [HR] 1·02, 95% CI 0·72-1·43, p=0·93); and 59 (3·0%) of 1945 of patients allocated to aspirin and 73 (3·8%) of 1936 patients allocated to control experienced major thrombosis, hospitalisation, or death (HR 0·80, 95% CI 0·57-1·13, p=0·21). Results for the primary outcome were consistent in all prespecified subgroups, including according to baseline vaccination status, timing of randomisation in relation to onset of symptoms (post-hoc analysis), and timing of enrolment according to the phase of the pandemic (post-hoc analysis). There were more serious adverse events with colchicine than with control (34 patients [1·8%] of 1939 vs 27 [1·4%] of 1942) but none in either group that led to discontinuation of study interventions. There was no increase in serious adverse events with aspirin versus control (31 [1·6%] vs 31 [1·6%]) and none that led to discontinuation of study interventions. INTERPRETATION: The results provide no support for the use of colchicine or aspirin to prevent disease progression or death in outpatients with COVID-19. FUNDING: Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, and Thistledown Foundation. TRANSLATIONS: For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial.

BACKGROUND: COVID-19 disease is accompanied by a dysregulated immune response and hypercoagulability. The Anti-Coronavirus Therapies (ACT) inpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with the combination of rivaroxaban and aspirin for prevention of disease progression in patients hospitalised with COVID-19. METHODS: The ACT inpatient, open-label, 2 × 2 factorial, randomised, controlled trial was done at 62 clinical centres in 11 countries. Patients aged at least 18 years with symptomatic, laboratory confirmed COVID-19 who were within 72 h of hospitalisation or worsening clinically if already hospitalised were randomly assigned (1:1) to receive colchicine 1·2 mg followed by 0·6 mg 2 h later and then 0·6 mg twice daily for 28 days versus usual care; and in a second (1:1) randomisation, to the combination of rivaroxaban 2·5 mg twice daily plus aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome, assessed at 45 days in the intention-to-treat population, for the colchicine randomisation was the composite of the need for high-flow oxygen, mechanical ventilation, or death; and for the rivaroxaban plus aspirin randomisation was the composite of major thrombosis (myocardial infarction, stroke, acute limb ischaemia, or pulmonary embolism), the need for high-flow oxygen, mechanical ventilation, or death. The trial is registered at www. CLINICALTRIALS: gov, NCT04324463 and is ongoing. FINDINGS: Between Oct 2, 2020, and Feb 10, 2022, at 62 sites in 11 countries, 2749 patients were randomly assigned to colchicine or control and the combination of rivaroxaban and aspirin or to the control. 2611 patients were included in the analysis of colchicine (n=1304) versus control (n=1307); 2119 patients were included in the analysis of rivaroxaban and aspirin (n=1063) versus control (n=1056). Follow-up was more than 98% complete. Overall, 368 (28·2%) of 1304 patients allocated to colchicine and 356 (27·2%) of 1307 allocated to control had a primary outcome (hazard ratio [HR] 1·04, 95% CI 0·90-1·21, p=0·58); and 281 (26·4%) of 1063 patients allocated to the combination of rivaroxaban and aspirin and 300 (28·4%) of 1056 allocated to control had a primary outcome (HR 0·92, 95% CI 0·78-1·09, p=0·32). Results were consistent in subgroups defined by vaccination status, disease severity at baseline, and timing of randomisation in relation to onset of symptoms. There was no increase in the number of patients who had at least one serious adverse event for colchicine versus control groups (87 [6·7%] of 1304 vs 90 [6·9%] of 1307) or with rivaroxaban and aspirin versus control groups (85 [8·0%] vs 91 [8·6%]). Among patients assigned to colchicine, 8 (0·61%) had adverse events that led to discontinuation of study drug, mostly gastrointestinal in nature. 17 (1·6%) patients assigned to the combination of rivaroxaban and aspirin had bleeding compared with seven (0·66%) of those allocated to control (p=0·042); the number of serious bleeding events was two (0·19%) versus six (0·57%), respectively (p=0·18). No patients assigned to rivaroxaban and aspirin had serious adverse events that led to discontinuation of study drug. INTERPRETATION: Among patients hospitalised with COVID-19, neither colchicine nor the combination of rivaroxaban and aspirin prevent disease progression or death. FUNDING: Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, Thistledown Foundation. TRANSLATIONS: For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation.

BACKGROUND: Testing of factor Xa inhibitors for the prevention of cardiovascular events in patients with rheumatic heart disease-associated atrial fibrillation has been limited. METHODS: We enrolled patients with atrial fibrillation and echocardiographically documented rheumatic heart disease who had any of the following: a CHA2DS2VASc score of at least 2 (on a scale from 0 to 9, with higher scores indicating a higher risk of stroke), a mitral-valve area of no more than 2 cm2, left atrial spontaneous echo contrast, or left atrial thrombus. Patients were randomly assigned to receive standard doses of rivaroxaban or dose-adjusted vitamin K antagonist. The primary efficacy outcome was a composite of stroke, systemic embolism, myocardial infarction, or death from vascular (cardiac or noncardiac) or unknown causes. We hypothesized that rivaroxaban therapy would be noninferior to vitamin K antagonist therapy. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis. RESULTS: Of 4565 enrolled patients, 4531 were included in the final analysis. The mean age of the patients was 50.5 years, and 72.3% were women. Permanent discontinuation of trial medication was more common with rivaroxaban than with vitamin K antagonist therapy at all visits. In the intention-to-treat analysis, 560 patients in the rivaroxaban group and 446 in the vitamin K antagonist group had a primary-outcome event. Survival curves were nonproportional. The restricted mean survival time was 1599 days in the rivaroxaban group and 1675 days in the vitamin K antagonist group (difference, -76 days; 95% confidence interval [CI], -121 to -31; P<0.001). A higher incidence of death occurred in the rivaroxaban group than in the vitamin K antagonist group (restricted mean survival time, 1608 days vs. 1680 days; difference, -72 days; 95% CI, -117 to -28). No significant between-group difference in the rate of major bleeding was noted. CONCLUSIONS: Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of bleeding. (Funded by Bayer; INVICTUS ClinicalTrials.gov number, NCT02832544.).

The Anti-Coronavirus Therapies (ACT) Trials: Design, Baseline Characteristics, and Challenges.

Background: Effective treatments for COVID-19 are urgently needed, but conducting randomized trials during the pandemic has been challenging. Methods: The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3500 outpatients and 2500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine vs usual care, and aspirin vs usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization, it is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine vs usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily vs usual care. The primary outcome for the colchicine randomization is need for high-flow oxygen, need for mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization, it is major thrombotic events, need for high-flow oxygen, need for mechanical ventilation, or death. Results: At the completion of enrollment on February 10, 2022, the outpatient trial had enrolled 3917 patients, and the inpatient trial had enrolled 2611 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals, and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic. Conclusions: The ACT trials will determine the efficacy of anti-inflammatory therapy with colchicine, and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban, across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials.

Contexte: Il est urgent de mettre au point des traitements efficaces contre la COVID-19, mais il n'est pas facile de réaliser des essais à répartition aléatoire dans un contexte pandémique. Méthodologie: Les essais internationaux factoriels ACT (Anti-Coronavirus Therapy) avaient un objectif d'inscription de 3 500 patients externes et de 2 500 patients hospitalisés présentant une COVID-19 symptomatique. L'essai mené auprès de patients externes visait à évaluer la colchicine par rapport aux soins habituels, et l'aspirine par rapport aux soins habituels. Le paramètre d'évaluation principal au terme de la répartition aléatoire des patients était l'hospitalisation ou le décès dans le groupe traité par la colchicine, et la thrombose majeure, l'hospitalisation ou le décès dans le groupe traité par l'aspirine. L'essai mené auprès de patients hospitalisés visant à évaluer la colchicine par rapport aux soins habituels, et un traitement associant le rivaroxaban à 2,5 mg deux fois par jour et l'aspirine à 100 mg une fois par jour par rapport aux soins habituels. Le paramètre d'évaluation principal au terme de la répartition aléatoire des patients était le recours à l'oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par la colchicine, et la survenue de manifestations thrombotiques majeures, le recours à l'oxygénothérapie à haut débit ou à la ventilation mécanique ou le décès dans le groupe traité par l'association rivaroxaban-aspirine. Résultats: À la fin de la période d'inscription, le 10 février 2022, 3 917 patients externes et 2 611 patients hospitalisés formaient la population des essais. Certains aspects se sont révélés problématiques, notamment le manque de données préliminaires sur les interventions à évaluer, les incertitudes liées aux taux d'événements prévus, les retards touchant les approbations réglementaires et éthiques et les interventions de recherche, de même que l'évolution de la pandémie de COVID-19. Conclusions: Les essais ACT détermineront l'efficacité du traitement anti-inflammatoire par la colchicine et du traitement antithrombotique par l'aspirine, administrée seule ou en association avec le rivaroxaban, contre la COVID-19 légère, modérée ou sévère. Les leçons tirées de ces essais orienteront la planification d'essais ultérieurs.

Machine Learning Assessment of Left Ventricular Diastolic Function Based on Electrocardiographic Features.

BACKGROUND: Left ventricular (LV) diastolic dysfunction is recognized as playing a major role in the pathophysiology of heart failure; however, clinical tools for identifying diastolic dysfunction before echocardiography remain imprecise. OBJECTIVES: This study sought to develop machine-learning models that quantitatively estimate myocardial relaxation using clinical and electrocardiography (ECG) variables as a first step in the detection of LV diastolic dysfunction. METHODS: A multicenter prospective study was conducted at 4 institutions in North America enrolling a total of 1,202 subjects. Patients from 3 institutions (n = 814) formed an internal cohort and were randomly divided into training and internal test sets (80:20). Machine-learning models were developed using signal-processed ECG, traditional ECG, and clinical features and were tested using the test set. Data from the fourth institution was reserved as an external test set (n = 388) to evaluate the model generalizability. RESULTS: Despite diversity in subjects, the machine-learning model predicted the quantitative values of the LV relaxation velocities (e') measured by echocardiography in both internal and external test sets (mean absolute error: 1.46 and 1.93 cm/s; adjusted R2 = 0.57 and 0.46, respectively). Analysis of the area under the receiver operating characteristic curve (AUC) revealed that the estimated e' discriminated the guideline-recommended thresholds for abnormal myocardial relaxation and diastolic and systolic dysfunction (LV ejection fraction) the internal (area under the curve [AUC]: 0.83, 0.76, and 0.75) and external test sets (0.84, 0.80, and 0.81), respectively. Moreover, the estimated e' allowed prediction of LV diastolic dysfunction based on multiple age- and sex-adjusted reference limits (AUC: 0.88 and 0.94 in the internal and external sets, respectively). CONCLUSIONS: A quantitative prediction of myocardial relaxation can be performed using easily obtained clinical and ECG features. This cost-effective strategy may be a valuable first clinical step for assessing the presence of LV dysfunction and may potentially aid in the early diagnosis and management of heart failure patients.

A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation.

Atrial fibrillation (AF), the most common arrhythmia, is a growing epidemic with substantial morbidity and economic burden. Mechanisms underlying vulnerability to AF remain poorly understood, which contributes to the current lack of highly effective therapies. Recognizing mechanistic subtypes of AF may guide an individualized approach to patient management. Here, we describe a family with a previously unreported syndrome characterized by early-onset AF (age <35 years), conduction disease and signs of a primary atrial myopathy. Phenotypic penetrance was complete in all mutation carriers, although complete disease expressivity appears to be age-dependent. We show that this syndrome is caused by a novel, heterozygous p.Glu11Lys mutation in the atrial-specific myosin light chain gene MYL4. In zebrafish, mutant MYL4 leads to disruption of sarcomeric structure, atrial enlargement and electrical abnormalities associated with human AF. These findings describe the cause of a rare subtype of AF due to a primary, atrial-specific sarcomeric defect.