Publications by authors named "David Conen"

235 Publications

Factors associated with health-related quality of life in heart failure in 23,000 patients from 40 countries: Results of the G-CHF Research Program.

Eur J Heart Fail 2022 May 15. Epub 2022 May 15.

Population Health Research Institute, McMaster University, Hamilton, Canada.

Aims: To examine clinical and social correlates of health-related quality of life (HRQL), in patients with heart failure (HF) from high- (HIC), upper middle- (UMIC), lower middle-(LMIC) and low-income (LIC) countries.

Methods And Results: Between 2017 and 2020, we enrolled 23,292 patients with HF (32% inpatients, 61% men) from 40 countries in the Global Congestive Heart Failure Study. We recorded HRQL at baseline using Kansas City Cardiomyopathy Questionnaire (KCCQ)-12. In a cross-sectional analysis, we compared age- and sex-adjusted mean KCCQ-12 summary scores (SS: 0-100, higher=better) between patients from different country income levels. We used multivariable linear regression examining correlations (estimated coefficients) of KCCQ-12-SS with sociodemographic-, comorbidity-, treatment- and symptom-covariates. The adjusted model (37 covariates) was informed by univariable findings, clinical importance and backward selection. Mean age was 63 years and 40% were in NYHA class III-IV. Average HRQL was 55±0.5. It was 62.5 (95% CI 62.0-63.1) in HIC, 56.8 (56.1-57.4) in UMIC, 48.6 (48.0-49.3) in LMIC, and 38.5 (37.3-39.7) in LICs (p<0.0001). Strong correlates (estimated coefficient [95% CI]) of KCCQ-12-SS were NYHA class III vs class I/II (-12.1 [-12.8 to -11.4] and class IV vs. class I/II (-16.5 [-17.7 to -15.3]), effort dyspnea (-9.5[-10.2 to -8.8]) and living in LIC vs. HIC (-5.8[-7.1 to -4.4]). Symptoms explained most of the KCCQ-12-SS variability (partial R =0.32 of total adjusted R =0.51), followed by sociodemographic factors (R =0.12). Results were consistent in populations across income levels.

Conclusion: The most important correlates of HRQL in HF patients relate to HF symptom severity, irrespective of country-income level.
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http://dx.doi.org/10.1002/ejhf.2535DOI Listing
May 2022

Association of Eligibility for a Sodium-Glucose Co-transporter 2 Inhibitor and Cardiovascular Events in Patients with Atrial Fibrillation.

Can J Cardiol 2022 May 10. Epub 2022 May 10.

Population Health Research Institute; Division of Cardiology, Department of Medicine, McMaster University. Electronic address:

Background: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) reduce heart failure (HF) in a broad range of populations, but they have not been studied specifically in patients with atrial fibrillation (AF). We aimed to examine the association between SGLT2i-eligibility and cardiovascular events in AF patients to evaluate the potential utility of SGLT2is for AF management.

Methods: We pooled data from two randomized controlled trials (RCT) of AF patients (RE-LY and ACTIVE-W). Among patients assigned to anticoagulation arms, those meeting the enrollment criteria from at least one of the phase 3 SGLT2i RCTs were classified as "SGLT2i-eligible" and the remainder as "SGLT2i-ineligible". The primary outcome was the composite of HF hospitalization or cardiovascular death.

Results: A total of 21,484 AF patients (mean age: 71.2±8.8, 36.1% women, median CHADS-VASc Score=3) were included. The proportion of AF patients eligible for an SGLT2i was 41.2%. SGLT2i-eligible patients had higher rates of cardiovascular death/hospitalization for HF (5.8 vs. 3.2/100 person-years, P<0.001), cardiovascular death (3.9 vs. 1.5/100 person-years, P<0.001), and hospitalization for HF (2.5 vs. 1.9/100 person-years, P<0.001). The age- and sex-adjusted model showed that SGLT2i-eligible patients were at a higher risk of cardiovascular death/hospitalization for HF (HR 1.97, 95% CI 1.79-2.17; P<0.001), cardiovascular death (HR 2.75, 95% CI 2.41-3.13, P<0.001), and hospitalization for HF (HR 1.41, 95% CI 1.23-1.62, P<0.001) than ineligible patients.

Conclusions: Most patients with AF do not currently have an indication for SGLT2is, but still have a substantial risk of cardiovascular events. Future randomized trials should evaluate the efficacy of SGLT2is in AF patients.
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http://dx.doi.org/10.1016/j.cjca.2022.05.004DOI Listing
May 2022

Renal Function and Body Mass Index Contribute to Serum Neurofilament Light Chain Levels in Elderly Patients With Atrial Fibrillation.

Front Neurosci 2022 14;16:819010. Epub 2022 Apr 14.

Department of Neurology, Multiple Sclerosis Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland.

Objective: Serum neurofilament light chain (sNfL) is increasingly used as a neuroaxonal injury biomarker in the elderly. Besides age, little is known about how other physiological factors like renal function and body mass index (BMI) alter its levels. Here, we investigated the association of estimated glomerular filtration rate (eGFR) and BMI with sNfL in a large sample of elderly patients with atrial fibrillation (AF).

Methods: This is a cross-sectional analysis from the Swiss-AF Cohort (NCT02105844). We measured sNfL using an ultrasensitive single-molecule array assay. We calculated eGFR using the chronic kidney disease epidemiology collaboration (CKD-EPI) creatinine (eGFR) and creatinine-cystatin C (eGFR) formulas, and BMI from weight and height measurements. We evaluated the role of eGFR and BMI as determinants of sNfL levels using multivariable linear regression and the adjusted R (R ).

Results: Among 2,277 Swiss-AF participants (mean age 73.3 years), eGFR showed an inverse curvilinear association with sNfL after adjustment for age and cardiovascular comorbidities. BMI also showed an independent, inverse linear association with sNfL. The R of models with age, eGFR, and BMI alone was 0.26, 0.35, and 0.02, respectively. A model with age and eGFR combined explained 45% of the sNfL variance. Sensitivity analyses (i) further adjusting for vascular brain lesions ( = 1,402 participants with MRI) and (ii) using eGFR yielded consistent results.

Interpretation: In an elderly AF cohort, both renal function and BMI were associated with sNfL, but only renal function explained a substantial proportion of the sNfL variance. This should be taken into account when using sNfL in elderly patients or patients with cardiovascular disease.
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http://dx.doi.org/10.3389/fnins.2022.819010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9047720PMC
April 2022

Elevated Lipoprotein(a) and Risk of Atrial Fibrillation: An Observational and Mendelian Randomization Study.

J Am Coll Cardiol 2022 04;79(16):1579-1590

Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Ontario, Canada. Electronic address:

Background: Atrial fibrillation (AF) is a cardiac arrhythmia associated with an elevated risk of stroke, heart failure, and mortality. However, preventative therapies are needed with ancillary benefits on its cardiovascular comorbidities. Lipoprotein(a) (Lp[a]) is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), which itself increases AF risk, but it remains unknown whether Lp(a) is a causal mediator of AF independent of ASCVD.

Objectives: This study investigated the role of Lp(a) in AF and whether it is independent of ASCVD.

Methods: Measured and genetically predicted Lp(a) levels were tested for association with 20,432 cases of incident AF in the UK Biobank (N = 435,579). Mendelian randomization analyses were performed by using summary-level data for AF from publicly available genome-wide association studies (N = 1,145,375).

Results: In the UK Biobank, each 50 nmol/L (23 mg/dL) increase in Lp(a) was associated with an increased risk of incident AF using measured Lp(a) (HR: 1.03; 95% CI: 1.02-1.04 ; P = 1.65 × 10) and genetically predicted Lp(a) (OR: 1.03; 95% CI: 1.02-1.05; P = 1.33 × 10). Mendelian randomization analyses using independent data replicated the effect (OR: 1.04 per 50 nmol/L Lp[a] increase; 95% CI: 1.03-1.05 per 50 nmol/L Lp[a] increase; P = 9.23 × 10). There was no evidence of risk-conferring effect from low-density lipoprotein cholesterol or triglycerides, and only 39% (95% CI: 27%-73%) of Lp(a) risk was mediated through ASCVD, suggesting that Lp(a) partly influences AF independent of its known effects on ASCVD.

Conclusions: Our findings implicate Lp(a) as a potential causal mediator in the development of AF which show that the effects of Lp(a) extend across myocardial tissues. Ongoing clinical trials for Lp(a)-lowering therapies should evaluate effects on AF prevention.
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http://dx.doi.org/10.1016/j.jacc.2022.02.018DOI Listing
April 2022

Association of pulmonary vein isolation and major cardiovascular events in patients with atrial fibrillation.

Clin Res Cardiol 2022 Apr 11. Epub 2022 Apr 11.

Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Patients with atrial fibrillation (AF) face an increased risk of adverse cardiovascular events. Evidence suggests that early rhythm control including AF ablation may reduce this risk.

Methods: To compare the risks for cardiovascular events in AF patients with and without pulmonary vein isolation (PVI), we analysed data from two prospective cohort studies in Switzerland (n = 3968). A total of 325 patients who had undergone PVI during a 1-year observational period were assigned to the PVI group. Using coarsened exact matching, 2193 patients were assigned to the non-PVI group. Outcomes were all-cause mortality, hospital admission for acute heart failure, a composite of stroke, transient ischemic attack and systemic embolism (Stroke/TIA/SE), myocardial infarction (MI), and bleedings. We calculated multivariable adjusted Cox proportional-hazards models.

Results: Overall, 2518 patients were included, median age was 66 years [IQR 61.0, 71.0], 25.8% were female. After a median follow-up time of 3.9 years, fewer patients in the PVI group died from any cause (incidence per 100 patient-years 0.64 versus 1.87, HR 0.39, 95%CI 0.19-0.79, p = 0.009) or were admitted to hospital for acute heart failure (incidence per 100 patient-years 0.52 versus 1.72, HR 0.44, 95%CI 0.21-0.95, p = 0.035). There was no significant association between PVI and Stroke/TIA/SE (HR 0.94, 95%CI 0.52-1.69, p = 0.80), MI (HR 0.43, 95%CI 0.11-1.63, p = 0.20) or bleeding (HR 0.75, 95% CI 0.50-1.12, p = 0.20).

Conclusions: In our matched comparison, patients in the PVI group had a lower incidence rate of all-cause mortality and hospital admission for acute heart failure compared to the non-PVI group.

Clinicaltrials:

Gov Identifier: NCT02105844, April 7th 2014.
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http://dx.doi.org/10.1007/s00392-022-02015-0DOI Listing
April 2022

Tranexamic Acid in Patients Undergoing Noncardiac Surgery.

N Engl J Med 2022 Apr 2. Epub 2022 Apr 2.

From the Population Health Research Institute (P.J.D., M.M., D.C., F.K.B., S.N.O., M.K.W., A.L., R.P.W., M.H.M., J.V., J.E., I.C., K. Balasubramanian, S.I.B., D. Stillo, T.C., P.S.R., E.P.B.-C., J.S., W.M., S.Y.), the Departments of Health Research Methods, Evidence, and Impact (P.J.D., M.M., D.C., F.K.B., S.N.O., M.K.W., A.X.G., S.I.B., J.S., G.G.), Medicine (P.J.D., M.M., D.C., F.K.B., M.K.W., A.P., V.T., J.E., P.L.G., E.P.B.-C., W.M., G.G., S.Y.), Surgery (A.L., R.P.W.), and Anesthesia (J.S., T.V.) and the School of Nursing (M.H.M.), McMaster University, Hamilton, the Departments of Medicine (A.X.G., P.S.R.) and Epidemiology and Biostatistics (A.X.G.), Western University, London, and the Department of Anesthesiology and Perioperative Medicine, Queen's University and Kingston Health Sciences Centre, Kingston (J.L.P.), ON, the Department of Medicine, Centre Hospitalier de l'Université de Montréal (E.D.), and the Department of Medicine, Jewish General Hospital, McGill University (T.C.), Montreal, and the Department of Medicine, University of Saskatchewan, Saskatoon (M.P.) - all in Canada; the Discipline of Acute Care Medicine, University of Adelaide (T.W.P.), and the Department of Anaesthesia, Royal Adelaide Hospital (T.W.P.), Adelaide, SA, and the Department of Anaesthesia and Perioperative Medicine, Monash University (T.R.), and the Department of Critical Care Medicine, Melbourne Medical School, University of Melbourne (K.L.), Melbourne, VIC - all in Australia; the Department of Anesthesiology and Intensive Care, E. Meshalkin National Medical Research Center (V.L.), and the Department of Anesthesiology and Intensive Care (V.L.) and the Department of Anesthesiology, V. Zelman Institute of Medicine and Psychology (S.V.A.), Novosibirsk State University, Novosibirsk, Saint Petersburg State University Hospital, Saint Petersburg (S.E.), and V. Negovsky Reanimatology Research Institute, Anesthesia and Intensive Care Department, First Moscow State Medical University (Sechenov University), Moscow (V.V.L.) - all in Russia; the Departments of Outcomes Research (D.I.S., K.R., A.T.) and General Anesthesia (K.R., A.T.) and the Anesthesiology Institute (D.I.S., K.R., A.T.), Cleveland Clinic, Cleveland; Chinese University of Hong Kong, Shatin, China (M.T.V.C., W.K.K.W.); Iberoamerican Cochrane Center, Public Health and Clinical Epidemiology Service, Institut d'Investigació Biomèdica Sant Pau, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (M.J.M.-Z.), the Department of Anesthesiology and Intensive Care, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona (M.N.), and the Anesthesiology Department, Santa Creu i Sant Pau University Hospital (P.P.), Barcelona, and the Trauma and Orthopedic Surgery Department, Hospital Clínico Universitario de Valladolid, Valladolid (H.J.A.) - all in Spain; the Department of Anesthesiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia (C.-Y.W.); St. John's Medical College, Bangalore (D.X., M.R.), and the Department of Gastrointestinal Surgery, Surat Institute of Digestive Sciences Hospital and Research Center, Surat (K. Bhatt) - both in India; the Department of Anesthesiology and Intensive Care, IRCCS San Raffaele Scientific Institute, Vita Salute San Raffaele University, Milan (G.L.); the Department of Orthopedic and Trauma Surgery, Deventer Ziekenhuis, Deventer, the Netherlands (Y.V.K.); Jagiellonian University Medical College, Center for Intensive Care and Perioperative Medicine, Krakow, Poland (W.S.); Centre Hospitalier Universitaire Brugmann, Université Libre de Bruxelles, Brussels (D. Schmartz); the Department of Anesthesia, Auckland City Hospital, and the School of Health Sciences, University of Auckland, Auckland, New Zealand (T.G.S.); the Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany (M.W.); the Department of Anesthesia and Intensive Care, Copenhagen University Hospital-Bispebjerg and Frederiksberg, and the Department of Clinical Medicine, University of Copenhagen, Copenhagen (C.S.M.); Shifa International Hospital, Islamabad, Pakistan (M.A.); Departamento de Epidemiología y Estudios en Salud, Universidad de Los Andes, and Servicio de Anestesiología, Clínica Santa María, Santiago, Chile (D.T.); the Department of Anesthesia, General Intensive Care Medicine and Pain Medicine, Medical University of Vienna, Vienna (E.F.); Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, National Institute for Health Technology Assessment, and Hospital Moinhos de Vento, Porto Alegre, Brazil (C.A.P.); and the Department of Anesthesia, Hospital Paris Saint Joseph, University of Paris, Paris (P.A.).

Background: Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding.

Methods: We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025.

Results: A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, -2.6 percentage points; 95% CI, -3.8 to -1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, -1.1 to 1.7; one-sided P = 0.04 for noninferiority).

Conclusions: Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 ClinicalTrials.gov number, NCT03505723.).
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http://dx.doi.org/10.1056/NEJMoa2201171DOI Listing
April 2022

Association between ventricular repolarization parameters and cardiovascular death in patients of the SWISS-AF cohort.

Int J Cardiol 2022 06 9;356:53-59. Epub 2022 Mar 9.

Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy; Cardiotech Lab, Centro Cardiologico Monzino IRCCS, Milan, Italy. Electronic address:

Background: The effect of the ventricular repolarization heterogeneity has not been systematically assessed in patients with atrial fibrillation (AF). Aim of this study is to assess ventricular repolarization heterogeneity as predictor of cardiovascular (CV) death and/or other CV events in patients with AF.

Methods: From the multicenter prospective Swiss-AF (Swiss Atrial Fibrillation) Cohort Study, we enrolled 1711 patients who were in sinus rhythm (995) or AF (716). Resting ECG recordings of 5-min duration were obtained at baseline. Parameters assessing ventricular repolarization were computed (QTc, Tpeak-Tend, J-Tpeak and V-index).

Results: During AF, the V-index was found repeatable (no differences when computed over the whole recording, on the first 2.5-min and on the last 2.5-min segments). During a mean follow-up time of 2.6 ± 1.0 years, 90 patients died for CV reasons. In bivariate Cox regression analysis (adjusted for age only), the V-index was associated with an increased risk of CV death, both in the subgroup of patients in sinus rhythm (SR) as well as those in AF. In multivariate analysis adjusted for clinical risk factors and medications, both prolonged QTc and V-index were independently associated with an increased risk of CV death (QTc: hazard ratio [HR] 2.78, 95% CI 1.79-4.32, p < 0.001; V-index: HR 1.73, 95% CI 1.12-2.69, p = 0.014).

Conclusions: QTc and V-index, measured in a single 5-min ECG recording, were independent predictors of CV death in a cohort of patients with AF and might be a valuable tool for further risk stratification to guide patient management. Clinical Trial Identifier Swiss-AF study: NCT02105844.
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http://dx.doi.org/10.1016/j.ijcard.2022.03.009DOI Listing
June 2022

High-Sensitivity Troponin I after Cardiac Surgery and 30-Day Mortality.

N Engl J Med 2022 03;386(9):827-836

From McMaster University (P.J.D., A.L., M.H.M., E.P.B.-C., N.D., D.C., P.A.K., M.J.M., J.S., Y.L.M., R.M., S.F.L., S.I.B., S.H., F.K.B., G.H.G., S.Y., R.P.W.), Hamilton Health Sciences (P.J.D., A.L., E.P.B.-C., N.D., D.C., P.A.K., Y.L.M., F.K.B., G.H.G., S.Y., R.P.W.), and the Population Health Research Institute (P.J.D., A.L., M.H.M., E.P.B.-C., D.C., M.J.M., K.B., J.S., Y.L.M., R.M., S.F.L., S.I.B., F.K.B., S.P., J.V., S.Y., R.P.W.), Hamilton, Queen's University, Kingston (R.V.A., J.L.P.), and Sunnybrook Health Sciences Centre and the University of Toronto, Toronto (S.C., S.F.) - all in Ontario, Canada; the Chinese University of Hong Kong, Hong Kong (M.T.V.C., M.J.U.), and the First Affiliated Hospital of Xinjiang Medical University, Urumqi (H.Z.) - both in China; E. Meshalkin National Medical Research Center (V.V.L., M.A.) and Novosibirsk State University (V.V.L.), Novosibirsk, and the Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo (D.S.) - all in Russia; IRCCS San Raffaele Scientific Institute (G.L., E.F., F.M.) and Vita-Salute San Raffaele University (G.L., F.M.), Milan, the University of Foggia, Foggia (D.P.), and Santa Maria Hospital GVM Care and Research, Bari (D.P., V.M.) - all in Italy; the University of Malaya, Kuala Lumpur, Malaysia (C.Y.W.); Hospital de la Santa Creu i Sant Pau (G.U., M.M.) and Institut d'Investigació Biomèdica Sant Pau-CIBERESP (G.U.) - both in Barcelona; Instituto do Coração, Hospital das Clinicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo (L.A.H.), and Hospital Moinhos de Vento (C.A.P.), Hospital de Clínicas de Porto Alegre (C.A.P.), and Instituto de Cardiologia do Rio Grande do Sul (R.S.), Porto Alegre - all in Brazil; Royal Perth Hospital and the University of Western Australia - both in Perth (G.S.H.); the University of Edinburgh, Edinburgh (N.L.M.), the Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool (J.D.M.), and the Royal Wolverhampton NHS Trust, Wolverhampton (J.S.B.) - all in the United Kingdom; the University of California, Los Angeles, Los Angeles (E.M.); the University of Arizona College of Medicine, Tucson (J.S.A.); and Auckland City Hospital and the University of Auckland - both in Auckland, New Zealand (H.D.W.).

Background: Consensus recommendations regarding the threshold levels of cardiac troponin elevations for the definition of perioperative myocardial infarction and clinically important periprocedural myocardial injury in patients undergoing cardiac surgery range widely (from >10 times to ≥70 times the upper reference limit for the assay). Limited evidence is available to support these recommendations.

Methods: We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery. High-sensitivity cardiac troponin I measurements (upper reference limit, 26 ng per liter) were obtained 3 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We performed Cox analyses using a regression spline that explored the relationship between peak troponin measurements and 30-day mortality, adjusting for scores on the European System for Cardiac Operative Risk Evaluation II (which estimates the risk of death after cardiac surgery on the basis of 18 variables, including age and sex).

Results: Of 13,862 patients included in the study, 296 (2.1%) died within 30 days after surgery. Among patients who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold troponin level, measured within 1 day after surgery, that was associated with an adjusted hazard ratio of more than 1.00 for death within 30 days was 5670 ng per liter (95% confidence interval [CI], 1045 to 8260), a level 218 times the upper reference limit. Among patients who underwent other cardiac surgery, the corresponding threshold troponin level was 12,981 ng per liter (95% CI, 2673 to 16,591), a level 499 times the upper reference limit.

Conclusions: The levels of high-sensitivity troponin I after cardiac surgery that were associated with an increased risk of death within 30 days were substantially higher than levels currently recommended to define clinically important periprocedural myocardial injury. (Funded by the Canadian Institutes of Health Research and others; VISION Cardiac Surgery ClinicalTrials.gov number, NCT01842568.).
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http://dx.doi.org/10.1056/NEJMoa2000803DOI Listing
March 2022

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin.

J Am Soc Nephrol 2022 03;33(3):511-529

Centre for Genomic & Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom.

Background: Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown.

Methods: We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing.

Results: Two genome-wide significant signals were identified for uUMOD: a novel locus ( 1.24E-08) over the gene coding for KRT40, a type 1 keratin expressed in the kidney, and the locus ( 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over and . Two genome-wide significant signals for uUCR were identified at the locus and at the novel locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion.

Conclusions: Common variants in , , , and associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the locus on kidney function.
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http://dx.doi.org/10.1681/ASN.2021040491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8975067PMC
March 2022

Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study.

Lancet Neurol 2022 03;21(3):246-257

Neurologic Clinic and Policlinic, MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland. Electronic address:

Background: Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies.

Methods: For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry.

Findings: We obtained 10 133 blood samples from 5390 people (median samples per patient 1 [IQR 1-2] in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 [IQR 3·0-8·0]). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35-4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08-6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry.

Interpretation: The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials.

Funding: Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche.
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http://dx.doi.org/10.1016/S1474-4422(22)00009-6DOI Listing
March 2022

Silent brain infarcts impact on cognitive function in atrial fibrillation.

Eur Heart J 2022 Feb 17. Epub 2022 Feb 17.

Department of Neurology and Stroke Center, University Hospital Basel, University of Basel, Basel, Switzerland.

Aims: We aimed to investigate the association of clinically overt and silent brain lesions with cognitive function in atrial fibrillation (AF) patients.

Methods And Results: We enrolled 1227 AF patients in a prospective, multicentre cohort study (Swiss-AF). Patients underwent standardized brain magnetic resonance imaging (MRI) at baseline and after 2 years. We quantified new small non-cortical infarcts (SNCIs) and large non-cortical or cortical infarcts (LNCCIs), white matter lesions (WML), and microbleeds (Mb). Clinically, silent infarcts were defined as new SNCI/LNCCI on follow-up MRI in patients without a clinical stroke or transient ischaemic attack (TIA) during follow-up. Cognition was assessed using validated tests. The mean age was 71 years, 26.1% were females, and 89.9% were anticoagulated. Twenty-eight patients (2.3%) experienced a stroke/TIA during 2 years of follow-up. Of the 68 (5.5%) patients with ≥1 SNCI/LNCCI, 60 (88.2%) were anticoagulated at baseline and 58 (85.3%) had a silent infarct. Patients with brain infarcts had a larger decline in cognition [median (interquartile range)] changes in Cognitive Construct score [-0.12 (-0.22; -0.07)] than patients without new brain infarcts [0.07 (-0.09; 0.25)]. New WML or Mb were not associated with cognitive decline.

Conclusion: In a contemporary cohort of AF patients, 5.5% had a new brain infarct on MRI after 2 years. The majority of these infarcts was clinically silent and occurred in anticoagulated patients. Clinically, overt and silent brain infarcts had a similar impact on cognitive decline.

Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02105844, https://clinicaltrials.gov/ct2/show/NCT02105844.

Key Question: The incidence of clinically overt and silent brain infarcts, white matter lesions, and microbleeds, and their impact on cognition in atrial fibrillation (AF) patients are not known.

Key Finding: Over 2 years of follow-up, 5.5% of AF patients developed new brain infarcts, with the majority of them being clinically silent and occurring in anticoagulated patients. New clinically overt and silent brain infarcts were similarly associated with cognitive decline.

Take-home Message: In a contemporary cohort of AF patients, new brain infarcts are frequent despite a high anticoagulation rate. Our data suggest that anticoagulation alone may not be sufficient to prevent brain damage and cognitive decline in all AF patients.
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http://dx.doi.org/10.1093/eurheartj/ehac020DOI Listing
February 2022

Long-term risk of adverse outcomes according to atrial fibrillation type.

Sci Rep 2022 02 9;12(1):2208. Epub 2022 Feb 9.

Cardiovascular Research Institute Basel, University Hospital Basel, Basel, Switzerland.

Sustained forms of atrial fibrillation (AF) may be associated with a higher risk of adverse outcomes, but few if any long-term studies took into account changes of AF type and co-morbidities over time. We prospectively followed 3843 AF patients and collected information on AF type and co-morbidities during yearly follow-ups. The primary outcome was a composite of stroke or systemic embolism (SE). Secondary outcomes included myocardial infarction, hospitalization for congestive heart failure (CHF), bleeding and all-cause mortality. Multivariable adjusted Cox proportional hazards models with time-varying covariates were used to compare hazard ratios (HR) according to AF type. At baseline 1895 (49%), 1046 (27%) and 902 (24%) patients had paroxysmal, persistent and permanent AF and 3234 (84%) were anticoagulated. After a median (IQR) follow-up of 3.0 (1.9; 4.2) years, the incidence of stroke/SE was 1.0 per 100 patient-years. The incidence of myocardial infarction, CHF, bleeding and all-cause mortality was 0.7, 3.0, 2.9 and 2.7 per 100 patient-years, respectively. The multivariable adjusted (a) HRs (95% confidence interval) for stroke/SE were 1.13 (0.69; 1.85) and 1.27 (0.83; 1.95) for time-updated persistent and permanent AF, respectively. The corresponding aHRs were 1.23 (0.89, 1.69) and 1.45 (1.12; 1.87) for all-cause mortality, 1.34 (1.00; 1.80) and 1.30 (1.01; 1.67) for CHF, 0.91 (0.48; 1.72) and 0.95 (0.56; 1.59) for myocardial infarction, and 0.89 (0.70; 1.14) and 1.00 (0.81; 1.24) for bleeding. In this large prospective cohort of AF patients, time-updated AF type was not associated with incident stroke/SE.
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http://dx.doi.org/10.1038/s41598-022-05688-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8828824PMC
February 2022

Sex-specific differences in adverse outcome events among patients with atrial fibrillation.

Heart 2022 Feb 8. Epub 2022 Feb 8.

Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada

Objective: To assess whether women with atrial fibrillation (AF) have a higher risk of adverse events than men during long-term follow-up since controversial data have been published.

Methods: In the context of two very similar observational multicentre cohort studies, we prospectively followed 3894 patients (28% women) with previously documented AF for a median of 4.02 (3.00-5.83) years. The primary outcome was a composite of ischaemic stroke, myocardial infarction and cardiovascular death. Secondary outcomes included the individual components of the composite outcome, hospitalisation for heart failure, major and clinically relevant non-major bleeding, stroke or systemic embolism and non-cardiovascular death.

Results: Mean age was 73.1 years in women vs 70.8 years in men. The incidence of the primary endpoint in women versus men was 2.46 vs 3.24 per 100 patient-years, respectively (adjusted HR (aHR) 0.74, 95% CI 0.58 to 0.94; p=0.01). Women died less frequently from cardiovascular (aHR 0.57, 95% CI 0.41 to 0.78; p<0.001) and non-cardiovascular causes (aHR 0.68, 95% CI 0.47 to 0.98; p=0.04). There were no significant sex-specific differences in stroke (incidence 1.05 vs 1.00; aHR 1.02, 95% CI 0.70 to 1.49, p=0.93), myocardial infarction (incidence 0.67 vs 0.72; aHR 0.98, 95% CI 0.61 to 1.57, p=0.94), major and clinically relevant non-major bleeding (incidence 4.51 vs 4.34; aHR 0.95, 95% CI 0.79 to 1.15, p=0.63) or heart failure hospitalisation (incidence 3.28 vs 3.07; aHR 1.06, 95% CI 0.85 to 1.32, p=0.60).

Conclusion: In this large study of patients with established AF, women had a lower risk of death than men, but there were no sex-specific differences in other adverse outcomes.
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http://dx.doi.org/10.1136/heartjnl-2021-320122DOI Listing
February 2022

Biomarkers associated with rhythm status after cardioversion in patients with atrial fibrillation.

Sci Rep 2022 01 31;12(1):1680. Epub 2022 Jan 31.

Population Health Research Institute, McMaster University, Hamilton, ON, Canada.

Biomarkers may help to improve our knowledge about the complex pathophysiology of atrial fibrillation (AF). In this study we sought to identify significant changes in biomarkers and clinical measures in patients with and without AF recurrence after electrical cardioversion. We measured 21 conventional and new biomarkers before and 30 days after electrical cardioversion and assessed the associations of changes in biomarker levels with rhythm status at follow-up. Significant between-group changes were observed for bone morphogenetic protein 10 (BMP10), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and total bilirubin. Their respective changes were - 10.4%, - 62.0% and - 25.6% in patients with sinus rhythm, and 3.1%, 1.1% and - 9.4% in patients with recurrent AF, for a between-group difference of - 13.5% (95% confidence interval [CI] - 19.3% to - 7.6%; P < 0.001), - 63.1% (95% CI - 76.6% to - 49.6%; P < 0.001) and - 16.3% (95% CI - 27.9% to - 4.7%; P = 0.007). In multivariable models, the reductions of BMP10 and NT-proBNP were significantly associated with follow-up rhythm status (β coefficient per 1 - SD decrease, - 3.85; 95% CI - 6.34 to - 1.35; P = 0.003 for BMP10 and - 5.84; 95% CI - 10.22 to - 1.47; P = 0.009 for NT-proBNP. In conclusion, changes in BMP10 und NT-proBNP levels were independently associated with rhythm status after cardioversion, suggesting that these markers may be dependent on the actual heart rhythm.
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http://dx.doi.org/10.1038/s41598-022-05769-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8803959PMC
January 2022

Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery.

Trials 2022 Jan 31;23(1):101. Epub 2022 Jan 31.

Department of Anesthesia, General Intensive Care and Pain Management, Medical University of Vienna, Vienna, Austria.

Background: For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes.

Methods: The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization.

Discussion: Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality.

Trial Registration: ClinicalTrials.gov NCT03505723. Registered on 23 April 2018.
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http://dx.doi.org/10.1186/s13063-021-05992-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8805242PMC
January 2022

Atrial Fibrillation and Dementia: A Report From the AF-SCREEN International Collaboration.

Circulation 2022 02 31;145(5):392-409. Epub 2022 Jan 31.

Department of Community Medicine, UiT The Arctic University of Norway, Tromsø (M.L.L.).

Growing evidence suggests a consistent association between atrial fibrillation (AF) and cognitive impairment and dementia that is independent of clinical stroke. This report from the AF-SCREEN International Collaboration summarizes the evidence linking AF to cognitive impairment and dementia. It provides guidance on the investigation and management of dementia in patients with AF on the basis of best available evidence. The document also addresses suspected pathophysiologic mechanisms and identifies knowledge gaps for future research. Whereas AF and dementia share numerous risk factors, the association appears to be independent of these variables. Nevertheless, the evidence remains inconclusive regarding a direct causal effect. Several pathophysiologic mechanisms have been proposed, some of which are potentially amenable to early intervention, including cerebral microinfarction, AF-related cerebral hypoperfusion, inflammation, microhemorrhage, brain atrophy, and systemic atherosclerotic vascular disease. The mitigating role of oral anticoagulation in specific subgroups (eg, low stroke risk, short duration or silent AF, after successful AF ablation, or atrial cardiopathy) and the effect of rhythm versus rate control strategies remain unknown. Likewise, screening for AF (in cognitively normal or cognitively impaired patients) and screening for cognitive impairment in patients with AF are debated. The pathophysiology of dementia and therapeutic strategies to reduce cognitive impairment warrant further investigation in individuals with AF. Cognition should be evaluated in future AF studies and integrated with patient-specific outcome priorities and patient preferences. Further large-scale prospective studies and randomized trials are needed to establish whether AF is a risk factor for cognitive impairment, to investigate strategies to prevent dementia, and to determine whether screening for unknown AF followed by targeted therapy might prevent or reduce cognitive impairment and dementia.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055018DOI Listing
February 2022

Short-term and Long-term Risk of Stroke in Patients With Perioperative Atrial Fibrillation After Cardiac Surgery: Systematic Review and Meta-analysis.

CJC Open 2022 Jan 16;4(1):85-96. Epub 2021 Sep 16.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Background: Perioperative atrial fibrillation (POAF) after cardiac surgery has been associated with an increased risk of stroke in some studies. However, the exact magnitude of this association during short-term and long-term follow-up remains unclear.

Methods: We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) for the time period from database inception to October 2020. We included observational studies with ≥ 100 patients that reported data on short-term or long-term stroke risk in patients with and without POAF after cardiac surgery. Data were pooled using random-effects models. We reported summary risk ratios (RRs) for studies reporting multivariable adjusted results and calculated absolute risk differences (ARDs) with 95% confidence intervals (CIs).

Results: A total of 55 studies with 540,209 patients were included. POAF was associated with both an increased relative risk (RR 1.69; 95% CI, 1.41-2.03; I = 82%; 9 studies) and absolute risk of short-term stroke (4.5% vs 2.5%; ARD 2.0%; 95% CI, 1.28-2.89). POAF was associated with an increased relative risk (RR 1.20; 95% CI, 1.12-1.29; I = 16%; 10 studies) and absolute risk of long-term stroke (1.06 vs 0.88 per 100 patient-years; ARD 0.18 per 100 patient-years; 95% CI, 0.07-0.26). Sensitivity analyses of high-quality studies and studies reporting either ischemic or embolic strokes yielded similar findings.

Conclusions: POAF after cardiac surgery was associated with an increased risk of both short-term and long-term stroke. However, the long-term stroke ARD was small, and whether these patients will benefit from long-term oral anticoagulation therapy is unclear.
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http://dx.doi.org/10.1016/j.cjco.2021.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767142PMC
January 2022

Estimated incidence of previously undetected atrial fibrillation on a 14-day continuous electrocardiographic monitor and associated risk of stroke.

Europace 2022 Jan 21. Epub 2022 Jan 21.

Population Health Research Institute, 237 Barton St E C3-109, Hamilton, ON L8L 2X2, Canada.

Aims: There is uncertainty about whether and how to perform screening for atrial fibrillation (AF). To estimate the incidence of previously undetected AF that would be captured using a continuous 14-day ECG monitor and the associated risk of stroke.

Methods And Results: We analysed data from a cohort of patients >65 years old with hypertension and a pacemaker, but without known AF. For each participant, we simulated 1000 ECG monitors by randomly selecting 14-day windows in the 6 months following enrolment and calculated the average AF burden (total time in AF). We used Cox proportional hazards models adjusted for CHA2DS2-VASc score to estimate the risk of subsequent ischaemic stroke or systemic embolism (SSE) associated with burdens of AF > and <6 min. Among 2470 participants, the median CHA2DS2-VASc score was 4.0, and 44 patients experienced SSE after 6 months following enrolment. The proportion of participants with an AF burden >6 min was 3.10% (95% CI 2.53-3.72). This was consistent across strata of age and CHA2DS2-VASc scores. Over a mean follow-up of 2.4 years, the rate of SSE among patients with <6 min of AF was 0.70%/year, compared to 2.18%/year (adjusted HR 3.02; 95% CI 1.39-6.56) in those with >6 min of AF.

Conclusions: Approximately 3% of individuals aged >65 years with hypertension may have more than 6 min of AF detected by a 14-day ECG monitor. This is associated with a stroke risk of over 2% per year. Whether oral anticoagulation will reduce stroke in these patients is unknown.
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http://dx.doi.org/10.1093/europace/euab324DOI Listing
January 2022

Effect of a Perioperative Hypotension-Avoidance Strategy Versus a Hypertension-Avoidance Strategy on the Risk of Acute Kidney Injury: A Clinical Research Protocol for a Substudy of the POISE-3 Randomized Clinical Trial.

Can J Kidney Health Dis 2022 7;9:20543581211069225. Epub 2022 Jan 7.

Population Health Research Institute, Hamilton, ON, Canada.

Background: Most patients who take antihypertensive medications continue taking them on the morning of surgery and during the perioperative period. However, growing evidence suggests this practice may contribute to perioperative hypotension and a higher risk of complications. This protocol describes an acute kidney injury substudy of the Perioperative Ischemic Evaluation-3 (POISE-3) trial, which is testing the effect of a perioperative hypotension-avoidance strategy versus a hypertension-avoidance strategy in patients undergoing noncardiac surgery.

Objective: To conduct a substudy of POISE-3 to determine whether a perioperative hypotension-avoidance strategy reduces the risk of acute kidney injury compared with a hypertension-avoidance strategy.

Design: Randomized clinical trial with 1:1 randomization to the intervention (a perioperative hypotension-avoidance strategy) or control (a hypertension-avoidance strategy).

Intervention: If the presurgery systolic blood pressure (SBP) is <130 mmHg, all antihypertensive medications are withheld on the morning of surgery. If the SBP is ≥130 mmHg, some medications (but not angiotensin receptor blockers [ACEIs], angiotensin receptor blockers [ARBs], or renin inhibitors) may be continued in a stepwise manner. During surgery, the patients' mean arterial pressure (MAP) is maintained at ≥80 mmHg. During the first 48 hours after surgery, some antihypertensive medications (but not ACEIs, ARBs, or renin inhibitors) may be restarted in a stepwise manner if the SBP is ≥130 mmHg.

Control: Patients receive their usual antihypertensive medications before and after surgery. The patients' MAP is maintained at ≥60 mmHg from anesthetic induction until the end of surgery.

Setting: Recruitment from 108 centers in 22 countries from 2018 to 2021.

Patients: Patients (~6800) aged ≥45 years having noncardiac surgery who have or are at risk of atherosclerotic disease and who routinely take antihypertensive medications.

Measurements: The primary outcome of the substudy is postoperative acute kidney injury, defined as an increase in serum creatinine concentration of either ≥26.5 μmol/L (≥0.3 mg/dL) within 48 hours of randomization or ≥50% within 7 days of randomization.

Methods: The primary analysis (intention-to-treat) will examine the relative risk and 95% confidence interval of acute kidney injury in the intervention versus control group. We will repeat the primary analysis using alternative definitions of acute kidney injury and examine effect modification by preexisting chronic kidney disease, defined as a prerandomization estimated glomerular filtration rate <60 mL/min/1.73 m.

Results: Substudy results will be analyzed in 2022.

Limitations: It is not possible to mask patients or providers to the intervention; however, objective measures will be used to assess acute kidney injury.

Conclusions: This substudy will provide generalizable estimates of the effect of a perioperative hypotension-avoidance strategy on the risk of acute kidney injury.
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http://dx.doi.org/10.1177/20543581211069225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8744204PMC
January 2022

Incidence and Predictors of Heart Failure in Patients With Atrial Fibrillation.

CJC Open 2021 Dec 8;3(12):1482-1489. Epub 2021 Aug 8.

Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

Background: Heart failure (HF) is a frequent cause of hospitalization and death in patients with atrial fibrillation (AF). Identifying AF patients at risk of HF hospitalization could help select individuals for intensive follow-up and treatment.

Methods: We pooled data from 3 randomized trials (ACTIVE-A, RE-LY, AVERROES) of AF patients, for derivation and internal validation of a risk score for first HF hospitalization. Secondary endpoints were cardiovascular death and a composite of HF hospitalizations and cardiovascular death.

Results: In 23,503 patients, the mean age was 71.3 years, and 62% were male. Over a mean follow-up of 2.0 years, 875 patients (3.7%) experienced their first HF hospitalization, and 1037 patients (4.4%) died from cardiovascular causes. Incidence rates per 100 patient-years were 1.85 for HF hospitalizations, 2.15 for cardiovascular death, and 3.71 for the composite. Independent predictors for HF hospitalizations included the following: increased age, weight, heart rate and serum creatinine level, lower height and systolic blood pressure, diabetes, vascular disease, valvular disease, heart rhythm, left ventricular hypertrophy, and intraventricular conduction delay. The C-statistic (95% confidence intervals by bootstrap simulations) was 0.717 (0.705-0.732). At 2 years of follow-up, the incidence rate of the primary outcome increased across risk-score quintiles: 0.49, 0.87, 1.29, 2.44, and 4.51 per 100 patient-years, respectively. Patients in the highest quintile had an absolute risk of 6.8% for the primary endpoint at 2 years.

Conclusions: In a large AF population, new-onset HF was common. A combination of characteristics can identify high-risk patients for whom strategies to prevent HF should be considered.
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http://dx.doi.org/10.1016/j.cjco.2021.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712577PMC
December 2021

Long-Term Follow-up of Enhanced Holter-Electrocardiography Monitoring in Acute Ischemic Stroke.

J Stroke 2022 Jan 17;24(1):98-107. Epub 2021 Dec 17.

Clinic and Policlinic for Cardiology, University Hospital Leipzig, Leipzig, Germany.

Background And Purpose: Prolonged electrocardiography (ECG)-monitoring in stroke patients improves the detection of paroxysmal atrial fibrillation (pAF). However, most randomized studies only had short follow-up. We aimed to provide 3-year follow-up data for AF detection and stroke recurrence risk.

Methods: We randomized 402 patients aged ≥60 years with acute ischemic strokes without AF to either enhanced and prolonged monitoring (EPM; 3×10-day Holter-ECG-monitoring) or standard-of-care (≥24 hours ECG-monitoring). The endpoint of the current analysis was AF within 36 months analyzed by intention to treat. Long-term follow-up was performed for 36 months.

Results: Two hundred and seventy-four patients (80%) participated in the extended follow-up (median duration of follow-up was 36 months [interquartile range, 12 to 36]). During the first 6 months, more AF was documented in the EPM arm compared to the control arm (13.5% vs. 5.1%; 95% confidence interval, 2.9% to 14.4%; P=0.004). During months 6 to 36, AF was less detected in the EPM intervention arm than in the control arm (2.0% vs. 7.3%; 95% confidence interval, 0.7% to 9.9%; P=0.028). Overall, the detection rate of AF within 36 months was numerically higher within the EPM group (15.0% vs. 11.1%, P=0.30). Numerically less patients in the EPM arm had recurrent ischemic strokes (5.5% vs. 9.1%, P=0.18), transient ischemic attacks (3.0% vs. 4.5%, P=0.44) or died (4.5% vs. 6.6%, P=0.37).

Conclusions: Enhanced and prolonged ECG monitoring increased AF detection during the first six months, but there was significantly more clinical AF during months 6 to 36 observed in the usual-care arm. This suggests that EPM leads to an earlier detection of clinically relevant AF.
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http://dx.doi.org/10.5853/jos.2021.01207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8829482PMC
January 2022

Continuous Noninvasive Remote Automated Blood Pressure Monitoring With Novel Wearable Technology: A Preliminary Validation Study.

JMIR Mhealth Uhealth 2022 02 28;10(2):e24916. Epub 2022 Feb 28.

Population Health Research Institute, Hamilton, ON, Canada.

Background: Wearable continuous monitoring biosensor technologies have the potential to transform postoperative care with early detection of impending clinical deterioration.

Objective: Our aim was to validate the accuracy of Cloud DX Vitaliti continuous vital signs monitor (CVSM) continuous noninvasive blood pressure (cNIBP) measurements in postsurgical patients. A secondary aim was to examine user acceptance of the Vitaliti CVSM with respect to comfort, ease of application, sustainability of positioning, and aesthetics.

Methods: Included participants were ≥18 years old and recovering from surgery in a cardiac intensive care unit (ICU). We targeted a maximum recruitment of 80 participants for verification and acceptance testing. We also oversampled to minimize the effect of unforeseen interruptions and other challenges to the study. Validation procedures were according to the International Standards Organization (ISO) 81060-2:2018 standards for wearable, cuffless blood pressure (BP) measuring devices. Baseline BP was determined from the gold-standard ICU arterial catheter. The Vitaliti CVSM was calibrated against the reference arterial catheter. In static (seated in bed) and supine positions, 3 cNIBP measurements, each 30 seconds, were taken for each patient with the Vitaliti CVSM and an invasive arterial catheter. At the conclusion of each test session, captured cNIBP measurements were extracted using MediCollector BEDSIDE data extraction software, and Vitaliti CVSM measurements were extracted to a secure laptop through a cable connection. The errors of these determinations were calculated. Participants were interviewed about device acceptability.

Results: The validation analysis included data for 20 patients. The average times from calibration to first measurement in the static position and to first measurement in the supine position were 133.85 seconds (2 minutes 14 seconds) and 535.15 seconds (8 minutes 55 seconds), respectively. The overall mean errors of determination for the static position were -0.621 (SD 4.640) mm Hg for systolic blood pressure (SBP) and 0.457 (SD 1.675) mm Hg for diastolic blood pressure (DBP). Errors of determination were slightly higher for the supine position, at 2.722 (SD 5.207) mm Hg for SBP and 2.650 (SD 3.221) mm Hg for DBP. The majority rated the Vitaliti CVSM as comfortable. This study was limited to evaluation of the device during a very short validation period after calibration (ie, that commenced within 2 minutes after calibration and lasted for a short duration of time).

Conclusions: We found that the Cloud DX's Vitaliti CVSM demonstrated cNIBP measurement in compliance with ISO 81060-2:2018 standards in the context of evaluation that commenced within 2 minutes of device calibration; this device was also well-received by patients in a postsurgical ICU setting. Future studies will examine the accuracy of the Vitaliti CVSM in ambulatory contexts, with attention to assessment over a longer duration and the impact of excessive patient motion on data artifacts and signal quality.

Trial Registration: ClinicalTrials.gov NCT03493867; https://clinicaltrials.gov/ct2/show/NCT03493867.
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http://dx.doi.org/10.2196/24916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8922156PMC
February 2022

Association of Diabetes With Atrial Fibrillation Phenotype and Cardiac and Neurological Comorbidities: Insights From the Swiss-AF Study.

J Am Heart Assoc 2021 11 10;10(22):e021800. Epub 2021 Nov 10.

Department of Cardiology InselspitalBern University HospitalUniversity of Bern Switzerland.

Background Diabetes is a major risk factor for atrial fibrillation (AF). However, it remains unclear whether individual AF phenotype and related comorbidities differ between patients who have AF with and without diabetes. This study investigated the association of diabetes with AF phenotype and cardiac and neurological comorbidities in patients with documented AF. Methods and Results Participants in the multicenter Swiss-AF (Swiss Atrial Fibrillation) study with data on diabetes and AF phenotype were eligible. Primary outcomes were parameters of AF phenotype, including AF type, AF symptoms, and quality of life (assessed by the European Quality of Life-5 Dimensions Questionnaire [EQ-5D]). Secondary outcomes were cardiac (ie, history of hypertension, myocardial infarction, and heart failure) and neurological (ie, history of stroke and cognitive impairment) comorbidities. The cross-sectional association of diabetes with these outcomes was assessed using logistic and linear regression, adjusted for age, sex, and cardiovascular risk factors. We included 2411 patients with AF (27.4% women; median age, 73.6 years). Diabetes was not associated with nonparoxysmal AF (odds ratio [OR], 1.01; 95% CI, 0.81-1.27). Patients with diabetes less often perceived AF symptoms (OR, 0.74; 95% CI, 0.59-0.92) but had worse quality of life (β=-4.54; 95% CI, -6.40 to -2.68) than those without diabetes. Patients with diabetes were more likely to have cardiac (hypertension [OR, 3.04; 95% CI, 2.19-4.22], myocardial infarction [OR, 1.55; 95% CI, 1.18-2.03], heart failure [OR, 1.99; 95% CI, 1.57-2.51]) and neurological (stroke [OR, 1.39, 95% CI, 1.03-1.87], cognitive impairment [OR, 1.75, 95% CI, 1.39-2.21]) comorbidities. Conclusions Patients who have AF with diabetes less often perceive AF symptoms but have worse quality of life and more cardiac and neurological comorbidities than those without diabetes. This raises the question of whether patients with diabetes should be systematically screened for silent AF. Registration URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02105844.
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http://dx.doi.org/10.1161/JAHA.121.021800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8751921PMC
November 2021

Post-discharge after surgery Virtual Care with Remote Automated Monitoring-1 (PVC-RAM-1) technology versus standard care: randomised controlled trial.

BMJ 2021 09 30;374:n2209. Epub 2021 Sep 30.

Department of Anesthesia and Perioperative Medicine, Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada.

Objective: To determine if virtual care with remote automated monitoring (RAM) technology versus standard care increases days alive at home among adults discharged after non-elective surgery during the covid-19 pandemic.

Design: Multicentre randomised controlled trial.

Setting: 8 acute care hospitals in Canada.

Participants: 905 adults (≥40 years) who resided in areas with mobile phone coverage and were to be discharged from hospital after non-elective surgery were randomised either to virtual care and RAM (n=451) or to standard care (n=454). 903 participants (99.8%) completed the 31 day follow-up.

Intervention: Participants in the experimental group received a tablet computer and RAM technology that measured blood pressure, heart rate, respiratory rate, oxygen saturation, temperature, and body weight. For 30 days the participants took daily biophysical measurements and photographs of their wound and interacted with nurses virtually. Participants in the standard care group received post-hospital discharge management according to the centre's usual care. Patients, healthcare providers, and data collectors were aware of patients' group allocations. Outcome adjudicators were blinded to group allocation.

Main Outcome Measures: The primary outcome was days alive at home during 31 days of follow-up. The 12 secondary outcomes included acute hospital care, detection and correction of drug errors, and pain at 7, 15, and 30 days after randomisation.

Results: All 905 participants (mean age 63.1 years) were analysed in the groups to which they were randomised. Days alive at home during 31 days of follow-up were 29.7 in the virtual care group and 29.5 in the standard care group: relative risk 1.01 (95% confidence interval 0.99 to 1.02); absolute difference 0.2% (95% confidence interval -0.5% to 0.9%). 99 participants (22.0%) in the virtual care group and 124 (27.3%) in the standard care group required acute hospital care: relative risk 0.80 (0.64 to 1.01); absolute difference 5.3% (-0.3% to 10.9%). More participants in the virtual care group than standard care group had a drug error detected (134 (29.7%) 25 (5.5%); absolute difference 24.2%, 19.5% to 28.9%) and a drug error corrected (absolute difference 24.4%, 19.9% to 28.9%). Fewer participants in the virtual care group than standard care group reported pain at 7, 15, and 30 days after randomisation: absolute differences 13.9% (7.4% to 20.4%), 11.9% (5.1% to 18.7%), and 9.6% (2.9% to 16.3%), respectively. Beneficial effects proved substantially larger in centres with a higher rate of care escalation.

Conclusion: Virtual care with RAM shows promise in improving outcomes important to patients and to optimal health system function.

Trial Registration: ClinicalTrials.gov NCT04344665.
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http://dx.doi.org/10.1136/bmj.n2209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477638PMC
September 2021

LVS-HARMED Risk Score for Incident Heart Failure in Patients With Atrial Fibrillation Who Present to the Emergency Department: Data from a World-Wide Registry.

J Am Heart Assoc 2021 09 13;10(18):e017735. Epub 2021 Sep 13.

Population Health Research Institute McMaster University Hamilton Onatrio Canada.

Background Heart failure (HF) is a common complication to atrial fibrillation (AF), leading to rehospitalization and death. Early identification of patients with AF at risk for HF might improve outcomes. We aimed to derive a score to predict 1-year risk of new-onset HF after an emergency department (ED) visit with AF. Methods and Results The RE-LY AF (Randomized Evaluation of Long-Term Anticoagulant Therapy) registry enrolled patients with AF presenting to an ED in 47 countries, and followed them for a year. The end point was HF hospitalization and/or HF death. Among 15 400 ED patients, 9765 had no prior HF (mean age, 64.9±14.9 years). Within 1 year, new-onset HF developed in 6.8% of patients, of whom 21% died of HF. Independent predictors of HF included left ventricular hypertrophy (odds ratio [OR], 1.47; 95% CI, 1.19-1.82), valvular heart disease (OR, 1.55; 95% CI, 1.18-2.04), smoking (OR, 1.42; 95% CI, 1.12-1.78), height (OR, 0.93; 95% CI, 0.90-0.95 per 3 cm), age (OR, 1.11; 95% CI, 1.07-1.15 per 5 years), rheumatic heart disease (OR, 1.77, 95% CI, 1.24-2.51), prior myocardial infarction (OR, 1.85; 95% CI, 1.45-2.36), remaining in AF at ED discharge (OR, 1.86; 95% CI, 1.46-2.36), and diabetes (OR, 1.33; 95% CI, 1.09-1.64). A continuous risk prediction score (LVS-HARMED [left ventricular, valvular heart disease, smoking or other tobacco use, height, age, rheumatic heart disease, myocardial infarction, emergency department discharge rhythm, and diabetes]) had good discrimination (C statistic, 0.735; 95% CI, 0.716-0.755). Validation was conducted internally using bootstrapping (optimism-corrected C statistic, 0.705) and externally (C statistic, 0.699). The 1-year incidence of HF hospitalization and/or HF death across quartile groups of the score was 1.1%, 4.5%, 6.9%, and 14.4%, respectively. LVS-HARMED also predicted incident stroke (C statistic, 0.753; 95% CI, 0.728-0.778). Conclusions The LVS-HARMED score predicts new-onset HF after an ED visit for AF. Preventative strategies should be considered in patients with high LVS-HARMED HF risk.
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http://dx.doi.org/10.1161/JAHA.120.017735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649506PMC
September 2021

Sodium-Glucose Co-Transporter Inhibitors and Atrial Fibrillation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

J Am Heart Assoc 2021 09 28;10(17):e022222. Epub 2021 Aug 28.

Department of Health Research Methods, Evidence and Impact McMaster University Hamilton Ontario Canada.

Background Sodium-glucose co-transporter (SGLT) inhibitors reduce cardiovascular outcomes including mortality in several populations; however, their effect on atrial fibrillation/flutter (AF) remains unclear. Our objective was to determine whether SGLT inhibitors reduce AF and whether a history of AF modifies the effect of SGLT inhibitors on the composite of heart failure hospitalization or cardiovascular death. Methods and Results We searched MEDLINE, Embase, and CENTRAL to March 2021. Pairs of reviewers identified randomized controlled trials that compared an SGLT inhibitor with placebo or no therapy. We pooled data using RevMan 5.4.1, assessed risk of bias using the Cochrane tool, and determined the overall quality of evidence using Grades of Recommendation, Assessment, Development and Evaluation. Thirty-one eligible trials reported on AF events (75 279 participants, mean age 62 years, 35.0% women). Moderate quality evidence supported a lower risk of serious AF events with SGLT inhibitors (1.1% versus 1.5%; risk ratio 0.75 [95% CI, 0.66-0.86]; I=0%). A similar reduction in total AF events was also noted with SGLT inhibitors. Three trials reported on heart failure hospitalization/cardiovascular death stratified by a baseline history of AF (18 832 participants, mean age 66 years, 38.1% women); in patients with a history of AF, SGLT inhibitors resulted in a lower risk in the composite of heart failure hospitalization or cardiovascular death (hazard ratio, 0.70 [95% CI, 0.57-0.85]; I=0%)-similar to the effect estimate for patients without AF, value for interaction: 1.00. Conclusions SGLT inhibitors may reduce AF events and likely reduce heart failure hospitalization/cardiovascular death to a similar extent in patients with and without AF.
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http://dx.doi.org/10.1161/JAHA.121.022222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649253PMC
September 2021

Subclinical thyroid function and cardiovascular events in patients with atrial fibrillation.

Eur J Endocrinol 2021 Aug 3;185(3):375-385. Epub 2021 Aug 3.

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

Objective: To evaluate if subclinical thyroid dysfunction is associated with cardiovascular (CV) risk in patients with atrial fibrillation (AF).

Methods: Swiss-AF is a prospective cohort of community-dwelling participants aged ≥ 65 years with AF. Primary outcome was a composite endpoint of CV events (myocardial infarctions, stroke/transitory ischemic events, systemic embolism, heart failure (HF) hospitalizations, CV deaths). Secondary outcomes were component endpoints, total mortality, and AF-progression. Exposures were thyroid dysfunction categories, TSH and fT4. Sensitivity analyses were performed for amiodarone use, thyroid hormones use, and competing events.

Results: 2415 patients were included (mean age: 73.2 years; 27% women). 196 (8.4%) had subclinical hypothyroidism and 53 (2.3%) subclinical hyperthyroidism. Subclinical thyroid dysfunction was not associated with CV events, during a median follow-up of 2.1 years (max 5 years): age- and sex-adjusted hazard ratio (adjHR) of 0.99 (95% CI: 0.69-1.41) for subclinical hypothyroidism and 0.55 (95% CI: 0.23-1.32) for subclinical hyperthyroidism. Results remained robust following multivariable adjustment and sensitivity analyses. In euthyroid patients, fT4 levels were associated with an increased risk for the composite endpoint and HF (adjHR: 1.46, 95% CI: 1.04-2.05; adjHR: 1.70, 95% CI: 1.08-2.66, respectively, for the highest quintile vs the middle quintile). Results remained similar following multivariable adjustment and remained significant for HF in sensitivity analyses. No association between subclinical thyroid dysfunction and total mortality or AF-progression was found.

Conclusions: Subclinical hypothyroidism was not associated with increased CV risk in AF patients. Higher levels of fT4 with normal TSH were associated with a higher risk for HF.
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http://dx.doi.org/10.1530/EJE-20-1442DOI Listing
August 2021

Cardiac autonomic function and cognitive performance in patients with atrial fibrillation.

Clin Res Cardiol 2022 Jan 22;111(1):60-69. Epub 2021 Jun 22.

Department of Cardiology, Cardiovascular Research Institute Basel, University Hospital Basel, Basel, Switzerland.

Background: Atrial fibrillation (AF) is associated with loss of cognition and dementia. Cardiac autonomic dysfunction has been linked to cognitive decline. We aimed to investigate if reduced cardiac autonomic function (CAF) is associated with cognitive impairment in AF patients.

Methods: Patients with paroxysmal, persistent and permanent AF were enrolled from a multicenter cohort study if they had AF ("AF group") or sinus rhythm ("SR group") on a baseline 5 min ECG recording. Parameters quantifying CAF (heart rate variability triangular index (HRVI), mean heart rate (MHR), RMSSD, SDNN, total power and power in the VLF, LF, HF ranges) were calculated. We used the Montreal Cognitive Assessment (MoCA) to assess global cognitive function.

Results: 1685 AF patients with a mean age of 73 ± 8 years, 29% females, were included. MoCA score was 24.5 ± 3.2 in the AF group (N = 710 patients) and 25.4 ± 3.2 in the SR group (N = 975 patients). After adjusting for multiple confounders, lower HRVI was associated with lower MoCA scores, both in the SR group [β = 0.049; 95% confidence interval (CI) 0.016-0.081; p = 0.003] and in the AF group (β = 0.068; 95% CI 0.020-0.116; p = 0.006). In the AF group, higher MHR was associated with a poorer performance in the MoCA (β =  - 0.008; 95% CI - 0.014 to - 0.002; p = 0.014). We found no convincing evidence of association for other CAF parameters with cognition.

Conclusion: Our data suggest that impaired CAF is associated with worse cognitive performance in patients with AF. Among standard HRV parameters, HRVI might be the most promising ECG index.

Trial Registration: ClinicalTrials.gov Identifier: NCT02105844.
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http://dx.doi.org/10.1007/s00392-021-01900-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766386PMC
January 2022
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