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The safety of continuing human epidermal growth factor receptor 2 (HER2)-targeted therapy in women with mild cardiotoxicity remains unclear. We performed a retrospective matched cohort study of 14 patients with human epidermal growth factor receptor 2-positive breast cancer receiving sequential anthracycline and trastuzumab therapy, nested within the E valuation of M yocardial Changes During Br east A denocarcinoma Therapy to Detect C ardiotoxicity E arlier With MRI (EMBRACE-MRI) trial. Among patients who developed cardiotoxicity and were treated with heart failure therapy, we compared those who had trastuzumab therapy interrupted to a matched cohort who continued trastuzumab therapy. By a median of 2.5 years of follow-up, no significant differences were present between the groups in the proportion with magnetic resonance imaging-measured left ventricular ejection fraction < 40%, magnetic resonance imaging-measured left ventricular volumes, left ventricular ejection fraction, edema, fibrotic markers, cardiopulmonary fitness, or quality of life., (© 2024 The Authors.)

Background: "Secondary" atrial fibrillation (AF) denotes AF that is precipitated by short-term triggers and that may be reversible. Using administrative data to study secondary AF is of interest, but the ability of these data to verify secondary AF has not been studied., Methods: We conducted a cross-sectional analysis of 1000 randomly selected hospitalizations of patients discharged alive between January 1, 2016 and March 31, 2020, with AF coded as the most responsible diagnosis (type 1), post-admit comorbidity (type 2), or secondary diagnosis (type 3). We compared diagnosis types to AF category (secondary or not) as determined by a physician blinded to the discharge diagnosis type. We calculated the positive predictive value (PPV) of the designation of secondary AF in comparison to physician determination., Results: A total of 421 hospitalizations had AF documented as a type 2 diagnosis; this had a PPV of 94.8% for physician determination of secondary AF. After excluding hospitalizations with preexisting AF, and those for which AF type could not be determined by the physician, the PPV of a type 2 diagnosis (n = 391) for secondary AF was 99.7%. Type 3 diagnoses of AF (n = 222) mostly captured hospitalizations with preexisting AF (87.8% of type 3 diagnoses)., Conclusions: A type 2 diagnosis can be used to verify secondary AF in people who were first diagnosed with AF while hospitalized for other causes. This verification facilitates cohort studies and clinical trial recruitment of people with this AF subtype, although it should not be used to determine the prevalence or incidence of secondary AF., (© 2023 The Authors.)

Background: Sodium glucose cotransporter-2 inhibitors (SGLT2is) are hypothesized to reduce the risk of anthracycline-associated cardiotoxicity., Objectives: This study sought to determine the association between SGLT2is and cardiovascular disease (CVD) after anthracycline-containing chemotherapy., Methods: Using administrative data sets, we conducted a population-based cohort study of people >65 years of age with treated diabetes and no prior heart failure (HF) who received anthracyclines between January 1, 2016, and December 31, 2019. After estimating propensity scores for SGLT2i use, the average treatment effects for the treated weights were used to reduce baseline differences between SGLT2i-exposed and -unexposed controls. The outcomes were hospitalization for HF, incident HF diagnoses (in- or out-of-hospital), and documentation of any CVD in future hospitalizations. Death was treated as a competing risk. Cause-specific HRs for each outcome were determined for SGLT2i-treated people relative to unexposed controls., Results: We studied 933 patients (median age 71.0 years, 62.2% female), 99 of whom were SGLT2i treated. During a median follow-up of 1.6 years, there were 31 hospitalizations for HF (0 in the SGLT2i group), 93 new HF diagnoses, and 74 hospitalizations with documented CVD. Relative to controls, SGLT2i exposure was associated with HR of 0 for HF hospitalization ( P < 0.001) but no significant difference in incident HF diagnosis (HR: 0.55; 95% CI: 0.23-1.31; P = 0.18) or CVD diagnosis (HR: 0.39; 95% CI: 0.12-1.28; P = 0.12). There was no significant difference in mortality (HR: 0.63; 95% CI: 0.36-1.11; P = 0.11)., Conclusions: SGLT2is may reduce the rate of HF hospitalization after anthracycline-containing chemotherapy. This hypothesis warrants further testing in randomized controlled trials., Competing Interests: Analysis of this study was funded by the Ted Rogers Centre for Heart Research (to Dr Thavendiranathan). Dr Abdel-Qadir is supported by a National New Investigator Award from the Heart and Stroke Foundation of Canada. Dr Thavendiranathan is supported by a Tier II Canada Research Chair in CardioOncology. The funding sources had no role in the conduct of the study, the decision to publish or the preparation of the manuscript. Dr Abdel-Qadir has received honoraria from Amgen, AstraZeneca, and Jazz Pharmaceuticals. Dr Thavendiranathan has received speaker honoraria from Amgen, Boehringer Ingelheim, and Takeda. This study was supported by ICES, an independent, nonprofit research institute funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). Parts of this material are based on data and/or information compiled and provided by Ontario Health, the Ontario Ministry of Health, and the Canadian Institute of Health Information (CIHI). Parts of this report are based on Ontario Registrar General information on deaths, the original source of which is Service Ontario. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources (ICES, CIHI, Ontario Health, ORG, or the Ontario MOH/ MLTC); no endorsement is intended or should be inferred. Dr Neilan has been a consultant to and received fees from Bristol Myers Squibb, Genentech, CRC Oncology, Roche, Sanofi and Parexel Imaging Pharmaceuticals, outside of the current work. Dr Neilan also reports grant funding from Astra Zeneca and Bristol Myers Squibb outside of the current work. Dr Neilan is supported by a gift from A. Curt Greer and Pamela Kohlberg and from Christina and Paul Kazilionis, the Michael and Kathryn Park Endowed Chair in Cardiology, a Hassenfeld Scholar Award, and has additional grant funding from the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL137562, K24HL150238). All other authors have reported that they have no relationships to the contents of this paper to disclose., (© 2023 Published by Elsevier on behalf of the American College of Cardiology Foundation.)

Background: While men have experienced higher risks of SARS-CoV-2 infection compared to women, an analysis of sex differences by age in severe outcomes during the acute phase of infection is lacking., Objectives: The purpose of this study was to assess heterogeneity in severe outcome risks by age and sex by conducting a retrospective cohort study of community-dwelling adults in Ontario who tested positive for SARS-CoV-2 infection during the first 3 waves., Methods: Adjusted odds ratios were estimated using multilevel multivariable logistic regression models including an interaction term for age and sex. The primary outcome was a composite of severe outcomes (hospitalization for a cardiovascular (CV) event, intensive care unit admission, mechanical ventilation, or death) within 30 days., Results: Among 30,736, 199,132, and 186,131 adults who tested positive during the first 3 waves, 1,908 (6.2%), 5,437 (2.7%), and 5,653 (3.0%) experienced a severe outcome within 30 days. For all outcomes, the sex-specific risk depended on age (all P for interaction <0.05). Men with SARS-CoV-2 infection experienced a higher risk of outcomes than infected women of the same age, except for the risk of all-cause hospitalization being higher for young women than men (ages 18-45 years) during waves 2 and 3. The sex disparity in CV hospitalization across all ages either persisted or increased with each subsequent wave., Conclusions: To mitigate risks in subsequent waves, it is helpful to further understand the factors that contribute to the generally higher risks faced by men across all ages, and the persistent or increasing sex disparity in the risk of CV hospitalization., Competing Interests: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Ms Behrouzi has received research grant support to her institutions from Boehringer Ingelheim, Lilly, and Sanofi-Aventis, outside the submitted work. Dr Farkouh has received research grants from Amgen, Novartis, and Novo Nordisk, outside the submitted work. Dr Goodman reports research grant support (eg, steering committee or data and safety monitoring committee) and/or speaker/consulting honoraria (eg, advisory boards) from: Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, Valeo Pharma; and salary support/honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Failure Society, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, TIMI Study Group (Brigham Health). Dr Udell has received research grant support to his institutions from AstraZeneca, Novartis, and Sanofi; reported service as a consultant for Amgen, Boehringer Ingelheim, Janssen, Merck, Novartis, Novavax, and Sanofi; and received honoraria from Boehringer Ingelheim and Janssen outside the submitted work. No other disclosures were reported. This study received funding from a 10.13039/501100000024Canadian Institutes for Health Research (CIHR) Strategy for Patient-Oriented Research Innovative Clinical Trial Multi-year grant (MYG-151211), a Ted Rogers Centre for Heart Research Innovation Fund - COVID-19 Award, and in part by the Peter Munk Cardiac Centre Innovation Fund. Ms Behrouzi is supported by a 10.13039/501100000024CIHR Canada Graduate Scholarship – Doctoral (CGS D) award, a 10.13039/501100003579University of Toronto MD/PhD studentship, and a Ted Rogers Centre for Heart Research Doctoral Award. Dr Atzema is supported by Mid-Career Investigator Awards from the 10.13039/100004411Heart and Stroke Foundation, Sunnybrook Health Sciences Centre, and 10.13039/100012665ICES. Dr Kapral holds the Lillian Love Chair in Women’s Health from the University Health Network/University of Toronto. Dr Kaul holds a CIHR Sex and Gender Science Chair and a Heart and Stroke Foundation Chair in Cardiovascular Research. Dr Goodman was supported by the 10.13039/100004411Heart and Stroke Foundation of Ontario/10.13039/501100003579University of Toronto Polo Chair. Dr Austin is supported by a Mid-Career Investigator Award from the 10.13039/100004411Heart and Stroke Foundation. Dr McAlister holds the Alberta Health Services Chair in Cardiovascular Outcomes Research. Dr Lee is the Ted Rogers Chair in Heart Function Outcomes, University Health Network, University of Toronto. Dr Udell is supported by a 10.13039/100013873Government of Ontario Early Researcher Award (ER15-11-037), a Clinician Scientist Merit Award, Department of Medicine, University of Toronto, Peter Munk Cardiac Centre, Women’s College Research Institute and Department of Medicine, Women’s College Hospital. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Appropriate selection of patients with stable coronary artery disease (CAD) for coronary angiography is dependent on the pretest probability of obstructive CAD; however, little is known about the potential differences in CAD by race and ethnic groups., Objectives: The purpose of this study was to evaluate the association of race and ethnicity with coronary obstruction in stable CAD., Methods: We evaluated first coronary angiography for CAD evaluation between 2012 and 2019 in Ontario, Canada. Race and ethnicity were identified by physicians. The main outcome was the rate of obstructive CAD (left main stenosis ≥50% or major epicardial vessel stenosis ≥70%). Multivariable logistic regression analyses evaluated the independent association of race and ethnicity with CAD., Results: Among 71,199 CAD patients, 14.0% were South Asian (SA), 4.4% were East Asian (EA), and 58,131 were White patients. SA patients were the youngest at 60.9 years vs 62.4 years for EA patients and 65.1 years for White patients but were most likely to have obstructive CAD (46.9%) (EA 43.0% and White patients 37.9%). SA patients had the highest prevalence of 3-vessel CAD at 13.4% (vs 12.5% in EA and 7.7% in White patients). The adjusted odds ratio was 67% higher (1.67; 95% CI: 1.59 to 1.75) for having obstructive CAD in SA patients than that in White patients. EA patients also had significantly increased adjusted odds of obstructive CAD compared with White patients (1.40; 95% CI: 1.29-1.52)., Conclusions: SA patients were younger at presentation but had the highest adjusted odds of obstructive CAD. Incorporation of race and ethnicity information may improve risk-prediction tools for detection of coronary obstruction., Competing Interests: This study was supported by 10.13039/100012665ICES, which is funded by an annual grant from the 10.13039/501100000226Ontario Ministry of Health and the Ministry of Long-Term Care. This study is funded in part by Foundation grants (FDN 154333) by the 10.13039/501100000024Canadian Institutes of Health Research (CIHR). The authors acknowledge that the clinical registry data used in this publication are from participating hospitals through CorHealth Ontario, which serves as an advisory body to the Minister of Health and Long-Term Care (MOHLTC), is funded by the MOHLTC, and is dedicated to improving the quality, efficiency, access, and equity in the delivery of the continuum of adult cardiac, vascular, and stroke services in Ontario, Canada. Dr Godoy has received the Frederick Banting and Charles Best Canada Graduate Scholarship (Doctoral Research Award) from the Canadian Institutes of Health Research. Dr Ko is supported by the Jack Tu Research Chair in Cardiovascular Outcomes Research, Sunnybrook hospital, and University of Toronto. All other authors have reported that they have no relationships relevant to the contents of this article to disclose., (© 2023 The Authors.)

Background: Women treated for breast cancer are at risk for worsening health-related quality of life (QoL), cardiac function, and cardiorespiratory fitness., Objectives: The aim of this study was to assess the associations of self-reported moderate to vigorous intensity physical activity (MVPA) during cancer treatment with concurrent measures of QoL and cardiac function and with post-treatment cardiorespiratory fitness in women with human epidermal growth factor receptor 2-positive breast cancer receiving sequential anthracyclines and trastuzumab., Methods: EMBRACE-MRI 1 (Evaluation of Myocardial Changes During Breast Adenocarcinoma Therapy to Detect Cardiotoxicity Earlier With MRI) study participants who completed questionnaires for MVPA (modified Godin Leisure Time Physical Activity Questionnaire) and QoL (EQ-5D-3L, Minnesota Living With Heart Failure Questionnaire) and cardiac imaging every 3 months during treatment and post-treatment cardiopulmonary exercise testing were included. Participants engaging in ≥90 minutes of MVPA each week were labeled "active." Generalized estimation equations and linear regression analyses were used to assess concurrent and post-treatment associations with MVPA and activity status, respectively., Results: Eighty-eight participants were included (mean age 51.4 ± 8.9 years). Mean MVPA minutes, QoL, and cardiac function (left ventricular ejection fraction, global longitudinal strain, E/A ratio, and E/e' ratio) worsened by 6 months into trastuzumab therapy. Higher MVPA (per 30 minutes) during treatment was associated with better concurrent overall (β = -0.42) and physical (β = -0.24) Minnesota Living With Heart Failure Questionnaire scores, EQ-5D-3L index (β = 0.003), visual analogue scale score (β = 0.43), diastolic function (E/A ratio; β = 0.01), and global longitudinal strain (β = 0.04) at each time point ( P  ≤ 0.01 for all). Greater cumulative MVPA over the treatment period was associated with higher post-treatment cardiorespiratory fitness (peak oxygen consumption; β = 0.06 per 30 minutes; P  < 0.001)., Conclusions: Higher self-reported MVPA during treatment for human epidermal growth factor receptor 2-positive breast cancer was associated with better QoL and diastolic and systolic left ventricular function measures during treatment and better post-treatment cardiorespiratory fitness., Competing Interests: This study was funded by an operating grant from the Canadian Institutes of Health Research (137132 and 142456) and the Ontario Early Research Award to Dr Thavendiranathan. Dr Thavendiranathan was supported by the Canadian Institutes of Health Research New Investigator Award (147814) and now by a Canada Research Chair in Cardiooncology. Dr Thavendiranathan is also supported by the Canadian Cancer Society / Canadian Institutes of Health Research's W. David Hargraft Grant. Dr Abdel-Qadir is supported by a National New Investigator Award from the Heart and Stroke Foundation of Canada. Ms Peck is funded by the Queen Elizabeth II/Heart and Stroke Foundation of Ontario Graduate Scholarships in Science and Technology at the University of Toronto. Dr Sabiston is supported by the Canada Research Chair Program. Dr Oh is supported by the GoodLife Fitness Chair in Cardiovascular Disease Prevention and Rehabilitation at the University Health Network. Dr Thavendiranathan has received speaker honoraria from Amgen, Boehringer Ingelheim, and Takeda. Dr Amir has received fees for expert testimony from Genentech/Roche. The University Health Network has a Master Research Agreement with Siemens Healthineers. Dr Abdel-Qadir has received honoraria from Amgen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Cardiac rehabilitation (CR) is endorsed to improve cardiovascular outcomes in cancer survivors. The quality of CR-based research in oncology has not been assessed., Objectives: The aim of this study was to evaluate the quality of reporting and evidence from CR-based intervention studies in oncology and to explore associations between intervention participation and outcomes., Methods: Systematic searches of 5 databases were conducted (January 2020) and updated (September 2021). Randomized and nonrandomized studies evaluating CR-based interventions in adult cancer survivors during and after treatment were eligible. Independent reviewers extracted data using 2 reporting guidelines (Template for Intervention Description and Replication and Consolidated Standards for Reporting Trials Harms extension), risk of bias (ROB) assessment tools (Cochrane ROB 2.0 and Cochrane Risk of Bias in Non-Randomized Studies of Interventions), and a combined inventory (Tool for the Assessment of Study Quality and reporting in Exercise). A meta-analysis was used to explore pre-intervention/post-intervention differences for commonly assessed outcomes., Results: Ten studies involving data from 685 survivors were included. The mean quality scores for intervention reporting (Template for Intervention Description and Replication) and harms (Consolidated Standards for Reporting Trials Harms extension) were 62% and 17%, respectively. There was moderate-to-high ROB across nonrandomized (Cochrane Risk of Bias in Non-Randomized Studies of Interventions score: 25%) and randomized (ROB 2.0 score: 50%) studies. The mean standardized cardiorespiratory fitness was higher (0.42; 95% CI: 0.27-0.57), fatigue was lower (-0.45; 95% CI: -0.55 to -0.34), and percent body fat (0.07; 95% CI: -0.23 to 0.38) was not different in survivors completing CR compared with those not completing CR., Conclusions: CR-based studies in oncology have low-to-moderate reporting quality and moderate-to-high ROB limiting interpretation, reproducibility, and translation of this evidence into practice., Competing Interests: Drs Abdel-Qadir, Thavendiranathan, Oh, Sabiston and Adams are supported by grants from the Canadian Cancer Society and the Canadian Institutes of Health Research (706710), the Heart and Stroke Foundation, Peter Munk Cardiac Centre Innovation Fund, and the MSH UHN AMO Innovation Fund. Drs Sabiston and Thavendiranathan are supported by the Canada Research Chair program. Dr Abdel-Qadir is supported by a National New Investigator Award (Heart and Stroke Foundation of Canada). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Crown Copyright © 2022 Published by Elsevier on behalf of the American College of Cardiology Foundation.)

Background: A simplified Canadian definition was recently developed to enable identification of individuals with familial hypercholesterolemia (FH) and severe hypercholesterolemia in the general population. Our objective was to use a modified version of this new definition to assess contemporary disease prevalence, treatment patterns, and low-density lipoprotein cholesterol (LDL-C) control in Ontario, Canada., Methods: We identified individuals aged 66 to 105 years who were alive as of January 1, 2011, using the Ca rdiovascular He alth in A mbulatory Care R esearch T eam (CANHEART) database, which was created by linking 19 population-based health databases in Ontario. Hypercholesterolemia was identified using LDL-C values. Cholesterol reduction and lipid-lowering treatment were assessed at time of diagnosis and after at least 2 and 5 years' follow-up., Results: Among 922,464 individuals, 2440 (0.26%) met criteria for definite or probable FH, and 72,893 (7.90%) for severe hypercholesterolemia. At diagnosis, mean LDL-C concentration was 9.52 mmol/L for those with definite FH, 5.83 mmol/L for those with probable FH, 5.73 mmol/L for those with severe hypercholesterolemia, and 3.33 mmol/L for all other individuals. After > 5 years, LDL-C concentration remained elevated at 3.58 mmol/L for those with definite FH, 2.72 mmol/L for those with probable FH, and 2.93 mmol/L for those with severe hypercholesteremia. Use of statin therapy was initially high (83% of those with definite FH, 78% of those with probable FH, 62% of those with severe hypercholesterolemia); however, fewer patients remained on statins at follow-up at > 5 years (62% of those with definite FH, 67% of those with probable FH, 58% of those with severe hypercholesterolemia)., Conclusions: Among older Ontarians, we estimated that 1 in 378 individuals had FH, and 1 in 13 had severe hypercholesterolemia. Despite being at substantially increased cardiovascular risk, these patients acheived suboptimal LDL-C level control and fewer were on medical therapy at follow-up., (© 2022 The Authors.)

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular disease (CVD) risk factor in individuals without acute myeloid leukemia (AML)., Objectives: The aim of this study was to examine the association between mutations associated with CHIP (CHIP-related mutations) identified in patients at AML diagnosis and the risk for cardiovascular events (CVEs)., Methods: This was a retrospective cohort study of 623 patients with AML treated between 2015 and 2018 who underwent DNA analysis. Cause-specific hazard regression models were used to study the associations between pathogenic mutations in common CHIP-related genes ( DNMT3A , TET2 , ASXL1 , JAK2 , TP53 , SRSF2 , and SF3B1 ) and the rate of CVEs (heart failure hospitalization, acute coronary syndrome, coronary artery revascularization, ischemic stroke, venous thromboembolism, and CVD death) and between CVE development and all-cause mortality., Results: Patients were 64.6 ± 15.3 years of age, 265 (42.5%) were women, and 63% had at least 1 CHIP-related mutation. Those with CHIP-related mutations were older (69.2 ± 12.3 vs 56.6 ± 16.6 years; P  < 0.001) and had a greater prevalence of CVD risk factors and CVD history. In adjusted analysis, the presence of any CHIP-related mutation was associated with a higher rate of CVEs (HR: 1.74; 95% CI: 1.03-2.93; P  = 0.037) among intensively treated patients (anthracycline based) but not the whole cohort (HR: 1.26; 95% CI: 0.81-1.97; P  = 0.31). TP53 (HR: 4.18; 95% CI: 2.07-8.47; P < 0.001) and ASXL1 (HR: 2.37; 95% CI: 1.21-4.63; P  = 0.012) mutations were associated with CVEs among intensively treated patients. Interval development of CVEs was associated with all-cause mortality (HR: 1.99; 95% CI: 1.45-2.73; P  < 0.001)., Conclusions: Among patients with AML treated with intensive chemotherapy, mutations in CHIP-related genes were associated with an increased risk for developing incident CVEs after AML diagnosis., Competing Interests: This study was supported by the Ontario Early Research Award. Dr Calvillo-Argüelles is supported by the Hold ’em for Life Oncology Clinician Scientist Award at the University of Toronto’s Faculty of Medicine. Dr Thavendiranathan is supported by the Canadian Institutes of Health Research New Investigator Award (147814) and a Canada Research Chair in Cardio-Oncology. Dr Abdel-Qadir is supported by a National New Investigator Award from the Heart and Stroke Foundation of Canada. Dr Schimmer is supported by the Canadian Institutes of Health Research, the Canadian Cancer Society, and the Ontario Institute of Cancer Research with funding provided by the Ontario Ministry of Research and Innovation, the Princess Margaret Cancer Centre Foundation, and the Ministry of Long Term Health and Planning in the Province of Ontario; and holds the Ronald N. Buick Chair in Oncology Research. Dr Natarajan is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148050, R01HL151283, and R01HL148565) and Fondation Leducq (TNE-18CVD04). Dr Thavendiranathan has received honoraria from BI, Takeda, and Amgen. Dr. Schuh has received honoraria from Takeda, Novartis, Jazz, and Otsuka Pharmaceuticals; has received research support from Medivir and Takeda; and owns stock in AbbVie Pharmaceuticals. Dr. Schimmer is named as an inventor on patent applications related to the use of double-negative T cells in AML and cancer. Dr Gupta has received honoraria from Novartis, Bristol Myers Squibb Celgene, Pfizer, and Sierra Oncology. Dr Abdel-Qadir has received honoraria from Amgen. Dr Yee has received honoraria from Celgene/Bristol Myers Squibb, Roche, Takeda, Pfizer, TaiHo and Novartis; and has received research funding from Astex, Forma Therapeutics, Jazz, Janssen, Onconova, Medimmune, Genenetch, and Tolero Pharmaceuticals. Dr Natarajan has received grant support from Amgen, AstraZeneca, Boston Scientific, Apple, and Novartis; has received personal fees from AstraZeneca, Apple, Genentech, Novartis, Blackstone Life Sciences, and Foresite Labs; and reports spousal employment at Vertex, all unrelated to the present work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Cardiorespiratory fitness (CRF) is reduced in cancer survivors and predicts cardiovascular disease (CVD)-related and all-cause mortality. However, routine measurement of CRF is not always feasible., Objectives: The purpose of this study was to identify clinical, cardiac biomarker, and imaging measures associated with reduced peak oxygen consumption (VO 2 peak) (measure of CRF) early post-breast cancer therapy to help inform CVD risk., Methods: Consecutive women with early-stage HER2+ breast cancer receiving anthracyclines and trastuzumab were recruited prospectively. Within 6 ± 2 weeks of trastuzumab completion, we collected clinical information, systolic/diastolic echocardiographic measures, high-sensitivity troponin I, B-type natriuretic peptide, and VO 2 peak using a cycle ergometer. Regression models were used to examine the association between VO 2 peak and clinical, imaging, and cardiac biomarkers individually and in combination., Results: Among 147 patients (age 52.2 ± 9.3 years), the mean VO 2 peak was 19.1 ± 5.0 mL O 2 ·kg -1 ·min -1 (84.2% ± 18.7% of predicted); 44% had a VO 2 peak below threshold for functional independence (<18 mL O 2 ·kg -1 ·min -1 ). In multivariable analysis, absolute global longitudinal strain (GLS) (β = 0.58; P = 0.007), age per 10 years (β: -1.61; P = 0.001), and E/e' (measure of diastolic filling pressures) (β = -0.45; P = 0.038) were associated with VO 2 peak. GLS added incremental value in explaining the variability in VO 2 peak. The combination of age ≥50 years, E/e' ≥7.8, and GLS <18% identified a high probability (85.7%) of compromised functional independence, whereas age <50 years, E/e' <7.8, and GLS ≥18% identified a low probability (0%). High-sensitivity troponin I and B-type natriuretic peptide were not associated with VO 2 peak., Conclusions: Readily available clinical measures were associated with VO 2 peak early post-breast cancer therapy. A combination of these parameters had good discrimination to identify patients with compromised functional independence and potentially increased future CVD risk., Competing Interests: This study was funded by an operating grant from the Canadian Institutes of Health Research (137132 and 142456); a Project Grant (1119955) from the National Health and Medical Research Council, Australia; an unrestricted grant from General Electric Healthcare; and personnel support from the Ontario Early Research Award. Dr Bonsignore is supported by the Canadian Institute of Health Research Fredrich Banting Doctoral Award. Dr Amir has received fees for expert testimony from Genentech/Roche. Dr Abdel-Qadir is supported by a National New Investigator Award from the Heart and Stroke Foundation of Canada; and has received honoraria from Amgen. Dr Wintersperger has received research support and speaker honorarium from Siemens Healthineers; and provides consultation to Bayer AG. Dr Haykowsky is funded by the Research Chair in Aging and Quality of life in the Faculty of Nursing at University of Alberta. Dr Thavendiranathan is supported by the Canadian Institutes of Health Research New Investigator Award (147814) and a Canada Research Chair in Cardio-oncology; and has received speaker honoraria from Amgen, Boehringer Ingelheim, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: The Bruton's Tyrosine Kinase Inhibitor ibrutinib is associated with ventricular arrhythmia (VA) and sudden death. However, the pro-arrhythmic electrophysiological dysregulation that results from ibrutinib with age and cardiovascular disease is unknown., Objectives: This study sought to investigate the acute effects of ibrutinib on left ventricular (LV) VA vulnerability, cytosolic calcium dynamics, and membrane electrophysiology in old and young spontaneous hypertensive rats (SHRs)., Methods: Langendorff-perfused hearts of young (10 to 14 weeks) and old (10 to 14 months) SHRs were treated with ibrutinib (0.1 μmol/l) or vehicle for 30 min. Simultaneously, LV epicardial action potential and cytosolic calcium transients were optically mapped following an incremental pacing protocol. Calcium and action potential dynamics parameters were analyzed. VA vulnerability was assessed by electrically inducing ventricular fibrillations (VFs) in each heart. Western blot analysis was performed on LV tissues., Results: Ibrutinib treatment resulted in higher vulnerability to VF in old SHR hearts (27.5 ± 7.5% vs. 5.7 ± 3.7%; p = 0.026) but not in young SHR hearts (8.0 ± 4.9% vs. 0%; p = 0.193). In old SHR hearts, following ibrutinib treatment, action potential duration (APD) alternans (p = 0.008) and APD alternans spatial discordance (p = 0.027) were more prominent. Moreover, calcium transient duration 50 was longer (p = 0.032), calcium amplitude alternans ratio was significantly lower (p = 0.001), and time-to-peak of calcium amplitude was shorter (p = 0.037). In young SHR hearts, there were no differences in calcium and APD dynamics., Conclusions: Ibrutinib-induced VA is associated with old age in SHR. Acute dysregulation of calcium and repolarization dynamics play important roles in ibrutinib-induced VF., Competing Interests: This study was supported by the generous contributions of the Crispino family and the Hang Tough Initiative. Dr. Nanthakumar is a consultant for Servier, Biosense Webster, Abbott, and BlueRock Therapeutics. Dr. Nanthakumar is a recipient of a Mid-Career Investigator Award from the Heart & Stroke Foundation of Ontario. Dr. Thavendiranathan (147814) is supported by the Canadian Institutes of Health Research New Investigator Award and a Canada Research Chair in Cardio-oncology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2020 The Authors.)