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Background: Cardiovascular disease (CVD) is associated with higher rates of incident cancer. Data are scarce regarding the association of incident CVD with oncologic outcomes after a cancer diagnosis., Objectives: This study sought to determine whether incident myocardial infarction (MI) or heart failure (HF) in breast cancer survivors is associated with oncologic outcomes., Methods: This was a population-based cohort study in Ontario, Canada, using linked administrative data sets of women diagnosed with first breast cancer between April 1, 2007, and March 31, 2015. A landmark analysis was conducted of women alive 2 years after breast cancer diagnosis, aged ≥40 years, and with available staging data and without recurrent/distant disease or preceding CVD. The exposure was a composite of MI and/or HF after the landmark date. The outcomes were cancer mortality, new non-breast malignancy diagnosis, and new chemotherapy initiation. Multivariable cause-specific hazards regression was used to determine the association of incident MI/HF (time-varying exposure) with outcomes., Results: A total of 30,694 women (median age of 60 years) were included, of whom 1,346 developed incident MI/HF at a median of 3.9 years after the landmark date. At 5 years, the cumulative incidence was 5.9% (95% CI: 5.6%-6.1%) for cancer death, 4.3% (95% CI: 4.1%-4.6%) for non-breast malignancy, and 25.7% (95% CI: 25.2%-26.2%) for new chemotherapy. Incident MI/HF was associated with a higher hazard of cancer death (HR: 3.94; 95% CI: 3.38-4.59), non-breast malignancy (HR: 1.39; 95% CI: 1.06-1.82), and new chemotherapy (HR: 1.25; 95% CI: 1.02-1.53)., Conclusions: Incident MI and/or HF after breast cancer treatment are associated with higher hazards of adverse oncologic outcomes, highlighting the need to prioritize care for these patients., Competing Interests: This work was funded by the Ted Rogers Program in Cardiotoxicity Prevention and the Early Career Women’s Heart and Brain Health Chair (from the Heart and Stroke Foundation of Canada and Canadian Institutes of Health Research) to Dr Abdel-Qadir. Dr Abdel-Qadir was funded by the National New Investigator Award from the Heart and Stroke Foundation of Canada. Dr Thavendiranathan (147814) was supported by a Canada Research Chair in Cardiooncology (CRC-2019-00097) and the Canadian Cancer Society/Canadian Institutes of Health Research’s W. David Hargraft Grant. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). This document used data adapted from the Statistics Canada Postal CodeOM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, which contains data copied under license from Canada Post Corporation and Statistics Canada. Parts of this material are based on data and/or information compiled and provided by the MOH, CIHI, and OH. Parts of this report are based on Ontario Registrar General (ORG) information on deaths, the original source of which is ServiceOntario. The views expressed therein are those of the author and do not necessarily reflect those of ORG or the Ministry of Public and Business Service Delivery. 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; no endorsement is intended or should be inferred. Dr Thavendiranathan has received consultation and speaker honoraria from Amgen, Boehringer Ingelheim, General Electric, and Takeda. Dr Amir has received honoraria from Sandoz and Seagen; and has provided consulting to AstraZeneca and Novartis. Dr Lee is the Ted Rogers Chair in Heart Function Outcomes, University Health Network, University of Toronto. Dr Abdel-Qadir has received consultation and speaker honoraria from Amgen, AstraZeneca and Jazz Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Novel risk stratification and non-invasive surveillance methods are needed in orthotopic heart transplant (OHT) to reduce morbidity and mortality post-transplant. Clonal hematopoiesis (CH) refers to the acquisition of specific gene mutations in hematopoietic stem cells linked to enhanced inflammation and worse cardiovascular outcomes. The purpose of this study was to investigate the association between CH and OHT. Blood samples were collected from 127 OHT recipients. Error-corrected sequencing was used to detect CH-associated mutations. We evaluated the association between CH and acute cellular rejection, CMV infection, cardiac allograft vasculopathy (CAV), malignancies, and survival. CH mutations were detected in 26 (20.5%) patients, mostly in DNMT3A, ASXL1, and TET2. Patients with CH showed a higher frequency of CAV grade 2 or 3 (0% vs. 18%, p < .001). Moreover, a higher mortality rate was observed in patients with CH (11 [42%] vs. 15 [15%], p = .008) with an adjusted hazard ratio of 2.9 (95% CI, 1.4-6.3; p = .003). CH was not associated with acute cellular rejection, CMV infection or malignancies. The prevalence of CH in OHT recipients is higher than previously reported for the general population of the same age group, with an associated higher prevalence of CAV and mortality., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Echocardiographic global longitudinal strain (GLS) is a useful measure for detection of cancer treatment-related cardiac dysfunction (CTRCD) but is influenced by blood pressure changes. This limitation may be overcome by assessment of myocardial work (MW), which incorporates blood pressure into the calculation., Objectives: This work aims to determine whether myocardial work indices (MWIs) can help diagnose or prognosticate CTRCD., Methods: In this prospective cohort study, 136 women undergoing anthracycline and trastuzumab treatment for HER2+ breast cancer, underwent serial echocardiograms and cardiac magnetic resonance pre- and post-anthracycline and every 3 months during trastuzumab. GLS, global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency were measured. CTRCD was defined with cardiac magnetic resonance. Generalized estimating equations quantified the association between changes in GLS and MWIs and CTRCD at the current (diagnosis) and subsequent visit (prognosis). Regression tree analysis was used to explore the combined use of GLS and MW for the diagnostic/prognostic assessment of CTRCD., Results: Baseline left ventricular ejection fraction (LVEF) was 63.2 ± 4.0%. Thirty-seven (27.2%) patients developed CTRCD. An absolute change in GLS (standardized odds ratio [sOR]: 1.97 [95% CI: 1.07-3.66]; P = 0.031) and GWI (sOR: 1.73 [95% CI: 1.04-2.85]; P = 0.033) were associated with concurrent CTRCD. An absolute change in GLS (sOR: 1.79 [95% CI: 1.22-2.62]; P = 0.003), GWI (sOR: 1.67 [95% CI: 1.20-2.32]; P = 0.003), and GCW (sOR: 1.65 [95% CI: 1.17-2.34]; P = 0.005) were associated with subsequent CTRCD. Change in GWI and GCW demonstrated incremental value over GLS and clinical factors for the diagnosis of concurrent CTRCD. In a small group with a GLS change <3.3% (absolute), and a >21 mm Hg reduction in systolic blood pressure, worsening of GWI identified patients with higher probability of concurrent CTRCD (24.0% vs 5.2%). MWIs did not improve identification of subsequent CTRCD beyond knowledge of GLS change., Conclusions: GLS can be used to diagnose and prognosticate cardiac magnetic resonance (CMR) defined CTRCD, with additional value from MWIs in selected cases. (Evaluation of Myocardial Changes During Breast Adenocarcinoma Therapy to Detect Cardiotoxicity Earlier With MRI [EMBRACE-MRI]; NCT02306538)., Competing Interests: Funding Support and Author Disclosures 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. University Health Network has a Master Research Agreement with Siemens Healthineers. Dr Amir has received fees for expert testimony from Genentech/Roche; and has received honoraria from Amgen. Dr Abdel-Qadir has received support from a National New Investigator Award from the Heart and Stroke Foundation of Canada. Dr Marwick has been supported in part by a Project Grant (1119955) from the National Health and Medical Research Council, Canberra, Australia; and has received an unrestricted grant from General Electric Healthcare, Horten, Norway, for the support of the SUCCOUR trial. Dr Thavendiranathan (147814) has been supported by the Canadian Institutes of Health Research New Investigator Award and a Canada Research Chair in Cardio-oncology; and has received speaker honorarium from Amgen, Boehringer Ingelheim, and Takeda. Dr Wintersperger has received research support and speaker honorarium from Siemens Healthineers; and provides consultation to Bayer AG., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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.)

Cancer-therapeutics-related cardiac dysfunction (CTRCD) is an important concern in women receiving trastuzumab therapy for HER2+ breast cancer. However, the ability to assess CTRCD risk remains limited. In this retrospective cohort study, we apply three published risk prediction models (Ezaz et al., NSABP-31 cardiac risk scores (CRS), and HFA-ICOS trastuzumab proforma) to 629 women (mean age 52.4 ± 10.9 years) with Stage I-III HER2+ breast cancer treated with trastuzumab ± anthracyclines to assess their performance to identify CTRCD during or immediately post treatment. Using these models, patients were classified into CTRCD risk categories according to the pre-treatment characteristics. With NSABP-31 CRS and HFA-ICOS proformas, patients in the highest risk category had a 1.7-to-2.4-fold higher relative risk of CTRCD than the low-risk category ( p = 0.010 and 0.005, respectively). However, with all three risk models, those in the low-risk category had a high absolute risk of CTRCD (15.5-25.5%). The discrimination of the models for CTRCD (AUC 0.51-0.60) and their calibration was limited. NSAP-31 CRS and HFA-ICOS proformas can identify relative differences in CTRCD risk between patients, but when considering absolute risk, they are only able to identify the highest risk patients. There remains an ongoing need for accurate CTRCD risk prediction models in women with HER2+ breast cancer.

Background: Immune checkpoint inhibitors (ICIs) have improved outcomes for many types of cancer. However, ICI therapies are associated with the development of myocarditis, an immune-mediated adverse event associated with a high mortality rate. Therefore, prompt diagnosis and early intervention are of outmost importance. There is limited data on the application of cardiovascular magnetic resonance (CMR)-based modified Lake Louise Criteria (mLLC) with the use of relaxometry techniques for the diagnosis of ICI myocarditis., Case Summary: Four cancer patients undergoing ICI treatment presented with various clinical symptoms and troponin elevation to emergency/ambulatory clinics within 10-21 days after ICI initiation. On the suspicion of possible ICI-related myocarditis all patients underwent CMR within a few days after admission. Applying mLLC including relaxometry techniques, all patients met 'non-ischaemic injury criteria', while 3/4 patients met 'oedema criteria'. In most patients, quantitative mapping revealed substantially increased T1 values, while T2 values were only mildly increased or normal. In two patients with follow-up, CMR demonstrated improvement in findings after immunosuppressive treatment. However, there was only limited agreement between the degree of high-sensitive troponin levels and T1/T2 levels., Discussion: The application of mLLC with T1/T2 mapping appears useful in the CMR diagnosis of acute ICI myocarditis with non-ischaemic myocardial injury criteria being the most common finding. The sensitivity of native T1 appears higher than T2 mapping in the acute diagnosis as well as in the assessment of treatment response. As troponin elevations may persist for some time with ICI myocarditis, CMR may represent an alternate strategy to monitor treatment response., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Ibrutinib reduces mortality in chronic lymphocytic leukemia (CLL). It increases the risk of atrial fibrillation (AF) and bleeding and there are concerns about heart failure (HF) and central nervous system ischemic events. The magnitude of these risks remains poorly quantified., Methods: Using linked administrative databases, we conducted a population-based cohort study of Ontario patients who were treated for CLL diagnosed between 2007 and 2019. We matched ibrutinib-treated patients with controls treated with chemotherapy but unexposed to ibrutinib on prior AF, age ≥ 66 years, anticoagulant exposure, and propensity for receiving ibrutinib. Study outcomes were AF-related health care contact, hospital-diagnosed bleeding, new diagnoses of HF, and hospitalizations for stroke and acute myocardial infarction (AMI). The cumulative incidence function was used to estimate absolute risks. We used cause-specific regression to study the association of ibrutinib with bleeding rates, while adjusting for anticoagulation as a time-varying covariate., Results: We matched 778 pairs of ibrutinib-treated and unexposed patients with CLL (N = 1,556). The 3-year incidence of AF-related health care contact was 22.7% (95% CI, 19.0 to 26.6) in ibrutinib-treated patients and 11.7% (95% CI, 9.0 to 14.8) in controls. The 3-year risk of hospital-diagnosed bleeding was 8.8% (95% CI, 6.5 to 11.7) in ibrutinib-treated patients and 3.1% (95% CI, 1.9 to 4.6) in controls. Ibrutinib-treated patients were more likely to start anticoagulation after the index date. After adjusting for anticoagulation as a time-varying covariate, ibrutinib remained positively associated with bleeding (HR, 2.58; 95% CI, 1.76 to 3.78). The 3-year risk of HF was 7.7% (95% CI, 5.4 to 10.6%) in ibrutinib-treated patients and 3.6% (95% CI, 2.2 to 5.4) in controls. There was no significant difference in the risk of ischemic stroke or AMI., Conclusion: Ibrutinib is associated with higher risk of AF, bleeding, and HF, but not AMI or stroke., Competing Interests: Husam Abdel-QadirEmployment: GlaxoSmithKline (I)Honoraria: Bausch Health (I), Valeant Pharmaceuticals International (I), Novartis (I), Janssen (I), ROC Skincare (I), Sanofi (I), Vivier (I)Consulting or Advisory Role: Bausch Health (I), LEO Pharma (I), Amgen Foundation (I), Procter & Gamble (I), Pfizer (I)Speakers' Bureau: Allergan (I), Biossance (I), Webber Naturals (I) Darryl LeongHonoraria: JanssenResearch Funding: Novartis Andrea PangResearch Funding: Everest Clinical Research Anca PricaHonoraria: AstraZeneca, Kite/GileadResearch Funding: Bristol Myers Squibb/Celgene Kumaraswamy NanthakumarConsulting or Advisory Role: Abbott Laboratories, BioSense WebsterResearch Funding: Abbott Laboratories, BioSense Webster Paaladinesh ThavendiranathanHonoraria: AmgenNo other potential conflicts of interest were reported.

Background: The prognosis of heart failure (HF) after early stage breast cancer (EBC) treatment with anthracyclines or trastuzumab is not well-characterized., Methods: Using administrative databases, women diagnosed with HF after receiving anthracyclines or trastuzumab for EBC in Ontario during 2007 to 2017 (the EBC-HF cohort) were categorized by cardiotoxic exposure (anthracycline alone, trastuzumab alone, sequential therapy with both agents) and matched on age with ≤3 cancer-free HF controls to compare baseline characteristics. To study prognosis after HF onset, we conducted a second match on age plus important HF prognostic factors. The cumulative incidence function was used to describe risk of hospitalization or emergency department visits (hospital presentations) for HF and cardiovascular death., Results: A total of 804 women with EBC developed HF after anthracyclines (n=312), trastuzumab (n=112), or sequential therapy (n=380); they had significantly fewer comorbidities than 2411 age-matched HF controls. After the second match, the anthracycline-HF cohort had a similar 5-year incidence of HF hospital presentations (16.5% [95% CI, 12.0%-21.7%]) as controls (17.1% [95% CI, 14.4%-20.1%]); the 5-year incidence was lower than matched controls for the trastuzumab-HF (9.7% [95% CI, 4.7%-16.9%]; controls 16.4% [95% CI, 12.1%-21.3%]; P =0.03) and sequential-HF cohorts (2.7% [95% CI, 1.4%-4.8%]; controls 10.8% [95% CI, 8.9%-13.0%]; P <0.001). At 5 years, the incidence of cardiovascular death was 2.9% (95% CI, 1.2%-5.9%) in the anthracycline-HF cohort vs. 9.5% (95% CI, 6.9%-12.6%) in controls, and 1.7% (0.6%-3.7%) for women developing HF after trastuzumab vs. 4.3% (95% CI, 3.1-5.8%) for controls., Conclusions: Women developing HF after cardiotoxic EBC chemotherapy have fewer comorbidities than cancer-free women with HF; trastuzumab-treated women who develop HF have better prognosis than matched HF controls.

Background Statins are hypothesized to reduce the risk of cardiotoxicity associated with anthracyclines and trastuzumab. Our aim was to study the association of statin exposure with hospitalization or emergency department visits (hospital presentations) for heart failure (HF) after anthracycline- and/or trastuzumab-containing chemotherapy for early breast cancer. Methods and Results Using linked administrative databases, we conducted a retrospective cohort study of women aged ≥66 years without prior HF who received anthracyclines or trastuzumab for newly diagnosed early breast cancer in Ontario between 2007 to 2017. Statin-exposed and unexposed women were matched 1:1 using propensity scores. Trastuzumab-treated women were also matched on anthracycline exposure. We matched 666 statin-discordant pairs of anthracycline-treated women and 390 pairs of trastuzumab-treated women (median age, 69 and 71 years, respectively). The 5-year cumulative incidence of HF hospital presentations after anthracyclines was 1.2% (95% CI, 0.5%-2.6%) in statin-exposed women and 2.9% (95% CI, 1.7%-4.6%) in unexposed women ( P value, 0.01). The cause-specific hazard ratio associated with statins in the anthracycline cohort was 0.45 (95% CI, 0.24-0.85; P value, 0.01). After trastuzumab, the 5-year cumulative incidence of HF hospital presentations was 2.7% (95% CI, 1.2%-5.2%) in statin-exposed women and 3.7% (95% CI, 2.0%-6.2%) in unexposed women ( P value 0.09). The cause-specific hazard ratio associated with statins in the trastuzumab cohort was 0.46 (95% CI, 0.20-1.07; P value, 0.07). Conclusions Statin-exposed women had a lower risk of HF hospital presentations after early breast cancer chemotherapy involving anthracyclines, with non-significant trends towards lower risk following trastuzumab. These findings support the development of randomized controlled trials of statins for prevention of cardiotoxicity.

Competing Interests: Intérêts concurrents: Aucun déclaré

Background: OSA conveys worse clinical outcomes in patients with coronary artery disease. The STOP-BANG score is a simple tool that evaluates the risk of OSA and can be added to the large number of clinical variables and scores that are obtained during the management of patients with myocardial infarction (MI). Currently, machine learning (ML) is able to select and integrate numerous variables to optimize prediction tasks., Research Question: Can the integration of STOP-BANG score with clinical data and scores through ML better identify patients who experienced an in-hospital cardiovascular event after acute MI?, Study Design and Methods: This is a prospective observational cohort study of 124 patients with acute MI of whom the STOP-BANG score classified 34 as low (27.4%), 30 as intermediate (24.2%), and 60 as high (48.4%) OSA-risk patients who were followed during hospitalization. ML implemented feature selection and integration across 47 variables (including STOP-BANG score, Killip class, GRACE score, and left ventricular ejection fraction) to identify those patients who experienced an in-hospital cardiovascular event (ie, death, ventricular arrhythmias, atrial fibrillation, recurrent angina, reinfarction, stroke, worsening heart failure, or cardiogenic shock) after definitive MI treatment. Receiver operating characteristic curves were used to compare ML performance against STOP-BANG score, Killip class, GRACE score, and left ventricular ejection fraction, independently., Results: There were an increasing proportion of cardiovascular events across the low, intermediate, and high OSA risk groups (P = .005). ML selected 7 accessible variables (ie, Killip class, leukocytes, GRACE score, c reactive protein, oxygen saturation, STOP-BANG score, and N-terminal prohormone of B-type natriuretic peptide); their integration outperformed all comparators (area under the curve, 0.83 [95% CI, 0.74-0.90]; P < .01)., Interpretation: The integration of the STOP-BANG score into clinical evaluation (considering Killip class, GRACE score, and simple laboratory values) of subjects who were admitted for an acute MI because of ML can significantly optimize the identification of patients who will experience an in-hospital cardiovascular event., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: There are limited data on the yield of routine cardiac imaging for trastuzumab-treated patients with breast cancer., Methods: We conducted a retrospective cohort study of patients with breast cancer treated with adjuvant trastuzumab between 2007 and 2012 at Princess Margaret Cancer Centre (Toronto, Canada). We classified imaging tests as clinically prompted or routinely ordered and determined whether each test led to changes in patient care. A generalized estimating equation model was used to determine if patient characteristics predicted routine studies more likely to change care. We analysed routine tests that were exclusively preceded by consecutive tests that did not change care to determine if their yield differed by time since trastuzumab start and the number of prior tests that did not change care., Results: We identified 448 patients who received 1735 cardiac imaging studies after trastuzumab initiation. Of 1555 routine tests, 44 led to changes in care (2.8%) for 43 patients, whereas 50 of 180 clinically prompted tests (27.8%) altered care in 29 patients (P-value < 0.001). Earlier stage cancer, diabetes, prior anthracyclines, and prior cardiovascular disease were associated with a higher likelihood of changes in care following routine tests (P-value < 0.05). Among routine tests that were exclusively preceded by consecutive tests that did not change care, tests ordered outside months 3-9 and those that followed ≥ 3 tests were even less likely to change care., Conclusions: Routine cardiac imaging tests rarely changed care for trastuzumab-treated patients with breast cancer, particularly among lower risk anthracycline-naïve women who had multiple prior tests that did not change care., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Despite the known risk of cardiotoxicity, anthracyclines are widely prescribed chemotherapeutic agents. They are broadly characterized as being a robust effector of cellular apoptosis in rapidly proliferating cells through its actions in the nucleus and formation of reactive oxygen species (ROS). And, despite the early use of dexrazoxane, no effective treatment strategy has emerged to prevent the development of cardiomyopathy, despite decades of study, suggesting that much more insight into the underlying mechanism of the development of cardiomyopathy is needed. In this review, we detail the specific intracellular activities of anthracyclines, from the cell membrane to the sarcoplasmic reticulum, and highlight potential therapeutic windows that represent the forefront of research into the underlying causes of anthracycline-induced cardiomyopathy., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Competing Interests: Competing interests: None declared.

Prolonged trastuzumab therapy is the standard of care for women with metastatic HER2 positive (HER2+) breast cancer. There are limited data on the incidence of cardiotoxicity, its treatment implication, and cardiac care in these patients. We retrospectively identified consecutive women who received >12 months of trastuzumab treatment at Princess Margaret Cancer Centre (Toronto, ON) from 2007 to 2012 for metastatic HER2 positive breast cancer and followed them until death or August 2018. Patients were included if a pretherapy multigated acquisition scan and ≥2 subsequent follow-up scans were available. The Cardiac Review and Evaluation Committee Criteria were used to identify cardiotoxicity. Baseline characteristics and outcomes (final left ventricular ejection fraction, change in LVEF, trastuzumab interruption) were compared in patients with and without cardiotoxicity. Cardiac care and treatment received were recorded. Sixty patients (mean age 52 ± 10.4 years) were included. The median trastuzumab exposure was 37 cycles (interquartile range 23 to 56) over 28 months (interquartile range 19 to 49) and 48% received previous anthracycline therapy. The cumulative incidence of cardiotoxicity was 35% (95% CI 23 to 48) at 3 years. Patients who developed cardiotoxicity were more likely to receive third-line cancer treatments and had lower final LVEF than patients without (54.9% ± 6.3% vs 64% ± 4.9%, p <0.001). Of the 23 patients with cardiotoxicity, 10 (43%) had trastuzumab interrupted for at least 1 cycle, only 7 (30%) patients were seen by a cardiologist and 4 (17%) received cardiac medications. In conclusion, patients with metastatic breast cancer receiving prolonged trastuzumab therapy appear to have high rates of cardiotoxicity. This was associated with high rates of trastuzumab interruption, but low rates of cardiology referral and cardiac treatment, reflecting a potential cardiac care gap., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Coronavirus Disease 2019 (COVID-19) has been associated with cardiovascular complications, including acute cardiac injury, heart failure, and cardiogenic shock (CS). The role of venoarterial extracorporeal membrane oxygenation (VA-ECMO) in the event of COVID-19-associated cardiovascular collapse has not been established. We reviewed the existing literature surrounding the role of VA-ECMO in the treatment of coronavirus-related cardiovascular collapse. COVID-19 is associated with a higher incidence of cardiovascular complications compared with previous coronavirus outbreaks (Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus). We found only 1 case report from China in which COVID-19-associated fulminant myocarditis and CS were successfully rescued using VA-ECMO as a bridge to recovery. We identified potential clinical scenarios (cardiac injury, myocardial infarction with and without obstructive coronary artery disease, viral myocarditis, and decompensated heart failure) leading to CS and risk factors for poor/uncertain benefit (age, sepsis, mixed/predominantly vasodilatory shock, prothrombotic state or coagulopathy, severe acute respiratory distress syndrome, multiorgan failure, or high-risk prognostic scores) specific to using VA-ECMO as a bridge to recovery in COVID-19 infection. Additional considerations and proposed recommendations specific to the COVID-19 pandemic were formulated with guidance from published data and expert consensus. A small subset of patients with cardiovascular complications from COVID-19 infection may progress to refractory CS. While accepting that resource scarcity may be the overwhelming concern for healthcare systems during this pandemic, VA-ECMO can be considered in highly selected cases of refractory CS and echocardiographic evidence of biventricular failure. The decision to initiate this therapy should take into consideration the availability of resources, perceived benefit, and risks of transmitting disease., (© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.)

Objectives: This study sought to evaluate the potential clinical impact of using 3-dimensional echocardiography (3DE) to measure left ventricular ejection fraction (LVEF) in patients considered for implantable cardioverter-defibrillator (ICD) implantation and to assess the predictive value of 3DE LVEF for arrhythmic events., Background: ICD therapy is currently recommended to prevent sudden cardiac death in patients with symptomatic heart failure and LVEF ≤35%, and in asymptomatic patients with ischemic heart disease and LVEF ≤30%. Two-dimensional echocardiography (2DE) is currently used to calculate LVEF. However, 3DE has been reported to be more reproducible and accurate than 2DE to measure LVEF., Methods: The study prospectively enrolled 172 patients with LV dysfunction (71% ischemic). Both 2DE and 3DE LVEF were obtained during the same study. The outcome was the occurrence of major arrhythmic events (sudden cardiac death, aborted cardiac arrest, appropriate ICD therapy)., Results: After a median follow up of 56 (range 18 to 65) months, major arrhythmic events occurred in 30% of the patients. Compared with 2DE, 3DE changed the assignment above or below the LVEF thresholds for ICD implantation in 20% of patients, most of them having 2DE LVEFs within ± 10% from threshold. By cause-specific hazard model, 3DE LVEF was the only independent predictor of the occurrence of major arrhythmic events., Conclusions: LVEF by 3DE was an independent predictor of major arrhythmic events and improved arrhythmic risk prediction in patients with LV dysfunction. When compared with 2DE LVEF, 3DE measurement of LVEF may change the decision to implant an ICD in a sizable number of patients., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Importance: Clonal hematopoiesis (CH) has been recently described as a novel driver for cancer and cardiovascular disease (CVD). Clonal hematopoiesis is a common, age-associated disorder marked by expansion of hematopoietic clones carrying recurrent somatic mutations. Current literature suggests that patients with CH have a higher risk of subsequent hematological malignant conditions and mortality attributable to excess CVD. This review discusses the association of cancer with CVD with CH as a potential unifying factor., Observations: The prevalence of CH varies based on the sequencing depth, diagnostic criteria, and patient age and ranges from less than 1% in those younger than 40 years to more than 15% to 20% in those 90 years and older. Clonal hematopoiesis is associated with a 0.5% to 1.0% absolute annual risk of hematological malignant condition and a 2-fold to 4-fold higher risk of coronary artery disease, stroke, and CVD deaths, independent of traditional cardiovascular risk factors. In fact, CH appears to have a relative risk similar to that of traditional cardiovascular risk factors for CVD. Experimental studies suggest that the link between CVD and CH is causal, with inflammation as 1 potential mechanism. There may be also a link between CH and CVD in survivors of cancer; however, data to support this association are currently limited., Conclusions and Relevance: Clonal hematopoiesis represents a premalignant state, with carriers having an increased risk of hematological malignant conditions. Although most carriers will not develop a malignant condition, CH confers an increased risk of CVD, possibly via inflammation. Clonal hematopoiesis may also contribute to CVD in survivors of cancer, although this hypothesis requires validation. Clinically, as advanced sequencing techniques become available, CH may pave the way for precision medicine in the field of cardio-oncology.

Background: Statins can reduce the risk of anthracycline-induced cardiotoxicity. Whether such cardioprotective effects can be seen in trastuzumab-treated patients has not been explored., Methods: Consecutive women with HER2+ breast cancer who received trastuzumab with or without anthracyclines were identified retrospectively. Patients receiving statins before and during cancer treatment were matched with 2 patients of the same age (± 2 years) and anthracycline exposure status but without statin treatment. The primary outcome was final left ventricular ejection fraction (LVEF). Analysis of covariance (ANCOVA) was used to assess the relationship between statin exposure and the final LVEF. A logistic regression model was constructed to assess the relationship between statin exposure and cardiotoxicity (secondary outcome)., Results: Included were 129 patients (62 ± 9 years). Forty-three received statins during cancer treatment. The median trastuzumab exposure time was 11.8 (interquartile range [IQR] 11 to 12) months. Seventy-two (56%) patients received anthracyclines. Compared with controls, patients treated with statins were more likely to have diabetes (37.2% vs 4.7%, P < 0.001), hypertension (58.1% vs 22.1%, P < 0.001), and coronary artery disease (11.6% vs 2.3%, P = 0.04). Within a median cardiac follow-up duration of 11 (IQR 9 to 18) months, the adjusted final LVEF was lower in the control group (61.2% vs 64.6%, P = 0.034). A significant change in LVEF was observed in the control group (median -6%, IQR -10% to -1% P < 0.001) but not in the statin group (median 0%, IQR -5% to +3%, P = 0.27). Upon adjusted analysis, statin treatment was independently associated with a lower risk of cardiotoxicity (odds ratio [OR] 0.32, 95% confidence interval [CI], 0.10-0.99, P = 0.049)., Conclusions: In women with HER2+ breast cancer receiving trastuzumab-based therapy with or without anthracyclines, concomitant use of statins was associated with a lower risk of cardiotoxicity., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)