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Proteasome inhibitors (PIs) are the backbone of combination treatments for patients with multiple myeloma and AL amyloidosis, while also indicated in Waldenström's macroglobulinemia and other malignancies. PIs act on proteasome peptidases, causing proteome instability due to accumulating aggregated, unfolded, and/or damaged polypeptides; sustained proteome instability then induces cell cycle arrest and/or apoptosis. Carfilzomib, an intravenous irreversible PI, exhibits a more severe cardiovascular toxicity profile as compared with the orally administered ixazomib or intravenous reversible PI such as bortezomib. Cardiovascular toxicity includes heart failure, hypertension, arrhythmias, and acute coronary syndromes. Because PIs are critical components of the treatment of hematological malignancies and amyloidosis, managing their cardiovascular toxicity involves identifying patients at risk, diagnosing toxicity early at the preclinical level, and offering cardioprotection if needed. Future research is required to elucidate underlying mechanisms, improve risk stratification, define the optimal management strategy, and develop new PIs with safe cardiovascular profiles., Competing Interests: Dr Janssen has been a consultant for Pfizer, Genesis Pharma, Amgen, and Takeda; has received research funding from Pfizer and Amgen; and has received honoraria and other paid expenses from Pfizer, Genesis Pharma, Amgen, and Takeda. Dr Dimopoulos has been a consultant, served on advisory boards, and has received personal fees/honoraria from BMS, Celgene, Takeda, Janssen, and Amgen; has received research funding from Takeda, Janssen, and Amgen; and has served on speakers bureaus for Celgene, Takeda, Janssen, and Amgen. Dr Stamatelopoulos has been a consultant for and received research funding and honoraria from Amgen. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Inflammation is a key determinant of cardiovascular outcomes, but its role in heart failure is uncertain. In patients with cardiometabolic disease enrolled in the prospective, multicenter ancillary study of CIRT (Cardiovascular Inflammation Reduction Trial), CIRT-CFR (Coronary Flow Reserve to Assess Cardiovascular Inflammation), impaired coronary flow reserve was independently associated with increased inflammation and myocardial strain despite well-controlled lipid, glycemic, and hemodynamic profiles. Inflammation modified the relationship between CFR and myocardial strain, disrupting the association between cardiac blood flow and function. Future studies are needed to investigate whether an early inflammation-mediated reduction in CFR capturing microvascular ischemia may lead to heart failure in patients with cardiometabolic disease. (Cardiovascular Inflammation Reduction Trial [CIRT]; NCT01594333; Coronary Flow Reserve to Assess Cardiovascular Inflammation [CIRT-CFR]; NCT02786134)., Competing Interests: This research was supported by National Institutes of Health (NIH) R01HL132021 (to Drs Di Carli and Taqueti) and K23HL135438 (to Dr Taqueti). Dr Shah was supported by NIH R01HL135008, R01HL143224, R01HL150342, R01HL14818, and K24HL152008. Dr Libby was supported by R01HL134892. Dr Shah has received research support from Novartis; and consulting fees from Philips Ultrasound and Edwards Lifesciences. Dr Dorbala has received research support from Pfizer, GE Healthcare, and Attralus; and consulting honoraria from Pfizer and GE Healthcare. Dr Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research; has received research support from TD Bank, AusculSciences, Siemens Healthineers, and Artrya; and has equity interest in General Electric. Dr Hage has received grant support from GE Healthcare, Novartis, and Idorsia Pharmaceuticals. Dr Beanlands holds the Chair in Cardiology at the University of Ottawa Heart Institute; is a University of Ottawa Distinguished Research Chair in Cardiovascular Imaging; and is a consultant for and has received grant funding from GE Healthcare, Lantheus Medical Imaging, and Jubilant DraxImage. Dr Libby is an unpaid consultant to or involved in clinical trials for Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Novartis, Pfizer, Sanofi-Regeneron; is on the Scientific Advisory Board for Amgen, Caristo, Cartesian, Corvidia Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, and XBiotech, Inc; is on the Board of Directors and has a financial interest in XBiotech, Inc; and has received research funding from Novartis, the American Heart Association, the RRM Charitable Fund, and the Simard Fund. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 Published by Elsevier on behalf of the American College of Cardiology Foundation.)

Background: Immune checkpoint inhibitors (ICIs) are a central part of cancer therapy; however, cardiac complications, such as myocarditis, have the potential for significant morbidity and mortality. Within this population, the clinical significance of longitudinal strain (LS) remains unknown., Objectives: This study sought to define the changes in LS in ICI-treated patients, and their associations with high-sensitivity troponin I (hsTnI) and myocarditis., Methods: We conducted a retrospective cohort study of patients who received ICIs at our hospital from April 2017 to September 2021. All patients underwent echocardiography and blood sampling at standardized time intervals. We measured the changes in global and regional LS before and after ICI administration. Age- and sex-adjusted Cox regression analysis was used to evaluate the association between LS and elevations in hsTnI and myocarditis., Results: In a cohort of 129 patients with a median follow-up period of 170 (IQR: 62-365) days; 6 and 18 patients had myocarditis and hsTnI elevation, respectively. In an age- and sex-adjusted Cox proportional hazards model, an early relative worsening of ≥10% in the basal and mid LS and ≥15% in global LS was associated with hsTnI elevation. Relative reductions in LS were not significantly associated with myocarditis; however, 4 of the 6 patients with myocarditis had relative reduction of ≥10% in the basal LS., Conclusions: An early worsening in the global and regional LS was associated with increased hsTnI in patients receiving ICIs. Assessment of LS early after ICI administration should be further studied as a strategy for risk stratification of ICI-treated patients., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 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.)

The field of cardio-oncology was born from the necessity for recognition and management of cardiovascular diseases among patients with cancer. This need for this specialty continues to grow as patients with cancer live longer as a result of lifesaving targeted and immunologic cancer therapies beyond the usual chemotherapy and/or radiation therapy. Often, potentially cardiotoxic anticancer treatment is necessary in patients with baseline cardiovascular disease. Moreover, patients may need to continue therapy in the setting of incident cancer therapy-associated cardiotoxicity. Herein, we present and discuss the concept of permissive cardiotoxicity as a novel term that represents an essential concept in the field of cardio-oncology and among practicing cardio-oncology specialists. It emphasizes a proactive rather than reactive approach to continuation of lifesaving cancer therapies in order to achieve the best oncologic outcome while mitigating associated and potentially off-target cardiotoxicities., Competing Interests: Dr Dent is a consultant to and has received honoraria from AstraZeneca and Novartis. Dr Lenihan is a consultant (modest) to AstraZeneca, Bristol Myers Squibb, Myocardial Solutions, Clementia, Intellia, Bridge Bio, OncXerna, and SecuraBio. Dr Okwuosa is a consultant to Antev. Dr Porter has received an unrestricted grant from the Sally and Cloud Cray Family Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

The mitochondrial dysfunction characteristic of heart failure (HF) is associated with changes in intracellular nicotinamide adenine dinucleotide (NAD + ) and NADH levels. Raising NAD + levels with the NAD + precursor, nicotinamide riboside (NR), may represent a novel HF treatment. In this 30-participant trial of patients with clinically stable HF with reduced ejection fraction, NR, at a dose of 1,000 mg twice daily, appeared to be safe and well tolerated, and approximately doubled whole blood NAD + levels. Intraindividual NAD + increases in response to NR correlated with increases in peripheral blood mononuclear cell basal ( R 2  = 0.413, P = 0.003) and maximal ( R 2  = 0.434, P = 0.002) respiration, and with decreased NLRP3 expression ( R 2  = 0.330, P =  0.020). (Nicotinamide Riboside in Systolic Heart Failure; NCT03423342)., Competing Interests: This trial was funded by National Heart, Lung, and Blood Institute grants HL126209 (to Drs Tian and O’Brien), HL126209-01S1 (to Drs O’Brien and Tian), and HL144937 (to Drs O’Brien and Tian) and T32 Fellowship HL007828 (to Dr Wang); American Heart Association Postdoctoral Fellowship Awards 15POST22560002 (to Dr Airhart) and 18POST34030098 (to Dr Wang); and a grant from the John L. Locke, Jr. Foundation (to Dr Wang). The University of Washington Institute for Translational Health Sciences is funded by UL1 TR002319 from the National Institutes of Health National Center for Advancing Translational Sciences. Nicotinamide riboside and matching placebo were supplied by ChromaDex, Inc. The company played no role in trial funding, design, conduct, data analysis or interpretation, nor in manuscript drafting or revision. Dr Tian is a member of the Scientific Advisory Board of Cytokinetics, USA. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Cardiomyopathy is a leading cause of late morbidity and mortality in childhood cancer survivors (CCS). Evidence-based guidelines recommend risk-stratified screening for cardiomyopathy, but the management approach for abnormalities detected when screening asymptomatic young adult CCS is poorly defined., Objectives: The aims of this study were to build upon existing guidelines by describing the expert consensus-based cardiomyopathy screening practices, management approach, and clinical rationale for the management of young adult CCS with screening-detected abnormalities and to identify areas of controversy in practice., Methods: A multispecialty Delphi panel of 40 physicians with expertise in cancer survivorship completed 3 iterative rounds of semi-open-ended questionnaires regarding their approaches to the management of asymptomatic young adult CCS at risk for cardiomyopathy (screening practices, referrals, cardiac testing, laboratory studies, medications). Consensus was defined as ≥90% panelist agreement with recommendation., Results: The response rate was 100% for all 3 rounds. Panelists reached consensus on the timing and frequency of echocardiographic screening for anthracycline-associated cardiomyopathy, monitoring during pregnancy, laboratory testing for modifiable cardiac risk factors, and referral to cardiology for ejection fraction ≤50% or preserved ejection fraction with diastolic dysfunction. Controversial areas (<75% agreement) included chest radiation dose threshold to merit screening, indications for advanced cardiac imaging and cardiac serum biomarkers for follow-up of abnormal echocardiographic findings, and medical management of asymptomatic left ventricular systolic dysfunction., Conclusions: Expert practice is largely consistent with existing risk-based screening guidelines. Some recommendations for managing abnormalities detected on screening echocardiography remain controversial. The rationale offered by experts for divergent approaches may help guide clinical decisions in the absence of guidelines specific to young adult CCS., Competing Interests: This work was supported by National Institutes of Health T32 research training grant CA136432-12 to Dr Aziz-Bose and the Jack and Dorothy Byrne Foundation. Dr Nohria is a consultant for AstraZeneca, Bantam Pharmaceuticals, Boehringer Ingelheim, and Takeda Oncology; and has received research support from Amgen. Dr Yock has received in-kind software support from Mim Software for a multicenter Pediatric Radiation Registry (Pediatric Proton/Photon Consortium Registry). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Objectives: To determine whether hearts reanimated with normothermic regional perfusion (NRP) have clinically detectable changes in function using echocardiography comparing the prearrest and post-NRP imaging. As heart transplantation from donation after circulatory death (DCD) continues to increase, preliminary results suggest outcomes comparable with donation after brain death. It is unknown whether the obligatory period of warm ischemia experienced during DCD withdrawal process causes immediate changes in cardiac allograft function following in situ reanimation., Methods: We retrospectively reviewed and compared predonation with postreanimation echocardiographic findings in all DCD donors at our institution from January to October 2021. All DCD donor organs were reanimated with in situ thoracoabdominal NRP after circulatory death. Echocardiographic assessment included (1) 2-dimensional and speckle-tracking measures of chamber size and function; (2) ejection fraction; (3) fractional area change; and (4) global longitudinal strain., Results: Altogether, 4 DCD heart donations were performed during the study period. Basic demographics and withdrawal ischemic time periods are reported. There were no changes in left ventricular ejection fraction and right ventricular fractional area change when comparing the predonation and the postreanimation echocardiogram. There was a minimal, nonstatistically significant decrease in left ventricular global longitudinal strain and right ventricular free-wall systolic strain in 3 of the 4 donors following reanimation., Conclusions: DCD cardiac allografts reanimated with NRP demonstrated no change in echocardiographic parameters used for a standard predonation donor heart evaluation. Findings suggest cardiac function of DCD allografts reanimated with thoracoabdominal NRP is not adversely impacted by limited period of warm ischemia following circulatory arrest., (© 2022 The Author(s).)

Objective: To assess the prevalence of low-flow state (LFS) with left ventricular (LV) stroke volume index of less than 35 mL/m 2 and the demographics, clinical and echocardiographic characteristics associated with LV remodeling and function in a Hispanic/Latino population., Participants and Methods: The study included 1346 asymptomatic participants from the Hispanic Community Health Study/Study of Latinos with normal LV ejection fraction (≥55%) and no valvular heart disease. LV volume, mass and left atrial volume, LV ejection fraction, global longitudinal strain, and myocardial contraction fraction were measured by echocardiography. The participants were divided into LFS or normal flow state (NFS: stroke volume index ≥35 mL/m 2 ). Demographics, clinical and echocardiographic characteristics, and measures of LV remodeling and function were compared between the LFS and NFS groups., Results: The prevalence of LFS was 41%. In comparison with NFS, the LFS had lower LV mass index (77.2±0.96 g/m 2 vs 84.6±0.86 g/m 2 ; P <.001), left atrial volume index (20.6±0.35 mL/m 2 vs 23.5±0.37 mL/m 2 ; P <.001), global longitudinal strain (-16.8±0.16% vs -17.7±0.17%; P <.001), and myocardial contraction fraction (43.3±0.63% vs 55.7±0.64%; P <.001). There was no significant difference in the relative wall thickness (LFS: 0.40±0.004 vs NFS: 0.40±0.005; P =.57). The LFS group had significantly higher hemoglobin A1c (6.18±0.07% vs 5.97±0.04%; P =.01) than the NFS group., Conclusion: A high prevalence of LFS associated with echocardiographic characteristics reflecting unfavorable LV remodeling and function was observed in a Hispanic/Latino population. Further studies of the prognostic significance of LFS in a large multiethnic population are warranted., (© 2022 The Authors.)

Background: Higher levels of physical activity are associated with a lower risk of cardiovascular disease in the general population. Whether the same holds for women who underwent treatment for breast cancer is unclear., Objectives: The aim of this study was to evaluate the association between physical activity in a typical week in the past 12 months and cardiac dysfunction in breast cancer survivors., Methods: We used data from a cohort of breast cancer survivors who were treated at ages 40 to 50 years (N = 559). The association between physical activity and global longitudinal strain (GLS) and left ventricular ejection fraction (LVEF) was evaluated using both linear and modified Poisson regression analyses adjusted for relevant confounders., Results: In total, 559 breast cancer survivors were included, with median age of 55.5 years and a median time since treatment of 10.2 years. GLS was less favorable in inactive survivors (-17.1%) than in moderately inactive (-18.4%), moderately active (-18.2%), and active survivors (-18.5%), with an adjusted significant difference for active versus inactive survivors (β = -1.31; 95% CI: -2.55 to -0.06)). Moderately active (n = 57/130) and active survivors (n = 87/124) had significantly lower risks of abnormal GLS (defined as >-18%) compared with inactive survivors (n = 17/26) (RR: 0.65 [95% CI: 0.45-0.94] and RR: 0.61 [95% CI: 0.43-0.87], respectively). LVEF, in normal ranges in all activity categories, was not associated with physical activity., Conclusions: In long-term breast cancer survivors, higher physical activity levels were associated with improved GLS but not LVEF, with the relatively largest benefit for doing any activity versus none. This finding suggests that increasing physical activity may contribute to cardiovascular health benefits, especially in inactive survivors., Competing Interests: This work was financially supported by Pink Ribbon/Dutch Cancer Society (grant 2012.WO39.C143). Dr Sonke has received institutional research support from AstraZeneca, Merck, Novarits, Roche, and Seagen; and is a consultant for Biovica. Dr Gietema has received grants from Roche, Siemens, and Abbvie paid to his institution. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: The role of left ventricular (LV) mechanical dispersion estimated after an ST elevation acute myocardial infarction (STEMI) remains unclear., Methods: The study participants were 208 consecutive patients (152 men, age = 72 years) presenting with STEMI for the first time who underwent primary percutaneous coronary intervention (PCI) within 12 h of STEMI onset. Within 48 h of PCI (mean = 24 h), 2D and 3D speckle-tracking echocardiography were performed. The global longitudinal strain (GLS) was calculated using 3D (3D-GLS) and 2D (2D-GLS) speckle tracking. Mechanical dispersion was defined using the standard deviation (SD) of the time to regional peak longitudinal strain (LS) for all 16 segments for both 2D-STE and 3D-STE (2D-LS-SD, 3D-LS-SD). Infarct size was estimated by Tc99m-sestamibi as the total area of < 50% of the uptake area at 2 weeks. The patients were followed up for a longer period of time (median118months) and checked for major adverse cardiac events (MACE: cardiac death, heart failure)., Results: During follow-up, 55 patients experienced MACE. The cut-off values were determined using receiver operating characteristic curves. The multivariate analysis revealed that a 3D-LS-SD > 56.7 ms was a significant predictor of MACEs (hazard ratio = 1.991, 95% confidence interval 1.033-3.613, p = 0.03), but 2D-LS-SD > 58.1 ms was not an independent predictor of MACEs (hazard ratio = 1.577, 95% confidence interval 0.815-3.042, p = 0.1). Furthermore, the combination of 3D-GLS and 3D-LS-SD had accurate predictability for MACE, as shown by the Kaplan-Meier curves (log rank, χ 2  = 94.1, p < 0.0001)., Conclusions: LV mechanical dispersion besides 3D-GLS assessed by 3D-STE immediately after PCI can predict long-term prognosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Focused transthoracic echocardiography (fTTE) has emerged as a critical diagnostic tool during the COVID-19 pandemic, allowing for efficient cardiac imaging while minimizing staff exposure. The utility of fTTE in predicting clinical outcomes in COVID-19 remains under investigation., Methods: We conducted a retrospective study of 2,266 hospitalized patients at Rush University Medical Center with COVID-19 infection between March and November 2020 who received a fTTE. fTTE data were analyzed for association with primary adverse outcomes (60-day mortality) and with secondary adverse outcomes (need for renal replacement therapy, need for invasive ventilation, shock, and venous thromboembolism)., Results: Of the 427 hospitalized patients who had a fTTE performed (mean 62 years, 43% female), 109 (26%) had died by 60 days. Among patients with an available fTTE measurement, right ventricular (RV) dilation was noted in 34% (106/309), 43% (166/386) had RV dysfunction, and 17% (72/421) had left ventricular (LV) dysfunction. In multivariable models accounting for fTTE data, RV dilation was significantly associated with 60-day mortality (OR 1.93 [CI 1.13-3.3], p = 0.016). LV dysfunction was not significantly associated with 60-day mortality (OR 0.95 [CI: 0.51-1.78], p = 0.87)., Conclusions: Abnormalities in RV echocardiographic parameters are adverse prognosticators in COVID-19 disease. Patients with RV dilation experienced double the risk for 60-day mortality due to COVID-19. To our knowledge, this is the largest study to date that highlights the adverse prognostic implications of RV dilation as determined through fTTE in hospitalized COVID-19 patients., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Volgman – Research support: NIH IND Number 119127; NIH NINR R01NR018443; Novartis CTQJ230A12001. Consulting: MSD/Bayer Virtual Global Advisory Board Member, Bristol Myers Squibb Foundation Diverse Clinical Investigator Career Development Program (DCICDP), National Advisory Committee (NAC), Janssen Health Equity/Diversity Advisory Board, NIH Clinical Trials. Stock ownership: Apple Inc. stock. The remaining authors report no relationships that could be construed as a conflict of interest., (© 2022 The Authors.)

Cardiotoxicity is a relatively frequent and potentially serious side effect of traditional and targeted cancer therapies. Both general measures and specific pharmacologic cardioprotective interventions as well as imaging- and biomarker-based surveillance strategies to identify patients at high risk have been tested in randomized controlled trials to prevent or attenuate cancer therapy-related cardiotoxic effects. Although meta-analyses including early trials suggest an overall beneficial effect, there is substantial heterogeneity in results. Recent randomized controlled trials of neurohormonal inhibitors in patients receiving anthracyclines and/or human epidermal growth factor receptor 2-targeted therapies have shown a lower rate of cancer therapy-related cardiac dysfunction than previously reported and a modest or no sustained effect of the interventions. Data on preventive cardioprotective strategies for novel cancer drugs are lacking. Larger, prospective multicenter randomized clinical trials testing traditional and novel interventions are required to more accurately define the benefit of different cardioprotective strategies and to refine risk prediction and identify patients who are likely to benefit., Competing Interests: Drs Heck and Gulati were supported by grants from the National Programme for Clinical Therapy Research in the Specialist Health Service (KLINBEFORSK). Dr Gulati has received speaker honoraria from Novartis, AstraZeneca, Orion Pharma, and Bristol Myers Squibb. Dr Omland has served on advisory boards for Abbott Diagnostics, Roche Diagnostics, and Bayer; has received research support from Abbott Diagnostics, Novartis, Roche Diagnostics, Singulex, and SomaLogic via Akershus University Hospital; and has received speaker or consulting honoraria from Roche Diagnostics, Siemens Healthineers, and CardiNor. Dr Heck has reported that she has no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Purpose: This study assessed a functional protocol to identify myocarditis or myocardial involvement in competitive athletes following SARS-CoV2 infection., Methods: We prospectively evaluated competitive athletes (n = 174) for myocarditis or myocardial involvement using the Multidisciplinary Inquiry of Athletes in Miami (MIAMI) protocol, a median of 18.5 (IQR 16-25) days following diagnosis of COVID-19 infection. The protocol included biomarker analysis, ECG, cardiopulmonary stress echocardiography testing with global longitudinal strain (GLS), and targeted cardiac MRI for athletes with abnormal findings. Patients were followed for median of 148 days., Results: We evaluated 52 females and 122 males, with median age 21 (IQR: 19, 22) years. Five (2.9%) had evidence of myocardial involvement, including definite or probable myocarditis (n = 2). Three of the 5 athletes with myocarditis or myocardial involvement had clinically significant abnormalities during stress testing including ventricular ectopy, wall motion abnormalities and/or elevated VE/VCO2, while the other two athletes had resting ECG abnormalities. VO2 max , left ventricular ejection fraction and GLS were similar between those with or without myocardial involvement. No adverse events were reported in the 169 athletes cleared to exercise at a median follow-up of 148 (IQR108,211) days. Patients who were initially restricted from exercise had no adverse sequelae and were cleared to resume training between 3 and 12 months post diagnosis., Conclusions: Screening protocols that include exercise testing may enhance the sensitivity of detecting COVID-19 related myocardial involvement following recovery from SARS-CoV2 infection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The University of Miami is an equity owner in Longeveron Inc., which has licensed intellectual property from the University of Miami., (© 2022 The Authors.)

Background: Cirrhotic cardiomyopathy refers to the structural and functional changes in the heart leading to either impaired systolic, diastolic, electrocardiographic, and neurohormonal changes associated with cirrhosis and portal hypertension. Cirrhotic cardiomyopathy is present in 50% of patients with cirrhosis and is clinically seen as impaired contractility, diastolic dysfunction, hyperdynamic circulation, and electromechanical desynchrony such as QT prolongation. In this review, we will discuss the cardiac physiology principles underlying cirrhotic cardiomyopathy, imaging techniques such as cardiac magnetic resonance imaging and scintigraphy, cardiac biomarkers, and newer echocardiographic techniques such as tissue Doppler imaging and speckle tracking, and emerging treatments to improve outcomes., Methods: We reviewed available literature from MEDLINE for randomized controlled trials, cohort studies, cross-sectional studies, and real-world outcomes using the search terms "cirrhotic cardiomyopathy," "left ventricular diastolic dysfunction," "heart failure in cirrhosis," "liver transplantation," and "coronary artery disease"., Results: Cirrhotic cardiomyopathy is associated with increased risk of complications such as hepatorenal syndrome, refractory ascites, impaired response to stressors including sepsis, bleeding or transplantation, poor health-related quality of life and increased morbidity and mortality. The evaluation of cirrhotic cardiomyopathy should also guide the feasibility of procedures such as transjugular intrahepatic portosystemic shunt, dose titration protocol of betablockers, and liver transplantation. The use of targeted heart rate reduction is of interest to improve cardiac filling and improve the cardiac output using repurposed heart failure drugs such as ivabradine. Liver transplantation may also reverse the cirrhotic cardiomyopathy; however, careful cardiac evaluation is necessary to rule out coronary artery disease and improve cardiac outcomes in the perioperative period., Conclusion: More data are needed on the new diagnostic criteria, molecular and biochemical changes, and repurposed drugs in cirrhotic cardiomyopathy. The use of advanced imaging techniques should be incorporated in clinical practice., (© 2021 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Relaxin is a pleiotropic hormone shown to confer cardioprotection in several preclinical models of cardiac ischemia-reperfusion injury. In the present study, the effects of up-regulating relaxin family peptide receptor 1 (RXFP1) via adeno-associated virus serotype 9 (AAV9) vectors were investigated in a mouse model of myocardial infarction. AAV9-RXFP1 vectors were generated and injected in adult male CD1 mice. Up-regulation of Rxfp1 was confirmed via quantitative polymerase chain reaction, and overexpressing animals showed increased sensitivity to relaxin-induced ventricular inotropic response. Overexpressing animals also demonstrated reduced infarct size and preserved cardiac function 24 hours after ischemia-reperfusion. Up-regulation of RXFP1 via AAV9 vectors has potential therapeutic utility in preventing adverse remodeling after myocardial infarction., Competing Interests: This study was supported by the American Heart Association (grant 18PRE33990001 to Mr Devarakonda), the Wright Center for Clinical and Translational Research Center (Wright Scholarship to Mr Devarakonda), and the National Institutes of Health (grants R01HL142281, R21AG053654, R01HL133167, and R35HL155651 to Dr Salloum). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Objectives: The aim of this study was to characterize the cardiovascular disease (CVD) profile and describe the incidence and characteristics of cardiovascular (CV) events in patients with esophageal cancer (EC) following chemoradiation and surgery., Background: Underlying CVD is a concern in patients with EC receiving curative treatment with chemoradiation and surgery., Methods: Consecutive patients with EC referred for curative treatment were enrolled. Clinical CVD status, ongoing CVD treatment, cardiac function, and physical performance were assessed before chemoradiation. During a 90-day follow-up period, all CV events were noted and classified after in-depth medical record review. CV events were defined by major adverse CV events (transient ischemic attack, imaging-verified new stroke, unstable angina, heart failure or cardiomyopathy) or by Common Terminology Criteria for Adverse Events grade ≥3 (arrhythmia, thromboembolic events, or pericardial effusion requiring pericardiocentesis)., Results: Among 55 patients enrolled (median age 67 years; range: 50-86 years; 89% men), 22% had CVD prior to chemoradiation, and 11% with pre-existing CVD were inadequately treated according to current CV guidelines. Thirteen patients (24%) developed 15 events during follow-up. Pre-existing atrial fibrillation and a dilated left atrium were significantly associated with subsequent CV events. Left ventricular (LV) systolic dysfunction was frequently noted; 51% had impaired LV global longitudinal strain (<18%), and 16% had LV ejection fraction <50%., Conclusions: A systematic cardiac evaluation prior to chemoradiation in patients with EC revealed a high prevalence of undetected CVD, inadequately treated pre-existing CVD, and a high incidence of CV events after chemoradiation. These findings highlight the need for a systematic baseline cardiac examination in patients with EC to optimize CVD treatment. (Impact of Cancer Therapy on Myocardial Function in Patients With Esophagus Cancer [Heartcheck]; NCT03619317)., Competing Interests: This research was supported by the Danish Cancer Society, the Carpenter Jorgen Holm and Wife Elisa F. Hansen’s Memorial Scholarship, and Radiumstationens Research Fund. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Background: Long-term survivors of Hodgkin lymphoma (HL) and mediastinal non-Hodgkin lymphoma experience late adverse effects of radiotherapy and/or anthracycline-containing chemotherapy, leading to premature cardiovascular morbidity and mortality., Objectives: The aim of this study was to identify markers for subclinical cardiovascular disease using cardiovascular magnetic resonance (CMR) in survivors of HL and non-Hodgkin lymphoma., Methods: CMR was performed in 80 lymphoma survivors treated with mediastinal radiotherapy with or without anthracyclines, and results were compared with those among 40 healthy control subjects matched for age and sex., Results: Of the 80 lymphoma survivors, 98% had histories of HL, the mean age was 47 ± 11 years, and 54% were male. Median radiotherapy dose was 36 Gy (interquartile range: 36-40 Gy), and radiotherapy was combined with anthracyclines in 70 lymphoma survivors (88%). Mean time between diagnosis and CMR was 20 ± 8 years. Significantly lower left ventricular (LV) ejection fraction (53% ± 5% vs 60% ± 5%; P  < 0.001) and LV mass (47 ± 10 g/m 2 vs 56 ± 8 g/m 2 ; P  < 0.001) and higher LV end-systolic volume (37 ± 8 mL/m 2 vs 33 ± 7 mL/m 2 ; P  = 0.013) were found in lymphoma survivors. LV global strain parameters were also significantly worse in lymphoma survivors ( P  < 0.02 for all). Native myocardial T1 was significantly higher in lymphoma survivors compared with healthy control subjects (980 ± 33 ms vs 964 ± 25 ms; P  = 0.007), and late gadolinium enhancement was present in 11% of the survivors., Conclusions: Long-term lymphoma survivors have detectable changes in LV function and native myocardial T1 on CMR. Further longitudinal studies are needed to assess the implication of these changes in relation to treatment and clinical outcome., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 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.)

Objectives: This study examines the early and midterm safety, efficacy, and durability of mitral valve repair for primary mitral regurgitation (MR) using the ChordArt device (CoreMedic) for chordal replacement., Methods: Five patients with symptomatic severe primary degenerative MR due to isolated central posterior leaflet prolapse/flail were treated with the ChordArt device in a transseptal surgical approach and followed prospectively with periodical clinical and echocardiographic assessments for 2 years., Results: Reduction of MR immediately after the implantation of artificial chords was achieved in all patients showing no or trace MR (<1+/4+). In all patients, MR <1+ was maintained during 24 months of follow-up. No dehiscence, detachment, or dislocation of the implanted ChordArt devices was observed. Transthoracic echocardiography showed that left ventricle end diastolic diameter significantly decreased during the whole follow-up period in comparison to baseline condition, especially at discharge and 1-month follow-up. Left ventricle end systolic diameter also significantly decreased during the whole follow-up period in comparison to baseline condition. Left atrial volume significantly decreased during the follow-up period in comparison to discharge. No major adverse events, as defined per protocol, were observed during the intervention or during the follow-up period., Conclusions: The ChordArt device allows successful treatment of primary degenerative MR due to posterior mitral leaflet prolapse or flail, with a good safety profile and promising immediate clinical and echocardiographic benefits that are confirmed up to 24 months., (© 2021 The Author(s).)

Background: Prevalence of both degenerative severe aortic stenosis (AS) and transthyretin cardiac amyloidosis (ATTR-CA) increases with age. Dual disease (AS+myocardial ATTR-CA) occurs in significant proportion of patients undergoing surgical aortic valve replacement (SAVR)., Objectives: This study aimed to determine the prevalence of ATTR-CA in severe AS in the Indian population, identify noninvasive predictors of its diagnosis, and understand its impact on prognosis., Methods: Symptomatic severe AS patients aged ≥65 years undergoing SAVR were enrolled. ATTR-CA diagnosis was based on preoperative 99m-technetium pyrophosphate (PYP) scan and intraoperatively obtained basal interventricular septum biopsy for myocardial ATTR-CA, and excised native aortic valve for isolated valvular ATTR-CA. Primary amyloidosis was excluded by serum/urine protein electrophoresis with serum immunofixation., Results: SAVR was performed in 46 AS patients (age 70 ± 5 years, 70% men). PYP scan was performed for 32 patients, with significant PYP uptake in 3 (n = 3 of 32, 9.4%), suggestive of myocardial ATTR-CA. On histopathological examination, none of the interventricular septum biopsy specimens had amyloid deposits, whereas 33 (71.7%) native aortic valves showed amyloid deposits, of which 19 (57.6%) had transthyretin deposition suggestive of isolated valvular amyloidosis. Noninvasive markers of dual disease included low myocardial contraction fraction (median [interquartile range], 28.8% [23.8% to 39.1%] vs 15.3% [9.3% to 16.1%]; P  = 0.006), deceleration time (215 [144 to 236] ms vs 88 [60 to 106] ms; P  = 0.009) and global longitudinal strain (-18.7% [-21.1% to -16.9%] vs -14.2% [-17.0% to -9.7%]; P  = 0.030). At 1-year follow-up, 2 patients died (4.3%); 1 each in myocardial ATTR-CA negative and positive groups (3.4% vs 33.3%; P  = 0.477)., Conclusions: Dual disease is not uncommon in India. Isolated valvular amyloidosis in severe AS is much more common., Competing Interests: Dr Dorbala has received consulting fees from Pfizer, GE Healthcare, and Ionetix; and has received grant support from Pfizer, GE Healthcare, and Attralus. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Background: Radiation therapy (RT) results in myocardial changes consisting of diffuse fibrosis, which may result in changes in diastolic function., Objectives: The aim of this study was to explore RT-associated changes in left ventricular (LV) diastolic function., Methods: Sixty chemotherapy-naive patients with left-sided, early-stage breast cancer were studied with speckle tracking echocardiography at 3 time points: prior to, immediately after, and 3 years after RT. Global and regional early diastolic strain rate (SRe) were quantified, as were parameters of systolic function., Results: Regional changes in SRe, particularly the apical and anteroseptal segments, were observed over time and were more evident than global changes. The apical SRe declined from a median of 1.24 (interquartile range: 1.01 to 1.39) s -1 at baseline to 1.02 (interquartile range: 0.79 to 1.15) s -1 at 3 years of follow-up (p < 0.001). This decline was associated with the left ventricular maximal radiation dose (β = 0.36, p = 0.007). The global SRe was <1.00 s -1 (SRe dep ) in 11 (18.3%) patients at baseline, 21 (35%) patients (p = 0.013) post-RT, and 17 (28.3%) patients (p = 0.051) at 3 years. SRe dep post-RT was independently associated with baseline cardiac abnormalities (odds ratio: 0.26; 95% confidence interval: 0.08 to 0.84; p = 0.025); SRe dep at 3 years of follow-up was associated with the baseline Charlson comorbidity index (odds ratio: 2.36; 95% confidence interval: 1.17 to 4.77; p = 0.017). Diastolic function abnormalities were evident even in patients with preserved global longitudinal strain at 3 years., Conclusions: RT resulted in changes in the SRe in the apical and anteroseptal segments over 3 years of follow-up. Changes in SRe apical segments were present even in patients with preserved systolic function and were independently associated with RT dose and cardiovascular comorbidities., Competing Interests: This study has received funding from nonprofit trusts: Paavo and Eila Salonen Legacy, the Finnish Foundation for Cardiovascular Research, and the Finnish Society of Oncology. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)