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Visual Abstract, Highlights • PON-1 is an HDL-associated cardioprotective enzyme that prevents oxidized-LDL formation and has not previously been studied in cardio-oncology. • To determine the associations between PON-1 and the development of CTRCD, the Pon and Aryl serum enzymatic activity levels of PON-1 were quantified in a cohort of 225 patients with breast cancer receiving doxorubicin with or without trastuzumab. • After doxorubicin completion, the activity levels of both Pon and Aryl were significantly decreased. • Early increases in the Pon enzymatic activity of PON-1 were associated with increased risk of CTRCD. • With further study, PON-1 activity may provide insight into mechanistic risk prediction of CTRCD with doxorubicin chemotherapy., Summary The objective of this study was to determine associations of paraoxonase-1 (PON-1) with development of cancer therapy–related cardiac dysfunction (CTRCD). PON-1 is a cardioprotective enzyme associated with high-density lipoprotein that prevents oxidized low-density lipoprotein formation. Given the role of oxidative stress in doxorubicin-induced cardiotoxicity, PON-1 activity may have relevance for the prediction of CTRCD. In 225 patients with breast cancer receiving doxorubicin with or without trastuzumab, we quantified PON-1 activity through its paraoxonase (Pon) and arylesterase (Aryl) enzymatic activity at baseline, during, and after doxorubicin completion. Echocardiograms were performed at baseline, during therapy, and annually. CTRCD was defined as a decrease in left ventricular ejection fraction by ≥10% from baseline to

Background Anti-CD19 chimeric antigen receptor (CAR) T cell therapy holds great promise in the treatment of patients with hematologic malignancies. A high occurrence of cardiac dysfunction has been noted in children treated with CAR T cell therapy. Objectives The aim of this study was to define the occurrence of major adverse cardiovascular events (MACE) in adult patients treated with CAR T cell therapy and assess the relationships among clinical factors, echocardiographic parameters, laboratory values, and cardiovascular outcomes. Methods Baseline clinical, laboratory, and echocardiographic parameters were collected in 145 adult patients undergoing CAR T cell therapy. MACE included cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke, and de novo cardiac arrhythmia. Baseline parameters associated with MACE were identified using Cox proportional cause-specific hazards regression analysis. Results Thirty-one patients had MACE (41 events) at a median time of 11 days (interquartile range: 6 to 151 days) after CAR T cell infusion. The median follow-up period was 456 days (interquartile range: 128 to 1,214 days). Sixty-one patients died. Cytokine release syndrome (CRS) occurred 176 times in 104 patients; the median time to CRS was 6 days (interquartile range: 1 to 8 days). The Kaplan-Meier estimates for MACE and CRS at 30 days were 17% and 53%, respectively. The Kaplan-Meier estimates for survival at 1 year was 71%. Multivariable Cox proportional cause-specific hazards regression analysis determined that baseline creatinine and grade 3 or 4 CRS were independently associated with MACE. Conclusions Patients treated with CAR T cell therapy are at an increased risk for MACE and may benefit from cardiovascular surveillance. Further large prospective studies are needed to confirm the incidence and risk factors predictive of MACE.

Background: There is limited evidence regarding the impact of cardiology involvement in the care of cancer patients. Objectives: This study evaluated the impact of cardiology involvement on guideline-adherent cardiovascular monitoring and risk factor management in patients with breast cancer treated with trastuzumab. Methods: In a single-center retrospective cohort study, electronic health records from 1,047 patients with breast cancer receiving trastuzumab between January 2009 and July 2018 were evaluated. A visit to a cardiology provider beginning from the 3 months before cancer therapy initiation until the last contact date defined cardiology involvement. Guideline-adherent monitoring, defined by echocardiography assessment within the 4 months before trastuzumab initiation and follow-up echocardiography at least every 4 months during therapy, was compared in patients with and without cardiology involvement before treatment initiation. Multivariable associations between cardiology involvement and the time-varying risk factors blood pressure and body mass index (BMI) were assessed by using generalized estimating equations. Results: Cardiology involvement occurred in 293 (28%) patients. A higher proportion of patients with cardiology involvement before trastuzumab initiation had guideline-adherent monitoring (76.4% vs. 60.1%; p = 0.007). Cardiology involvement was associated with an average 1.5 mm Hg (95% CI: –2.9 to –0.1; p = 0.035) lower systolic blood pressure, which was more pronounced in those with hypertension (–2.7 mm Hg; 95% CI: –4.6 to –0.7; p = 0.007). Cardiology involvement was associated with a lower BMI in patients with baseline BMI ≥25 kg/m2 (mean difference: –0.5 kg/m2; 95% CI: –1.0 to –0.1; p = 0.027). Conclusions: Cardiology involvement in patients with breast cancer treated with trastuzumab is associated with greater adherence to cardiovascular monitoring and modest improvements in risk factor control.

Guidelines for the diagnosis, management, and surveillance of cancer patients have evolved with the single goal of improving patient care based on established data when available, or in the absence of firm data, on the standard practices of those with broad experience in actual hands-on patient care. Two initiatives intended to disseminate information to cardio-oncologists, were discussed in this session: the first, from the American Society of Clinical Oncology was focused on available data and the confidence level of that data; the second, from The European Society of Cardiology was a position paper. Interestingly, notwithstanding the somewhat different focus, there is considerable agreement between these two initiatives. Nevertheless, guidelines my not be applicable to all afflicted patients, and may raise questions as to when deviations from published standards should be considered. Such deviations may result in allegations of failure to meet standards of care or legal liability.

Chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment of patients with relapsed and refractory hematologic malignancies and is increasingly investigated as a therapeutic option of other malignancies. The main adverse effect of CAR T-cell therapy is potentially life-threatening cytokine release syndrome (CRS). Clinical cardiovascular (CV) manifestations of CRS include tachycardia, hypotension, troponin elevation, reduced left ventricular ejection fraction, pulmonary edema, and cardiogenic shock. Although insults related to CRS toxicity might be transient and reversible in most instances in patients with adequate CV reserve, they can be particularly challenging in higher-risk, often elderly patients with pre-existing CV disease. As the use of CAR T-cell therapy expands to include a wider patient population, careful patient selection, pre-treatment cardiac evaluation, and CV risk stratification should be considered within the CAR T-cell treatment protocol. Early diagnosis and management of CV complications in patients with CRS require awareness and multidisciplinary collaboration.

The discipline of cardio-oncology has expanded at a remarkable pace. Recent developments and challenges to clinicians who practice cardio-oncology were presented at the Global Cardio-Oncology Summit on October 3 to 4, 2019, in São Paulo, Brazil. Here, we present the top 10 priorities for our field that were discussed at the meeting, and also detail a potential path forward to address these challenges. Defining robust predictors of cardiotoxicity, clarifying the role of cardioprotection, managing and preventing thromboembolism, improving hematopoietic stem cell transplant outcomes, personalizing cardiac interventions, building the cardio-oncology community, detecting and treating cardiovascular events associated with immunotherapy, understanding tyrosine kinase inhibitor cardiotoxicity, and enhancing survivorship care are all priorities for the field. The path forward requires a commitment to research, education, and excellence in clinical care to improve our patients' lives., Central Illustration, Highlights • The discipline of cardio-oncology has enjoyed extensive and complex development at a breathtaking pace. • Extensive ongoing clinical and basic research continue to shape and formulate the practice of cardio-oncology. • The path forward for the field needs to be centered on excellence in clinical care, transformative research, and broad education principles.

Regulation of T-cell signaling through immune checkpoint inhibition, including programmed cell-death protein (PD)-1, creates a remarkable antimalignancy response. Immune-related adverse events result from immune system over-activation. Mahmood et al. [(1)][1] found a multicenter prevalence of 1.14

Cardiovascular disease and cancer are the 2 main causes of death in the United States. They intersect on multiple levels, sharing common causal mechanisms and epidemiological risk factors. The growing prevalence and complexity of cardiovascular disease and cancer have resulted in the development of the discipline of cardio-oncology. Preparing the cardiovascular workforce for the care of a growing population of cancer patients is necessary to enhance the delivery of high-quality cardiovascular care for patients with cancer. The goal of this review is to present the dedicated efforts of the cardio-oncology community to meet the growing need for education and training of cardiovascular practitioners providing care to cancer patients and survivors. Integration in general cardiology training programs and the efforts of the stakeholder organizations serve as an example of how a multidimensional, innovative approach can address provider education and training needs in a relatively new discipline.

BackgroundBreast cancer is the most common female cancer worldwide. Effective therapies including doxorubicin and trastuzumab have improved survival, but are associated with a substantial risk of cardiovascular disease. Mechanisms underlying cancer treatment-induced cardiotoxicity (CTC) are poorly understood and have largely focused on cardiomyocyte damage, although other cellular populations in the heart such as the cardiac endothelium, may play an important role in cardiac damage. We treated a breast tumor-bearing mouse model with doxorubicin and trastuzumab to investigate the role of the cardiac endothelium in the development of CTC.MethodsImmune compromised mice were inoculated in the 4th mammary fat pad with human breast cancer cells overexpressing HER2 (BT474). When tumors were palpable, mice were treated weekly with doxorubicin (5 mg/kg) and trastuzumab (4 mg/kg). The cardiac phenotype of mice was assessed by echocardiography and histological evaluation of the heart. Cardiac vascular damage was assayed by in vivo permeability assays and primary cultures of murine cardiac endothelial cells were used to assay doxorubicin toxicity in vitro.ResultsThe growth of BT474 breast tumors in Balb/c Nude mice was suppressed upon treatment with doxorubicin and trastuzumab. Mice treated for 4 months with doxorubicin and trastuzumab maintained body weights, but demonstrated an echocardiographic phenotype consistent with preserved left ventricular (LV) ejection fraction, decreased LV mass and increased filling pressures (E/e’). Histological staining with Masson’s trichrome and Picrosirius red showed extensive fibrosis and increased collagen deposition in the ventricular myocardium surrounding blood vessels of treated mice compared to untreated mice. Evans blue permeability assays demonstrated increased cardiac vasculature permeability while primary cardiac endothelial cells exposed to doxorubicin in vitro showed increased cell death as compared to lung or liver endothelial cells.ConclusionsAn orthotopic mouse model of human breast cancer in Nude mice treated with doxorubicin and trastuzumab resulted in a cardiac vascular defect accompanied by preserved LV ejection fraction, decreased LV mass, suggesting mild diastolic dysfunction and cardiac remodeling consistent with subclinical cardiotoxicity. Our data suggest that cardiac endothelium is more sensitive to doxorubicin therapy as compared to other organ endothelium and cardiac endothelial damage may correlate with breast cancer treatment-induced cardiotoxicity.

The innovative development of cancer therapies has led to an unprecedented improvement in survival outcomes and a wide array of treatment-related toxicities, including those that are cardiovascular in nature. Aging of the population further adds to the number of patients being treated for cancer, especially those with comorbidities. Such pre-existing and developing cardiovascular diseases pose some of the greatest risks of morbidity and mortality in patients with cancer. Addressing the complex cardiovascular needs of these patients has become increasingly important, resulting in an imperative for an intersecting discipline: cardio-oncology. Over the past decade, there has been a remarkable rise of cardio-oncology clinics and service lines. This development, however, has occurred in a vacuum of standard practice and training guidelines, although these are being actively pursued. In this council perspective document, the authors delineate the scope of practice in cardio-oncology and the proposed training requirements, as well as the necessary core competencies. This document also serves as a roadmap toward confirming cardio-oncology as a subspecialty in medicine.

Objectives: The purpose of this study was to investigate the occurrence and develop a risk score for heart failure (HF) in acute leukemia. Background: Knowledge is scarce regarding the incidence and risk factors of symptomatic HF in patients with acute leukemia. Methods: Baseline clinical and echocardiographic parameters, including indices of cardiac function (left ventricular ejection fraction and myocardial strain [global longitudinal strain; GLS]), were obtained in 450 patients with acute leukemia treated with anthracyclines, before chemotherapy initiation. Potential risk factors for HF were evaluated using Fine and Gray’s regression analysis, and from this, a 21-point risk score was generated. Results: Forty patients (8.9%) developed HF. The HF risk score included a baseline GLS >−15% (indicative of greater impairment) (6 points), baseline left ventricular ejection fraction 60 years (1 point). Patients were stratified into low (score 0 to 6), moderate (score 7 to 13), and high risk (score 14 to 21). The estimated 1-year cumulative incidence of HF for low-, moderate-, and high-risk groups was 1.0%, 13.6%, and 35.0%, respectively (p < 0.001). The HF risk score was also predictive of all-cause mortality (p < 0.001). After adjustment for age and leukemia type, however, only GLS was significantly associated with all-cause mortality (hazard ratio: 1.73; 95% confidence interval: 1.30 to 2.31; p < 0.001). Conclusions: We developed a baseline risk score to determine risk of HF in patients with acute leukemia. Additional studies are needed to determine the external validity of these findings.

Background: Fluoropyrimidine chemotherapy [5-fluorouracil (5-FU) and capecitabine] are commonly used agents in the treatment of various solid malignancies. However, their use has been limited by cardiac toxicity, presenting as a wide spectrum of asymptomatic (e.g., EKG changes) and symptomatic (e.g., chest pain) manifestations related to coronary vasospasm leading to myocardial ischemia. Historically, patients with suspected coronary vasospasm have been treated with traditional acute ischemic workup and various combinations of anti-anginal therapies. In addition, most patients typically are not rechallenged with fluoropyrimidine after experiencing initial cardiovascular side-effects with resulting interruption of planned chemotherapy regimens. Methods: We report a case series of 11 consecutive patients in a single-center with suspected fluoropyrimidine-induced coronary vasospasm who were successfully rechallenged with the culprit drug to allow for planned chemotherapy completion. Our protocol utilized rechallenge with bolus infusional regimen of intravenous fluoropyrimidine chemotherapy and oral capecitabine with cardioprotective pretreatment with two calcium blockers and long-acting oral nitrate therapy. Results: We were successfully able to continue and complete the previously planned first-line chemotherapy regimen for all 11 patients with minimal therapeutic interruption. There have been no cardiac events or evidence of recurrent coronary spasm after completion of therapy with discontinuation of prophylactic medications upon therapy completion. Conclusions: We report a single-institution experience of successful rechallenge with fluoropyrimidines with careful cardiac monitoring and the combined use of calcium channel blockers and long-acting nitrates. With further study, this algorithm can be used to safely continue fluoropyrimidines, a potentially curative regimen in the treatment of many solid tumors.

Background Oxidative/nitrosative stress and endothelial dysfunction are hypothesized to be central to cancer therapeutics–related cardiac dysfunction (CTRCD). However, the relationship between circulating arginine-nitric oxide (NO) metabolites and CTRCD remains unstudied. Objectives This study sought to examine the relationship between arginine-NO metabolites and CTRCD in a prospective cohort of 170 breast cancer patients treated with doxorubicin with or without trastuzumab. Methods Plasma levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA) were quantified at baseline, 1 month, and 2 months after doxorubicin initiation. Determinants of baseline biomarker levels were identified using multivariable linear regression, and Cox regression defined the association between baseline levels and 1- or 2-month biomarker changes and CTRCD rate in 139 participants with quantitated echocardiograms at all time points. Results Age, hypertension, body mass index, and African-American race were independently associated with ≥1 of baseline citrulline, ADMA, SDMA, and MMA levels. Decreases in arginine and citrulline and increases in ADMA were observed at 1 and 2 months (all p Conclusions In breast cancer patients undergoing doxorubicin therapy, early alterations in arginine-NO metabolite levels occurred, and early biomarker changes were associated with a greater CTRCD rate. Our findings highlight the potential mechanistic and translational relevance of this pathway to CTRCD.

Aims The presence of cancer can complicate treatment choices for patients with atrial fibrillation (AF) increasing both the risk of thrombotic and bleeding events. Methods and results Using data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we aimed to characterize AF patients with cancer, to describe their management and to assess the association between cancer and cardiovascular (CV) outcomes. Among 9749 patients, 23.8% had history of cancer (57% solid malignancy, 1.3% leukaemia, 3.3% lymphoma, 40% other type, and 2.2% metastatic cancer). Patients with history of cancer were older, more likely to have CV disease, CV risk factors, and prior gastrointestinal bleeding. No difference in antiarrhythmic and antithrombotic therapy was observed between those with and without cancer. Patients with history of cancer had a significantly higher risk of death (7.8 vs. 4.9 deaths per 100 patient-years follow-up, P = 0.0003) mainly driven by non-CV death (4.2 vs. 2.4 per 100 patient-years follow-up; P = 0.0004) and higher risk of major bleeding (5.1 vs. 3.5 per 100 patient-years follow-up; P = 0.02) compared with non-cancer patients; no differences were observed in risks of strokes/non-central nervous system embolism (1.96 vs. 1.48, P = 0.74) and CV death (2.89 vs. 2.07, P = 0.35) between the two groups. Conclusion A history of cancer is common among AF patients with up to one in four patients having both. Antithrombotic therapy, rates of cerebrovascular accident, other thrombotic events and cardiac death were similar in AF patients with or without a history of cancer. Patients with cancer, however, were at higher risk of major bleeding and non-CV death.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

PURPOSE Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs. PATIENTS AND METHODS Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs. RESULTS Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib ( P = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; P < .001). Elevated natriuretic peptides occurring mid–first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; P < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank P = .01) and overall survival (log-rank P < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications. CONCLUSION CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.

Chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment of patients with relapsed and refractory hematologic malignancies and is increasingly investigated as therapeutic option of other malignancies. The main adverse effect of CAR T-cell therapy is potentially life-threatening cytokine release syndrome (CRS). Clinical cardiovascular (CV) manifestations of CRS include tachycardia, hypotension, troponin elevation, reduced left ventricular ejection fraction (LVEF), pulmonary edema and cardiogenic shock. Although insults related to CRS toxicity might be transient and reversible in most instances in patients with adequate CV reserve, they can be particularly challenging in higher-risk, often elderly patients with pre-existing CV disease. As the use of CAR T-cell therapy expands to include wider patient population, careful patient selection, pre-treatment cardiac evaluation and CV risk stratification should be considered within the CAR T-cell treatment protocol. Early diagnosis and management of CV complications in patients with CRS require awareness and multidisciplinary collaboration.

Objectives This study sought to determine the relationships between echocardiography-derived measures of myocardial mechanics and cancer therapeutics–related cardiac dysfunction (CTRCD). Background Doxorubicin and trastuzumab are highly effective breast cancer therapies, but have a substantial risk of CTRCD. There is a critical need for the early detection of patients at increased risk of toxicity. Methods We performed a prospective, longitudinal cohort study of breast cancer participants undergoing doxorubicin and/or trastuzumab therapy. Echocardiography was performed prior to therapy initiation (baseline) and at standardized follow-up intervals during and after completion of therapy. Ejection fraction (EF), strain, strain rate, and ventricular-arterial coupling (effective arterial elastance [Ea]/end-systolic elastance [Ees sb ]) were quantitated. CTRCD was defined as a ≥10% reduction in EF from baseline to Results In total, 135 participants contributed 517 echocardiograms to the analysis. Over a median follow-up time of 1.9 years (interquartile range: 0.9 to 2.4 years), 21 participants (15%) developed CTRCD. In adjusted models, baseline levels and changes in Ea/Ees sb , circumferential strain, and circumferential strain rate were associated with 21% to 38% increased odds of CTRCD (p sb (area under the curve: 0.703; 95% confidence interval: 0.583 to 0.807) and circumferential strain (area under the curve: 0.655; 95% confidence interval: 0.517 to 0.767) demonstrated the greatest predictive utility. Sensitivity analyses using an alternative CTRCD definition did not impact our results. Conclusions Over an extended follow-up time, ventricular-arterial coupling and circumferential strain were strongly predictive of CTRCD. Our findings suggest a noninvasive strategy to identify high-risk patients prior to, during, and after cardiotoxic cancer therapy.

We characterized cardiologist involvement and its impact on adherence to cardiovascular (CV) function monitoring and CV risk factor management in breast cancer patients treated with trastuzumab. We conducted a retrospective cohort study using electronic health records from 1047 breast cancer

Background Breast cancer therapies are associated with a risk of cardiac dysfunction, most commonly defined by changes in left ventricular ejection fraction (LVEF). Recently, the authors identified 3 classes of LVEF change after exposure to anthracyclines and/or trastuzumab using latent class growth modeling. The objective of the current study was to characterize the clinical, biochemical, and functional profiles associated with LVEF trajectory class membership. Methods Transthoracic echocardiography and biomarker assessments were performed and questionnaires were administered at standardized intervals in a longitudinal cohort of 314 patients with breast cancer who were treated with anthracyclines and/or trastuzumab. Univariable and multivariable multinomial regression analyses evaluated associations between baseline variables and LVEF trajectory class membership. Generalized estimating equations were used to define mean changes in cardiovascular measures over time within each class. Results Among the 3 distinct subgroups of LVEF changes identified (stable [class 1]; modest, persistent decline [class 2]; and significant early decline followed by partial recovery [class 3]), higher baseline LVEF, radiotherapy, and sequential therapy with anthracyclines and/or trastuzumab were associated with class 2 or 3 membership. Sustained abnormalities in longitudinal strain and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were observed in patients in class 2, as were heart failure symptoms. Similar abnormalities were observed in patients in class 3, but there was a trend toward recovery, particularly for longitudinal strain. Conclusions Patients with modest, persistent LVEF declines experienced sustained abnormalities in imaging and biochemical markers of cardiac function and heart failure symptoms. Further investigation is needed to characterize the long-term risk of heart failure, particularly in those with modest LVEF declines.

This study determined the effects of doxorubicin and/or trastuzumab on diastolic function and the relationship between diastolic function and systolic dysfunction.Doxorubicin and trastuzumab can result in left ventricular ejection fraction (LVEF) declines. However, the effects of these therapies on diastolic function remain incompletely defined.In a rigorously phenotyped, longitudinal cohort study of 362 breast cancer participants treated with doxorubicin, doxorubicin followed by trastuzumab, or trastuzumab alone, changes in diastolic function were evaluated using linear models estimated via generalized estimating equations. Associations between baseline and changes in diastolic function with LVEF and longitudinal strain were also determined using generalized estimating equations. The Kaplan-Meier estimator derived the proportion of participants who experienced incident diastolic dysfunction. Cox proportional hazards models estimated the associations between participant characteristics and diastolic dysfunction risk, and between diastolic function and cancer therapy-related cardiac dysfunction risk, defined by an LVEF decline of ≥10% to 50%.Over a median of 2.1 years (interquartile range [IQR]: 1.3 to 4.2 years), participants treated with doxorubicin or doxorubicin followed by trastuzumab demonstrated a persistent worsening in diastolic function, with reductions in the E/A ratio, lateral and septal e' velocities, and increases in E/e' (p 0.01). These changes were not observed with trastuzumab alone. Incident abnormal diastolic function grade occurred in 60% at 1 year, 70% by 2 years, and 80% by 3 years. Abnormal diastolic function grade was associated with a subsequent decrease in LVEF (-2.1%; 95% confidence intervals [CI]: -3.1 to -1.2; p 0.001) and worsening in longitudinal strain (0.6%; 95% CI: 0.1 to 1.1; p = 0.013) over time. Changes in E/e' ratio were modestly associated with worsening longitudinal strain (0.1%; 95% CI: 0.0 to 0.2; p = 0.022).A modest, persistent worsening of diastolic function is observed with contemporary breast cancer therapy. Abnormal and worsening diastolic dysfunction is associated with a small risk of subsequent systolic dysfunction. (Cardiotoxicity of Cancer Therapy [CCT]; NCT01173341).

This cohort study describes patterns of development, management strategies, and long-term vascular consequences of hypertension associated with ibrutinib in the non–clinical trial setting.

Introduction Fluoropyrimidines (FPDs) are a fundamental component of many chemotherapy regimens. Cardiotoxic adverse events (AEs) such as angina, ischemia, arrhythmias, and cardiomyopathy associated with 5-fluorouracil (5-FU) and capecitabine (CAPE) have been sparingly described in studies, primarily through case reports. Data from the 1990s revealed an estimated incidence of 0.5% to 19%, with cardiovascular fatalities occurring in ≤28%. The current use of FPDs includes multiple dosing regimens, oral or intravenous delivery, and administration with additional cardiotoxic therapies. As such, it is imperative to better define the cardiotoxicity risk in the modern treatment era. We comprehensively evaluated the incidence, prevalence, and ascertainment of cardiovascular risk factors and disease within ECOG-ACRIN (Eastern Cooperative Group Cancer Research Group – American College of Radiology Imaging Network) Cancer Research Group clinical trials incorporating 5-FU and CAPE. Materials and Methods Case report forms and clinical study reports from the ECOG-ACRIN Cancer Research Group database of phase II and III clinical trials incorporating 5-FU and CAPE were evaluated. A total of 16 trials from 2002 to 2017 were identified that had used bolus 5-FU (n = 1), continuous infusion 5-FU (n = 10) or CAPE (n = 5). Results A history of cardiovascular disease was variably defined and was an exclusion criterion in 13 of the 16 studies (81%). The baseline risk factors and history of cardiac disease were specifically collected in only 3 studies (19%). All studies collected cardiovascular AEs using the Common Terminology Criteria for Adverse Events version available at the time of the study. Fewer than half (7 of 16; 44%) of the study case report forms had also specifically requested information on cardiac ischemia/infarction. In the 12 completed studies with clinical study reports, the following AEs were reported: dyspnea, ≤16%; arrhythmias, ≤6%; and angina, ischemia, and elevated troponin, ≤5%. Some trials only recorded cardiac AEs that were possibly associated with the novel drug being studied and not those attributed to the standard of care in the 5-FU/CAPE arm, further decreasing the numerical incidence. Conclusion Inconsistent clinical trial reporting of cardiac AEs precluded accurate and precise delineation of the epidemiology of FPD-related cardiovascular AEs. Prospective knowledge of the definition and natural history will lead to the development of risk factor stratification and prechemotherapy interventions to reduce or prevent cardiotoxicity. We propose that the prospective collection of baseline cardiac data and prespecified cardiac endpoints are necessary to fully understand the incidence and cardiac risk of FDPs.

Importance Cardiovascular adverse events (CVAE) with carfilzomib in patients with multiple myeloma can be potentially life-threatening and remain incompletely characterized. We performed the first systematic review and meta-analysis of carfilzomib-associated CVAE. Objective To determine the incidence of carfilzomib-associated CVAE and to compare the rates of carfilzomib CVAE among different doses and companion therapies. Data Sources PubMed, EMBASE, Web of Science, and clinicaltrials.gov were queried for the keywords “carfilzomib,” “Kyprolis,” and “PX-171” through January 1, 2017. Study Selection Phase 1 to 3 prospective clinical trials of carfilzomib in patients with multiple myeloma with evaluable toxic effects data were eligible for meta-analysis. Data Extraction and Synthesis Data were independently extracted by 2 reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Pooled incidence rates and relative risks (for randomized trials) and 95% confidence intervals were calculated using a random effects model. Subgroup analyses were performed to assess study-level characteristics associated with CVAE. Main Outcomes and Measures Cardiovascular adverse events were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grades 3 or higher AEs and study characteristics were recorded. Results A total of 514 studies were assessed for eligibility. Of those, 24 studies were eligible, including a total of 2594 patients with multiple myeloma. All-grade and grades 3 and higher CVAE were seen in 617 (18.1%) and 274 (8.2%), respectively. Phase 2 or 3 studies and carfilzomib doses of 45 mg/m2or higher were associated with high-grade CVAE. Median age older than 65 years, prior myeloma therapies, and concurrent myeloma therapies were not associated with CVAE. For the 3 randomized clinical trials, the summary relative risk of all-grade and grade 3 or higher CVAE for patients receiving carfilzomib compared with noncarfilzomib-receiving control patients were 1.8 and 2.2, respectively. Conclusions and Relevance Carfilzomib was associated with a significant incidence of CVAE, with higher rates seen with higher doses of carfilzomib. Phase 1 studies may be underdetecting CVAE. Future studies are needed to identify patients at high risk for CVAE, develop optimal monitoring strategies, and explore strategies to mitigate these risks.

Many existing and emerging cancer therapies have a significant effect on the cardiovascular health of patients with cancer and cancer survivors. This paper examines current aspects of interdisciplinary cardio-oncology clinical care delivery and education in the United States and outlines how these data provide a platform for future development of the field. We present the results of the nationwide survey on cardio-oncology services, practices, and opinions, conducted among chiefs of cardiology and program directors, which demonstrate ranges of clinical activities and identify significant interest for increased educational opportunities and expert training of cardiovascular physicians in this field. The survey respondents recognized clinical relevance but emphasized lack of national guidelines, lack of funds, and limited awareness and infrastructure as the main challenges for development and growth of cardio-oncology. We discuss potential solutions to unmet needs through interdisciplinary collaboration and the active roles of professional societies and other stakeholders.

With remarkable progress in cancer diagnosis and therapy, there are growing numbers of cancer survivors with almost 15 million current survivors in the United States. Because of the recognition that cardiovascular morbidity and mortality play an important role in outcomes of cancer survivors, understanding the unique cardiac needs of survivors and existing evidence for care is essential to cardio-oncology and survivorship care. Cancer survivors are a heterogeneous population with several potentially cardiotoxic exposures and several potential, and not mutually exclusive, complications of therapy (for instance cardiomyopathy and premature atherosclerosis) making uniform guidelines difficult to implement. Using case-based presentations, this chapter will address basic assessment and management of cardiac function and risk in cancer survivors. Best practices for assessment of survivors based on treatment modality (i.e., chemotherapy and/or radiation therapy) and host-related factors (i.e., age at diagnosis and pre-existing risk factors) are described.

PURPOSE: We characterized the early changes in cardiovascular biomarkers with contemporary thoracic radiation therapy (RT) and evaluated their associations with radiation dose-volume metrics including mean heart dose (MHD), V5, and V30. METHODS AND MATERIALS: In a prospective longitudinal study of 87 patients with breast cancer, lung cancer, or mediastinal lymphoma treated with photon or proton thoracic RT, blood samples were obtained pre-RTand after completion of RT (median, 20 days; interquartile range [IQR], 1–35). High-sensitivity cardiac troponin T, N-terminal proB-type natriuretic peptide, placental growth factor (PIGF), and growth differentiation factor 15 (GDF-15) were measured. Associations between MHD, V5 and V30, and biomarker levels and associations between echocardiography-derived measures of cardiac function and biomarker levels were assessed in multivariable linear regression models. Analyses were performed according to the following subgroups: (1) breast cancer alone and (2) lung cancer and lymphoma combined. RESULTS: The median (IQR) estimates of MHD ranged from 1.3Gy(0.9–2.4) inbreast cancer (n = 60) to 6.8Gy (5.4–10.2) inmediastinallymphoma (nZ14) and 8.4Gy(6.7–16.1) in lung cancer (n = 13) patients (P < .001). There were no significant increases in biomarker levels from pre-RT to post-RT in breast cancer. In lung cancer/lymphoma, PIGF increased from a median (IQR) of 20 ng/L (16–26) to 22 ng/L (16–30) (P = .005), and GDF-15 increased from 1171 ng/L (755–2493) to 1887 ng/L (9033763) (P = .006). MHD, V5, and V30 were significantly associated with post-RT PIGF and GDF-15 levels in multivariable models. Changes in biomarkers were not significantly associated with changes in echocardiography-derived measures of cardiac function. CONCLUSION: Contemporary thoracic RT induces acute abnormalities in vascular and inflammatory biomarkers that are associated with radiation dose-volume metrics, particularly in lung cancer and mediastinal lymphoma. Long-term follow-up studies are needed to determine the impact of these changes on the development of overt cardiac disease.

Doxorubicin and trastuzumab, commonly used in the treatment of breast cancer, can result in left ventricular ejection fraction (LVEF) declines and heart failure (HF). However, the effects of these therapies on diastolic function remain incompletely defined. In a prospective longitudinal cohort

Results from several recent studies in chronic lymphocytic leukemia (CLL) have demonstrated an association between ibrutinib exposure and the development of atrial fibrillation, estimated incidence of 11% with long-term follow up. This is a common cause of ibrutinib discontinuation. Risk factors for atrial fibrillation include advanced age, hypertension (HTN), mitral valve disease (MVD), left atrial remodeling, coronary artery disease (CAD) and risk factors for cardiovascular dysfunction We conducted a retrospective case control study using the presence of left atrial abnormality identified on pre-ibrutinib EKGs, defined as either (1) Lead II-bifed p wave, with 40 mcsec between peaks for ≥ 2.5 mm wide ≥ 100 msec in duration, (2) Lead V1-biphasic P wave with terminal portion ≥ 40 msec in duration or terminal portion ≥ 1 mm deep or (3) PR interval ≥ 200 msec (intra-atrial conduction delay) as a predictor for development of atrial fibrillation. 183 consecutively CLL patients treated with ibrutinib were identified. 44 patients met inclusion criteria (20 cases, 24 controls). 20 (11.3%) of patients developed atrial fibrillation. Left atrial enlargement was identified as a significant predictor of development of atrial fibrillation (OR 9.1, 95% CI 2.2–37.3, p=0.02). Age, baseline HTN, CAD, diabetes, age and sex were not significant predictors. Area under the ROC curve for the model was estimated to be 75%. LAA identified by EKG is a moderately specific and sensitive finding that can identify patients at increased risk for this toxicity.

Background Electrocardiographic changes may manifest in patients with pericardial effusions. PR segment changes are frequently overlooked, but when present, can provide diagnostic significance. The diagnostic value of PR segment changes in determining benign versus malignant pericardial disease in cancer patients with pericardial effusions has not been investigated. We aimed to determine the relationship between PR segment changes and malignant pericardial disease in cancer patients presenting with pericardial effusions. Methods Consecutive patients with active malignancy who underwent surgical subxiphoid pericardial window by a single thoracic surgeon between 2011 and 2014 were included in this study. A total of 104 pre- and post-operative ECGs were reviewed, and PR depression or elevation was defined by deviation of at least 0.5 millivolts from the TP segment using a magnifying glass. Pericardial fluid cytology, flow cytometry and tissue biopsy were evaluated. Baseline characteristics and co-morbidities were compared between cancer patients with benign and malignant pericardial effusions. Results A total of 26 patients with active malignancy and pericardial effusion who underwent pericardial window over the study period were included. Eighteen (69 %) patients had isoelectric PR segments, of whom none (0 %) had evidence of malignant pericardial disease (100 % negative predictive value). Eight (31 %) patients had significant ECG findings (PR segment depression in leads II, III and/or aVF as well as PR elevation in aVR/V1), all 8 (100 %) of whom had pathologically confirmed malignant pericardial disease (100 % positive predictive value). PR segment changes in all 8 patients persisted (up to 11 months) on post-operative serial ECGs. The PR segment changes had no relationship to heart rate or the time of atrial-ventricular conduction. Conclusions In patients with active cancer presenting with pericardial effusion, the presence of PR segment changes is highly predictive of active malignant pericardial disease. When present, PR changes typically persist on serial ECGs even after pericardial window.

Breast cancer is commonly diagnosed in postmenopausal women, the majority of whom express 1 or more cardiovascular disease risk factors. Cardiovascular disease poses a significant competing risk for morbidity and mortality among nonmetastatic breast cancer survivors. Adjuvant systemic therapies may result in late-cardiac toxicity decades after treatment completion. The cumulative incidence of treatment-related cardiotoxic outcomes may be as high as 33% after some adjuvant breast cancer therapies. Breast cancer treatment-induced cardiotoxicity may manifest as cardiomyopathy, coronary ischemia, thromboembolism, arrhythmias and conduction abnormalities, and valvular and pericardial disease. Evidence indicates that preexisting cardiovascular conditions such as hypertension or left ventricular dysfunction may compound the adverse effects of cardiotoxic treatments. There are currently no published clinical practice guidelines that address ongoing cardiac surveillance for cardiotoxicity after breast cancer, and existing guidelines for monitoring and promoting cardiovascular health in older women are often not followed. The multidisciplinary prospective surveillance system proposed elsewhere in this supplement would allow for earlier detection of cardiotoxicity from treatment and may improve monitoring of cardiovascular health in the growing population of breast cancer survivors.

Background: The renin angiotensin system RAS modulates hematopoiesis via local effects in the bone marrow. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) may adversely impact hematopoiesis and time to engraftment in patients undergoing stem cell transplant (SCT). Our study assesses whether the use of ACEi or ARBs delays time to engraftment in patients with multiple myeloma undergoing a melphalan based autologous SCT. Methods: A retrospective review of 58 patients who underwent autologous SCT with a melphalan 200 mg/m2 conditioning regimen for multiple myeloma between January 1 and December 31, 2010 was performed. Results: Of 58 evaluable patients, 47 underwent autologous SCT without an ACEi or ARB (control group), and 11 patients were given ACEi or ARBs (treatment group). Mean time to neutrophil engraftment was 11.5 days in the control group, and 11.3 days in treatment group (p = 0.60). Mean time to platelet engraftment in control group was 13.5 days and 15.1 days in treatment group (p = 0.2). There was no statistically significant difference between groups in time to neutropenic fever and length of hospital stay. Conclusion: Our study demonstrates no significant difference in time to engraftment, incidence of neutropenic fever, or length of hospital stay between patients receiving ACEi or ARBS compared to control subjects. We demonstrate that use of low to moderate dose ACEi or ARB does not lead to prolonged time to engraftment and is safe to use in patients undergoing autologous SCT for multiple myeloma.

As breast cancer survival increases, cardiotoxicity associated with chemotherapeutic regimens such as anthracyclines and trastuzumab becomes a more significant issue. Assessment of the left ventricular (LV) ejection fraction fails to detect subtle alterations in LV function. The objective of this study was to evaluate whether more sensitive echocardiographic measurements and biomarkers could predict future cardiac dysfunction in chemotherapy-treated patients. Forty-three patients diagnosed with breast cancer who received anthracyclines and trastuzumab therapy underwent echocardiography and blood sampling at 3 time points (baseline and 3 and 6 months during the course of chemotherapy). The LV ejection fraction; peak systolic myocardial longitudinal, radial, and circumferential strain; echocardiographic markers of diastolic function; N-terminal pro-B-type natriuretic peptide; and high-sensitivity cardiac troponin I were measured. Nine patients (21%) developed cardiotoxicity (1 at 3 months and 8 at 6 months) as defined by the Cardiac Review and Evaluation Committee reviewing trastuzumab. A decrease in longitudinal strain from baseline to 3 months and detectable high-sensitivity cardiac troponin I at 3 months were independent predictors of the development of cardiotoxicity at 6 months. The LV ejection fraction, parameters of diastolic function, and N-terminal pro-B-type natriuretic peptide did not predict cardiotoxicity. In conclusion, cardiac troponin plasma concentrations and longitudinal strain predict the development of cardiotoxicity in patients treated with anthracyclines and trastuzumab. The 2 parameters may be useful to detect chemotherapy-treated patients who may benefit from alternative therapies, potentially decreasing the incidence of cardiotoxicity and its associated morbidity and mortality.

Increases in the number of adult cancer survivors and other issues have forced the oncology community to examine, evaluate, and alter the cancer care paradigm. Pediatric oncologists are grappling with the task of transitioning a growing population of adult survivors of childhood cancer to adult medicine, while oncologists caring for adult cancer survivors are seeking models of follow-up care that are acceptable to patients and providers. Workforce and access-to-care issues suggest that primary care providers will see more cancer survivors in their practices across time, although it is unclear how prepared they are for this task. Translational research is needed to develop evidence-based clinical care and survivorship care plans. A broad picture of the evolving field of adult cancer survivorship is presented. The recent focus on young adult survivors of childhood cancer, an overview of translational research needed to inform the physical and psychosocial care of cancer survivors, and the roles of primary and specialty care providers managing this population is examined. Finally, an overview of evolving treatment summary and care plan initiatives is presented.

Background Targeting HER-2/neu with Trastuzumab has been associated with development of cardiac toxicity.

Advances in cancer treatments have brought hope to patients with these diseases once thought to be incurable. However, these same treatments can inadvertently harm healthy cells and affect systems unrelated to the cancer, especially the cardiovascular system [1]. A precise definition of cardiotoxicity is still lacking [2]. However, an overwhelming body of evidence has established that patients exposed to antitumor therapies have several laboratory or clinical indices of cardiovascular dysfunction and that become more evident as patients live longer. As a result, patients with cancer who have or who are at risk of cardiovascular toxicity are now being treated collaboratively by oncologists-hematologists, radiotherapists, and cardiologists, which has led to a new interdisciplinary field, cardio-oncology. The journal Cardio-Oncology is a dedicated forum for oncologists, cardiologists, researchers, and other health providers who care for patients who have survived or who are being treated for cancer. It also provides the opportunity for the latest and highest quality evidence in this emerging field to be widely shared in the medical community. The mission of Cardio-Oncology is to publish research that addresses the balance between curing cancer and limiting the adverse cardiovascular effects of cancer treatment. To achieve this mission, we welcome a broad range of original research and review articles addressing many questions in this complex field from a multidisciplinary approach. Cardio-oncology has many areas of research. Here, we highlight some of the more pressing issues in the field and invite authors to submit for publication their work on these and other issues. First, we have to better understand the risks of cardiovascular toxicity to establish effective prevention and surveillance protocols. A lack of awareness or underestimating the cardiovascular risks of cancer treatment

BACKGROUND Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity. METHODS In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro–B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered. RESULTS Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10–1.71), P = 0.02; PlGF 3.78 (1.30–11.0), P = 0.047; GDF-15 1.71 (1.15–2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions. CONCLUSIONS Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts.

Evidence supporting the role of hematopoietic stem cell transplantation (SCT) in the therapy of multiple myeloma (MM) is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published medical literature and for grading the quality of the evidence, the strength of the evidence, and the strength of the treatment recommendations. Treatment recommendations based on the evidence presented in the review were made unanimously by a panel of MM experts. Recommendations for SCT as an effective therapy for MM include the following: SCT is preferred to standard chemotherapy as de novo therapy; SCT is preferred as de novo rather than salvage therapy; autologous peripheral blood stem cell transplantation (PBSCT) is preferred to bone marrow transplantation (BMT); and melphalan is preferred to melphalan plus total body irradiation as the conditioning regimen for autologous SCT. Recommendations that SCT is not effective include the following: current purging techniques of bone marrow. Recommendations of equivalence include the following: PBSCT using CD34+ selected or unselected stem cells. No recommendation is made for indications or transplantation techniques that have not been adequately studied, including the following: SCT versus standard chemotherapy as salvage therapy, tandem autologous SCT, autologous or allogeneic SCT as a high-dose sequential regimen, allogeneic BMT versus PBSCT, a preferred allogeneic myeloablative or non-myeloablative conditioning regimen, and maintenance therapy post–autologous SCT with interferon alpha post-SCT. The priority area of needed future research is maintenance therapy posttransplantation with nothing versus interferon alpha versus other agents such as corticosteroids or thalidomide or its derivatives. © 2003 American Society for Blood and Marrow Transplantation Biology of Blood and Marrow Transplantation 9:4-37 (2003)

8018 Background: The incidence and nature of cardiovascular adverse events (CVAEs) with carfilzomib (CFZ) in multiple myeloma (MM) remain incompletely defined. We performed the first systematic review and meta-analysis of CFZ CVAEs. Methods: PubMed was queried for the keywords “carfilzomib,” “Kyprolis,” and “PX-171.” Phase 1-3 clinical trials of carfilzomib in MM with evaluable toxicity data were included. CVAEs were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grade ≥3 CVAEs and study characteristics were recorded. Summary incidence rates and relative risks (for randomized trials) with 95% confidence intervals were calculated using the logistic-normal random-effects model. Subgroup analyses were performed using study level covariates. Results: 514 studies were reviewed. 2623 MM patients from 25 eligible studies were included. Incidence rates are summarized in the table. All grade and grade ≥3 CVAEs were seen in 16.8% and 7.6 %, respectively. Phase 2 or 3 studies, carfilzomib doses ≥45mg/m2, and longer infusion length were study characteristics associated with high-grade cardiac AEs (p65, prior MM therapies, and concurrent MM therapies were not associated with CVAEs (p>.05). For the three randomized trials, the relative risk of all-grade and grade ≥3 CVAEs were 1.75 and 2.25, respectively (p