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Cardioprotective therapies represent an important avenue to reduce treatment-limiting cardiotoxicities in patients receiving chemotherapy. However, the optimal duration, strategy and long-term efficacy of empiric cardio-protection remains unknown.Leveraging the MEDLINE/Pubmed, CENTRAL and clinicaltrials.gov databases, we identified all randomised controlled trials investigating cardioprotective therapies from inception to November 2021 (PROSPERO-ID:CRD42021265006). Cardioprotective classes included ACEIs, ARBs, Beta-blockers, dexrazoxane (DEX), statins and mineralocorticoid receptor antagonists. The primary end-point was new-onset heart failure (HF). Secondary outcomes were the mean difference in left ventricular ejection fraction (LVEF) change, hypotension and all-cause mortality. Network meta-analyses were used to assess the cardioprotective effects of each therapy to deduce the most effective therapies. Both analyses were performed using a Bayesian random effects model to estimate risk ratios (RR) and 95% credible intervals (95% CrI).Overall, from 726 articles, 39 trials evaluating 5931 participants (38.0 ± 19.1 years, 72.0% females) were identified. The use of any cardioprotective strategy associated with reduction in new-onset HF (RR:0.32; 95% CrI:0.19-0.55), improved LVEF (mean difference: 3.92%; 95% CrI:2.81-5.07), increased hypotension (RR:3.27; 95% CrI:1.38-9.87) and no difference in mortality. Based on control arms, the number-needed-to-treat for 'any' cardioprotective therapy to prevent one incident HF event was 45, including a number-needed-to-treat of 21 with ≥1 year of therapy. Dexrazoxane was most effective at HF prevention (Surface Under the Cumulative Ranking curve: 81.47%), and mineralocorticoid receptor antagonists were most effective at preserving LVEF (Surface Under the Cumulative Ranking curve: 99.22%).Cardiotoxicity remains a challenge for patients requiring anticancer therapies. The initiation of extended duration cardioprotection reduces incident HF. Additional head-to-head trials are needed.

Over the last several decades, advancements in cancer screening and treatment have significantly improved cancer mortality and overall quality of life. Unfortunately, non-cancer-related side effects, including cardiovascular toxicities can impact the continued delivery of these treatments. Arrhythmias are an increasingly recognized class of cardiotoxicity that can occur as a direct consequence of the treatment or secondary to another type of toxicity such as heart failure, myocarditis, or ischemia. Atrial arrhythmias, particularly atrial fibrillation (AF) are most commonly encountered, however, ventricular- and bradyarrhythmias can also occur, albeit at lower rates. Treatment strategies tailored to patients with cancer are essential to allow for the safe delivery of the cancer treatment without affecting short- or long-term oncologic or cardiovascular outcomes.

Cardiovascular disease is a leading cause of death in cancer survivors, after recurrence of the primary tumor or occurrence of a secondary malignancy. Consequently, the interdisciplinary field of cardio-oncology has grown rapidly in recent years to address the cardiovascular care needs of this unique population through clinical care and research initiatives. Here, the authors discuss the ideal infrastructure for training and career development in cardio-oncology translational and implementation science and emphasize the importance of the multidisciplinary cardiovascular team for both research and patient care. Cardio-oncology training opportunities in general cardiology, hematology/oncology, and specialized cardio-oncology clinical and research fellowships are also considered.

Background Anthracyclines remain a key treatment for many malignancies but can increase the risk of heart failure or cardiomyopathy. Specific guidelines recommend echocardiography and serum cardiac biomarkers such as BNP (B‐type natriuretic peptide) or NT‐proBNP (N‐terminal proBNP) evaluation before and 6 to 12 months after treatment. Our objective was to evaluate associations between racial and ethnic groups in cardiac surveillance of survivors of cancer after exposure to anthracyclines. Methods and Results Adult patients in the OneFlorida Consortium without prior cardiovascular disease who received at least 2 cycles of anthracyclines were included in the analysis. Multivariable logistic regression was performed to estimate the odds ratios (ORs) and 95% CIs for receiving cardiac surveillance at baseline before anthracycline therapy, 6 months after, and 12 months after anthracycline exposure among different racial and ethnic groups. Among the entire cohort of 5430 patients, 63.4% had a baseline echocardiogram, with 22.3% receiving an echocardiogram at 6 months and 25% at 12 months. Non‐Hispanic Black (NHB) patients had a lower likelihood of receiving a baseline echocardiogram than Non‐Hispanic White (NHW) patients (OR, 0.75 [95% CI, 0.63–0.88]; P =0.0006) or any baseline cardiac surveillance (OR, 0.76 [95% CI, 0.64–0.89]; P =0.001). Compared with NHW patients, Hispanic patients received significantly less cardiac surveillance at the 6‐month (OR, 0.84 [95% CI, 0.72–0.98]; P =0.03) and 12‐month (OR, 0.85 [95% CI, 0.74–0.98]; P =0.03) time points, respectively. Conclusions There were significant racial and ethnic differences in cardiac surveillance among survivors of cancer at baseline and following anthracycline‐based treatment in NHB and Hispanic cohorts. Health care providers need to be cognizant of these social inequities and initiate efforts to ensure recommended cardiac surveillance occurs following anthracyclines.

Background Chimeric antigen receptor T- Cell (CAR-T) immunotherapy has been a breakthrough treatment for various hematological malignancies. However, cardiotoxicities such as new-onset heart failure, arrhythmia, acute coronary syndrome and cardiovascular death occur in 10–15% of patients treated with CAR-T. This study aims to investigate the changes in cardiac and inflammatory biomarkers in CAR-T therapy to determine the role of pro-inflammatory cytokines. Methods In this observational study, ninety consecutive patients treated with CAR-T underwent baseline cardiac investigation with electrocardiogram (ECG), transthoracic echocardiogram (TTE), troponin-I, and B-type natriuretic peptide (BNP). Follow-up ECG, troponin-I and BNP were obtained five days post- CAR-T. In a subset of patients (N = 53), serum inflammatory cytokines interleukin (IL)-2, IL-6, IL-15, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and angiopoietin 1 & 2 were tested serially, including baseline and daily during hospitalization. Adverse cardiac events were defined as new-onset cardiomyopathy/heart failure, acute coronary syndrome, arrhythmia and cardiovascular death. Results Eleven patients (12%) had adverse cardiac events (one with new-onset cardiomyopathy and ten with new-onset atrial fibrillation). Adverse cardiac events appear to have occurred among patients with advanced age (77 vs. 66 years; p = 0.002), higher baseline creatinine (0.9 vs. 0.7 mg/dL; 0.007) and higher left atrial volume index (23.9 vs. 16.9mL/m2; p = 0.042). Day 5 BNP levels (125 vs. 63pg/mL; p = 0.019), but not troponin-I, were higher in patients with adverse cardiac events, compared to those without. The maximum levels of IL-6 (3855.0 vs. 254.0 pg/mL; p = 0.021), IFN-γ (474.0 vs. 48.8pg/mL; p = 0.006) and IL-15 (70.2 vs. 39.2pg/mL; p = 0.026) were also higher in the adverse cardiac events group. However, cardiac and inflammatory biomarker levels were not associated with cardiac events. Patients who developed cardiac events did not exhibit worse survival compared to patients without cardiac events (Log-rank p = 0.200). Conclusion Adverse cardiac events, predominantly atrial fibrillation, occur commonly after CAR-T (12%). The changes in serial inflammatory cytokine after CAR-T in the setting of adverse cardiac events suggests pro-inflammation as a pathophysiology and require further investigation for their role in adverse cardiac events. Tweet brief handle CAR-T related Cardiotoxicity has elevated cardiac and inflammatory biomarkers. #CARTCell #CardioOnc #CardioImmunology.

Introduction The risk of hemorrhagic transformation (HT) in the early phase of acute ischemic stroke (AIS) remains unknown, leading to potential unnecessary delays in initiation of anticoagulation for secondary stroke prevention. We sought to assess the rate of HT associated withdirect oral anticoagulant (DOAC) initiation within and beyond 48 hours after AIS, using a pooled analysis of available published data. Methods A pooled analysis of 6 studies (4 prospective observational blinded outcome studies and2 randomized trials) of DOAC initiation within 14 days of AIS or transient ischemic attack (TIA) was conducted. The primary endpoint was incident radiographic HT on follow‐up imaging. Secondary endpoints included symptomatic HT, new parenchymal hemorrhage, recurrent ischemic events, extracranial hemorrhage, mortality within the study period, and follow‐up modified Rankin Scale score.The results were reported as odds ratio (OR) andhazard ratio (HR)with 95% confidence interval (CI). Results We evaluated 509 patients; median infarct volume was1.5 (0.1‐7.8) ml, andmedian National Institutes of Health Stroke Scale was2 (0‐3).Incident radiographic HT was seen on follow‐up scan in 34 (6.8%) patients.DOAC initiation within 48 hours from index event was not associated with incident HT (adjusted OR 0.67, [0.30 – 1.50]P = 0.32).No patients developed symptomatic HT.Conversely, 31 (6.1%) patients developedrecurrent ischemic events, 64% of which occurred within 14 days.Initiating a DOAC within 48 hours of onset was associated with a trend towards lower rates of recurrent ischemic events, but this was not statistically significant (HR 0.42, [0.17 – 1.008]P = 0.052). In contrast to HT,recurrent ischemic events were associated with poor functional outcomes (OR = 6.8, [2.84 – 16.24], p< 0.001). Conclusions Initiation of DOAC within 48 hours after stroke was not associated with decreased risk of recurrent ischemic events, or increasedincident risk of HT. Both recurrent ischemic events and incident HT occurred at similar rates.Unlike HT, however, recurrent ischemic events were associated with poor outcomes.

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

We aim to determine the cumulative and comparative risk of cardiovascular events associated with different Immunomodulatory Drugs (iMiDs) and Proteasome Inhibitor (PIs) in Multiple Myeloma (MM) patients through pairwise and network meta-analysis. Electronic searches were conducted using Ovid MEDLINE, EMBASE, CINAHL, Web of Science, and Clinical Trial Registry (Clinical Trials.gov) up to May 2021. Phase 3 randomized clinical trials (RCTs) reporting cardiotoxicity in MM patients (newly diagnoses and/or relapsed) treated with iMiD and/or PI. Studies, where iMiD or PI was used alongside the chemotherapy versus placebo or no additional drugs (control) in the other arm were included. The primary outcome was the presence of cardiotoxicity after follow-up. Pairwise meta-analysis and network meta-analysis were performed using the frequentist's approach to estimate the odds ratio (OR). Twenty RCTs with 10,373 MM patients were included in this analysis. Eleven studies compared iMiDs with control, seven studies compared PIs with control, and two studies compared bortezomib against carfilzomib. CTACE high-grade (≥grade 3) cardiotoxic events were increased with iMiDs compared to their control counterpart (OR 2.05; 95% CI 1.30-3.26). Similar high-grade cardiotoxicity was also noted more frequently with PI use when compared to the control group (OR 1.67; 95% CI 1.17-2.40). Among the PIs, carfilzomib was associated with a maximum risk of cardiotoxicity (OR 2.68; 95% CI 1.63-4.40). There was no evidence of publication bias among studies. iMiDs and PIs, particularly carfilzomib, appear to be associated with increased risk of high-grade cardiovascular events in MM patients.

The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.

Aims The national incidence, risk factors, and associated mortality of atrial fibrillation (AF) in breast cancer patients are unknown. Methods and results Using the Surveillance, Epidemiology, and End Results-Medicare-linked database, we identified females, ≥66 years old, with a new primary diagnosis of breast cancer from 2007 through 2014. These patients were individually matched 1:1 to Medicare enrolees without cancer, and each pair was followed for 1 year to identify a primary outcome of AF. Cumulative incidence was calculated using competing risk survival statistics. Following this, identifying risk factors of AF among breast cancer patients was conducted using the adjusted Cox proportional hazards model. Finally, Kaplan–Meier methods and adjusted Cox proportional hazards modelling were performed to estimate mortality in breast cancer patients with incident and prevalent AF. This study included 85 423 breast cancer patients. Among these 9425 (11.0%) had AF diagnosis prior to the breast cancer diagnosis. New-onset AF was diagnosed in 2993 (3.9%) patients in a 1-year period after the breast cancer diagnosis [incidence 3.3%, 95% confidence interval (CI) 3.0–3.5%, at 1 year; higher rate in the first 60 days (0.6%/month)]. Comparatively, the incidence of new-onset AF in matched non-cancer controls was 1.8% (95% CI 1.6–2.0%). Apart from traditional demographic and cardiovascular risk factors, breast cancer stage was strongly associated with the development of AF [American Joint Committee on Cancer (AJCC) Stage II/III/IV vs. I: adjusted hazard ratio (aHR) 1.51/2.63/4.21, respectively]. New-onset AF after breast cancer diagnosis (aHR 3.00) is associated with increased 1-year cardiovascular mortality. Conclusion AF incidence is significantly higher in women after a breast cancer diagnosis. Higher breast cancer stages at diagnos are significantly associated with a higher risk of AF. New-onset AF in the new breast cancer diagnosis setting increases 1-year cardiovascular mortality but not breast cancer-related mortality. Key Question What are the incidence, prevalence, risk factors and mortality outcomes of atrial fibrillation (AF) in a multi-ethnic representative United States cohort of breast cancer patients? Key Finding Annual incidence for AF is 3.9% with highest rate in the first 60 days after cancer diagnosis. Cancer stage and grade are the strongest risk factors for AF. New onset AF after breast cancer increases all-cause and cardiovascular mortality. Take Home Message AF incidence is higher in breast cancer patients and is associated with later stage and grade at diagnosis of breast cancer. Involving cardio-oncology in those who develop AF after cancer diagnosis should be encouraged to improve their cardiovascular and overall prognosis.

Purpose:The comparative cardiovascular risk profiles of available hormone therapies for the treatment of prostate cancer is not known.Materials and Methods:We queried the U.S. Food and Drug Adminis...

Global circumferential strain (GCS) and global radial strain (GRS) are reduced with cytotoxic chemotherapy. There are limited data on the effect of immune checkpoint inhibitor (ICI) myocarditis on GCS and GRS.This study aimed to detail the role of GCS and GRS in ICI myocarditis.In this retrospective study, GCS and GRS from 75 cases of patients with ICI myocarditis and 50 ICI-treated patients without myocarditis (controls) were compared. Pre-ICI GCS and GRS were available for 12 cases and 50 controls. Measurements were performed in a core laboratory blinded to group and time. Major adverse cardiovascular events (MACEs) were defined as a composite of cardiogenic shock, cardiac arrest, complete heart block, and cardiac death.Cases and controls were similar in age (66 ± 15 years vs 63 ± 12 years; P = 0.20), sex (male: 73% vs 61%; P = 0.20) and cancer type (P = 0.08). Pre-ICI GCS and GRS were also similar (GCS: 22.6% ± 3.4% vs 23.5% ± 3.8%; P = 0.14; GRS: 45.5% ± 6.2% vs 43.6% ± 8.8%; P = 0.24). Overall, 56% (n=42) of patients with myocarditis presented with preserved left ventricular ejection fraction (LVEF). GCS and GRS were lower in myocarditis compared with on-ICI controls (GCS: 17.5% ± 4.2% vs 23.6% ± 3.0%; P< 0.001; GRS: 28.6% ± 6.7% vs 47.0% ± 7.4%; P< 0.001). Over a median follow-up of 30days, 28 cardiovascular events occurred. A GCS (HR: 4.9 [95%CI: 1.6-15.0]; P = 0.005) and GRS (HR: 3.9 [95%CI: 1.4-10.8]; P = 0.008) below the median was associated with an increased event rate. In receiver-operating characteristic (ROC) curves, GCS (AUC: 0.80 [95%CI: 0.70-0.91]) and GRS (AUC: 0.76 [95%CI: 0.64-0.88]) showed better performance than cardiac troponin T (cTnT) (AUC: 0.70 [95%CI: 0.58-0.82]), LVEF (AUC: 0.69 [95%CI: 0.56-0.81]), and age (AUC: 0.54 [95%CI: 0.40-0.68]). Net reclassification index and integrated discrimination improvement demonstrated incremental prognostic utility of GRS over LVEF (P = 0.04) and GCS over cTnT (P = 0.002).GCS and GRS are lower in ICI myocarditis, and the magnitude of reduction has prognostic significance.

Precision medicine has ushered in a new era of targeted treatments for numerous malignancies, leading to improvements in overall survival. Unlike traditional chemotherapy, many molecular targeted antineoplastic agents are available in oral formulation, leading to enhanced patient convenience and a perception of reduced risk of adverse effects. Although oral antineoplastic agents are generally well-tolerated, cardiovascular toxicities are being reported with increasing frequency in part due to U.S. Food and Drug Administration and manufacturer recommended cardiac monitoring. Monitoring strategies have focused on left ventricular dysfunction, hypertension, and QT prolongation/arrhythmias. Given the rapid pace of development and availability of new oral antineoplastic agents, the purpose of this review is to provide clinicians with an up-to-date practical approach to monitoring and management of cardiovascular toxicities with the aim of improving overall outcomes for patients with cancer.

Cancer-related mortality has significantly declined over the past several decades as a result of improved screening, diagnostics, and therapeutics. Although cancer patients and survivors are living longer, there is increased risk of both short-term and long-term cardiovascular complications, including arrhythmia. In this review, we highlight the current evidence detailing the connections between atrial fibrillation and cancer, provide insight into the mechanisms driving this relationship, and share practical considerations for the management of atrial fibrillation in cancer patients and cancer survivors.Atrial fibrillation is an increasingly recognized condition among cancer patients, with epidemiological data showing increased incidence and worse outcomes in patients with cancer. Studies also describe a bidirectional relationship between cancer and atrial fibrillation, attributable in part to shared risk factors but also potentially due to shared biology. Cancer treatment-associated arrhythmia is an active area of investigation, with ongoing research to identify the mechanisms and pathophysiology behind this phenomenon. Furthermore, management of atrial fibrillation in patients with cancer presents unique challenges, particularly in management of anti-coagulation. Cancer patients have increased risk of developing atrial fibrillation due to the shared risk factors and biology of the two conditions. Moreover, various cancer therapeutics are known to be arrhythmogenic; however, mechanisms remain unclear. Further research is needed to better understand the pathophysiology of atrial fibrillation in cancer patient in order to establish prevention and treatment strategies specific to this population.

Background The aim of this study is to assess the burden of AF-related hospitalizations inclusive of inflation-adjusted cost-of-care and length-of-stay (LOS) among cancer patients and the impact of direct current cardioversion (DCCV) on these outcomes. Methods Using the National Inpatient Sample (NIS), patients hospitalized with either a primary or secondary diagnosis of AF and comorbid cancer were identified and both cost of hospitalization and LOS were evaluated for each group. Subgroup analyses were performed for specific cancer types (breast, lung, colon, prostate and lymphoma), and those receiving DCCV. Results The prevalence of co-morbid AF was 8.2 million (16%) and 35.5 million (10%) among those with vs. those without cancer, respectively (odds ratio = 1.6, 95% confidence interval = 1.5–1.7; P P P Conclusions AF related admissions are increasing for all populations especially amongst those patients with a comorbid diagnosis of cancer, including all cancer subtypes evaluated. Among those patients who underwent DCCV, cancer patients had longer length of stay and increased health care costs.

Cancer patients face a higher risk of future myocardial infarction (MI), even after completion of anticancer therapies. MI is a critical source of physical and financial stress in non-cancer patients, but its impacts associated with cancer patients also saddled with the worry (stress) of potential reoccurrence is unknown. Therefore, we aimed to quantify MI’s stress and financial burden after surviving cancer and compare to those never diagnosed with cancer. Utilizing cross-sectional national survey data from 2013–2018 derived from publicly available U.S. datasets, the National Health Interview Survey (NHIS), and economic data from the National Inpatient Sample (NIS), we compared the socio-economic outcomes among those with MI by cancer-status. We adjusted for social, demographic, and clinical factors. Overall, 19,504 (10.2%) of the 189,836 NHIS survey responders reported having cancer for more than 1 year. There was an increased prevalence of MI among cancer survivors compared to non-cancer patients (8.8% vs. 3.2%, P0.05). There was no difference in annual residual family income by cancer status; however, 3 lowest deciles of residual income representing 21.1% cancer-survivor with MI had a residual income of

Background Atrial fibrillation (AF) is a common cardiovascular complication affecting patients with cancer, but management strategies are not well established. Objectives The purpose of this retrospective cohort study was to evaluate cross-sectional patterns of anticoagulation (AC) use in patients with cancer with AF or atrial flutter (AFL) on the basis of their risk for stroke and bleeding. Methods Patients with cancer and electrocardiograms showing AF or AFL performed at Moffitt Cancer Center in either the inpatient or outpatient setting were included in this retrospective analysis. We described percentages of AC prescription by stroke and bleeding risk, as determined by individual CHA2DS2-VASc and HAS-BLED scores, respectively. Multivariable logistic regression evaluated clinical variables independently associated with anticoagulant prescription. Results The prevalence of electrocardiography-documented AF or AFL was 4.8% (n = 472). The mean CHA2DS2-VASc score was 2.8 ± 1.4. Among patients with CHA2DS2-VASc scores ≥2 and HAS-BLED scores, Central Illustration

Adoptive cellular therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has emerged as an effective treatment option for unresectable stage III/IV metastatic melanoma. Acute toxicities, particularly cardiovascular (CV), can have a significant effect on the completion of therapy. We abstracted information on 43 patients who received ACT-TIL treatment for melanoma at the Moffitt Cancer Center between 2010 and 2016. The Student t tests and χ2 tests were used to compare patient characteristics by presence versus absence of specific CV complications. In this cohort, 32.6% developed hypotension requiring treatment with intravenous fluids and pressors, 14% atrial fibrillation, and 2.3% troponin elevations suggestive of myocardial damage. No patients developed clinical heart failure, and among the patients that underwent echocardiography, there was no significant difference in mean left ventricular ejection fraction before or after therapy (62.9% vs. 63.5%, respectively, P=0.79). There was also no statistically significant difference in survival between those with and without CV complications (overall survival=61.9%, mean: 26.0 mo and progression-free survival=45.2%, mean: 18.1 mo). CV toxicities are common in ACT-TIL protocols; however, survival does not appear to be significantly affected. Further research is needed to define mechanisms and potential prevention strategies to help clinicians manage these complications and mitigate risk.

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

Patients with pre-existing cardiovascular disease and risk factors are more likely to experience adverse outcomes associated with the novel coronavirus disease-2019 (COVID-19). Additionally, consistent reports of cardiac injury and de novo cardiac complications, including possible myocarditis, arrhythmia, and heart failure in patients without prior cardiovascular disease or significant risk factors, are emerging, possibly due to an accentuated host immune response and cytokine release syndrome. As the spread of the virus increases exponentially, many patients will require medical care either for COVID-19 related or traditional cardiovascular issues. While the COVID-19 pandemic is dominating the attention of the healthcare system, there is an unmet need for a standardized approach to deal with COVID-19 associated and other traditional cardiovascular issues during this period. We provide consensus guidance for the management of various cardiovascular conditions during the ongoing COVID-19 pandemic with the goal of providing the best care to all patients and minimizing the risk of exposure to frontline healthcare workers.

Introduction: Precise risk of hemorrhagic transformation (HT) in acute ischemic stroke (AIS) remains unknown, leading to delays in anticoagulation initiation for secondary stroke prevention. We sought to assess the rate of HT associated with direct oral anticoagulant (DOAC) initiation within and beyond 48 h post-AIS. Methods: A pooled analysis of DOAC initiation within 14 days of AIS or transient ischemic attack (TIA) was conducted with six studies (four prospective open label treatment, blinded outcome studies and two randomized trials; NCT02295826 and NCT02283294). The primary endpoint was incident radiographic HT on follow-up imaging (days 7–30). Secondary endpoints included symptomatic HT, new parenchymal hemorrhage, recurrent ischemic events, extracranial hemorrhage, study period mortality, and follow-up modified Rankin Scale score. The results were reported as odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI). Results: We evaluated 509 patients; median infarct volume was 1.5 (0.1–7.8) ml, and median National Institutes of Health Stroke Scale was 2 (0–3). Incident radiographic HT was seen on follow-up scan in 34 (6.8%) patients. DOAC initiation within 48 h from index event was not associated with incident HT (adjusted OR 0.67, [0.30–1.50] P = 0.32). No patients developed symptomatic HT. Conversely, 31 (6.1%) patients developed recurrent ischemic events, 64% of which occurred within 14 days. Initiating a DOAC within 48 h of onset was associated with similar recurrent ischemic event rates compared with those in which treatment was delayed (HR: 0.42, [0.17–1.008] P = 0.052). In contrast to HT, recurrent ischemic events were associated with poor functional outcomes (OR = 6.8, [2.84–16.24], p Conclusions: In this pooled analysis, initiation of DOAC within 48 h post-stroke was not associated with increased incident risk of HT, and none developed symptomatic HT. The analysis was underpowered to determine the effect of early DOAC use upon recurrent ischemic events.

The development of cardiovascular toxicity attributable to anticancer drugs is a pivotal event that is associated with cardiovascular morbidity as well as with worse cancer‐specific and overall outcomes. Although broad consensus exists regarding the importance of cardiovascular safety assessment in cancer drug development, real‐world data suggest that cardiovascular events are significantly underestimated in oncology trials. This drug safety discrepancy has profound implications on drug development decisions, risk‐benefit evaluation, formulation of surveillance and prevention protocols, and survivorship. In this article, we review the contemporary cardiovascular safety evaluation of new pharmaceuticals in hematology and oncology, spanning from in vitro pharmacodynamic testing to randomized clinical trials. We argue that cardiovascular safety assessment of anticancer drugs should be reformed and propose practical strategies, including development and validation of preclinical assays, expansion of oncology trial eligibility, incorporation of cardiovascular end points in early‐phase studies, and design of longitudinal multi‐institutional cardiotoxicity registries.

Introduction: Combination therapy of Immunomodulatory drugs (iMiDs) (Thalidomide, Lenalidomide, Pomalidomide) and Proteasome Inhibitors (PIs) (Bortezomib, Carfilzomib, Ixazomib) constitutes the backbone of treatment in MM patients. Cardiotoxic side-effect profile of iMiDs is not well-documented. Although Carfilzomib has been associated with cardiotoxicity, whether its adverse effects also mirror the class-specific cardiotoxic profile of PI remain obscure. Proper assessment of cardiotoxicity due to treatment reagents is necessary for optimal patient management. In this pairwise meta-analysis, we explored direct cardiotoxicity with iMiDs and PIs use in patients with multiple myeloma (MM). Hypothesis: Treatment with iMiDs and PIs in MM patients leads to independent cardiotoxicity that is associated with individual class of drugs. Methods: Published randomized control trials (RCTs) were searched up to May 2021 reporting cardiotoxicity (cumulative reported events of ischemia, arrhythmia, failure, stenosis) in MM patients (newly diagnoses and/or relapsed) treated with iMiD and/or PI. Studies, where iMiD or PI were used atop the chemotherapy vs placebo or no additional drugs (control) in the other arm, were included. The primary outcome was presence of cardiotoxicity after follow-up. Meta-analysis was performed using frequentist’s approach to estimate odds ratio (OR). Results: Eighteen RCTs including 8,479 MM patients were included in this analysis. Eleven studies compared iMiDs and seven studies compared PIs with control. CTACE high-grade (≥ grade 3) cardiotoxic events were increased with iMiDs in comparison to their control counterpart (OR 2.05; 95% CI 1.30-3.26). Cardiotoxicity was also noted more frequently with PI use when compared to the control group (OR 1.47; 95% CI 1.19-1.82). Similar difference was observed between high-grade cardiotoxic complication between these groups. There was no evidence of publication bias among studies. Conclusions: Our results showed iMiDs and PIs are independently associated with cardiotoxicity, which may warrant increased awareness among treating physicians and close monitoring of patients. The adverse cardiac event profile with these drugs require further investigation in future studies.

Background Immune checkpoint inhibitor (ICI)-associated myocarditis is associated with a markedly increased risk of morbidity and mortality. The occurrence of ventricular arrhythmias (VA) in patients with ICI-associated myocarditis has not been well characterized. Purpose The aim of this study was to determine the characteristics and risk factors for severe VA in patients with ICI myocarditis. Methods The cohort consisted of 202 patients with ICI myocarditis. Ventricular arrhythmias were defined as a composite of sustained ventricular tachycardia and ventricular fibrillation. We used a multivariable logistic regression model to test the association between clinical variables and the development of VA. Results From a cohort of 202 patients with ICI myocarditis (67±13 years, 35% female, 60% hypertension, 23% diabetes mellitus), 41 (20.3%) developed VA, of which, 33 had VT and 8 had VF. The median time from admission to VF was 144 hours and to VT was 72 hours. A VA occurred in 17.5% of patients with a normal LVEF, and 25% of patients with reduced LVEF. On univariate analysis, a QRS duration >110ms (OR 2.88, 95% CI 1.40 to 6.16, P=0.005) and a QTc duration >470ms were associated with an increased probability of VA (OR 2.58, 95% CI 1.23, 5.41, P=0.012). The association remained significant after adjustment for age and gender. Additionally, a longer time from admission to initiation of corticosteroids was associated with a higher probability of VA (OR 1.06, 95% CI 1.01 to 1.13, P=0.027). The association between the time from admission to administration of corticosteroids and probability of VA remained significant after adjustment for age, gender, and LVEF on admission (OR, 1.06, 95% CI 1.00, 1.13, P=0.037) where each 6-hour delay in the initiation of corticosteroids was associated with a 4% increase in the risk for VA. Conclusions Ventricular arrhythmias are common in the setting of ICI myocarditis and are observed in patients presenting with both a preserved and a reduced LVEF. Wider QRS and longer QT at presentation and longer time from admission to initiation of corticosteroids were associated with an increased risk of VA. Funding Acknowledgement Type of funding sources: None.

Cardiometabolic disease (CMD) is the most common preventable cause of death in the world. A number of components are included in the spectrum of CMD, such as metabolic syndrome/obesity, hyperglycemia/diabetes, dyslipidemia, and hypertension, which are independently associated with cardiovascular disease risk. These conditions often occur together, and patients with cancer frequently undergo treatments that can generate or worsen CMD. This review highlights and presents mechanistic and epidemiological evidence regarding CMD in four categories of anticancer medications, namely, mTOR/PI3K-Akt inhibitors, multi-targeted tyrosine kinase inhibitor (TKI), immune checkpoint inhibitor therapy, and endocrine therapy. Patients taking these medications need careful monitoring during therapy. There is a role for cardio-oncology and onco-primary care specialists in optimally managing patients at risk to mitigate CMD during treatment with these and other investigational anti-cancer medications.

Background: The TEEL Study was an open labeled, non-randomized; phase I dose escalation followed by a planned phase Ib dose expansion trial of Tamoxifen (Tam) with Ribociclib (Ribo) in adult patients with advanced ER+ (HER2 negative) breast cancer. Ribo is an inhibitor of cyclin D1/CDK4 and CDK6 and has been successfully combined with Letrozole to improve PFS. This trial was done to examine the safety of the combination of Tam and Ribo in pre- and post-menopausal pts. The goal of the phase 1 expansion was to help confirm safety and develop a daily dosing schedule. Both Tam and Ribo were known to cause QTC prolongation and this was a major safety concern of the study. Method: This was an open labeled, non-randomized, phase I escalation study with a phase Ib dose expansion. The phase I portion of the study was a dose escalation to determine the safety of the combination and to determine the MTD and the RP2D for Ribo with Tam. Breast cancer patients with HR+/HER2- locally advanced or metastatic breast cancer with any prior endocrine therapy and up to two lines of prior cytotoxic chemotherapy regimens administered in the metastatic or locally advanced setting. The planned Phase Ib dose expansion was not done but was planned to better characterize the toxicity profile and assess the anti-tumor activity Ribo + Tam and to further evaluate the safety of the combination. Triplicate EKG were done at baseline, at C1D1, C1D15, C1D22, and then every subsequent cycle at day 1. Results: A total of 12 patients were screened and 7 patients were enrolled (with 5 screen failures). Ribociclib was given at 400 mg po daily for 21 days on and 7 days off. Tamoxifen was given per standard at 20 mg daily. The best response was partial response. Each cycle was 4 weeks and 1 patient remained on this combination for at least 12 cycles with PR, after cycle 3 and SD thereafter. Two patients developed significant QTC prolongation. Pt. # 3 was taken off study for QTC prolongation after cycle 8 with QTC >501. Prior to that, her treatment had been interrupted twice due to QTC prolongation. Her First EKG was manually calculated at: QT 370ms, QTcb 427ms, QTcf 407ms. Her Longest EKG: QT 402ms, QTcb 514ms, QTcf 473ms. Pt #12 was also taken off study during cycle 6 due to QTC>501. Her first EKG: QTc382ms, QTcb 480ms, QTcf 445ms. “Longest ekg” QTc 432ms, QTcb 496ms, QTcf 473ms. Both of these patients had prolonged QTC based on manual EKG. Dose limiting toxicity was noted in patient #10 who was noted to develop progression of disease (new leptomeningeal disease) after cycle 1 and subsequently had a CVA off study, thought to be associated with progressive disease. Table 1 describes highest QTC vs. cycle of therapy and there does not appear to be evidence of worsening prolongation with the number of cycles on study drugs. Other AEs were noted - please see table 2 for AEs. Conclusions: The combination of Tam and Ribo was not considered to be safe and there were two DLTs in the phase 1 part of the study, leading to the early stopping. The phase I expansion was not completed. There were 5 events of prolonged QTC, one event was determined to be a DLT. The other DLT was a CVA described above (associated with CNS disease). Unfortunately, the combination was limited by the synergistic effects of QTC prolongation of both Tam and Ribo. The importance of manually calculating the EKGs and utilizing the Fridericia formula was noted in this study. The Fidercicia is more accurate in oncology patients as it demonstrates less overcorrection than the Bazzett formula at faster heart rates which a were re quite common in cancer patients. Rational limits must be implemented to ensure patient safety without unnecessary withholding of potentially lifesaving cancer therapies. The relative risk of arrhythmia is 1.2 for QT intervals >500ms and is exceedingly low at QT intervals less than 500ms. QTC duirng each cycleCyclesC1C3C5C7C9C10C11C12Pt. 1475475468465477457481477Pt. 2412421412Pt. 3463462494689479Pt. 8450443Pt. 10420Pt. 11431435437Pt. 12480475513525 Citation Format: Roohi Ismail-Khan, Hatem Soliman, Deanna Hogue, Hyo Sook Han, Martine Extermann, Michael Fradley. The cardo-oncology concerns of combining tamoxifen and ribociclib based on the TEEL trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-05.

Background Chimeric antigen receptors redirect T cells (CAR-T) to target cancer cells. There are limited data characterizing cardiac toxicity and cardiovascular (CV) events among adults treated with CAR-T. Objectives The purpose of this study was to evaluate the possible cardiac toxicities of CAR-T. Methods The registry included 137 patients who received CAR-T. Covariates included the occurrence and grade of cytokine release syndrome (CRS) and the administration of tocilizumab for CRS. Cardiac toxicity was defined as a decrease in the left ventricular ejection fraction or an increase in serum troponin. Cardiovascular events were a composite of arrhythmias, decompensated heart failure, and CV death. Results The median age was 62 years (interquartile range [IQR]: 54 to 70 years), 67% were male, 88% had lymphoma, and 8% had myeloma. Approximately 50% were treated with commercial CAR-T (Yescarta or Kymriah), and the remainder received noncommercial products. CRS, occurring a median of 5 days (IQR: 2 to 7 days) after CAR-T, occurred in 59%, and 39% were grade ≥2. Tocilizumab was administered to 56 patients (41%) with CRS, at a median of 27 h (IQR: 16 to 48 h) after onset. An elevated troponin occurred in 29 of 53 tested patients (54%), and a decreased left ventricular ejection fraction in 8 of 29 (28%); each occurred only in patients with grade ≥2 CRS. There were 17 CV events (12%, 6 CV deaths, 6 decompensated heart failure, and 5 arrhythmias; median time to event of 21 days), all occurred with grade ≥2 CRS (31% patients with grade ≥2 CRS), and 95% of events occurred after an elevated troponin. The duration between CRS onset and tocilizumab administration was associated with CV events, where the risk increased 1.7-fold with each 12-h delay to tocilizumab. Conclusions Among adults, cardiac injury and CV events are common post–CAR-T. There was a graded relationship among CRS, elevated troponin, and CV events, and a shorter time from CRS onset to tocilizumab was associated with a lower rate of CV events.

Multiple cancer therapies are associated with cardiac arrhythmias through a variety of pathophysiologic mechanisms. Atrial fibrillation and atrial flutter are common during cancer therapy but should rarely limit continued delivery of therapy. Ventricular arrhythmias are not common during cancer therapy and are more often secondary to other cardiac pathologies. QT interval monitoring is recommended for some agents, although it is often not a reliable predictor of ventricular arrhythmias. Bradyarrhythmias are common and rarely require intervention, but special attention must be paid to heart block in checkpoint inhibitor therapy.

The objective of this study was to determine whether survival and post-arrest procedural utilization following in-hospital cardiac arrest (IHCA) differ in patients with and without comorbid cancer.We retrospectively reviewed all adult (age ≥18 years old) hospital admissions complicated by IHCA from 2003 to 2014 using the National Inpatient Sample (NIS) dataset. Utilizing propensity score matching using age, gender, race, insurance, all hospital level variables, HCUP mortality score, diabetes, hypertension and cardiopulmonary resuscitation use, rates of survival to hospital discharge and post-arrest procedural utilization were compared.From 2003 to 2014, there were a total of 1,893,768 hospitalizations complicated by IHCA, of which 112,926 occurred in patients with history of cancer. In a propensity matched cohort from 2012 to 2014, those with cancer were less likely to survive the hospitalization (31% vs. 46%, p 0.0001). Following an IHCA, rates of procedural utilization in patients with cancer were significantly less when compared to those without a concurrent malignancy: coronary angiography (4.0% vs. 13.0%), percutaneous coronary intervention (2.2% and 8.0%), targeted temperature management (0.8% vs. 6.0%); p 0.0001 for all comparisons. This patient population was less likely to have acute coronary syndrome (12.6% vs. 27.0%) or congestive heart failure (24.5% vs. 38.2%); p 0.0001 for both comparisons. Survival improved in both groups over the study period (p 0.0001).Patients with a history of cancer who sustain IHCA are less likely to receive post-arrest procedures and survive to hospital discharge. Given the expected rise in the rates of cancer survivorship, these findings highlight the need for broader application of potentially life-saving interventions to lower risk cancer patients who have sustained a cardiac arrest.

There is increasing evidence that rates of atrial arrhythmias (AA), specifically atrial fibrillation and flutter are elevated in patients treated with the tyrosine kinase inhibitor, ibrutinib; however, the exact risk of ibrutinib-associated AA is not definitively established. We conducted a retrospective study of 137 patients diagnosed with B-cell malignancies treated with ibrutinib compared with 106 patients treated with chemotherapy for the same cancers in order to quantify the rates and risk of AA in a "real-world" sample of cancer patients. Fisher's exact test was used to evaluate for any statistically significant differences between groups. Logistic regression was used to generate odds ratios, adjusting for potential confounders. Incidence of AA was 14% (n = 17) in ibrutinib-treated patients compared with 3% (n = 3) in patients treated with chemotherapy (p = 0.009). Ibrutinib-treated patients were significantly older (mean age 67 vs 63 years, p = 0.003); however, there were no other significant differences in baseline characteristics. Ibrutinib use, age, hypertension, and previous use of ACE inhibitors, angiotensin receptor blocker use, β blocker use, and aspirin use were independently associated with incident arrhythmias. In multivariable analysis, patients treated with ibrutinib were associated with a 5-fold increased risk of developing AA (odds ratio = 5.18, 95% confidence interval 1.42 to 18.89). In conclusion, the rates and risk of AA are higher in patients treated with ibrutinib compared with chemotherapy, and this study provides strong evidence that ibrutinib itself is an independent risk factor for the development of incident AA.

Melanoma is the least common but most dangerous skin cancer, accounting for 75% of all deaths from a primary cutaneous malignancy, with incidence rates rising significantly over the last decade. Traditional treatments for melanoma including interferon and cytotoxic chemotherapy had marginal efficacy. With the advent of targeted and immunotherapies, the prognosis for patients with advanced melanoma has significantly improved including those with metastatic disease to the heart. BRAF and MEK inhibitors as well as immune checkpoint inhibitors have become front line therapy for eligible patients with metastatic melanoma and have led to long-term durable response and in some cases can be curative. Despite these oncologic advances, various treatment-limiting side effects can occur. In particular, cardiovascular toxicities can contribute to overall morbidity and mortality in these patients. Toxicities range from asymptomatic QT prolongation and mild LV dysfunction to fulminant myocarditis and potentially life-threatening arrhythmias. A multidisciplinary approach to the care of these patients which includes cardio-oncology evaluation is necessary to develop both risk mitigation and treatment strategies to ensure patients continue receiving necessary and effective melanoma treatments while minimizing long-term adverse cardiovascular effects.

Purpose of Review To give an overview of the role of social media (SoMe) in cardio-oncology during the COVID-19 pandemic. Recent Findings SoMe has been critical in fostering education, outreach, awareness, collaboration, dissemination of information, and advocacy in cardio-oncology. This has become increasingly evident during the COVID-19 pandemic, during which SoMe has helped share best practices, community, and research focused on the impact of COVID-19 in cardiology and hematology/oncology, with cardio-oncology at the interface of these two subspecialty fields. Summary A strength of SoMe is the ability to amplify a message in real-time, globally, with minimal investment of resources. This has been particularly beneficial for the emerging field of cardio-hematology/cardio-oncology, a field focused on the interplay of cancer and cardiovascular disease. SoMe field especially during the COVID-19 pandemic. We illustrate how social media has supported innovation (including telemedicine), amplification of healthcare workers’ voice, and illumination of pre-existing and continued health disparities within the field of cardio-oncology during the pandemic.

Background Immune checkpoint inhibitors (ICIs) are a novel class of anticancer agents that have demonstrated clinical response for both solid and hematological malignancies. ICIs are associated with development of immune-related adverse events including cardiotoxicity. We estimated the incidence of newly diagnosed cardiovascular disease in patients treated with ICIs at a large, tertiary care center. Methods All patients with a cancer diagnosis who received any ICI treatment in the University of Florida’s Integrated Data Repository from 2011 to 2017 were included. Cardiovascular disease was defined as a new ICD diagnosis code for cardiomyopathy, heart failure, arrhythmia, heart block, pericardial disease, or myocarditis after initiation of ICI treatment. Results Of 102,701 patients with a diagnosis of malignancy, 424 patients received at least one ICI. Sixty-two (14.6%) patients were diagnosed with at least one new cardiovascular disease after initiation of ICI therapy. Of the 374 patients receiving one ICI, 21 (5.6%) developed heart failure. Of the 49 patients who received two ICIs sequentially, three (6.1%) developed heart failure and/or cardiomyopathy. Incident cardiovascular disease was diagnosed at a median of 63 days after initial ICI exposure. One patient developed myocarditis 28 days after receiving nivolumab. Mortality in ICI treated patients with a concomitant diagnosis of incident cardiovascular disease was higher compared to those who did not (66.1% vs. 41.4%, odds ratio = 2.77, 1.55–4.95, p = 0.0006). Conclusions This study suggests a high incidence of newly diagnosed cardiovascular disease after the initiation of ICI therapy in a real-world clinical setting.

Background and Purpose: It is unknown when to start anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF). Early anticoagulation may prevent recurrent infarctions but may provoke hemorrhagic transformation as AF strokes are typically larger and hemorrhagic transformation-prone. Later anticoagulation may prevent hemorrhagic transformation but increases risk of secondary stroke in this time frame. Our aim was to compare early anticoagulation with apixaban in AF patients with stroke or transient ischemic attack (TIA) versus warfarin administration at later intervals. Methods: AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) was an open-label, randomized controlled trial comparing the safety of early use of apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized AIS ( Results: Although AREST ended prematurely after a national guideline focused update recommended direct oral anticoagulants over warfarin for AF, it revealed that apixaban had statistically similar yet generally numerically lower rates of recurrent strokes/TIA (14.6% versus 19.2%, P =0.78), death (4.9% versus 8.5%, P =0.68), fatal strokes (2.4% versus 8.5%, P =0.37), symptomatic hemorrhages (0% versus 2.1%), and the primary composite outcome of fatal stroke, recurrent ischemic stroke, or TIA (17.1% versus 25.5%, P =0.44). One symptomatic intracerebral hemorrhage occurred on warfarin, none on apixaban. Five asymptomatic hemorrhagic transformation occurred in each arm. Conclusions: Early initiation of anticoagulation after TIA, small-, or medium-sized AIS from AF does not appear to compromise patient safety. Potential efficacy of early initiation of anticoagulation remains to be determined from larger pivotal trials. Registration: URL: https://www.clinicaltrials.gov/ ; Unique identifier: NCT02283294.

Precision medicine has ushered in a new era of targeted treatments for numerous malignancies, leading to improvements in overall survival. Unlike traditional chemotherapy, many molecular targeted antineoplastic agents are available in oral formulation, leading to enhanced patient convenience and a perception of reduced risk of adverse effects. Although oral antineoplastic agents are generally well-tolerated, cardiovascular toxicities are being reported with increasing frequency in part due to U.S. Food and Drug Administration and manufacturer recommended cardiac monitoring. Monitoring strategies have focused on left ventricular dysfunction, hypertension, and QT prolongation/arrhythmias. Given the rapid pace of development and availability of new oral antineoplastic agents, the purpose of this review is to provide clinicians with an up-to-date practical approach to monitoring and management of cardiovascular toxicities with the aim of improving overall outcomes for patients with cancer.

The number of patients with cancer-related cardiovascular disorders is increasing. This is attributed to increased survival of cancer patients who live longer (and are thus at risk for age-related cardiovascular disease) and the cardiovascular toxicities of many newer cancer drugs. Anthracyclines have been long associated with the development of dilated cardiomyopathy, especially when used with trastuzumab. Antiangiogenic targeted therapies cause new or worsening of pre-existing hypertension. Immune checkpoint inhibitors (ICIs) are associated with an increased incidence of myocarditis, while radiation therapy is associated with ischemic heart disease, valve dysfunction, conduction abnormalities, pericardial disease, and cardiomyopathy. Additionally, some cytotoxic chemotherapeutics, such as cisplatin, increase the risk of venous thromboembolism, while some antimetabolites such as fluoropyrimidines have long been associated with a broad range of cardiotoxicities. This chapter focuses on the cardiovascular conditions associated with cancer and its management, including cardiomyopathy, myocarditis, arrhythmia, valvular heart disease, and ischemic and non-ischemic vascular disease. As with any pathologic entity, the frontline efforts are geared toward treatment of those with the most emergent or severe manifestations of the disease. Simultaneous efforts are targeted at prevention of the occurrence or progression of disease. Here, we briefly discuss putative underlying mechanisms whereby cancer and its treatments can lead to the development of emergent cardiovascular conditions in oncologic patients and provide guidance for clinicians. Finally, we end the chapter with brief comments on implications for cardio-oncology during the COVID-19 pandemic and beyond.

Multiple myeloma (MM) is the second most frequent hematologic cancer in the United States. Carfilzomib (CFZ), an irreversible proteasome inhibitor being used to treat relapsed and refractory MM, has been associated with cardiotoxicity, including heart failure. We hypothesized that a multi-omics approach integrating data from different omics would provide insights into the mechanisms of CFZ-related cardiovascular adverse events (CVAEs). Plasma samples were collected from 13 MM patients treated with CFZ (including 7 with CVAEs and 6 with no CVAEs) at the University of Florida Health Cancer Center. These samples were evaluated in global metabolomic profiling, global proteomic profiling, and microRNA (miRNA) profiling. Integrative pathway analysis was performed to identify genes and pathways differentially expressed between patients with and without CVAEs. The proteomics analysis identified the up-regulation of lactate dehydrogenase B (LDHB) [fold change (FC) = 8.2, p = 0.01] in patients who experienced CVAEs. The metabolomics analysis identified lower plasma abundance of pyruvate (FC = 0.16, p = 0.0004) and higher abundance of lactate (FC = 2.4, p = 0.0001) in patients with CVAEs. Differential expression analysis of miRNAs profiling identified mir-146b to be up-regulatein (FC = 14, p = 0.046) in patients with CVAE. Pathway analysis suggested that the pyruvate fermentation to lactate pathway is associated with CFZ-CVAEs. In this pilot multi-omics integrative analysis, we observed the down-regulation of pyruvate and up-regulation of LDHB among patients who experienced CVAEs, suggesting the importance of the pyruvate oxidation pathway associated with mitochondrial dysfunction. Validation and further investigation in a larger independent cohort are warranted to better understand the mechanisms of CFZ-CVAEs.

Objective Women with breast cancer (BCA) and cardiovascular disease (CVD) risk factors are at increased risk of developing cardiovascular complications when exposed to potentially cardiotoxic cancer therapy. The benefit of aggressive CVD risk factor modification to reduce adverse treatment-related psychologic and biologic effects is not well established. Methods Using a single group pre-test, post-test design, 33 women with BCA receiving anthracycline and/or trastuzumab therapy participated in a 6-month comprehensive CVD risk reduction program involving formal cardio-oncology evaluation along with regular motivational counseling for improved nutrition and physical activity. Study parameters were assessed at baseline and 6 months with paired t-tests used to evaluate changes after the intervention. Results The mental component summary score assessed by SF-36V2 improved significantly after program completion (45.0 to 48.8, effect size 0.37, p = 0.017), however the physical component summary score declined (46.2 to 40.9, effect size − 0.53, p = 0.004). Despite this decline in perceived physical health, markers of health-related fitness and nutritional status were maintained or improved. Systolic and diastolic blood pressure also improved after the intervention (136.7 to 124.1 mmHg, p = 0.001 and 84.0 to 78.7 mmHg, p = 0.031, respectively). No significant change in resting heart rate, body mass index, lipids, hemoglobin A1C, or left ventricular ejection fraction was observed. Conclusions Patient-reported mental health improved significantly in women with BCA enrolled in a comprehensive CVD risk reduction program despite exposure to potentially cardiotoxic therapies. This study provides preliminary data for future randomized controlled trials evaluating the effects CVD risk reduction program in high-risk breast cancer cohorts.

Our knowledge of associated cardiotoxicities from novel therapeutics in oncology continues to expand. These include arrhythmias from cancer-therapy induced cardiomyopathy resulting from both direct and indirect effects on cardiomyocytes and other mechanisms that can adversely impact cardiovascular outcomes and overall mortality. In this review, we focus on both the arrhythmias of various classes of oncologic agents as well as the use of cardiac implantable electronic devices (cardioverter-defibrillators, permanent pacemakers, and cardiac resynchronization therapy) in cardio-oncology patients.

Introduction: Cyclin Dependent Kinase (CDK) 4/6 inhibitors are a novel class of cancer therapeutics which have significantly improved survival in patients with hormone receptor positive, HER2 negative metastatic breast cancer. There is little data regarding the epidemiology of cardiotoxicity with these therapies. Methods: Using the OneFlorida Data Trust , adult patients without prior cardiovascular disease who received at least one CDK 4/6 inhibitor between January 1, 2012 and December 31, 2018 were included in the analysis. CAEs identified from ICD 9/10 codes include: new hypertension (HTN); arrhythmias (excluding sudden cardiac death); new hypertension (HTN); heart failure/cardiomyopathy; ischemic heart disease, pericardial disease. Log-rank tests were performed to compare time to all-cause mortality in patients with or without CAE. Multivariable cox proportional hazard regressions were performed to estimate the hazard ratio (HR) and 95% confidence interval (CI) for mortality adjusting for age, gender, race, obesity, HTN, diabetes (DM) and hyperlipidemia (HLD). Results: A total of 1,035, predominantly female (96%) patients were included in the analysis. The mean age was 61±13 years, and CV risk factors were prevalent at baseline: obesity (17.1%), HTN (22.2%), DM (9.9%), HLD (10.5%). Cardiotoxicity occurred in 174 (16.8%) patients of which 30 (17.2%) died (p Conclusions: Cardiotoxicity is common with CDK 4/6 inhibitors and are associated with overall increased mortality and arrhythmias and HTN accounting for a significant proportion of this finding. Patients taking CDK 4/6 inhibitors should be monitored for CAEs with aggressive risk mitigation strategies to minimize morbidity and mortality.

Introduction: Ibrutinib is a widely used treatment option for patients with chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom’s macroglobulinemia. There is limited investigation on the relationship between ibrutinib and the development of ventricular arrhythmias. Hypothesis: We hypothesized that the incidence of ventricular arrhythmias in patients taking ibrutinib compared to the patients on other treatment regimens would be higher. Methods: We performed an aggregate data meta-analysis on nine studies to examine the incidence of ventricular arrhythmias. We further assessed a meta-regression analysis to evaluate the effect of duration of therapy on incidence of ventricular arrhythmias. Relative risk (RR) and 95% confidence intervals (CI) were estimated using a random-effects model. Results: Of 3809 patients being treated with ibrutinib, the incidence of ventricular arrhythmias was almost 8-fold higher in patients being treated with ibrutinib compared to other tyrosine kinase inhibitors (TKIs), other chemotherapies, or immunotherapy. (RR 8.13, 95% CI 4.37-15.10, p Conclusions: For patients treated with ibrutinib, there was a markedly higher rate of ventricular arrhythmias and an increased incidence with longer duration of treatment. These data highlight the need for guidelines on surveillance and management for ventricular arrhythmias for patients taking ibrutinib.

Introduction: Anthracyclines remain a key treatment for many malignancies but can increase the risk of heart failure or cardiomyopathy. Different guidelines recommend echocardiography (echo) and BNP or NT-proBNP evaluation before and 6-12 months after treatment. It is unknown however if racial/ethnic disparities exist in the cardiac surveillance of cancer survivors exposed to anthracyclines. Hypothesis: Racial/ethnic disparities are present in the adoption rates of cardiac surveillance guidelines among survivors treated with anthracyclines. Methods: Adult patients in the OneFlorida Consortium without prior cardiovascular disease who received at least 2 cycles of anthracyclines were included in the analysis. Multivariable logistic regression was performed to estimate the odds ratios (OR) and 95% confidence intervals (CI) for receiving echo, BNP or NT-proBNP at 6 months prior (baseline), 6 months after (6M), and 12 months after (12M) treatment among different racial/ethnic groups. Results: A total of 2758 patients were identified, with mean age of 54 ± 16 years and 60% were women. Among the entire cohort, 43% had a baseline echo, with 18% receiving an echo at 6M and 21% at 12M. BNP or NT-proBNP were lower: 5.3% at baseline, 6.5% at 6M and 8.7% at 12M. The prevalence of baseline cardiovascular risk factors ranged from 13% for hyperlipidemia and diabetes to 19% for obesity and 29% for hypertension. Compared to Whites, Blacks (OR: 0.56, 95% CI: 0.45-0.70) and Hispanics (0.52, 0.43-0.64) were less likely to receive echo surveillance at baseline. These differences were also observed at 6M and 12M in Hispanics (Figure). Conclusions: Significant racial/ethnic differences in cardiac surveillance among cancer survivors were present before and after anthracycline-based treatment as Hispanics are least likely to receive cardiac surveillance. This points to the need for improved education and outreach to ensure all cancer survivors receive appropriate and equitable care.