key: cord-282783-ps5jyjkl
authors: nan
title: Full Issue PDF
date: 2020-09-30
journal: JACC: CardioOncology
DOI: 10.1016/s2666-0873(20)30180-0
sha: 
doc_id: 282783
cord_uid: ps5jyjkl

nan

disease, coronary artery disease, arrhythmias, and pericardial disease, depending on the exact cardiotoxic agent (3) .

In this State-of-the-Art Review, we focus on long-term cardiac diseases after treatment for childhood cancer. We discuss the prevalence, risk factors, prevention, prediction, and surveillance of cardiac disease in this population (Central Illustration). We systematically searched PubMed for studies that described cardiac adverse events in children treated with cardiotoxic cancer treatments.

We limited the search to full-text articles written in English and articles published within the last 10 years. We selected articles with a study cohort of which >50% were treated for childhood cancer before the age of 21 years. For studies describing the prevalence or cumulative incidence of heart failure, we reviewed articles with a minimum of 500 CCS; a minimum of 100 CCS was required for the other outcomes. Studies on primary prevention strategies were identified from previous Cochrane searches (4) (5) (6) . Based on these criteria, 74 studies were considered to be described in this review ( Figure 1 ). The full search strategy is provided in Supplemental Table 1 . (7) (8) (9) (10) (11) (12) (13) (14) (15) . Anthracyclines are clearly associated with cardiomyocyte damage.

Although the exact mechanism of anthracyclineinduced cardiotoxicity has not been fully elucidated, early studies indicate that cardiotoxicity through reduction-oxidation reaction cycling and the generation of reactive oxygen species may be the cause.

More recently, topoisomerase 2b has been proposed to be a mediator of doxorubicin-induced cardiac injury (16) .

Systolic dysfunction can eventually progress to heart failure. Heart failure is one of the most frequent cardiac late effects in CCS (17, 18) , and contributes to significant morbidity and non-cancer-related mortality later in life (19, 20) . A large cohort from the Childhood Cancer Survivor Study investigated the occurrence of heart failure, defined by the Common Terminology for Criteria Adverse Events as grade 3 to 5. Based on questionnaires concerning long-term CCS, the reported cumulative incidence is 4.8% by 45 years of age (17) . These results confirmed earlier reports that anthracyclines and chest RT are strongly associated with heart failure (21) . Recently, it has been shown that even low-to-moderate chest RT doses increase the risk of heart failure substantially (22, 23) . In the Dutch LATER (Late Effects After Childhood Cancer) cohort, Feijen et al. (10) reported a cumulative heart failure incidence of 10.6% 40 years after childhood cancer diagnosis in CCS who received cardiotoxic cancer treatment. Higher exposure to mitoxantrone and cyclophosphamide were suggested as novel treatment-related risk factors (10) .

Although mitoxantrone has traditionally been classified as an anthracycline, it has been suggested that mitoxantrone results in cardiotoxicity through mechanisms different from anthracyclines (24, 25) .

Mitoxantrone has a nonlinear dose-response relationship with heart failure risk (10, (26) (27) (28) , and compared to doxorubicin, mitoxantrone is 10 times more cardiotoxic. In addition, a younger age at diagnosis and presence of traditional cardiovascular risk factors may play a role in the development of heart failure (29) . The influence of sex on the development of myocardial dysfunction is still incompletely conclusive (8, 9, 11, 12, 30) .

CORONARY ARTERY DISEASE. The risk of coronary artery disease (CAD) is substantially increased in CCS. In the Childhood Cancer Survivor Study, the cumulative incidence of CAD by age 45 years was 5.3% in survivors with and without exposure to cardiotoxic cancer treatments (17) . This risk is dependent on chest RT dose with no established safe dose; this risk is also higher in males. The cumulative incidence of symptomatic CAD at age 50 years

The main risk factors for cardiac disease in childhood cancer survivors are anthracyclines, mitoxantrone, and chestdirected radiotherapy dose.

Primary prevention strategies may reduce the risk of anthracycline-induced cardiomyopathy.

There is an increased prevalence of traditional cardiovascular risk factors in childhood cancer survivors; screening and early management are important to modify risk.

Multivariable risk prediction models may help to individualize prevention and surveillance strategies.

increases to 20% in males exposed to >35 Gy of radiation (18, 31) . The St. Jude Lifetime cohort study detected CAD based on either history, electrocardiogram (ECG), or echocardiography in 3.8% of asymptomatic CCS 22.6 years after cardiotoxic therapy (30) . However, evidence from (non)invasive coronary angiography is scarce. A study evaluating computed tomography in asymptomatic Hodgkin lymphoma CCS 55 years old or younger (n ¼ 31) exposed to chest RT showed coronary artery lesions to be very proximal, placing large portions of the myocardium at risk (32) . VALVULAR (30, 33, 35) . Chest RT has been identified as an important risk factor that increases at higher doses (35) . Other risk factors are treatment with anthracyclines, hypertension, congenital heart disease, and younger age at diagnosis, although these have not been uniformly shown in all studies (11, 30, 33) . Mild tricuspid regurgitation was most prevalent in 2 studies describing valvular disease, but this is also very common in the general population (30, 33, 36) . In lymphoma CCS who were exposed to chest RT, valvular heart disease, defined as mild or higher for left sided valves and moderate or higher for right sided valves, was most frequently detected in the aortic and mitral valves (35) . Valvular abnormalities after chest RT are most likely caused by direct irradiation injury to the valve cusps or leaflets, causing thickening, fibrosis, and calcification (30, 37) .

These processes progress with age and increase in prevalence over time (30, 35) . Hence, CCS without echocardiographic abnormalities after a short followup period are still at risk of severe valvular heart disease.

PERICARDIAL DISEASE. Besides paraneoplastic and infectious causes, pericardial disease can arise from chest RT. Late constrictive pericarditis, in particular, can lead to disabling symptoms and a poor prognosis (38) . However, data on pericardial disease in CCS are limited. The Childhood Cancer Survivor Study showed a 10-fold higher risk of pericardial disease in all CCS versus siblings (30- year cumulative incidence, 3 .0%) and a dose-response relation with chest RT (11) .

A single-center study in CCS older than 5 years after diagnosis (n ¼ 1,362; 47% no cardiotoxic therapy), reported symptomatic pericarditis in only 2 CCS (18) .

Although the diagnosis of constrictive pericarditis is difficult by echocardiography, thickening of the pericardium as well as hemodynamic consequences (e.g., "septal bounce," abnormal respiratory variations in Doppler findings) can be suggestive. Upon high clinical suspicion, cardiac computed tomography, magnetic resonance imaging (MRI), and/or invasive hemodynamic evaluation may be needed to confirm the diagnosis (39) .

ARRHYTHMIAS. The prevalence of symptomatic cardiac arrhythmias in long-term CCS is reportedly low (11, 17, 18, 40) . In 10,724 CCS, the cumulative incidence of grade 3 to 5 arrhythmia by 45 years of age was 1.3% (17) . A subsequent study (n ¼ 23,462) showed that chest RT >35 Gy, anthracycline dose $250 mg/m 2 , dyslipidemia, and hypertension are risk factors for symptomatic arrhythmia (11) . Myocardial fibrosis caused by chest RT may contribute to the occurrence of arrhythmias. Other frequently used cancer agents for pediatric cancers such as cisplatin, cyclophosphamide, and tyrosine kinase inhibitors may also be associated with supraventricular and ventricular arrhythmias (41, 42) . Prolonged QTc interval, which has arrhythmogenic potential, has been shown in CCS who received anthracyclines with and without chest RT (43, 44) . Also, rhythm disturbances such as premature ectopic beats and atrioventricular blocks have been reported in CCS (45) (46) (47) . The literature on ECG abnormalities in large cohorts of long-term CCS is sparse (46, 47) , Data on the use of ambulatory ECG monitoring to define the prevalence of brady-and tachyarrhythmias induced by cardiotoxic cancer treatments are needed, but must be carefully weighed against the potential patient burden and clinical significance.

CHILDHOOD CANCER SURVIVORS PREVENTIVE MEASURES FOR CANCER TREATMENT-INDUCED CARDIOTOXICITY. As the risk of cardiac disease is high in chest RT and anthracycline-treated survivors, and as omitting or diminishing the use of cardiotoxic treatments is not always possible, prevention is critical (48) . Advanced radiotherapy techniques to minimize exposure to the heart have been developed; the impact of those improvements is reflected by the decrease in CAD in more recent treatment eras (11) .

Extensive research has been devoted to the identification of possible cardioprotective interventions during anthracycline treatment that do not have negative effects on antitumor efficacy or other noncardiac adverse effects. Below we discuss 3 preventive measures that have been studied during anthracycline treatment. We focus primarily on randomized controlled trials (RCTs) as they provide the highest level of evidence to answer this type of question. Because of developmental changes and the differences in the body composition of children, data from adults cannot be reliably extrapolated to children (49) .

D e x r a z o x a n e . Dexrazoxane is one of the most widely investigated cardioprotective pharmacologic interventions. It has been shown in adult cancer patients to prevent clinical and subclinical cardiac damage (4) . The few published pediatric RCTs have included participants diagnosed with leukemia, lymphoma, and sarcoma (50) (51) (52) . These studies suggest that there are no significant differences in clinical heart failure between dexrazoxane and control patients (4, 53) , although dexrazoxane might have a protective effect on asymptomatic cardiotoxicity (53, 54) . All studies included relatively short-term follow-up, and the impact on outcomes after longer follow-up is yet unknown.

Currently, dexrazoxane is not routinely used in clinical practice for all children treated with anthracyclines. This might be explained by a concern over interference with antitumor efficacy and the occurrence of secondary malignancies (55). However, high-quality evidence to support an increased risk of secondary malignancy is lacking. A Cochrane systematic review identified no significant differences between treatment groups (4) , which is in line with more recently published randomized trials (50, 53) .

A recently published nonrandomized study in pediatric patients with acute myeloid leukemia mortality. An overview of validated prediction models in CCS is provided in Supplemental Table 2 .

HEART FAILURE PREDICTION MODELS. Practical models to predict heart failure onset before the age of The discriminatory abilities of the model were further

shown by a cumulative incidence of heart failure at age 40 years of 0.5% in the low-risk group, whereas this was 11.7% in the high-risk group. Importantly, 45 .2% of the CCS were at low risk according to the model and thus unlikely to develop heart failure. (17) . Thus, early, at 5 years after diagnosis, cardiovascular risk factors have been shown to provide little incremental information to prediction models for heart failure and ischemic heart disease (29, 31) .

In a more recent study, diabetes, hypertension, and dyslipidemia were used in the prediction of heart failure and ischemic heart disease in CCS who were 20, 25, 30, or 35 years of age at time of prediction, with relative risks comparable to moderate doses of anthracyclines (74). Cardiovascular risk factors were present in approximately 10% of the CCS at the age of 35 years and were strong predictors of heart failure and ischemic heart disease. Although the discrimination of the prediction models improved with the addition of cardiovascular risk factors, the C statistics were modest for both events ranging from 0.69 to 0.79 in the derivation cohort with successful replication in the other one-half of the cohort. Both the heart failure and the ischemic heart disease predictions models showed good calibration. A small, very-highrisk group was identified with cumulative incidences of heart failure or ischemic heart disease of w10% at age 50 years; survivors in this very-high-risk group may benefit from more frequent surveillance and/or early interventions to modify their risk.

However, low-risk survivors who may be excluded from further surveillance could not be identified with these models as cumulative incidences of heart failure (w1.5% to 2.5%) and ischemic heart disease (w1% to 1.5%) were still significantly higher compared to siblings at the age of 50 years. In the context of prediction model-guided surveillance, this can be seen as the benefit of early detection of asymptomatic cardiac dysfunction among those who will develop heart failure (true positives) weighted against the potential harm of an unnecessary diagnostic workup and/or treatment in those who will not develop heart failure (false positives).

Through decision modeling using simulations it has been shown that routine echocardiographic surveillance for asymptomatic cardiomyopathy every 10 years may be more cost-effective, especially in those treated with an anthracycline dose <250 mg/m 2 (85).

Decision modeling provides weaker evidence on the clinical impact compared to an RCT, but it requires no follow-up and is less expensive to perform. Such analyses could be performed to assess clinical impact and cost-effectiveness before conducting an RCT.

There are different methods and techniques available to detect anthracycline treatment induced cardiomyopathy. Much of the research in detection of cardiac diseases is focused on improving early detection of myocardial dysfunction. We will describe diagnostic methods that have been studied over the past decade in CCS. an abnormal GLS in 28% of the cohort who were exposed to anthracyclines and/or chest RT and had normal LVEFs. Both cumulative anthracycline dose >300 mg/m 2 and any cardiac RT dose were associated with an increased risk for abnormal GLS (7) . It is currently unknown whether an abnormal GLS is associated with development of an LVEF <50% or clinical heart failure in CCS.

Diastolic dysfunction after cardiotoxic cancer treatment has also been described in CCS (8, 94) . In the St. Jude Lifetime cohort, diastolic dysfunction grades 1 to 3 (based on peak mitral flow velocity, mitral septal and lateral early diastolic velocity, and left atrial volume) was detected in 11% of all CCS who were exposed to cardiotoxic treatment and in 8.7%

with normal LVEF (7) . One must be aware of the dif- Table 1 ). The current lack of mechanistic insights for (9,10) tyrosine kinase inhibitor- (11) , and trastuzumab-related cardiotoxicity (12) . inflammation studied primarily to reduce major adverse cardiovascular events was associated with a significant reduction of lung malignancy (4).

Meta-analyses of therapies lowering low-density lipoprotein cholesterol (LDL-C) demonstrated that prevention of cardiovascular events was proportional to the absolute reduction in LDL-C levels with no major safety concerns, specifically no increase in malignancies (5, 6) . However, available data from previous LDL-C-lowering clinical trials have not systematically adjudicated data for malignancy, because these were not considered disease-related events (7) .

An increased rate of malignancy associated with the use of the combination of ezetimibe and simvastatin was unexpectedly reported in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial (8) , which compared simvastatin-ezetimibe to placebo in 1,873 adults with mild-to-moderate aortic stenosis over a median follow-up of 4.4 years (8).

Ezetimibe is a nonstatin drug that inhibits the intestinal absorption of cholesterol by targeting the transmembrane protein, Nieman-Pick C1-Like 1 (9) . It is recommended for further LDL-C reduction in combination with a statin (10 Values are median (25th, 75th percentiles) or n (%). Wilcoxon rank-sum test of differences between with and without primary malignancies for continuous variables. Chi-square test of frequencies between with and without malignancies for categorical variables. *The no-malignancy group summary statistics are based on patients without malignancy diagnosis prior to death, loss to follow-up or end of the study.

ACEI ¼ angiotensin-converting enzyme inhibitor; ACS ¼ acute coronary syndromes; ARB ¼ angiotensin receptor blocker; HDL-C ¼ high-density lipoprotein cholesterol; Hs-CRP ¼ high-sensitive C-reactive protein; IQR ¼ interquartile range; LDL-C ¼ low-density lipoprotein cholesterol; MI ¼ myocardial infarction; TRS2P ¼ TIMI Risk Score for Secondary Prevention (13) .

of the skin, as well as limiting malignancy events to only those with available pathology reports. We also performed a competing risk analysis integrating allcause death as a competing outcome in the model using Fine and Gray's method. Finally, we also evaluated the HRs in both arms with increasing duration of follow-up as done in previous publications (14, 15) .

All analyses were performed using SAS software, Simvastatin/ezetimibe (red) and placebo/ezetimibe (blue). The primary malignancy endpoint was defined as new, relapsing, or progressive malignancy (excluding nonmelanotic skin malignancy). The cumulative incidence plots were presented graphically using Kaplan-Meier product-limit method. CI ¼ confidence interval;

HR ¼ hazard ratio. 

Simvastatin/ezetimibe (red) and placebo/ezetimibe (blue). The cumulative incidence plots were presented graphically using Kaplan-Meier product-limit method. CI ¼ confidence interval; HR ¼ hazard ratio. Table 3) . Results were similar between treatment groups for deaths due to malignancy by location Table 2 . Values are n (%).

(p > 0.05 for each comparison) (Supplemental Table 4 ). Further analyses by gender showed no significant differences between treatment groups for both the primary malignancy endpoint (p > 0.05 for each comparison) (Supplemental Tables 5 and 6 ) and deaths due to malignancy (p > 0.05 for each comparison) (Supplemental Tables 7 and 8 ). Finally, we did not observe any differences in the extent of malignancy by treatment arm ( Table 4) .

In subgroup analyses, the rates of the primary malignancy endpoint were similar between treatment groups for each of the 8 pre-specified high-risk subgroups (each p for interaction >0.05) ( Figure 2 (Figure 3 ).

During the 7 years of follow-up, there was no divergence in the KM curves over time ( Figure 1) ;

the year-by-year HRs for the primary malignancy endpoint comparing the two treatment arms did not demonstrate a progressive trend over time ( Table 5) . The number of events and the 7-year Kaplan-Meier rates are shown. Total cholesterol: 25th percentile ¼144.0 mg/dl, 50th percentile ¼ 162.4 mg/dl and 75th percentile ¼ 181.0 mg/dl. Abbreviations as in Figure 2 .

Some concern has been expressed that statin and other LDL-C-lowering drugs might be carcinogenic and consequently part of the malignancy data was collected retrospectively. Fifth, although the analyses of outcomes stratified by subgroups were pre-specified, the power was low in these subgroups. Finally, we did not measure phytosterols or other potential protective or tumor-promoting factors in blood to evaluate the effect of ezetimibe on the potential mechanistic pathways related to malignancy.

We found that ezetimibe did not increase the rates of malignancy nor deaths due to malignancy in 17,708 patients with recent ACS treated with simvastatin and followed up for a median of 6 years totaling 96,377 patient-years of follow-up. ACKNOWLEDGMENT Therapies to reduce LDL-C such as statins or ezetimibe have significantly improved cardiovascular outcomes; this benefit has been ascribed to pleiotropic effects beyond lowering LDL-C. However, such pleiotropic mechanisms have raised safety concerns about long-term use. A potential carcinogenic effect has been of particular concern as earlier studies sug- 10-year risks in CANTOS were 26% (range 1% to 52%) and 13% (range 1% to 31%) for total cancer; 4% (range 0% to 13%) and 2% (range 0% to 6%) for colorectal cancer; and 5% (range 0% to 37%) and 2% (range 0% to 24%) for lung cancer.

CONCLUSIONS Lifetime and 10-year risk of total, colorectal, and lung cancer can be estimated reasonably well in patients with established CVD with readily available clinical predictors. With additional study, these tools could be used in clinical practice to further aid in the emphasis of healthy lifestyle changes and to guide thresholds for targeted diag- (12) . For the current study 9,322 patients were included, after exclusion of patients younger than 45 years or older than 80 years.

Detailed descriptions of the UCC-SMART cohort and the CANTOS trial have been published elsewhere (12) (13) (14) . The studies were approved by institutional review boards and all participants provided written informed consent. An overview of eligibility criteria is provided in Supplemental Table 1 . Missing data (per variable #1.1% for UCC-SMART and #0.2% for CANTOS) were singly imputed by weighted probability matching using multivariable regression for the baseline and outcome data. Complete case analysis yielded similar model coefficients.

Continuous variables were truncated at the 1st and 99th percentile to limit the effect of outliers on the model coefficients (i.e., leverage) (17) . To prevent overfitting, predictors were preselected based on presence in previously published risk prediction models of multiple cancer types. Antiplatelet use (aspirin, P2Y12-ADP receptor antagonist, or other, such as dipyridamole) was added as a predictor, due to its inclusion in multiple previously published prediction models for colorectal cancer and due to the common use of antiplatelet therapy in patients with CVD. Furthermore, it was required that the variables were readily clinically available, as well as present in the derivation dataset. This led to the following predictors: age, sex, smoking status, weight, height, alcohol use, use of antiplatelet medication, and diabetes mellitus (Supplemental Table 4 details an overview of predictor selection).

In addition, CRP was added as a predictor after a literature search for predictors of cancer was performed (3, 15, 18, 19) . Definitions of the predictors in the UCC-SMART cohort and CANTOS trial are provided in Supplemental Table 5 . was calculated for each following life-year. Next, for each subsequent age year the probability of being healthy and alive at the start of that time interval (age year) (e t þ1) was calculated by multiplying the survival probability (e t ) by the event-free survival probability during that year (1 À a t À b t ). These steps were repeated from the age at baseline of an individual patient to the maximum age of 90 years, and together these predictions form an individual lifetable (10, 23) .

The cancer-free life expectancy was determined as the age at which the median estimated cancer-free survival curve is 50%. For 10-year and lifetime risk of cancer, the cumulative cause-specific risks were truncated at 10 years after the age at baseline, and at the age of 90 years, respectively. 

CANTOS study populations are shown in Table 1 (1), leading to restricted variation in cancer types.

Our cancer prediction models performed reasonably well, and calibration plots before and after (7). Second, complex models based on machine learning would not be expected to provide improved performance or better prognostication in the current study, consistent with other large-scale external validation studies (8, 9) .

From a clinical perspective, a key concern should be whether the predictions from the risk calculator are well calibrated (5) . For example, the 70-year-old male in the example calculation sheet has a predicted 1.1% risk of lung cancer, while the risk may in fact be 0.5%, or 2%. This type of miscalibration has been common in earlier evaluations of lung cancer prediction models (10) . Indeed, the investigators state that "calibration is a more clinically relevant for risk (11) . It was recently rediscovered and presented through a "decision curve" (12, 13) , which is unfortunately missing from the current report.

Future work should consider the clinical decisionmaking perspective more fully, with net benefit in a decision curve as a step towards a more comprehensive cost-effectiveness analysis.

In sum, the presented risk calculator is very promising given its high-quality data sources, large Values are mean AE SD or %. *p < 0.05 across diuretic categories. †Defined as NT-proBNP >3,000 pg/ml or BNP >600 pg/ml. ‡Defined as troponin-T >0.05 ng/ml or troponin-I >0.1 ng/ml. ACE ¼ angiotensin converting enzyme; ARB ¼ angiotensin receptor blocker; ATTR ¼ transthyretin amyloidosis; BMI ¼ body mass index; BNP ¼ B-type natriuretic peptide; DBP ¼ diastolic blood pressure; eGFR ¼ glomerular filtration rate; GDMT ¼ guideline directed medical therapy; HF ¼ heart failure; LVEF ¼ left ventricular ejection fraction; MRA ¼ mineralocorticoid receptor antagonist; NT-proBNP ¼ N-terminal pro-B-type natriuretic peptide; NYHA ¼ New York Heart Association; SBP ¼ systolic blood pressure; SHFM ¼ Seattle Heart Failure Model. Table 3 ). Figure 3A) . Similarly, for the UK þ diuretic dose þ NYHA functional class model, survival was 6.5 years, 3.8 years, and 1.9 years for the low-, intermediate-, and high-risk groups, respectively (log-rank p < 0.001) ( Figure 3B ).

We also tested the ability of the risk scores to predict a combined outcome of mortality or cardiac transplantation ( Table 3 ). optimism-adjusted AUCs at 2 years ( Adding diuretic dose to the UK score increased the AUC from 0.711 to 0.787 and additionally adding NYHA functional class, increased it to 0.816. For diuretic dosing, 0 points were assigned for 0 mg/kg, 1 point for >0 to 0.5 mg/kg daily dose, 2 points for >0.5 to 1 mg/kg daily dose, and 3 points for >1 mg/kg daily dose. *Difference in discrimination slopes between 2 models, where the discrimination slope is the difference between the mean predicted probabilities for events and nonevents. †Sum of net proportions of persons with and without the event correctly assigned to a different risk category; ranges from À2 to 2. ‡Similar to the IDI except compares difference between median predicted probabilities.

IDI ¼ integrated discrimination improvement; NRI ¼ net reclassification index; other abbreviations as in Tables 1 and 2 . For diuretic dosing, 0 points were assigned for 0 mg/kg, 1 point for >0 to 0.5 mg/kg daily dose, 2 points for >0.5 to 1 mg/kg daily dose, and 3 points for >1 mg/kg daily dose.

Abbreviations as in Tables 1 to 3 .

Cheng et al. STUDY LIMITATIONS. Our cohort included both wtATTR and hATTR. It is possible that risk markers may be differentially predictive in these distinct cohorts because natural disease progression is more aggressive with hATTR, and there may also be differences between mutation types. Of note, the Mayo risk score (2) only the latter remained significant in multivariable analysis. Cardiovascular diagnosis usually includes imaging; thus cardiologists and patients have a tendency to focus on those results. Although cardiovascular imaging has revolutionized the diagnosis of cardiac amyloidosis, the role in prognosis is less clear.

When the addition of imaging variables to the staging systems is considered, the availability, reproducibility, and incremental value must also be considered.

In contrast to the current study, NYHA functional Rodney Falk appropriately coined the term "toxicinfiltrative cardiomyopathy" in reference to the toxicity of circulating light chains (AL) to cardiomyocytes in AL (7). Similar mechanisms of cardiomyocyte toxicity due to TTR oligomeric intermediates have been reported in ATTR (8, 9) .

Cardiac amyloidosis is not a simple infiltrative con- DOACs in Cancer such as those related to trial designs or the risk for contamination or crossover between the groups.

DATA SYNTHESIS AND ANALYSIS. We extracted data from the original primary publications (9) (10) (11) (12) The flowchart describes study search, screening, and selection processes.

Sabatino et al. were included in the systematic review and metaanalysis (9) (10) (11) (12) . The study flowchart is described in Figure 1 . Table 4 .

Supplemental Figure 1 . Overall, the risk for selection Table 1 . Figure 3D) . Overt bleeding that was associated with a decrease in the hemoglobin level of $2 g/dl, led to a transfusion of $2 U of blood, occurred in a critical site, or contributed to death

Overt bleeding that did not meet the criteria for major bleeding but was associated with the use of medical intervention, contact with a physician, interruption of the assigned treatment, discomfort, or impairment of activities of daily living.

McBane et al. (11) ; 2020

Overt bleeding plus a hemoglobin decrease of $2 g/dl or transfusion of $2 U of packed red blood cells, or intracranial, intraspinal/epidural, intraocular, retroperitoneal, pericardial, intra-articular, or intramuscular with compartment syndrome, or fatal bleeding

Overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, an unscheduled contact with the health care team, or temporary anticoagulant cessation GI ¼ gastrointestinal; other abbreviations as in Table 1 .

Sabatino et al. 

Over the past few years, the use of DOACs has revo- Values are n (%). *Basal cell or squamous cell carcinoma of the skin, primary brain tumor or known intracerebral metastases, and acute leukemia were not included in the CARAVAGGIO trial. †Basal cell or squamous cell carcinoma of the skin were not included in the SELECT-D trial. ‡Basal cell or squamous cell carcinoma of the skin were not included in the Hokusai VTE Cancer trial. §Other than brain tumors. ǁ Data not available, because brain tumors were included under "other tumors".

Abbreviations as in Tables 1 and 3 . The data from the CARAVAGGIO trial concerning the risk of major bleeding were particularly noteworthy. It appears that this finding was not related to any differences in the definition of major bleeding, because this was relatively consistent across trials ( Table 3 ). In contrast, the differences in reported major bleeding risk might have resulted from the heterogeneity in enrolled populations. Patients with primary brain tumors, brain metastases, and acute leukemia were excluded from the CARAVAGGIO trial. Patients with a recent diagnosis of testicular/retroperitoneal germ cell cancer and orchidectomy #8 weeks prior scheduled for cisplatin-based chemotherapy or active surveillance were recruited. Participants were stratified into 3 groups by management: 1) active surveillance for stage 1 low-risk disease; 2) 1 to 2 cycles of adjuvant bleomycin, etoposide, and cisplatin (BEP) chemotherapy for stage 1 high-risk disease; or 3) 3 to 4 cycles BEP chemotherapy for metastatic disease. Red circles illustrate study assessments. Blood samples were simultaneously drawn from each Table 2) . This remained numerically greater than baseline thereafter, but was not statistically significant. There were trends toward Abbreviations as in Table 2 . Table 2) . There was no differences between groups (p ¼ 0.285). Endothelial dysfunction is a key feature in de novo thrombosis and rupture of pre-existing atherosclerotic plaque (25) . As such, it is an important component to the risk of thrombotic cardiovascular events in the early period following cisplatin-based chemotherapy.

In our cell-based study, exposure of HAECs to cisplatin was associated with decreased t-PA mRNA expression and activation of Akt and ERK 1/2. In previous work, cisplatin has been shown to reduce endothelial cell survival and induce apoptosis in human dermal microvascular endothelial cells (HMEC-1) (26) and in the vasa nervorum in rats (27) . These data support the hypothesis that cisplatin induces direct endothelial toxic effects resulting in increased stress kinase signaling and a propensity for thrombosis via reduction in the capacity for endogenous fibrinolysis.

Although adverse thrombotic effects are most frequently observed in the early period following chemotherapy, cisplatin is detectable in serum for several years after treatment (28) . This chronic exposure may provoke low-grade endothelial stimulation and a consequent pro-atherogenic environment (28, 29) . Our subsequent assessment was with forearm venous occlusion plethysmography, the gold standard for assessing endothelial function (12) . In appears to be the time period of increased cardiovascular risk. While these effects predominantly occur in the early period after treatment, cisplatin is detectable in serum several years after treatment (28) . It remains possible that chronic exposure to low levels of cisplatin may cause low-grade endothelial stimulation that contributes to the pathophysiology underlying cardiovascular events occurring more than a decade after initial exposure (8, 28) .

Nephrotoxicity is a major, dose-limiting side effect of cisplatin that affects 20% to 40% of patients (4, 36) .

We found evidence of early nephrotoxicity following cancer an acute decrease in FMD was seen as early as with the first cycle of carboplatin and paclitaxel chemotherapy (11) . In conjunction with the current findings, one would conclude that the common denominator is platinum drugs and that there is no gender-related difference. Furthermore, one would conclude that platinum drugs seemingly induce relatively acute changes in endothelial cells that translate into a reduction in flow-mediated vasodilation and alterations in nitric oxide bioavailability. Interestingly, a prior study in testicular cancer survivors showed that those patients who were exposed to cisplatin-based chemotherapy nearly 3 to more than 20 years ago had a more severe reduction in FMD and higher levels of circulating endothelial cells than those not exposed (13) . The fact that cisplatin levels are detectable even nearly 30 years from therapy supports the theory of long-term exposure and endothelial injury (14) . A difference in vascular reactivity between cisplatin-exposed and cisplatin-nonexposed was not seen in the current study by Cameron et al. (10) . It is important, however, to realize that the vascular response was blunted in both groups, even in comparison with patients with metabolic syndrome (considered to account for the vascular outcomes in testicular cancer survivors as mentioned) (15) . Such results can also not be unequivocally attributed to hypogonadism (16, 17) . (3) (4) (5) (6) . In patients that survive beyond 5 years, mortality rates are 4 to 9 times higher than the general population, corresponding with a 30% shorter life expectancy regardless of age at transplantation (7) . The incidence of heart failure (HF) has been reported to be between 5.6% to 10.8%

in those who have survived at least 10 years after HSCT (4, 5, 8, 9) , and the risk of cardiovascular (CV) related mortality is 2 to 4 times higher in HSCT survivors than in the general population (4 were measured on separate occasions to reduce bias.

Studies followed current guidelines for evaluation of LV function and cardiotoxicity (14, 15) . Measurements were averaged from 3 consecutive heart cycles.

2D-LVEF was manually traced using the modified Simpson's biplane method (14) . 3D-LVEF was calculated with semiautomated software for endocardial detection, and was subsequently manually adjusted.

A 3D pyramid volume acquisition was obtained from 4 to 6 cardiac cycles, adjusting for depth and sector width (60 to 70 ), resulting in an average volume rate of 39 frames/s (range 29 to 51 frames/s). Sex-specific cutoffs for 2D-LVEF were used as recommended (14) . GLS (4, 8, 17, 18) . However, this study cannot discern the precise timing of LVSD onset, and one could potentially speculate that cardiac injury occurred at time of therapy, with a further worsening in LVSD over time. Another possible explanation is that young patients are at higher risk of heart disease due to organ immaturity and growth disturbances caused by cardiotoxic therapies (19) . This may explain the smaller LV size in survivors compared with control subjects, even after consideration for CV disease and confounders. Sex has previously been implicated as a risk factor for cardiotoxicity (8, (19) (20) (21) , but this association was not found in our study.

Cyclophosphamide has historically been noted to have cardiotoxic effects (22) . However, published data linking alkylating agents to long-term heart disease is scarce. In contrast, anthracycline exposure is known to cause myocyte depletion, and is shown to increase the risk of HF by 5-fold in long-term (8, 9, 19, 21, 23) .

In addition to cardiotoxic therapies, we found that traditional CV risk factors have a potential role in modifying the risk for LVSD in long-term survivors of allo-HSCT. CV risk factors are commonly reported in HSCT survivors, occurring more frequently in allo-HSCT compared with autologous-HSCT survivors, resulting in a higher prevalence of heart conditions in allo-HSCT survivors (6, 18, (24) (25) (26) . Survivors in this study had a high prevalence of CV risk factors, but at a level comparable to other studies (6, 18, 20, 21, (24) (25) (26) . Abbreviations as in Table 4 . treated with HSCT at various ages (5, 9, 20, 21, 24, 25) .

The significance of hypertension in contributing to prevailing cardiac disease in HSCT survivors has previously been shown (5, 21) . However, in our study,

given that the onset and duration of hypertension is unknown, it is unclear if the cumulative consequences of hypertension were fully manifested.

Indeed, the echocardiograms showed little evidence of concentric remodeling beyond a small but significant difference in indexed LV end-diastolic volume.

However, hypertension is known to cause myocardial fibrosis that leads to reduced longitudinal shortening of the heart (27) . This may explain why hypertension was found to be an independent predictor of GLS.

Hypothyroidism has been reported in 30% of longterm survivors of HSCT with busulfan conditioning (28) . Hypothyroidism was found in 9.6% in our cohort, although no association with LVSD was found in our data. Dyslipidemia has been reported in 13% to 52% of survivors of HSCT (5, 6, 18, 20, 24, 25) . In our study, GVHD was found to be a highly prevalent complication of allo-HSCT survivors. There is limited evidence that GVHD directly mediates myocardial damage. However, active chronic GVHD Values are median (25th, 75th percentiles), n (%), or mean AE SD. *Significant difference between anthracycline $300 mg/m 2 and <300 mg/m 2 in Bonferroni post hoc analysis (<0.05). †Significant difference with both treatment groups (anthracycline $300 mg/m 2 and <300 mg/m 2 ) with no anthracycline group in Bonferroni post hoc analysis (<0.05). ‡No significant difference between treatment groups in Bonferroni post hoc analysis. §Echocardiographical parameters are adjusted for covariates of age, heart rate, body mass index, and diastolic blood pressure. kSignificant difference between anthracyclines $300 mg/m 2 and no anthracycline in Bonferroni post hoc analysis (<0.05). ¶ASE cube formula (14) . Table 3 .

has been shown to be associated with a higher risk of CV death (5) . It is thought that the chronic inflammation processes instigated by GVHD results in endothelial damage leading to accelerated atherosclerosis (29) . We did not find GVHD (acute or chronic) to be consistently associated with LV systolic function, and found a very modest association with remodeling (15, 33) .

A remaining challenge with GLS is the lack of consensus in defining absolute cutoffs for dysfunction, variability, and intervendor differences (27) . The GLS cutoff used in our analysis was based on our normal data, using the same equipment and operator.

This value (À17%) is conservative when compared with a meta-analysis performed by Yingchoncharoen et al. (27) , which found the 95% CI for normal GLS to be À18.9% to À20.4% (27) . 1Â phosphate-buffered saline) and sacrificed 4 weeks later. As observed in previous studies (16, 23) , body mass at the time of sacrifice was lower (À12%) in the group administered with DOXO ( Table 1) . Lower body mass with DOXO was associated with lower heart, quadriceps, gastrocnemius, and epididymal white adipose tissue mass, food consumption (À17%), and water intake (À26%) ( Table 1 ). There were no significant differences in the mass of other tissues and organs (Supplemental Table 1 ). We first sought to establish that total ROS bioactivity was increased in HUVECs exposed to plasma from DOXO-treated mice compared with sham control mice. To do so, we assessed total cellular ROS using the CellROX fluorescent probe (Thermo Fisher [Waltham, Massachusetts]; catalog# C10422) and found that ROS bioactivity was greater in HUVECs incubated with plasma from DOXO-treated mice compared with sham control mice (p < 0.001) ( Figures 4A and 4E ).

Next, we aimed to determine if enhanced mitochondrial ROS contributed to the greater total HUVEC ROS induced by DOXO administration by assessing mitochondrial ROS bioactivity using the MitoSOX fluorescent probe (Thermo Fisher, Catalog# M36008).

We observed greater mitochondrial ROS in HUVECs exposed to plasma obtained from DOXO compared with sham-treated animals (p < 0.001) (Figures 4B and   4E ). To determine if this greater ROS bioactivity was linked to changes in mitochondrial volume, we Figure 2) . To determine associations of these plasma metabolites with mitochondrialspecific aortic ROS, we performed linear regression analyses. We found that plasma diphosphate (p ¼ 0.053) and lactate (p ¼ 0.067) tended to be positively associated with aortic mitochondrial ROS (Supplemental Figure 3) . A full report of metabolite abundance is provided in Supplemental Table 2 .

Dot blot array. To expand on this initial analysis of potential circulating signals influenced by DOXO treatment, we next targeted inflammatory pathways,

given that DOXO administration is associated with higher levels of pro-inflammatory proteins in the circulation (32) . To address this aim, we assessed plasma concentrations of 20 different cytokines and chemokines via a dot-blot array. We found that all but 2 of these markers did not differ significantly in plasma from DOXO-treated mice compared with sham control mice ( Table 2 ). The exceptions were the antiinflammatory cytokine interleukin-4, which was only slightly (<5%), but significantly (p ¼ 0.043) lower in the DOXO mice, and vascular endothelial growth factor-A (VEGF-A), which stood out as being 40% lower in the DOXO treated group (p < 0.001).

Moreover, plasma VEGF-A was inversely associated To accomplish this, we supplemented plasma from Table 3 ). 

DOXO chemotherapy has been shown to impair endothelial function (i.e., reduce EDD) in conduit arteries of cancer survivors (18) . However, the underlying mechanisms and associated therapeutic targets have not been established, because mechanism-focused investigations to date have been largely limited to endothelial cell culture models (35, 36) . In the present study, we first determined that These findings also are in agreement with previous work reporting excess production of mitochondrial ROS and impaired vascular endothelial function in mice with genetic SOD2 insufficiency (41) . It should be noted that other ROS generating pathways may also contribute, including oxido-reductases such as endothelial NO synthase or NADPH cytochrome P450 reductase (42) .

Another key finding from our experiments was that changes in the composition of the circulating milieu may contribute to DOXO treatment-associated anthracycline treatment in these same children (6) .

The decrease in NRG after anthracyclines has also been observed in adults undergoing anthracyclinebased chemotherapy, which is interpretable as a sign of vascular endothelial cell injury (7). Endothelial cell-derived NRG acts through the ERBB receptor tyrosine kinase family to regulate the growth and survival of cardiac myocytes, and protects from anthracycline cardiac cytotoxicity (8, 9) . MitoQ and other coenzyme Q10 preparations are available over the counter, and coenzyme Q10 supplementation has been studied not only as a way to limit injury to the cardiovascular system, but also kidney and reproductive organs (11, 12) . These prom- Table 1 ). Fulfilled criteria for myocarditis was based on European were receiving dexamethasone as palliative treatment for metastatic disease (Supplemental Table 3 ). and with other noncardiac irAEs. CRP in patients with no irAEs was <20 mg/l at baseline and between C6 and C8 also was not significantly different (p ¼ 0.168).

In this retrospective study of lung cancer patients receiving ICI, there was an 11% incidence of MACE to the rural population of eastern NC (12, 13) . Indeed, higher inflammatory signals and incidence of pneumonitis were also observed in this lung cancer population in comparison to those reported previously (13, 19) . Furthermore, in the lung cancer patients who received radiation, it has been suggested that the synergistic effect of radiotherapy and immunotherapy for priming of an endogenous antigenspecific immune response may contribute to a higher incidence of MACE by T-cell recognition of shared antigens (20) . Values are mean AE SD or n (%). *Analysis was not performed secondary to limited sample size.

BB ¼ beta-blocker; BNP ¼ brain natriuretic peptide; CAD ¼ coronary artery disease; CCB ¼ calcium channel blocker; CKD ¼ chronic kidney disease; COPD ¼ chronic obstructive pulmonary disease; CRP ¼ C-reactive protein; CVA ¼ cerebrovascular disease; DM ¼ diabetes mellitus; eGFR ¼ estimated glomerular filtration rate; HLD ¼ hyperlipidemia; HTN ¼ hypertension; NLR ¼ neutrophil-lymphocyte ratio; RAAS ¼ renin-angiotensinaldosterone system; WBC ¼ white blood cell count; other abbreviations as in Table 1 .

Timing of the development of MACE with a median delay of 46 days and a median of 3 doses from the first ICI administration in this study was similar to that previously reported (5, 21, 22) . In view of this timing of onset from earlier studies, there is a general recommendation that baseline and surveillance cardiac testing (echocardiogram, ECG, TnI and BNP) be considered during this potential MACE window period, noted as after the second and after the fourth ICI cycle administration (21) . Most of the present MACE cases were not associated with a decrease in EF from baseline, which is consistent with previous studies (18, 21) , suggesting that relying solely on EF in ICI-treated patients with MACE may be limited for the detection of iRCs. TnI was observed to be mildly elevated at the time of MACE. However, elevations in TnI have also been observed in cancer patients receiving cancer therapy, including ICIs without any cardiotoxicities (23, 24) , thus suggesting that its utility may also be limited for the detection of iRC.

As demonstrated by this study, symptoms of iRC may be variable, including nonspecific symptoms of our institution that observed a significant increase in CRP with nivolumab-related pneumonitis that was mitigated with use of tocilizumab (19) . Similar inflammatory-mediated mechanisms such as interleukin (IL)-6 may be observed in CAR T cell-related cardiotoxicities (26) further highlighting and extending the utility of CRP in the detection of iRCs.

Another inflammatory marker that has been previously studied in noncardiac irAEs and observed to be elevated at the time of irAE is NLR (8, 11) . NLR is easily obtained, inexpensive, and a routine test, and is calculated from the total white blood cell count that reflects the ratio of the innate (neutrophils) and the adaptive (lymphocyte) immune pathways, whereby an elevation results in an imbalanced toxic inflammatory response with release of cytokines (27) . We observed an increase in NLR in patients who experi- However, ICI treatment can result in immune-related adverse events (irAEs) targeting any organ. Cardiovascular irAEs, particularly myocarditis, have received considerable attention due to their potentially fatal outcome (3, 4) . ICI were initially tested and approved as single therapy in patients with metastatic melanoma, a cancer type that historically had few treatment options and poor survival (5) . Later, these therapies were tested in patients with lung cancer and renal cell carcinoma (6, 7) . In the latter studies, ICI were tested either in combination with or following exposure to classic chemotherapies or targeted therapies. As a result, there was a growing need to define the cardiovascular sequelae in lung cancer patients treated with ICI, where the cardiovascular risk was complicated by exposure to cardiotoxic nonimmune-based cancer therapies and a high prevalence of conventional cardiovascular risk factors (8) .

There was also a need to identify biomarkers or imaging approaches that screened for early cardiotoxic effects from immunotherapy and to identify patients at risk who would benefit from closer monitoring (9) . Histopathological analysis of the EMB specimen showed intense myocardial inflammation comprised of numerous giant cells associated with many mononuclear cells, and prominent myocyte necrosis ( Figure 1 ). Immunohistochemistry showed that the inflammatory cells were mainly CD68positive giant cells and macrophages and CD8-positive T-lymphocytes, many of them exhibiting granzyme B, perforin, and TIA1 cytotoxicity markers. PD-L1 was expressed only by inflammatory cells and not by cardiomyocytes. CD4 and CD20 lymphocytes as well as NKp46-positive NK cells were poorly represented (not shown). Immunohistochemistry for viral protein 1 detection was performed on heart biopsies and showed foci of positive cardiomyocytes surrounded by inflammatory infiltrates, indicating endomyocardial viral protein synthesis activities.

Steroids were gradually tapered and discontinued at 3 months in light of the viral analysis. Cardiac magnetic resonance imaging showed at 6 weeks: 1) resolution of myocardial edema (average myocardial T 2 ¼ 50 ms (Figure 1) , T 1 values of 917 ms, and extravascular volume decreased to 29%); 2) recovery of LVEF to 68%; and 3) improvement of right ventricular function with an ejection fraction of 44% at 6 weeks to 51% at 6 months follow-up. The cancer had not progressed at 6 months follow-up, and the patient reported normal functional status. ICI therapy was not restarted at the time of last follow-up.

This case highlights the heterogeneity of pathogenesis of acute myocarditis on ICI therapy. We describe here acute myocarditis with long-term ICI therapy, secondary to giant cell myocarditis due to enterovirus.

Giant cell myocarditis is uncommon; its pathogenesis is poorly understood, and prognosis is poor. Recent data from an international registry including 220 patients with histologically proven severe myocarditis demonstrated that giant cell myocarditis bears the worst prognosis (6). The favorable outcomes in our patient, Although the number of patients eligible to ICI treatment is increasing dramatically, the pathogenesis of myocarditis needs to be further investigated. Based on only 2 extensively studied cases (5) emerging clinical syndromes (9) . The American Heart Association (AHA) has recently proposed diagnostic criteria for ICI myocarditis diagnosis based mainly on clinical characteristics, abnormal biomarkers, and/or cardiac imaging abnormalities (9) . The recent publication of ICI myocarditis definitions by the AHA has the value of standardizing criteria to improve reporting. Steroids are the first-line front treatment of ICI myocarditis, despite poor evidence to support this, followed by other immune modulators, plasma exchange, or even CTLA-4 agonist (abatacept) infusions. In the present study case, steroids were introduced and then discontinued after the confirmation of active viral markers on EMB. Indeed, the prognosis of T-cell ICI myocarditis is partly driven by early initiation of steroid treatment (10), which should not be held when awaiting histological or viral results.

Endomyocardial biopsy is recommended whenever possible in fulminant myocarditis (9) . It is, however, likely to be overlooked in cancer patients. This case report emphasizes the risk for opportunistic viral infection during long-term ICI therapy and utility of biopsy. The first mechanism to be considered in the setting of ICI myocarditis is T-cell mediated, prompting steroids as a first-line therapy early after hospital admission.

Endomyocardial biopsy should be performed whenever possible to rule out infectious causes of myocarditis to guide therapy and further our understanding of the potential varying presentations of ICI myocarditis. were paramount in preventing discordant care, especially when her clinical status had many rapid changes while she was in the intensive care unit. She completed CAR T cell therapy and was discharged to acute rehabilitation after a one-month hospitalization. She was unable to be restarted on GDMT due to hypotension.

Her PA d was 6 mm Hg at discharge. The plan was to obtain a positron emission tomography scan after acute rehabilitation to reevaluate her cancer.

Her initial course at the facility was uncomplicated, and she was able to participate in physical therapy. She had weekly appointments in the oncology clinic and an appointment with the advanced HF team. The pro- patients (2) . Hypotension is typically treated with intravenous fluids to maintain systolic blood pressure >90 mm Hg. Third-spacing of fluids with capillary leak is common, and this can lead to noncardiogenic pulmonary edema. A single-center retrospective study demonstrated that 12% of patients developed the composite outcome of arrhythmias, decompensated HF, or cardiovascular mortality (3).

The cardiac toxicities associated with CAR T cell therapy have led many centers to view significant cardiovascular disease as a relative contraindication (4). In 2 of the main clinical trials for CAR T cell therapy in patients with refractory DLBCL, patients were excluded if their LVEF was #45% to 50% (4). Our team decided to proceed with CAR T cell therapy in the patient described in this report because of her lack of other comorbidities, preserved performance status, and normal invasive hemodynamics. It was also her only treatment option for refractory DLBCL.

The CardioMEMS device-which is typically used to manage outpatients with HF-was an essential component of our patient's medical treatment (5) . For example, at 2 periods in the patient's hospitalization she was found to have diffuse pulmonary infiltrates, hypoxemia, and hypotension. Her PA d was 10 and 23 mm Hg 

The incidence of secondary metastatic tumors to the heart is 22 to 132 times more common than primary malignant tumors, and estimated to be in the range of 0.7% to 3.5% at autopsy series in the general population, and up to 14.0% in patients with known malignancies (5, 6) . The incidence of cardiac metastases has increased over the past decades, likely due to improved life expectancy of oncological patients and advances in diagnosis (5, 6) . The most common primary malignancies metastasizing to the heart include lung cancer, breast cancer, malignant melanoma, germ cell tumors, and hematological malignancies (5-7).

The most frequent mode of metastatic spread of SCC of the cervix is via the lymphatics to the para-iliac and para-aortic lymph nodes (1). Hematogenous spread is unusual and most commonly involves the lungs, bone, liver, and brain (1). Cardiac metastases from cervical cancer are exceedingly rare (2) (3) (4) . The vast majority of cases have involved the right heart, presumably due to hematogenous spread of cervical cancer to the inferior vena cava via the uterine veins, coupled with filtration of tumor cells by the lungs.

Patients with cardiac metastases from cervical cancer present with a myriad of symptoms that depend on tumor location and size, leading to heart failure, arrhythmias, or tamponade (2-4). Many cases were diagnosed postmortem. Antemortem diagnosis was usually achieved by multimodality imaging including transthoracic and transesophageal echocardiography, CT angiography of the heart, CMR, and 18 F-FDG PET/CT (2-7). Tissue diagnosis should be pursued for prognostic implications and optimizing treatment, but may not be feasible.

Our patient had no symptoms related to the cardiac metastasis. The tumor was discovered by 18 F-FDG PET/CT during the process of initial clinical staging of the disease. 18 F-FDG PET/CT is a particularly useful imaging modality in this setting. Together with CMR for detailed tumor characterization, these imaging modalities provide a comprehensive assessment of disease status that is essential for optimal shared decision making (6, 7) .

The median survival of patients diagnosed with cardiac metastasis from cervical cancer is 4 months (0 to 13 months) (2) (3) (4) . The management of these patients should be individualized and discussed within a dedicated multidisciplinary tumor heart team (5-7). A multimodality treatment strategy including chemoradiation, biological therapy, and surgery is necessary to prolong survival and maintain quality of life. In this regard, in a prospective randomized trial, bevacizumab has been shown to improve survival when added to the commonly used platinum-paclitaxel and topotecan-paclitaxel chemotherapy regimens (8) . Of note, treatment with bevacizumab has been shown to be associated with increased incidence of adverse cardiovascular side-effects such as uncontrolled hypertension, thromboembolism, cardiac ischemia, and heart failure (8) . The decrease in LVEF in our patient occurred immediately after resection and remained stable, and our patient did not have severe cardiac limitations during follow-up. Her low LVEF was readily managed with cardiac medications.

Near-complete resection of the interventricular septum via a right ventriculotomy parallel to the interventricular septum. Reconstruction of the septum using a bovine pericardial patch (asterisk) sewn into the left ventricular side of the septum. LAD ¼ left anterior descending coronary artery; other abbreviations as in Figure 1 .

Surgical resection should be considered for isolated cardiac metastasis in patients with favorable response to initial therapy and in whom complete resection is deemed feasible (2-7). Our patient had excellent response of the disease in the cervix and of the single pelvic bone metastasis with no evidence of new disease, with the exception of the cardiac metastasis, which remained metabolically active. This is not an infrequent clinical phenomenon in patients with primary or secondary malignant tumors of the heart (7), presumably due to differential response of the tumor to cancer therapy in different tissue environments (9) . Given the patient's young age, good functional status, imaging suggesting feasibility of complete resection, as well as lack of an alternative effective treatment, we proceeded with surgery followed by intensive chemoradiation and bevacizumab with curative intent. Although the pathological examination in our case did not reveal residual tumor in the tissue specimen, surgical resection had an important impact on the design of her concurrent therapy and prognosis. The local recurrence supports the presence of tumor and findings of the pre-operative 18 F-FDG PET/CT, highlighting the potential for false-negative tumor histological examinations following neoadjuvant chemotherapy (10) . The radiological evidence of local recurrence in the area of slim resection margins-the basal-posterior septum-underscores the technical challenge of achieving complete R0 resection with clean margins when treating primary or secondary malignant tumors of the heart (6,7).

In summary, cardiac metastases from cervical cancer should be included in the differential diagnosis of secondary malignant tumors of the heart. We believe that the patient-specific, multimodality management with curative intent strategized and delivered by an experienced and dedicated multidisciplinary team was key to achieving exceptional survival in our patient. Twitter: @AyeletDaniels.

distribution in the basal inferolateral and anterolateral free wall of the left ventricle. The etiology of this scar was unclear because the patient had no prior cardiac history, and to our knowledge, ibrutinib had not been known to be associated with myocardial scar. No abnormality was noted in the right ventricular apical region, which was the likely origin of his VA.

Initially, the patient was managed with intravenous amiodarone for recurrent VT. After extensive multidisciplinary discussions among cardiology, electrophysiology and oncology teams, ibrutinib was discontinued due to its potential association with VT. The patient was started on metoprolol, and an implantable cardioverter-defibrillator (ICD) was placed for secondary prevention. In terms of AF, his CHA 2 DS 2 -VASc score was 1, and anticoagulation was deferred, particularly given the potential bleeding risks with ibrutinib (1).

Although it remained uncertain if ibrutinib played an integral role in the pathophysiology of VT, the medication was discontinued with close outpatient cardiology and oncology follow-up. Because he had been in remission for several years, he was not started on alternative therapy for WM. On follow-up visits with close surveillance every 3 months with CBC, comprehensive metabolic panel, and IgM levels, he continued to be without evidence of symptomatic cytopenias, hyperviscosity, hepatosplenomegaly, lymphadenopathy, neuropathy, amyloidosis, cryoglobulinemia, or cold agglutinemia and did not meet criteria for reinitiation of therapy. On ICD interrogation at 3 months after cessation of ibrutinib, there were no further arrhythmias.

Ibrutinib is an oral, irreversible Bruton's tyrosine kinase inhibitor used to treat a broad spectrum of B-cell proliferative disorders, including chronic lymphocytic leukemia (CLL) as first-line therapy, mantle cell lymphoma, marginal zone lymphoma, and WM (2) . Cardiovascular toxicities associated with ibrutinib are The association of ibrutinib with VAs is becoming increasingly recognized (3, 5, 6) . In randomized controlled trials, the incidence of all-grade VAs in patients treated with ibrutinib (n ¼ 1,157) compared with patients in the control arm (n ¼ 958) was 1.0% versus 0.4%, and for grade 3 or greater VAs was 0.3% versus 0% (7). In analyses from a U.S.-based comprehensive cancer registry cohort, male sex, previous AF, HF, coronary artery disease, diabetes, widened QRS, and valvular disease were associated with the development of any arrhythmias (VA and supraventricular tachyarrhythmias) (6). Among those without baseline HF or coronary artery disease, the estimated 100,000 person-year incidence rate for VAs was 596 compared with 48.1 among similar nonibrutinibtreated subjects, which suggested an observed versus expected relative risk of 12.4 (p < 0.001). Regarding drug dosage, in 1 study in which approximately 80% of the patients experienced VAs, 91% were taking at least 420 mg of ibrutinib per day, and only 9% were taking 280 mg or lower per day (3). Among those with ibrutinibassociated VAs, the median time-to-event was 16 months (range 0.7 to 57.6 months) (6).

Ibrutinib has been reported to cause polymorphic VT without QTc prolongation as well as in the absence of structural heart disease (8, 9) . Tomcsányi et al. (9) reported the case of a 74-year-old woman on ibrutinib for CLL with underlying left bundle branch block and AF who experienced ibrutinib-induced polymorphic VT in the absence of other causes (9) . The initiation of VT was not characterized by short-long-short cycles as is seen in torsade de pointes. In polymorphic VT not related to prolonged QT, an alteration in the cardiac calcium homeostasis associated with ryanodine receptor-calmodulin-dependent protein kinase pathways is suspected.

As such, it has been hypothesized that an interaction between these and PI3K-Akt pathways could potentially lead to polymorphic VT with ibrutinib (3).

Although the awareness of ibrutinib-associated VA is increasing, there are no published management guidelines. Our patient was initially treated with amiodarone, then started on a beta-blocker. In the case described by Tomcsányi et al. (9) , the patient was treated with amiodarone and remained arrhythmia-free for 4 months. Amiodarone was thereafter discontinued due to pulmonary toxicity, and discontinuation led to the recurrence of VT. Sotalol was found to be ineffective, as were Class I antiarrhythmic agents (9) . As ibrutinib is primarily metabolized by hepatic cytochrome P450 3A4 (CYP3A4), caution must be exercised when used in combination with amiodarone and the calcium-channel blockers diltiazem and verapamil, given that they inhibit CYP3A4 and potentially result in increased serum levels of ibrutinib (7) . Amiodarone may increase the plasma concentration of ibrutinib by 6-to 9-fold (1). Ibrutinib interruption or dose adjustment may be appropriate prior to the initiation of amiodarone. Furthermore, the Class IA antiarrhythmic quinidine and the beta-blockers carvedilol and nadolol also interact with ibrutinib, increasing the serum concentrations of the antiarrhythmic drugs (7) . According to the ibrutinib package insert, ibrutinib interruption is recommended for any nonhematological toxicity that is grade 3 or greater. Once the toxicity has resolved to grade 1 or baseline, ibrutinib may be reintroduced at a low dose (7) . For severe or refractory arrhythmias, such as seen in our patient, drug discontinuation may be necessary.

In general, ICD implantation is recommended for the secondary prevention of sudden cardiac death due to life-threatening VT/ventricular fibrillation in patients in whom a completely reversible cause cannot be identified (10) . Our patient had hemodynamically unstable VT episodes requiring resuscitation, and although ibrutinib was felt to be the culprit, the presence of delayed enhancement on cardiac magnetic resonance imaging made it difficult to rule out underlying structural heart disease, such as an infiltrative cardiomyopathy.

Additionally, an ICD is indicated if it is expected to improve overall mortality. Because our patient's long-term prognosis from WM was favorable, it was felt that he would benefit from an ICD, particularly because ibrutinib or another therapy could be indicated in the future. In patients with cancer whose overall prognosis is poor (i.e., low expectation of survival with an acceptable functional status beyond 1 year), ICD therapy is not recommended. As ibrutinib is often used in patients with CLL whose prognosis is generally favorable, ICDs for secondary prevention have a potential for long-term benefit. An additional advantage of an ICD is providing prognostic parameters, such as the burden of atrial arrhythmia, nonsustained VT, and treated episodes of VT/ ventricular fibrillation, which could help to risk-stratify patients in the future prior to reintroduction of potentially cardiotoxic drugs.

Ibrutinib is a Bruton's tyrosine kinase inhibitor associated with a well-known side effect of AF. Reported cases of VAs associated with ibrutinib are rare. We present a case of VT storm in a patient receiving ibrutinib for WM.

As the recognition of ibrutinib-associated VAs is increasing, more data are needed to guide best management strategies for VAs triggered by ibrutinib. The following clinical scenarios focused on cancer prevention highlight the value of systematic cardiovascular risk assessment in individuals at high risk of cancer who are treated with cancer risk-reducing therapies.

Recommendations regarding the evaluation of lipid abnormalities and the role of coronary artery calcium (CAC) scan are provided, balancing existing evidence with the need for rigorous data that specifically applies to cancer populations. In terms of additional potential cardiovascular risk factors, BRCA1 has been implicated in the repair of DNA double-stranded breaks, and its loss-of-function is associated with reduced cardiac performance and accelerated cardiomyocyte death in murine models. Human studies investigating the association between BRCA1/2 mutations and incident cardiovascular disease (CVD) have shown conflicting results, potentially due to variable sample sizes and ethnic-specific differences in the pathogenesis of CVD (1).

Bilateral prophylactic oophorectomy is associated with a 96% reduction in the risk of epithelial ovarian cancer in BRCA1/2 mutation carriers. In women younger than 45 years of age, the risk of cardiovascular death after surgical oophorectomy is 44% higher than that of healthy control subjects (2) . Premature menopause was shown to predict future coronary heart disease and stroke in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort and represents an important risk-enhancing factor (3).

The patient has a borderline-range (5% to 7.4%) estimated ASCVD risk in the presence of a risk-enhancing factor, namely premature menopause. Given this, we would advocate for a discussion regarding initiation of moderate-intensity statin therapy. However, the patient has expressed a preference to avoid taking additional medications. In this case, a CAC scan could help refine ASCVD risk assessment (4) . An Agatston score of $100 and/or a CAC score $75th percentile for the patient's age, sex, and race would suggest a benefit to statin initiation, although there are no randomized clinical trial data supporting the use of CAC in treatment decisions. A CAC score of 300 would increase this patient's 10-year coronary heart disease risk to 10% using the MESA risk score calculator, and would further support the use of lipid-lowering therapy.

Nicotine cessation should be a primary strategy to reduce CVD risk in this patient, while the importance of healthy lifestyle habits, normal-range blood pressure and lipid profile, weight loss, and glycemic control should also be emphasized. Aspirin and sulindac are commonly used, contemporary pharmacoprophylactic therapies in patients who are at high risk of colorectal cancer, with the former being the preferred drug for individuals with sporadic adenomas and the latter for those with FAP. In the late 1990s, celecoxib was approved for use in patients with FAP. The risk-reduction benefit appeared to be significant with a 31% lower colorectal polyp burden rate in FAP patients treated with celecoxib and a 15% lower incidence of duodenal polyps. However, in a large study of colorectal adenoma prevention, long-term use of celecoxib (200 or 400 mg twice daily) was associated with a 3.4-fold increased risk of death from CVD, myocardial infarction, stroke, or heart failure (5).

In addition, a meta-analysis of randomized controlled trials showed that celecoxib use was associated with a 3-fold increased risk of myocardial infarction. A subsequent prospective investigation, assessing the safety of a lower dose of celecoxib (200 mg daily), did not demonstrate a statistically significant hazard; as such, the cardiovascular risk mediated by celecoxib remains incompletely understood (6) . In 2004, due to high cardiovascular event rates, rofecoxib was removed from the market, and a black-box warning was issued for celecoxib the following year.

This patient is in an intermediate-risk ASCVD category, but has 2 additional factors that increase his likelihood of future cardiovascular events: chronic nonsteroidal anti-inflammatory drug (NSAID) use and a strong family history of premature ASCVD. Importantly, the presence of diabetes mellitus in an individual 40 to 75 years of age is an indication for the use of moderate-intensity statins regardless of ASCVD score, and in an individual It is important to understand that patients with FAP who are treated with preventive total colectomy have favorable long-term survival outcomes. The notion that CVD represents an important competing risk to cancer mortality should be conveyed and serve as a motivating factor to introduce lifestyle changes and consideration of pharmacological therapies. Consideration of chronic NSAID initiation in this patient, especially in the context of conventional cardiovascular risk factors, should prompt referral to an internist or cardiologist.

Numerous risk-reducing interventions are utilized by cardiologists and oncologists in patients at risk of developing cardiovascular disease or cancer. Some therapies used to lower the incidence of cancer in individuals at increased risk for malignancy (e.g., prophylactic bilateral oophorectomy in carriers of BRCA1/2 mutations, sulindac in patients with familial adenomatous polyposis) may potentially increase the risk of cardiovascular disease. Consideration of such interventions, particularly in individuals with coexisting cardiovascular risk factors or comorbidities, should prompt referral to cardiology for careful risk assessment and modification that integrates traditional risk factors and the effects of cancer risk-reducing therapies. ASCVD ¼ atherosclerotic cardiovascular disease; CV ¼ cardiovascular; NSAID ¼ nonsteroidal antiinflammatory drug. Importantly, decisions regarding long-term NSAID therapy should balance the reduced polyp and potential colorectal cancer rate with the increased CVD risk.

Attainment of optimal blood pressure and glycemic control should be targeted. In addition, a CAC scan could be considered. If highly abnormal, it could be used to counsel and motivate this patient to further modify his lifestyle (4) . It would also be reasonable to check a lipoprotein(a) level given the strong family history of premature atherosclerosis. Due to the expected long-term use of sulindac, statin therapy and improved lifestyle habits would be appropriate risk-reduction interventions in this case.

Cardiovascular risk assessment in individuals who are deemed to be at high risk for cancer is distinct from that in patients with an established cancer. Specific therapies aimed at reducing the risk of cancer may augment cardiovascular risk and deserve careful consideration. Two important tenets of cardiovascular risk assessment include evaluation of lipid abnormalities and understanding the role of CAC imaging in refining ASCVD risk stratification in this unique population.

Although more research is needed regarding the value of CAC burden in patients with cancer, available evidence suggests that elevated CAC scores are predictive of both future cardiovascular events and cancer. In a recent study, CAC >300, when compared with a score of 0, was associated with a 3.7-fold increase in the risk of CV death and a 30% increase in the risk of cancer death (7). The most common cause of death among individuals with 0 CAC was cancer (50%), whereas patients with CAC >300 experienced most of the mortality due to CVD.

In a study of 464 patients with locally-advanced nonsmall-cell lung cancer treated with thoracic radiation therapy, an increased CAC score, measured from planning radiation therapy computed tomography, was associated with an elevated risk of all-cause mortality (hazard ratio: 1.29; confidence interval: 1.0 to 1.6; p ¼ 0.027) (8) . In a separate analysis of breast cancer patients who had received radiation therapy, higher pre-RT CAC scores were associated with a higher likelihood of acute coronary syndrome at 9 years of follow-up (hazard ratio: 1.42; confidence interval: 0.49 to 4.17; p ¼ 0.519) (9) . Coronary calcification is therefore a predictor of CVD in the cancer population and further research is needed to better characterize the contribution of cause-specific mortality and cardiovascular events in cancer patients according to CAC levels (10) . Last, breast arterial calcifications detected on screening mammogram are an independent marker for the presence of coronary artery disease and may help identify women at higher risk of ASCVD.

Lipid-lowering therapies should be considered in patients with cardiovascular risk factors or disease, as per the standard ASCVD risk score. Particular medical interventions to decrease the risk of cancer, such as prophylactic oophorectomy or long-term nonsteroidal anti-inflammatory drugs, may increase the risk of ASCVD and should be regarded as deleterious factors.

In the coming decade, cardio-oncologists may be asked to assess and manage cardiovascular toxicities in individuals who receive cancer risk-reducing interventions but who are free of cancer. Given the increasing data supporting an overlap between the molecular and clinical underpinnings of cancer and heart disease, oncologists should consider involving their cardiovascular medicine colleagues for risk assessment and preemptive management. In addition, longitudinal cardiovascular safety evaluations of specific patient subgroups in whom prophylactic anticancer therapies are considered should be performed to provide an evidence-based understanding of the risks and benefits of such therapies. cardiotoxic risk (13) (14) (15) (16) ; and the intersection between cardiovascular disease and cancer in our patients (17) (18) (19) . In the second quarter of 2020 alone, we had nearly 130,000 article usage sessions, and each quarter, this number has grown. The work of our authors is being read for utilization in clinical practice and research, which is always the most important metric for a JACC journal.

As a physician scientist, I recognize that the choice of "which journal" is not an easy one and requires careful consideration. We remain committed to serving our authors and working tirelessly to ensure that the peer review process is respectful, fair, constructive, and as seamless as possible. Our average time to first decision in second quarter 2020 was 15 days, and we will strive to maintain this standard. We seek to partner and work collaboratively with our authors to ensure the highest quality contribution to our community. I am grateful to the reviewers, who provide timely, incisive insight and lend their valued expertise to help ensure the quality of our journal. We have had nearly 300 peer reviewers contribute their evalua- Over the next year, we will improve access to JACC:

CardioOncology through additional platform changes to improve searchability and integration across the JACC Journals.

Clinical, translational, and basic science original research manuscripts will continue to serve as our foundation. As we evaluate each manuscript, we will continue to ask ourselves the following key questions: Are the findings valid? Is the methodology rigorous? Is the topic of clinical importance?

Are the findings incremental to our current understanding of the topic and do they fulfill an evidence gap? What is the potential clinical impact and the potential for advancing the field? We will continue to publish State-of-the-Art Reviews and Primers, and similarly ask ourselves: is this an authoritative, critical appraisal of the literature? Is it comprehensive, yet focused? Is this data-driven and accurately reflective of the current evidence?

We will look to Clinical Case Challenges to provide evidence-based descriptions of unique cases that thoughtfully illustrate the diagnostic and therapeutic dilemmas that we as clinicians face as we care for our patients (20) . Our Viewpoints will continue to express opinion pieces on important and timely topics, and present thought-provoking, community-building, evidence-based perspectives.

We will continue to grow our international engagement events, podcasts, live Journal clubs, and dynamic case presentations, each occurring at least once per quarter. We also will launch a new "How To" series that will offer practical, evidence- 

Oncologists primarily consulted general cardiology (58%), as compared with cardio-oncology (38%) for evaluation of treatment-related cardiotoxicity.

Overall, a lack of awareness (63%) and lack of and education in the growing field of cardiooncology.

Considering these respondents likely represented a more engaged group of practitioners, there was a lack of general cardio-oncology knowledge, uncertainty of local available resources, and low reported rate of cooperation between cardiologists and oncologists.

Although we were not able to assess the reasoning for these observed practice patterns, as it was beyond the scope of this study, enhanced collaboration between disciplines will be important and necessary to deliver optimal cardiovascular and oncologic care to this patient group.

Previous studies indicate that approaches vary between cardiologists and oncologists when using cardio-oncology services for the treatment of patients with cancer. Peng et al. (7) reported that most cardiologists (55%) felt that they should monitor for cardiotoxicity even in the absence of symptoms.

However, the same study indicated that only 12.5% of oncologists shared this view. Furthermore, 50% of oncologists felt that cardiologists should be involved only when patients developed cardiotoxicities, but only 6.5% of cardiologists agreed with that opinion.

Most cardiologists believed that access to cardiooncology services would improve prognosis (88.3%), whereas only 45.8% of oncologists shared this view.

Our study did not directly address this same question, but found that only 38% of oncologists and 34% of cardiologists indicated that they felt "very comfortable" interacting with their colleagues for comanagement of cancer and heart disease. sadlerd@ccf.org. Twitter: @DSadlerMD, @FloridaACC, @FLASCO_ORG, @ACCinTouch, @Dr_Mike_Fradley, @Dr_RoohiKhan.

Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review

Natural his

A new staging system for cardiac transthyretin amyloidosis

Cardiovascular disease mortality after chemotherapy or surgery for testicular nonseminoma: a populationbased study

Testicular cancer: a

Mechanisms of cisplatin nephrotoxicity

White-Paper-1.pdf

A new equation to estimate glomerular filtration rate

Crosstalk between vascular redox and calcium signaling in hypertension involves TRPM2 (Transient Receptor Potential Melastatin 2) cation channel

Marked impairment of protease-activated receptor type 1-mediated vasodilation and fibrinolysis in cigarette smokers: smoking, thrombin, and vascular responses in vivo

Intra-arterial substance P mediated vasodilatation in the human forearm: pharmacology, reproducibility and tolerability

Role of the endothelium in the vascular effects of the thrombin receptor (protease-activated receptor type 1) in humans

Vascular effects of apelin in vivo in man

The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension

Fire simulation and cardiovascular health in firefighters

Vascular damage in testicular cancer patients: a study on endothelial activation by bleomycin and cisplatin in vitro

Antiangiointravascular ultrasound imaging for coronary thrombosis after cisplatin-based chemotherapy

Caspases and calpain are independent mediators of cisplatin-induced endothelial cell necrosis

Arterial events in cancer patients-the case of acute coronary thrombosis

Vascular toxic effects of cancer therapies

Treatmentrelated cardiovascular toxicity in long-term survivors of testicular cancer

Comprehensive characterisation of the vascular effects of cisplatin-based chemotherapy in patients with testicular cancer

Impact of platinum-based chemotherapy on the progression of atherosclerosis

Vascular fingerprint and vascular damage markers associated with vascular events in testicular cancer patients during and after chemotherapy

Cardiovascular risk in long-term survivors of testicular cancer

Long-term platinum retention after platinumbased chemotherapy in testicular cancer survivors: a 20-year follow-up study

Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually

Reduced mortality after allogeneic hematopoietic-cell transplantation

Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study

Vascular endothelium as 'novel' target of graft-versus-host disease

Pericarditis in patients with chronic graft-vs-host disease

National Institutes of Health hematopoietic cell transplantation late effects initiative: The Cardiovascular Disease and Associated Risk Factors Working Group Report

Prevalence of outpatient cancer treatment in the United States: estimates from the Medical Panel Expenditures Survey (MPES)

Chemotherapy-induced cardiotoxicity: detection, prevention, and management

Long-term chemotherapy-related cardiovascular morbidity

Cardiovascular disease in adult survivors of childhood cancer

Epirubicin versus doxorubicin: which is the anthracycline of choice for the treatment of breast cancer?

Gp91phox-containing NAD(P)H oxidase increases superoxide formation by doxorubicin and NADPH

Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin

Redox cycling of anthracyclines by cardiac mitochondria. I. Anthracycline radical formation by NADH dehydrogenase

Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis

Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin

Role of endothelium in doxorubicin-induced cardiomyopathy

A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin

Chemotherapeutic drugs and mitochondrial dysfunction: focus on doxorubicin, trastuzumab, and sunitinib

Glabridin prevents doxorubicin-induced cardiotoxicity through gut microbiota modulation and colonic macrophage polarization in mice

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Endothelial function in young adult survivors of childhood acute lymphoblastic leukemia

Cellular senescence promotes adverse effects of chemotherapy and cancer relapse

Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice

Sex differences in anthracycline-induced cardiotoxicity: the benefits of estrogens

Shortterm interleukin-37 treatment improves vascular endothelial function, endurance exercise capacity, and whole-body glucose metabolism in old mice

Doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle

Oxidant stress and endothelial cell dysfunction

Redox regulation of mitochondrial function

Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr1a P-glycoprotein

Redox homeostasis and antioxidant signaling: a metabolic interface between stress perception and physiological responses

Innovative Medicine: Basic Research and Development

Antioxidants and cancer prevention

Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy

Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin

Doxorubicin accumulation in individually electrophoresed organelles

Doxorubicin induces endotheliotoxicity and mitochondrial dysfunction

Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction

Rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthase

Mechanism of guanine-specific DNA damage by oxidative stress and its role in carcinogenesis and aging

Nuclear factor-{kappa}B activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans

Chronic supplementation with a mitochondrial antioxidant (MitoQ) improves vascular function in healthy older adults

The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients

A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease

Vitamin C mitigates oxidative/nitrosative stress and inflammation in doxorubicin-induced cardiomyopathy

Protective effects of mito-TEMPO against doxorubicin cardiotoxicity in mice

Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q. Biophys

The role of endothelins and their receptors in heart failure

Plasma endothelin-1 and doxorubicin cardiotoxicity

Plasma endothelin-1 as a marker for doxorubicin cardiotoxicity

Doxorubicin-induced oxidative stress and endothelial dysfunction in conduit arteries is prevented by mitochondrial-specific antioxidant treatment

Coenzyme q10 for prevention of anthracycline-induced cardiotoxicity

Anthracycline causes impaired

Ventricular-arterial coupling in breast cancer patients after treatment with anthracycline-containing adjuvant chemotherapy

Serum cardiovascular growth factors during doxorubicin chemotherapy in children with leukemia

Circulating neuregulin during the transition from stage a to stage b/c heart failure in a breast cancer cohort

Cardiac endothelial cells regulate ROS-induced cardiomyocyte apoptosis through neuregulin-1beta/ erbB4 signaling

Neuregulin-1 protects ventricular myocytes from anthracycline-induced apoptosis via erbB4-dependent activation of PI3-kinase/Akt

Endothelial cells regulate physiological cardiomyocyte growth via VEGFR2-mediated paracrine signaling

Protective mechanisms of coenzyme-Q10 may involve up-regulation of testicular P-glycoprotein in doxorubicin-induced toxicity

Reno-protective efficiency of coenzyme Q10 on Adriamycin-induced nephrotoxicity

Fundamental mechanisms of immune checkpoint blockade therapy

Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors

Immunerelated adverse events associated with immune checkpoint blockade

Fulminant myocarditis with combination immune checkpoint blockade

Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study

Immune checkpoint inhibitors-related cardiotoxicity

Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy

Cardiotoxicity of immune checkpoint inhibitors

Association between immune-related adverse events and clinical efficacy in patients with melanoma treated with nivolumab: a multicenter retrospective study

Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab

Healthy North Carolina 2020: social determinants of health indicators

10 Inflammatory signature difference in rural urban and regional occupational exposure in lung cancer

Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases

Myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology

What is the normal value of the neutrophil-to-lymphocyte ratio?

Immune checkpoint inhibitor-related adverse cardiovascular events in patients with lung cancer

Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade

Myocarditis in patients treated with immune checkpoint inhibitors

Influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors

Serial troponin for early detection of nivolumab cardiotoxicity in advanced non-small cell lung cancer patients

Prognostic value of troponin T in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy

Cardiovascular events among adults treated with chimeric antigen receptor T-Cells (CAR-T)

CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade

Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury

Impairment of the PD-1 pathway increases atherosclerotic lesion development and inflammation

Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice

CTLA4-IgG ameliorates homocysteine-accelerated atherosclerosis by inhibiting T-cell overactivation in apoE-/-mice

Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer

Trends in stage distribution for patients with nonsmall cell lung cancer: a National Cancer Database survey

Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer

Cardiovascular toxicities associated with immune checkpoint inhibitors

Fulminant myocarditis with combination immune checkpoint blockade

Improved survival with ipilimumab in patients with metastatic melanoma

Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer

Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma

Cardiovascular toxic effects of targeted cancer therapies

Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations

Characterization of Immune Checkpoint Inhibitor-Related Cardiotoxicity in Lung Cancer Patients From a Rural Setting

Grounding cardio-oncology in basic and clinical science

ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards)

Myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology

PD-1 modulates radiation-induced cardiac toxicity through cytotoxic T lymphocytes

Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study

KEY WORDS immune checkpoint inhibitors, inflammatory markers, myocarditis, neutrophil-tolymphocyte ratio

Management and outcomes of severe aortic stenosis in cancer patients

Healthcare Cost and Utilization Project (HCUP)

AHA/ACC focused update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

Transcatheter aortic valve replacement in oncology patients with severe aortic stenosis

Cardiac complications of thoracic irradiation

Roadmap for biomarkers of cancer therapy cardiotoxicity

Early changes in cardiovascular biomarkers with contemporary thoracic radiation therapy for breast cancer, lung cancer, and lymphoma

Normalization of ejection fraction in subjects with systolic heart failure. Is it really normal? A myocardial deformation study

Assessment of early radiation-induced changes in left ventricular function by myocardial strain imaging after breast radiation therapy

Late-Onset Giant Cell Myocarditis Due to Enterovirus During Treatment With Immune Checkpoint Inhibitors

I mmune checkpoint inhibitor (ICI) therapy has significantly improved the prognosis of many advanced cancers

Cardiovascular adverse effects such as myocarditis are uncommon, but bear high mortality rates of nearly 50% (2). ICI myocarditis typically occurs early, and potential factors associated with ICI myocarditis are combination therapy

However, the clinical presentation of ICI myocarditis is heterogeneous, with preserved left ventricular ejection fraction in one-half of the cases, and high rates of conduction abnormalities and ventricular arrhythmias (3). ICI myocarditis can also occur late, although notably, there is limited information on late-onset myocarditis with long-term ICI therapy

A 57-year-old male patient presented with myalgias and dyspnea after the 27th course of 2nd-line ICI monotherapy (Nivolumab [anti-PD-1] 3 mg/kg every 3 weeks) for metastatic renal cell carcinoma. The electrocardiogram showed sinus tachycardia, low QRS voltage, and T-wave inversion in the anterior leads with no ST-segment changes. Cardiac biomarkers were elevated (troponin I 4,700 ng/l, B-type natriuretic peptide 466 ng/l). Left heart catheterization revealed normal coronary arteries. Cardiac magnetic resonance ISSN

Cardiovascular imaging

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors

Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis

Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study

Clinical features, management, and outcomes of immune checkpoint inhibitorrelated cardiotoxicity

Myocarditis in patients treated with immune checkpoint inhibitors

Fulminant myocarditis with combination immune checkpoint blockade

Fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction

Comparative immunologic characterization of autoimmune giant cell myocarditis with ipilimumab

Aberrant PD-1 ligand expression contributes to the myocardial inflammatory injury caused by coxsackievirus B infection

Myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology

Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy

REPORT A 66-year-old woman with advanced diffuse large B-cell lymphoma (DLBCL) was referred for chimeric antigen receptor (CAR) T cell therapy. She was diagnosed with DLBCL 6 years prior to presentation and had no significant past medical history. She received a total of 10 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), with a lifetime exposure of doxorubicin >500 mg/m 2 . She underwent an autologous hematopoietic stem cell

Four years later, her DLBCL recurred, requiring 6 more cycles of R-CHOP. One month after she completed the last cycle, her transthoracic echocardiogram (TTE) demonstrated a left ventricular ejection fraction (LVEF) of 55% to 60% and global longitudinal strain of À12% (normal: À19% to À22%). Two months following therapy, she was admitted to the hospital with acute decompensated heart failure (HF)

Coronary computed tomography demonstrated mild coronary artery disease, and cardiac magnetic resonance imaging showed no evidence of infiltrative or inflammatory disease. She was presumed to have anthracycline-induced cardiomyopathy and was initiated on furosemide and guideline-directed medical therapy (GDMT), including lisinopril 2.5 mg and metoprolol succinate 12.5 mg daily. Up-titration of GDMT was limited, and spironolactone or eplerenone could not be added, secondary to hypotension. She was referred to a cardio-oncologist for risk stratification prior to CAR T cell therapy. She had good exercise tolerance, riding a stationary bike for 10 to 15 min at a time. A right heart catheterization (RHC) demonstrated mildly elevated biventricular filling pressures with normal cardiac output (right atrium 10 mm Hg, pulmonary artery 36/20/27 mm Hg

It was felt that CAR T cell therapy was her only therapeutic option. Multidisciplinary discussions between her hematologist/oncologist, cardio-oncologist, and advanced HF team were held to determine feasibility. derangements in blood pressure and oxygenation, ranging from mild hypotension and hypoxemia to ISSN

Dr. Bishop has received nonfinancial support from ArticulateScience LLC; and has received personal fees from United Healthcare, Seattle Genetics, Celgene, Juno Therapeutics, Novartis, CRISPR Therapeutics, Kite Pharma, and Pharmacyclics. Dr. Uriel has received grant support from Abbott

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information

Chimeric antigen receptor T-cell therapies for lymphoma

Chimeric antigen receptor T-cell therapy for cancer and heart: JACC council perspectives

Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T)

Yakoub-Agha I. An international survey on the management of patients receiving CAR T Cell therapy for haematological malignancies on behalf of the Chronic Malignancies Working Party of EBMT

Design and rationale of haemodynamic guidance with CardioMEMS in patients with a left ventricular assist device: the HEMO-VAD pilot study

Advances in diagnosis and treatment of metastatic cervical cancer

Cardiac metastasis in cervical cancer

A rare case of cardiac metastatic mass

Case report of cardiac metastasis from cervical squamous carcinoma and its literature review

Tumors metastatic to the heart

Cardiac tumors: JACC CardioOncology state-ofthe-art review

Surgery for tumors of the heart

Improved survival with bevacizumab in advanced cervical cancer

Differential growth and responsiveness to cancer therapy of tumor cells in different environments

akim@uchc.edu. Twitter: @AgnesSKim2, @HMadgula

Ibrutinibassociated atrial fibrillation

Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia

Cardiovascular toxicities associated with ibrutinib

The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis

Ventricular arrhythmias and sudden death in patients taking ibrutinib

Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies

Highlights of prescribing information

Ibrutinib, an approved tyrosine kinase inhibitor as a potential cause of recurrent polymorphic ventricular tachycardia

Ventricular tachycardia caused by ibrutinib

Dr. Kopecky has served as a consultant for Prime Therapeutics; has received research support from True Health; has served as Data Safety and Monitoring Board chair for Applied Clinical Intelligence; has served as a board member for Mayo Clinic Support Services; and has served as a task force member for Mayo Clinic CV P&T. Dr. Gersh has served as CRO for trials involving Edwards Percutaneous Valve Devices through Baim Institute; has served on the DSMB for the REPRISE Study

); has served as a general consultant for MyoKardia; and has served on the Steering Committee of the Garfield Study (Thrombosis Research Institute)

Risk of cardiovascular disease in women with BRCA1 and BRCA2 mutations

Increased cardiovascular mortality after early bilateral oophorectomy

Early menopause predicts future coronary heart disease and stroke: the Multi Ethnic Study of Atherosclerosis

Association of coronary artery calcium in adults aged 32 to 46 years with incident coronary heart disease and death

Cardiovascular risk associated with

Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis

Coronary artery calcium and the competing long-term risk of cardiovascular vs. cancer mortality: the CAC Consortium

Elevated coronary artery calcium quantified by a deep learning model from radiotherapy planning scans predicts mortality in lung cancer

Is the coronary artery calcium score associated with acute coronary events in breast cancer patients treated with radiotherapy?

Breast arterial calcium: a game changer in women's cardiovascular health?

JACC: CardioOncology: poised to serve a maturing, collaborative field

Proceedings from the Global Cardio-Oncology Summit

JACC: CardioOncology videos

Resiliency and our cardio-oncology community

The novel coronavirus disease (COVID-19) threat for patients with cardiovascular disease and cancer

COVID-19 clinical trials: a primer for the cardiovascular and cardiooncology communities

AL amyloidosis for the cardiologist and oncologist

Efficacy of neurohormonal therapies in preventing cardiotoxicity in patients with cancer undergoing chemotherapy

Safety of continuing trastuzumab despite mild cardiotoxicity: a phase I trial

Efficacy of dexrazoxane in preventing anthracycline cardiotoxicity in breast cancer

Repeated remote ischemic conditioning reduces doxorubicin-induced cardiotoxicity

Osimertinib-induced cardiotoxicity: a retrospective review of the FDA adverse events reporting system (FAERS)

Increase in blood pressure associated with tyrosine kinase inhibitors targeting vascular endothelial growth factor

CAR T-cell therapy-related cardiovascular outcomes and management: systemic disease or direct cardiotoxicity?

Cardiovascular safety of degarelix versus leuprolide for advanced prostate cancer: the PRONOUNCE trial study design

Hypertension in cancer patients and survivors: epidemiology, diagnosis, and management

Increased cancer prevalence in peripartum cardiomyopathy

Ischemia and bleeding in cancer patients undergoing percutaneous coronary intervention

Infiltrative lymphoma-associated bradycardia and cardiac conduction abnormalities

Deaths: leading causes for 2017

The economic burden of chronic cardiovascular disease for major insurers

Health of patients with cancer and cancer survivors

An international survey of healthcare providers' knowledge of cardiac complications of cancer treatments

Practices in management of cancer treatmentrelated cardiovascular toxicity: a cardio-oncology survey

ACC Multistate Chapter Cardio Oncology network to improve physician participation, awareness, and education in Cardio Oncology

Myocardial ischemia: Leading the differential diagnosis of polymorphic VT in a 68-year-old man was acute coronary syndrome.Heart failure (HF): He did not have symptoms or signs of hyperviscosity syndrome or HF. Systemic amyloidosis associated with WM leading to amyloid cardiomyopathy was also considered.Drug toxicity: A high index of suspicion was maintained about the potential association between ibrutinib and ventricular arrhythmia (VA).

Electrocardiogram at the time of evaluation by emergency medical services showed AF with a ventricular rate of 120 beats/min and nonspecific ST/T-wave abnormalities. Complete blood count, serum electrolytes, and renal function were within normal limits at the time of admission, and serial serum troponin levels were undetectable. A transthoracic echocardiogram showed normal biventricular size and function with no regional wall motion abnormalities. Furthermore, coronary angiography demonstrated very mild luminal irregularities without obstructive disease. In the cardiac intensive care unit, he was noted to have multiple premature ventricular complexes and nonsustained VT with a left bundle branch block morphology and right superior axis, indicating an origin at the right ventricular apex (Figure 2 ). He underwent cardiac magnetic resonance imaging, which demonstrated a small area of mid-myocardial delayed enhancement in a nonvascular