key: cord-0031070-skp0ejp4
authors: Ohman, Rachel E.; Yang, Eric H.; Abel, Melissa L.
title: Inequity in Cardio‐Oncology: Identifying Disparities in Cardiotoxicity and Links to Cardiac and Cancer Outcomes
date: 2021-12-16
journal: J Am Heart Assoc
DOI: 10.1161/jaha.121.023852
sha: ce65d8c109c40276c0a2a3aa24f01b743ccf77a7
doc_id: 31070
cord_uid: skp0ejp4

Minority and underresourced communities experience disproportionately high rates of fatal cancer and cardiovascular disease. The intersection of these disparities within the multidisciplinary field of cardio‐oncology is in critical need of examination, given the risk of perpetuating health inequities in the growing vulnerable population of patients with cancer and cardiovascular disease. This review identifies 13 cohort studies and 2 meta‐analyses investigating disparate outcomes in treatment‐associated cardiotoxicity and situates these data within the context of oncologic disparities, preexisting cardiovascular disparities, and potential system‐level inequities. Black survivors of breast cancer have elevated risks of cardiotoxicity morbidity and mortality compared with White counterparts. Adolescent and young adult survivors of cancer with lower socioeconomic status experience worsened cardiovascular outcomes compared with those of higher socioeconomic status. Female patients treated with anthracyclines or radiation have higher risks of cardiotoxicity compared with male patients. Given the paucity of data, our understanding of these racial and ethnic, socioeconomic, and sex and gender disparities remains limited and large‐scale studies are needed for elucidation. Prioritizing this research while addressing clinical trial inclusion and access to specialist care is paramount to reducing health inequity.

C ardiovascular disease (CVD) and cancer are the leading causes of death in the United States, with a disproportionate burden of illness among Black patients, lower income communities, and other minority groups. [1] [2] [3] [4] [5] Incidence and mortality disparities in cancer and CVD remain pervasive because of complex interactions of social determinants of health including social, economic, geographic, and cultural factors that affect underlying biology and health-related behaviors. [1] [2] [3] [6] [7] [8] [9] [10] [11] These social determinants of health are thought to be modulated by sex and gender 12 and structural racism 13,14 -defined as economic, institutional, cultural, and historical forces that systematically advantage White populations and disadvantage racial and ethnic minority populations. Such disparities have been magnified by the COVID-19 pandemic, which unevenly has affected underresourced communities and racial and ethnic minority patients in the United States. [15] [16] [17] Cancer health disparities may be intertwined with cardiac outcomes, particularly given the rising overall incidence of cancer (owing to improved cancer screening and survival among common cancers) 1,2,4 that coincides with the increasing prevalence of CVD among patients with cancer.

Metabolic effects of malignancy, direct adverse effects of cancer therapeutics, and indirect effects of treatment (eg, physical deconditioning) have profound impacts on the cardiovascular health of patients with cancer. [18] [19] [20] [21] Indeed, CVD has become a significant cause of morbidity and mortality among survivors of cancer. 22, 23 For instance, among postmenopausal women with hormone receptor positive breast cancer, CVD has been shown to rival or exceed recurrent malignancy as the most common cause of death. 24 with an estimated 16.9 million people in the United States living with a history of cancer, 4 the prevalence of CVD among survivors of cancer continues to increase. The multidisciplinary field of cardio-oncology has emerged to balance cancer treatment with the prevention and management of associated cardiac disease. Collaborations across oncology and cardiology have developed rapidly to address this imperative, with a growing understanding of the cardiotoxicity of cancer treatment in context of other cardiovascular risk factors. Preexisting cardiovascular risk factors and CVD are now known to be associated strongly with posttreatment cardiac dysfunction. [25] [26] [27] [28] [29] Given the cross-talk between cancer and cardiac disease, it is critical that we elucidate disparities in cardio-oncology in order to improve health outcomes for the most vulnerable patients including Black populations and other minority populations with cancer. Unfortunately, our current understanding of intersectional disparities within cardio-oncology is limited by a marked paucity of data. Two recently published reviews focus on racial and ethnic disparities in cardiooncology, 30 ,31 but our narrative review summarizes the available literature on disparities in cardiotoxicity outcomes across race and ethnicity, sex and gender, and socioeconomic status (SES) among patients with cancer in the United States. We situate these data in the context of disparities in cancer and preexisting CVD, as these bodies of knowledge provide important context for data interpretation. Studies to date on disparities in cardiotoxicity are limited in number and scope, but the available data presented here merit discussion to inform future investigations on disparities in cardiooncology and help create actionable strategies for equitable care.

It is important for even the general cardiologist to understand basic cancer disparities together with cardiovascular ones given that most patients with cancer are more likely to have access to a general cardiologist than a cardio-oncology specialist. Disparities exist across nearly all aspects of oncologic care from screening to survivorship. 1, 8 On average, patients of lower SES have increased cancer incidence and decreased survival compared with their higher SES counterparts. 2 Individual SES is shaped by a multitude of factors including education, employment status and occupation, income, wealth, and health insurance. Unfortunately, the socioeconomic gap in cancer appears to be widening: a 2017 longitudinal study of cancer mortality demonstrated that inequalities based on SES increased from 1979 to 2011, primarily because of disproportionally improved mortality for high SES patients. 32 The impact of this widening gap is likely to be felt broadly given the rising overall incidence of cancer.

Even after controlling for income, significant disparities persist for racial and ethnic minority patients with cancer in the United States. 33 Within this review, we refer to "racial and ethnic" populations with the understanding that race and ethnicity are social constructs that reference diverse groups of people. Racial and ethnic minority populations are categorized by the US Office of Management and Budget into Black populations, Hispanic/Latino populations (referred to as Hispanic/Latinx in this review), Asian populations and Native Hawaiian/other Pacific Islander populations (referred to as Asian and Pacific Islander in this review), and American Indian and Alaska Native (AIAN) populations, 6 though it bears noting that this grouping does not address ancestry, genetic admixture, immigration status, or regional communities. For most cancers, White patients are more likely than patients of other races and ethnicities to be diagnosed at earlier stages, receive aggressive care, and have improved chances of survival even when accounting for staging. 1, 4, 7, 34 Survival rates are lower for Black patients and AIAN patients in comparison to White patients for each major type of cancer except for renal and pancreatic cancer, for which mortality is approximately the same. 1 Although there are some instances of genetic differences in tumor biology (eg, the increased incidence of triple hormone receptor negative breast cancer in Black women), tumor genetics do not equate germline genetics and differential treatment responses alone do not account for racial and ethnic disparities in cancer outcomes. 7, 35 Similarly, SES alone does not account for racial and ethnic cancer disparities. 33 Various other social determinants of health including environmental pollution exposures, neighborhood safety-related concerns, and perceived racial discrimination have been implicated in these disparities, 2, 7, 8 influenced by ongoing structural racism. 36, 37 Sex and gender disparities as well as geographic disparities also persist among patients with cancer. Male patients across different races/ethnicities and ages continue to have increased rates of cancer and worsened prognosis in comparison to female patients. 1 The reasons for this are not understood completely but are thought to reflect differences in health-related behaviors, comorbid risk factors, and sex hormones. 1 

Disparities within preexisting cardiovascular risk factors and CVD must be addressed given their strong association with posttreatment cardiac dysfunction. [25] [26] [27] [28] [29] Additionally, understanding cardiovascular disparities may provide valuable insight for discussions on understudied disparities in cardio-oncology. Despite a decline in cardiovascular mortality nationwide, the burden of CVD remains disparately distributed among underresourced communities and racial and ethnic minority populations. [9] [10] [11] These disparities are discussed comprehensively in recent scientific statements and advisories from the American Heart Association, 9, 10, [39] [40] [41] [42] in a recent workshop from the National Heart, Lung, and Blood Institute, 11 and most recently in a comprehensive narrative review. 43 Race and ethnicity, SES, neighborhood resources and environmental features, sex and gender, and cultural factors including psychosocial stress (eg, from racial discrimination), acculturation among immigrant communities, and social cohesion have been associated with disparate incidence and mortality from CVD. [9] [10] [11] [39] [40] [41] [42] 44, 45 As described in a recent American Heart Association presidential advisory, 13 these factors are in turn influenced by structural racism. Forces of structural racism as well as other forms of racism, including interpersonal, are known to have downstream effects that modulate social determinants of health and perpetuate social, economic, and health inequities in general as well as cardiovascular health. 13, 14, 46, 47 However, racism is infrequently named in published literature as a contributor to health disparities, and little research has been done to evaluate in detail its effects on health. 13, 48 Some genome-wide association studies have identified genetic loci differentially associated with CVD in Black populations 9 and AIAN populations 41 as well as some polymorphisms associated with CVD across racial and ethnic groups, 40 but these data must be considered in context of the variability of results from replication studies, complex interaction between genes and environment, and risks of overattributing importance to genetic risk alleles at the expense of addressing significant contributions from social and structural determinants of health. 9, 40, 41 Black populations bear a disproportionately high burden of CVD and associated cardiovascular risk factors when compared with White counterparts. 9, 43 Black patients have been shown to have earlier ages of onset as well as higher incidence of hypertension, dyslipidemia, diabetes, and obesity when compared with White patients. They also have been shown to experience earlier onset as well as higher incidence and mortality of heart failure, sudden cardiac arrest, cerebrovascular disease, and peripheral arterial disease. 9 Additionally, they have experienced smaller decreases in the incidence of coronary artery disease in comparison to White populations. 9 These disparities have been associated with a multitude of factors including SES and other social determinants of health. 9,10 However, persistence of these disparities among Black patients across the socioeconomic spectrum also implicates social epigenetic factors including psychosocial stress from racial discrimination and structural racism itself, 13 although the scope of its impact requires further investigation as mentioned previously. In addition to explicit forms of racism, implicit bias continues to contribute to disparities. 10 For example, Black patients are less likely than White counterparts to receive cardiac catheterization for suspected angina 49 and, together with other racial and ethnic minority patients, are less likely than White patients to receive cardiopulmonary resuscitation for out-of-hospital arrest. 50 Genetic differences alone do not explain these differences for the reasons mentioned previously, as well as the clear genetic heterogeneity and admixture among populations of African descent. 51, 52 Disparities among Hispanic/Latinx as well as Asian and Pacific Islander (API) populations are masked by the reporting of disparities data in aggregate. Although some studies have shown a lower incidence of CVD among Hispanic/Latinx populations, recent discussions have emphasized the heterogeneity among this population and the variability of cardiac risk profiles among groups of different national origin or ancestral heritage. 39, 43, 53 Preliminary investigations suggest contributions from social determinants of health including language discordance, health literacy, cultural traditions, and psychosocial stress from perceived discrimination. 39 Heterogeneity among people of API descent also continues to be masked by surveys and studies that gather data on API patients in aggregate. 40 Among immigrant Hispanic/Latinx populations as well as immigrant API populations born outside the United States, acculturation and duration of US residence have been associated with worsened cardiovascular risk factors and CVD. 39, 40 However, the direct relationship between social determinants of health, perceived discrimination, acculturation, and structural racism has not been explored for any of these groups. 13, 39, 40 AIAN populations experience the highest morbidity and mortality from CVD of any subgroup in the United States. 41, 54 These populations share the same traditional cardiovascular risk factors as other groups, but with some distinctions: among AIAN populations, diabetes is the single-most important risk factor for CVD, Ohman et al Disparities in Cardiotoxicity Outcomes with a 3-fold elevated risk of diabetes in comparison to White populations. 41 Additionally, renal impairment is a unique independent risk factor for predicting CVD. 41 Common social determinants of health including poverty, education, unemployment, and housing also affect CVD in this population, as well as distinct environmental factors including toxic metal exposure and groundwater contamination. 41 The influence of governmental exploitation and structural discrimination has been referenced in relation to these CVD disparities but has not been investigated comprehensively. The absolute numbers of women living with and dying from CVD are greater than those for men, and coronary artery disease mortality rates are rising for women aged 35 to 44 years. 12 Although women and men share the same cardiovascular risk factors, the prevalence of some risk factors differ: women older than 65 years old and women older than 20 years old have a higher prevalence than men for hypertension and diabetes, respectively. 12 Additionally, rates of physical inactivity are higher for women than men. 12 These differences may be influenced by gender-based health behaviors. 12 Additionally, psychosocial stress from marital tension and the stress of traditional caregiving gender roles may contribute to cardiovascular risk factors. 12 Upstream factors of sexism also have been associated with increased risk of posttraumatic stress disorder, psychosocial stress, and health-related behaviors like alcohol and tobacco use. 12, 55 In the medical domain, inadequate treatment by providers in the management of acute and chronic cardiac disease may also be contributing to sex and gender disparities. Women with known coronary artery disease are less likely to be on appropriate lipid-lowering therapy and aspirin for secondary prevention. 56, 57 Although women are more likely to be treated for hypertension than men, they have achieved poorer levels of blood pressure control when matched for age, ethnicity, and comorbidities. 56 Women are also less likely to achieve a hemoglobin A1c target of <7% for appropriate diabetes control and cardiac risk mitigation. 56 It is well-established that the clinical presentation and inpatient treatment of acute coronary syndrome differs between men and women, and several studies have demonstrated that fewer women are started on evidence-based secondary prevention medications on discharge. 57 The reasons for these examples of substandard treatment need to be explored further, but implicit bias may play a contributory role. Implicit bias has been shown to influence gender-based decision-making in coronary artery disease, 49,58 but additional research is needed.

The persistence of race and ethnicity, socioeconomic, and sex and gender disparities among patients with CVD is deeply concerning, and raises the alarm for parallel disparities in interdisciplinary areas of medical care including cardio-oncology.

Although many studies on treatment-associated cardiotoxicity primarily define this entity as clinical heart failure and/or radiographic measurements of left ventricular systolic dysfunction, possible adverse shortand long-term cardiovascular effects encompass systolic and/or diastolic dysfunction, valvular disease, conduction abnormalities, coronary artery disease, impaired cardiac remodeling, disrupted mechanisms of cardiac homeostasis, vascular disease, and thrombosis. 59, 60 Such adverse effects have been associated with nearly all categories of cancer therapy.

To inform our discussion of disparities in treatmentassociated cardiotoxicity, the most common and clinically relevant cardiotoxicity manifestations are summarized here (Table 1) . [61] [62] [63] [64] [65] [66] [67] [68] Comprehensively documenting the heterogeneous spectrum of shortand long-term cardiotoxicities seen in both historical and novel cancer therapeutics is beyond the scope of this review; these cardiotoxicities are described elsewhere. 59, 60, 62, 63, [69] [70] [71] [72] In the available guidelines for the prevention, screening, surveillance, and attenuation of cancer treatmentassociated cardiotoxicity from the American Society of Clinical Oncology, 25 European Society of Medical Oncology, 73 and the American Heart Association, 74 the identification of patients at elevated risk is viewed as the first step in reducing cardiotoxicity. In identifying these patients, it is imperative to recognize which patients have predisposing cardiovascular risk factors and preexisting cardiac disease. Age as well as preexisting diabetes, hypertension, hyperlipidemia, and tobacco smoking have been associated with an increased risk of cardiac dysfunction among patients with cancer treated with anthracyclines or trastuzumab. [26] [27] [28] [29] A large-scale retrospective study found that among patients treated for breast cancer, lung cancer, multiple myeloma, and non-Hodgkin lymphoma, the presence of 2 or more cardiovascular risk factors conferred an even higher risk of post-treatment CVD. 75 The presence of preexisting reduced systolic function and coronary artery disease has also been linked to increased rates of treatment-associated cardiotoxicity. [27] [28] [29] The shared risk factors for cancer and CVD are thought to influence the pathogenesis of both disease entities as well as treatment-associated cardiotoxicity. 76, 77 

We suspect that the screening, surveillance, and management of treatment-associated cardiotoxicity is influenced by social and structural determinants of health Ohman et al Disparities in Cardiotoxicity Outcomes including health insurance status, geographic distance from specialty care, and transportation barriers. Many people with cancer still do not have access to health insurance: among states that did not pursue Affordable Care Act Medicaid expansions, 1 in 5 survivors of cancer remains uninsured. 78 Even among those with insurance, cardio-oncology specialists are not readily accessible to most people. Despite the rapid growth of the field, 79 specialized cardio-oncology training and patient access to cardio-oncology care is still limited worldand nationwide. Indeed, few cardiology fellowships offer formal training in cardio-oncology 80 and institutions with cardio-oncology services are clustered geographically in the Northeast and California. 80 Even in communities with access to cardio-oncology providers, some patients may face local barriers to transportation that can impede regular access to specialist care. Among the general population in the United States, transportation barriers to medical care have been shown to have a disproportionately powerful influence on patients of lower SES and those with chronic conditions. 81 Ultimately, patients with cancer may find it difficult to access cardio-oncology care because of inadequate insurance coverage, distance from cardio-oncology providers, and barriers to transportation. The degree to which these barriers mediate disparities in cardiotoxicity screening and management must be explored further.

Among strategies for cardiotoxicity prevention, additional socioeconomic factors may contribute to The overall incidence of radiation-induced cardiotoxicity varies depending on dose and historical era. Incidence of fatal radiation-associated cardiotoxicity is estimated at 1% to 7%.

References: 61-68. 82, 83 but is substantially more expensive than standard formulations. Continuous infusion of anthracycline therapy has been associated with lower risks of subclinical and clinical cardiotoxicity 84 but comes with elevated costs. The degree to which these cost differentials for less cardiotoxic therapies contribute to disparate cardiac outcomes among patients with cancer is not yet known.

We suspect that inadequate representation of diverse study participants in clinical studies on cardioprotective strategies for prevention of treatment-associated cardiotoxicity may also contribute to outcome disparities. It is well-established that racial and ethnic minority patients have been underrepresented in seminal clinical trials that resulted in Food and Drug Administration drug approvals for cancer therapeutics. 85 Cardioprotection studies have investigated neurohormonal agents (including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and beta blockers), statins, exercise, and dexrazoxane. Only 21% of identified cohort studies and clinical trials on cardioprotective therapies provide either demographic information on the race and ethnicity of study participants or demographic information on participants' socioeconomic status or other social determinants of health, though it does bear noting that some of the included studies were conducted in European countries with universal health care (Table S1 ). In accordance with the National Institutes of Health Revitalization Act, 115 achieving diverse representation in clinical trials on cardioprotective therapies must be made a priority. Doing so will require direct targeting of known barriers to clinical trial enrollment (including patient trust, healthcare access, education, and communication) 116 as well as explorations of factors specific to cardioprotection studies.

Additional investigation is needed on the impact of healthcare system distrust on cardio-oncology care delivery. Many racial and ethnic minority populations in the United States have developed distrust of institutionalized healthcare settings, 117 influenced by the history of slavery, living legacy of oppression, and exploitation of Black and brown bodies in instances such as the Tuskegee syphilis experiment 118 and government-sanctioned coerced sterilization of women of color, immigrants, and people with disabilities during the eugenics movement in the United States. 119 Medical distrust has been associated with decreased participation in clinical research and decreased use of general healthcare services as well as oncologic care. [120] [121] [122] The unstudied impact of medical distrust on participations in cardio-oncology care is of great concern. Specifically, we must investigate how patient distrust shapes participation in preventative cardiotoxicity screening as well as treatment for detected cardiac dysfunction in the context of noxious medical and radiation treatments for cancer.

There are limited data on outcome disparities in treatment-related cardiotoxicity. Our literature review identified 13 observational cohort studies and 2 systematic reviews with meta-analyses. Most of the studies identified in our review addressed disparate outcomes according to race and ethnicity among patients with breast cancer. Few investigations have examined disparities in other types of cancer or among other underrepresented groups. The major findings on outcomes disparities in treatment-associated cardiotoxicity are presented in the following sections and summarized visually (Figure 1 ).

Most studies to date explore differences in cardiovascular outcomes between Black and White patients with breast cancer. Black women diagnosed with breast cancer are 40% more likely to die than their White counterparts. 123 Differences in cardiotoxicity are hypothesized to contribute to this disparity, particularly as Black women are more likely to have underlying CVD and more frequently have high-risk cancer requiring cardiotoxic treatment. 124 Available research on this topic collectively supports this hypothesis (Table 2 125-133 and summarized in Figure 1 ). Black patients with HER2+ breast cancer treated with trastuzumab are more likely to develop cardiotoxicity as defined by declines in left ventricular ejection fraction. 128 131 although it is not clear that the degree of risk factor control was evaluated. Importantly, the development of cardiotoxicity correlated strongly with treatment cessation. An earlier retrospective cohort study at Howard University also found that Black patients treated with doxorubicin were more likely than non-Black patients to develop early cardiotoxicity, 125 although these patients were compared with non-Black control subjects in a separate cohort study. A national multicenter prospective cohort study of patients with metastatic HER2+ breast cancer found that Black patients with diabetes or hypertension were more likely to experience cardiotoxicity after trastuzumab compared with White counterparts with the same conditions, although levels of statistical significance were not reported. 127 In a meta-analysis of 18 studies across North America and Europe in which patients were treated with anthracycline therapy for a variety of cancers, Black race as well as cardiovascular risk factors were independent predictors of clinical and subclinical cardiotoxicity 134 ; this analysis is not shown in Table 2 . Mortality from CVD among Black patients with breast cancer is strikingly elevated (summarized in Figure 1 ). One of the largest studies on this topic used SEER (Surveillance, Epidemiology, and End Results) data to compare death from breast cancer and CVD retrospectively between 43 562 Black and 364 025 White patients with invasive breast cancer. 132 Note that these groups were characterized as non-Hispanic Black and White patients. The results showed that the cumulative incidence of CVD-related mortality was 129 This survival disparity may be due partially to differences in preexisting cardiovascular risk factors: in a regional retrospective cohort study among 1254 patients with invasive breast cancer, hypertension was an independent predictor of the survival disparity between Black American and White survivors. 126 Preliminary research suggests that cardiovascular risk among API patients with breast cancer varies by national origin and immigration status (included in Table 2 and summarized in Figure 1) . A retrospective cohort study used SEER registry data to investigate mortality differences among 44 531 API patients with invasive breast cancer in comparison to 462 005 White counterparts. 130 Although API patients in aggregate had lower risks of CVD-related mortality, breast cancer mortality, and all-cause mortality, Hawaiian women had a higher hazard of cardiovascular mortality compared with White patients. Pacific Islander women had elevated risk for breast cancerspecific and all-cause mortalities in comparison to White women. The grouping of API patients together in clinical research may mask such underlying disparities, and groups at higher risk such as Hawaiian and Pacific Islander women may need additional screening. Interestingly, US-born API survivors of breast cancer were found to have a higher hazard of cardiovascular mortality when compared with immigrant API survivors of breast cancer. The effects of acculturation and associated lifestyle changes likely contribute to the higher risk of CVD among API women born in the United States.

There are even fewer published studies on socioeconomic disparities in treatment-associated cardiotoxicity, although preliminary data demonstrate the impact of health insurance status, poverty, and geographic region (summarized in Figure 1 ). Among adolescent and young adult (AYA) survivors of various types of cancer, Black race as well as lower SES have been associated independently with increased risks of CVD and CVDassociated mortality. In a retrospective cohort study of 79 167 survivors of AYA cancer ages 15 to 39 years old, Black patients had an elevated risk of CVD in comparison to White patients (hazard ratio [HR], 1.55; 95% CI, 1.33-1.81). 135 Cancer types included breast cancer, thyroid cancer, melanoma, testicular cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, acute lymphoid leukemia, acute myeloid leukemia, soft tissue sarcoma, bone sarcoma, colorectal cancer, central nervous system cancer, cervical cancer, and ovarian cancer. Additionally, uninsured or publicly insured patients had an elevated risk of CVD in comparison to patients with private or military insurance (HR, 1.78; 95% CI, 1.61-1.96), and those who resided in lower SES neighborhoods had increased risks of CVD in comparison to patients living in the highest SES neighborhoods (HR, 1.66; 95% CI, 1.42-1.93). 135 An even larger retrospective cohort study from SEER registry data among 242 940 AYA women and 158 347 AYA men with a broad spectrum of primary malignancies found that increasingly severe degrees of poverty were associated with increased risks of CVD mortality even after adjusting for race and ethnicity (HR, 1.18; 95% CI, 1.01-1.38 for quartile 2; HR, 1.37; 95% CI, 1.18-1.60 for quartile 3; HR, 1.41; 95% CI, 1.17-1.70 for quartile 4 below poverty line for women; HR, 1.11; 95% CI, 0.96-1.29 for quartile 2; HR, 1.35; 95% CI, 1.16-1.57 for quartile 3; and HR, 1.31; 95% CI, 1.09-1.58 for quartile 4 below the poverty line for men). 136 Additionally, education below high school levels was associated with increased risks of CVD mortality among both AYA women and men with cancer even after adjusting for race and ethnicity. 136 Geographic region was also found to have a significant impact: AYA patients residing in the South had increased risks of CVD mortality in comparison to patients living in the Northeast (HR, 1.40; 95% CI, 1.15-1.71 for AYA women and HR, 1.42; 95% CI, 1.16-1.73 for AYA men); no other regions demonstrated significant differences. 136 

There is a notable paucity of published studies on cardiotoxicity outcome disparities according to sex and gender (Table 3 [137] [138] [139] and summarized in Figure 1) 138 Notably, White patients made up 75% of this study. A smaller retrospective cohort study of pediatric survivors of cancer treated with doxorubicin showed that 45% of female patients developed depressed contractility compared with 12% of male patients. 137 This disparate cardiotoxicity incidence widened with higher cumulative doses of doxorubicin. Similarly, a recent meta-analysis of 10 observational studies among patients receiving radiation for Hodgkin lymphoma discovered sex and gender disparities for cardiovascular mortality. 139 Women had an aggregate incidence of life-threatening cardiovascular events and mortality almost 4 times higher than men. However, this study did not match male and female patients by radiation therapy dose, age of cancer diagnosis, or method of cardiotoxicity diagnosis. Additionally, none of the 3 mentioned studies presented data on preexisting CVD or risk factors, nor did they control for other covariates such as SES or healthcare access.

We provide a visual summary of our findings on outcome disparities according to race and ethnicity, socioeconomic status, and sex and gender in treatment-associated cardiotoxicity with a depiction of contributing etiologies (Figure 1 ). The studies reviewed here have prominent limitations-most notably, size and the lack of controlling for relevant covariates. Many of these studies did not account for variables such as disease stage, preexisting cardiovascular risk factors, or CVD. Most studies did not control for socioeconomic factors, geographic factors, or other social variables. Further research is necessary to determine to what degree the observed disparities among Black women with breast cancer exist within other cancer types, as well as among other racial and ethnic groups including diverse API, Hispanic/Latinx, and AIAN communities. Additional research is needed to examine the interactions of individual and neighborhood SES with other social determinants of health as well as broader dynamics of structural racism within the context of CVD among patients with cancer. Further research is required to elucidate the conflicting difference in sex and gender disparities among women described here in comparison to prior literature that cites worsened outcomes in men. Additionally, future investigations on sex and gender disparities should be broadened to include other groups subject to sex-and gender-based discrimination, including lesbian, gay, bisexual, transgender, queer (or questioning), asexual (or allied), and intersex patients.

The intersection of these different disparities is deeply worrisome for potential compounding effects on disparities in cardiotoxicity and extreme vulnerability to inequity. This should be explored further not only for Black women with cancer but also for Hispanic/Latinx and API women (with attention paid to acculturation effects) as well AIAN women. It is important to note that although AIAN communities have the highest risk for CVD in the general population, there are no available studies on cardiotoxicity among this population. In addition, younger women who receive oncologic therapy with elevated risk of atherosclerotic disease 70 should be considered in the context of the increasing rates of coronary artery disease among the general population of young women ages 35 to 44 years old. 12 Given that the culprit contributing variables to general cardiovascular disparities extend beyond socioeconomic factors alone and include other social determinants of health as well as upstream structural racism and sexism 10, 13, 43, 55 (Figure 1 ), future research in cardio-oncology must also investigate the relationship of these factors to cardiotoxicity outcomes.

Based on our review of the literature and current practices, we propose actionable strategies within clinical practice, investigative research, and community engagement to reduce disparities in cardio-oncology ( Figure 2 ). In addition to developing standardized protocols for cardiovascular screening, risk factor optimization, and cardiotoxicity treatment per American Society of Clinical Oncology and American Heart Association guidelines, we propose developing effective tools to assess patient social and structural vulnerabilities at the time of care establishment in order to identify patients in need of additional interdisciplinary resources. Leveraging telehealth services from the COVID-19 era may improve healthcare access for some patients without immediate access to cardio-oncology providers or with personal or structural circumstances that challenge regular care. However, creative and informed approaches will be needed for populations with limited resources, as preliminary research on telehealth use during the COVID-19 pandemic demonstrates that patients of color, older patients, patients who do not speak English, and patients from disadvantaged backgrounds have participated less in telemedicine and virtual video visits. 140, 141 Additionally, we recommend longitudinal implicit bias training for all healthcare workers to decrease the interference of implicit bias with equitable care and recommend peer review of practice patterns to reduce substandard or inappropriate treatment of under-represented minorities and women.

Among research-based strategies, we call for an expansion of health disparities research as discussed previously to the level of rigorous large-scale studies investigating different types of disparities among Ohman et al Disparities in Cardiotoxicity Outcomes diverse types of cancer and cardiotoxic treatment. These disparities should be evaluated in the context of comprehensive social determinants of health and forces of systemic discrimination. Encouragingly, the American Heart Association recently solicited research on cardio-oncology disparities, with the aim to devise a disparities research network focused on collaborative basic, clinical, and population-based investigations. 142 In addition to research expansion, we urge the robust recruitment of underrepresented groups to clinical trials for cancer therapeutics and cardioprotective agents, inclusive of patients with known cardiovascular comorbidities. In both health disparities studies and therapy-based clinical trials, we recommend that data on social determinants of health be collected among all study participants.

To inform these investigations, cultural and structural competency training should be pursued to improve clinician and scientist understanding of health determinants. These strategies should be partnered with community initiatives to improve care access and patient outcomes. Initiatives to consider include communitybased participatory research to explore barriers to cardio-oncologic care as well as community group collaborations to improve outreach to community members. Ongoing efforts should also be made to promote the diverse representation of clinicians and scientists involved in cardio-oncology clinical care and research. Although addressing broader systemlevel policies requires collaboration among many political, legal, and social groups, there is also a critical need for physician political advocacy in conversations on public health crises including poverty, housing insecurity, insufficient health insurance, and structural racism.

The general cardiologist has an important role in the collaborative work of reducing cardio-oncology disparities. General cardiology practitioners are needed to help screen for CVD, aggressively manage cardiovascular risk factors, and refer early to cardio-oncologists when possible. In areas where cardio-oncology providers are not available, general cardiologists should assume the collaborative role with a patient's oncology team. This requires diligent screening practices as well as an accurate understanding of which patients are most at risk for CVD and treatment-associated cardiotoxicity. Individual cardiology and oncology providers are not able to single-handedly change social or structural determinants of health, but they can commit to some of the clinical, research, and community strategies offered here to help reduce disparities.

Disparities in CVD and CVD-related mortality will be an important area of study as the landscape of cancer treatment modalities continues to evolve. By further Strategies that can be taken by individual clinicians, scientists, and provider groups to reduce outcome disparities and improve cardiovascular and cancer-associated health equity in the cardio-oncology population. SES indicates socioeconomic status. Created by biore nder.com. 

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Speaking up against inequity and racism

Sex and gender: modifiers of health, disease, and medicine

Status of cardiovascular disease and stroke in Hispanics/Latinos in the United States: a science advisory from the

Call to action: cardiovascular disease in Asian Americans: a science advisory from the

American Heart Association Council on E. Cardiovascular health in American Indians and Alaska Natives: a scientific statement from the

American Heart Association Council on E, Prevention, Council on Quality of C. Importance of housing and cardiovascular health and well-being: a scientific statement from the American Heart Association

State of the nation's cardiovascular health and targeting health equity in the United States: a narrative review

Cardiovascular mortality differences-place matters

Relation between neighborhood environments and obesity in the Multi-Ethnic Study of Atherosclerosis

Racism and health: evidence and needed research

Is racism a fundamental cause of inequalities in health?

Naming Institutionalized racism in the public health literature: a systematic literature review

The effect of race and sex on physicians' recommendations for cardiac catheterization

Out-of-hospital cardiac arrest surveillance-cardiac arrest registry to enhance survival (CARES), United States

African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping

The genetic structure and history of Africans and African Americans

Prevalence of major cardiovascular risk factors and cardiovascular diseases among Hispanic/Latino individuals of diverse backgrounds in the United States

Rising tide of cardiovascular disease in American Indians. The Strong Heart Study

Sex differences in cardiovascular health: does sexism influence women's health?

Recognizing and improving health care disparities in the prevention of cardiovascular disease in women

Women are less likely to get secondary prevention medications and cardiac rehabilitation

Implicit gender bias and the use of cardiovascular tests among cardiologists

Cardio-oncology: an update on cardiotoxicity of cancer-related treatment

Cardiotoxic effects of chemotherapy: a review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system

Cardiotoxicity due to targeted anticancer agents: a growing challenge

Cardiotoxicity of anticancer treatments: epidemiology, detection, and management

Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention

Rare incidence of congestive heart failure in gastrointestinal stromal tumor and other sarcoma patients receiving imatinib mesylate

Radiationassociated cardiovascular disease

Radiation-induced cardiovascular disease

Managing cardiotoxicity associated with immune checkpoint inhibitors

The cardiovascular complications of chimeric antigen receptor T cell therapy

Cardiovascular toxic effects of targeted cancer therapies

Vascular toxic effects of cancer therapies

Vascular toxicities of cancer therapies: the old and the new-an evolving avenue

Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia

Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines

Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the

Cardiovascular disease among survivors of adult-onset cancer: a community-based retrospective cohort study

Common risk factors for heart failure and cancer

Bidirectional relationship between cancer and heart failure: old and new issues in cardio-oncology

The Affordable Care Act improved health insurance coverage and cardiovascular-related screening rates for cancer survivors seen in community health centers

Cardio-oncology education and training: JACC council perspectives

Preparing the cardiovascular workforce to care for oncology patients: JACC review topic of the week

Transportation barriers to health care in the United States: findings from the National Health Interview Survey

Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as firstline therapy of metastatic breast carcinoma

Different anthracycline derivates for reducing cardiotoxicity in cancer patients

Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials

Disparity of race reporting and representation in clinical trials leading to cancer drug approvals from

The effect of an aerobic exercise bout 24 h prior to each doxorubicin treatment for breast cancer on markers of cardiotoxicity and treatment symptoms: a RCT

Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone

Anthracyclineinduced cardiomyopathy: clinical relevance and response to pharmacologic therapy

Prevention of highdose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition

Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallel-group, randomized, controlled study with 36-month follow-up

Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies)

Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study

Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol

Protective effects of carvedilol against anthracycline-induced cardiomyopathy

Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy

Multidisciplinary approach to novel therapies in cardio-oncology research (MANTICORE 101-Breast): a randomized trial for the prevention of trastuzumabassociated cardiotoxicity

Carvedilol for prevention of chemotherapy-related cardiotoxicity: the CECCY trial

Anthracyclineinduced cardiotoxicity: a multicenter randomised trial comparing two strategies for guiding prevention with enalapril: the International CardioOncology Society-one trial

Randomized trial of lisinopril versus carvedilol Ohman et al Disparities in Cardiotoxicity Outcomes to prevent trastuzumab cardiotoxicity in patients with breast cancer

Efficiency of atorvastatin in the protection of anthracyclineinduced cardiomyopathy

Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study

Cardioprotective effect of statins in patients with HER2-positive breast cancer receiving trastuzumab therapy

ICRF-187 permits longer treatment with doxorubicin in women with breast cancer

Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer

Randomized trial of the cardioprotective agent ICRF-187 in pediatric sarcoma patients treated with doxorubicin

Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer

Randomized prospective clinical trial of highdose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas

The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia

Effect of epirubicin-based chemotherapy and dexrazoxane supplementation on QT dispersion in non-Hodgkin lymphoma patients

Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/ metastatic breast cancer patients treated with anthracycline-based chemotherapy

Dexrazoxane protects breast cancer patients with diabetes from chemotherapy-induced cardiotoxicity

Dexrazoxane added to doxorubicin-based adjuvant chemotherapy of breast cancer: a retrospective cohort study with a comparative analysis of toxicity and survival

cardioprotective effect of dexrazoxane in patients with HER2-positive breast cancer who receive anthracycline based adjuvant chemotherapy followed by trastuzumab

Upfront dexrazoxane for the reduction of anthracycline-induced cardiotoxicity in adults with preexisting cardiomyopathy and cancer: a consecutive case series

NIH Revitalization Act: hearing before the Subcommittee on Health and the Environment of the Committee on Energy and Commerce, House of Representatives, One Hundred Third Congress, first session, on H.R. 4, a bill to amend the Public

The role of diverse populations in US clinical trials

Towards a more inclusive and dynamic understanding of medical mistrust informed by science

The Tuskegee Syphilis Study, 1932 to 1972: implications for HIV education and AIDS risk education programs in the black community

Eugenics and involuntary sterilization

Mistrust of health care organizations is associated with underutilization of health services

Healthcare system distrust and the breast cancer continuum of care

Healthcare system distrust, physician trust, and patient discordance with adjuvant breast cancer treatment recommendations

SEER cancer statistics review

Epidemiology of health disparities in relation to the biology of estrogen receptor-negative breast cancer

Doxorubicin cardiotoxicity in African Americans

Hypertension is an independent predictor of survival disparity between African-American and white breast cancer patients

Racial disparities in treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer

Trastuzumab-induced cardiomyopathy: incidence and associated risk factors in an inner-city population

Racial differences in breast cancer, cardiovascular disease, and all-cause mortality among women with ductal carcinoma in situ of the breast

Risk of cancer-specific, cardiovascular, and all-cause mortality among Asian and Pacific Islander breast cancer survivors in the United States

Racial disparities in the rate of cardiotoxicity of HER2-targeted therapies among women with early breast cancer

Race differences in cardiovascular disease and breast cancer mortality among US women diagnosed with invasive breast cancer

A balancing act: racial disparities in cardiovascular disease mortality among women diagnosed with breast cancer

Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity

Cardiovascular disease incidence in adolescent and young adult cancer survivors: a retrospective cohort study

Disparities in mortality from noncancer causes among adolescents and young adults with cancer

Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer

Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience

Gender disparity in cardiovascular mortality following radiation therapy for Hodgkin's lymphoma: a systematic review

Patient characteristics associated with telemedicine access for primary and specialty ambulatory care during the COVID-19 pandemic

Telemedicine outpatient cardiovascular care during the COVID-19 pandemic: bridging or opening the digital divide?

Request for Applications for the Disparities in Cardio-Oncology Strategically Focused Research Network

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