Social Determinants of Health in Cardio-Oncology

Abstract

Addressing the need for more equitable cardio-oncology care requires attention to existing disparities in cardio-oncologic disease prevention and outcomes. This is particularly important among those affected by adverse social determinants of health (SDOH). The intricate relationship of SDOH, cancer diagnosis, and outcomes from cardiotoxicities associated with oncologic therapies is influenced by sociopolitical, economic, and cultural factors. Furthermore, mechanisms in cell signaling and epigenetic effects on gene expression link adverse SDOH to cancer and the CVD-related complications of oncologic therapies. To mitigate these disparities, a multifaceted strategy is needed that includes attention to health care access, policy, and community engagement for improved disease screening and management. Interdisciplinary teams must also promote cultural humility and competency and leverage new health technology to foster collaboration in addressing the impact of adverse SDOH in cardio-oncologic outcomes.

Central Illustration

Highlights

• •The impact of SDOH on cardiovascular outcomes among patients with cancer remains understudied.
• •Common mechanistic pathways exist between SDOH and cancer therapy–related cardiotoxicities.
• •Integration of SDOH into the prevention and management of cardio-oncology outcomes is needed.

Introduction

State of the science

Social determinants of health (SDOH) are the conditions within which people are born, live, work, and age. They reflect systemic, structural (economic and environmental [ie, built, social, and food]), and psychosocial factors that play a critical role in cardiovascular disease (CVD) outcomes.¹ For instance, prolonged exposure to adverse SDOH is directly associated with the development of CVD risk factors and poor cardiovascular health behaviors (ie, smoking, physical inactivity, low-quality dietary intake, and poor sleep quality). Moreover, chronic psychosocial and environmental stressors related to adverse SDOH trigger biologic pathways,² such as activation of the sympathetic nervous system, the hypothalamic-pituitary-adrenal axis, and the neural-hematopoietic axis, to create a proinflammatory milieu that promotes cancer,³ diabetes mellitus,⁴ and CVD.⁵

The relationship between SDOH and CVD extends across the life span, and this relationship is true among cancer survivors, particularly childhood cancer survivors. Well-known cardiovascular risk factors among childhood cancer survivors include hypertension, obesity, dyslipidemia, and prediabetes. Similarly, among both childhood and adult survivors of cancer, there is an increased risk of early-onset acquired heart disease, stroke, and arrhythmia.^6,7 Childhood cancer survivors are more likely to have elevated blood pressure (38.4% vs control, 30.1%; P = 0.04).⁸ Moreover, 1 in 8 childhood adult survivors of childhood cancer will experience a life-threatening cardiovascular event within 30 years after oncologic therapy.^7,9

Adverse CVD outcomes can either be associated with cancer therapy or occur independently of systemic cancer therapy or radiation therapy.^9,10 Prior research suggests that when diagnosed with hypertension, adult survivors of childhood cancers who received chest-directed radiotherapy have a 28 times greater relative risk of coronary artery disease (relative excess risk because of interaction: 27.9; 95% CI: 14.6-51.0) and an 18 times greater relative risk of heart failure (relative excess risk because of interaction: 18.3; 95% CI: 7.6-37.4) compared to survivors without any cardiotoxic or radiation exposure.⁷ Pediatric and adult childhood cancer survivors are more likely to develop cardiomyopathy, heart failure, and valvular heart disease, whereas adult survivors are more likely to develop coronary artery disease decades before their age-matched peers.^7,9 Furthermore, there is an increased CVD mortality risk among non-Hispanic Black (NHB) adults compared to non-Hispanic White (NHW) adults with cancer that mirrors the disproportionate adverse SDOH burden they face¹¹ and this racial difference is attenuated by taking into consideration education and household income.¹⁶ This evidence demonstrates the complex interplay between cancer therapy, cardiovascular health, and the urgent need to further expand our understanding of the role of SDOH on CVD outcomes for cancer patients.

Available evidence supports a clear relationship between SDOH and CVD.¹ In this review, we apply the health equity framework by Powell-Wiley et al¹ to examine current evidence relating SDOH to CVD development in the setting of cancer and cancer therapeutics for both childhood and adult cancer survivors. We identify epidemiologic and translational studies of mechanistic pathways that connect oncologic treatments to CVD and examine the impact of SDOH on these pathways. We highlight SDOH domains salient to cardio-oncology for childhood and adult populations and provide future directions for integrating SDOH into interventions to reduce disparities and promote health equity in cardio-oncologic outcomes.

Disparities in cardio-oncology outcomes

Significant disparities in excess CVD risk related to cancer and specific cancer therapeutics continue to exist in groups traditionally under-represented in biomedical research (Table 1).¹² Table 1 illustrates key examples of SDOH domains that have been demonstrated in prior research to impact disparities in cardio-oncology populations. As noted, NHB populations have the highest comorbid age-adjusted CVD- and cancer-related mortality compared to NHW populations in the United States.¹³ Although racial and ethnic differences in survival among childhood cancer patients are attenuated when adjusting for health insurance and area-level social deprivation index,¹⁴ current evidence suggests that patient populations who are exposed to clustered, adverse SDOH over their lifetime are disproportionately burdened by the cardiovascular side effects of cancer and cancer therapeutics. Thus, historically under-represented populations often experience the intersectional effects of several SDOH domains concurrently, which may influence their health-seeking behaviors and CVD outcomes.^1,2

Table 1.

Specific SDOH and Impact on Cardio-Oncology Patient Survival and Cardiovascular Health

SDOH Factor	Example SDOH Measures Used	Impact on CV Health of Oncology Patients
Structural racism and discrimination	Self-reported race	Among women diagnosed with noninvasive breast cancer who received therapies with potential cardiotoxicity, higher hazards of CVD mortality were observed among NHB women compared with NHW women.133
	Social Vulnerability index	Communities with high social vulnerability have higher age-adjusted mortality rates for comorbid cancer and CVD.13
Education and health care access	Highest level of education attained extracted from death certificates	Increased age-adjusted cancer mortality rates from 1989 to 2018 among individuals with <12 years of education but decreased among those with 12 or more years of education demonstrating an increased cancer mortality gap between the least educated and most educated for most malignancies.32
Socioeconomic factors	County-level poverty	Increased CVD mortality with increased county-level poverty among women diagnosed with cancer from 1987 to 2015.30
	SEER definition of having medical coverage: private insurance, Medicare, or military coverage	Presence of non-Medicaid insurance is associated with lower CVD mortality in cancer patients compared to those without insurance or with Medicaid.123
Neighborhood and built environment	Area deprivation index	Residence in areas with higher area deprivation associated with 5- to 8-fold all-cause death in the St. Jude Lifetime cohort.17
Community context and social risk: food access	County-level percentage of individuals experiencing food insecurity	Increased age-adjusted incidence and mortality with increased food insecurity.44,45
Psychosocial/social environment	The Medical Outcomes Study 36-item Short Form Health Survey version 2	Obesity, a CVD risk factor, is associated with health-related quality of life among adult survivors of childhood cancer.51

CVD = cardiovascular disease; NHB = non-Hispanic Black; NHW = non-Hispanic White; SDOH = social determinants of health; SEER = Surveillance, Epidemiology, and End Results.

Among childhood cancer survivors, NHB populations, Hispanic/Latinx populations, and individuals with lower household income and education are less likely to have health insurance and more likely to have obesity or diabetes.¹⁵ NHB childhood cancer survivors are also more likely to have hypertension and other CVD risk factors, whereas Hispanic/Latinx cancer survivors have higher rates of CVD-related deaths.¹⁶ Living in a census block group with a high area deprivation index (ADI) (ie, more resource deprived) is independently associated with increased mortality risk among childhood cancer survivors.^17,18 The current evidence on disparities among cardio-oncology patients highlights the importance of a life course approach when examining the impact of SDOH on the cardiovascular outcomes related to cancer and its therapeutics.

The role of SDOH domains in cardio-oncologic disparities

The social determinants of cardio-oncologic health disparities framework (Figure 1) integrates Powell-Wiley et al’s health equity–focused framework¹ with the drivers of inequity in cardio-oncology¹² to illustrate the increased burden and worsened outcomes relating to the intersection of adverse SDOH with cardiovascular outcomes in patients with cancer. Structural SDOH domains within the framework reflect the sociopolitical, economic, and cultural context (ie, structural racism and discrimination, access to quality education and health care, socioeconomic status [SES], and neighborhood environment) that shape the social risks and lived experience of an individual within a specific social and community context (intermediate SDOH domain).^1,19 Overall, these structural and intermediate SDOH domains serve as antecedents that affect chronic stress burden and health-seeking behaviors of individuals. Health-seeking behaviors are goal-oriented actions in pursuit of symptom identification, interpretation, and management.²⁰ These health-seeking behaviors can affect biologic pathways that determine CVD outcomes in patients with cancer. Guided by the proposed framework, we highlight specific examples of SDOH domains that affect health-seeking behaviors and cardio-oncologic outcomes for disparate population groups.

Figure 1.

The Social Determinants of Cardio-Oncologic Disparities

Disparities in cardio-oncologic outcomes are shaped by the trickle-down effects of systemic-, social-, and community-level factors at an individual’s social position. Marginalized individuals who experience the intersectional effects of multiple negative social determinants of health may also experience a double burden of poor cardiovascular disease outcomes and cancer mortality.

Structural racism and discrimination

Structural racism and discrimination represent systemic policies and ideologies that disadvantage under-represented populations, thereby promoting disparities in CVD risk and outcomes among those with cancer. It is perpetuated through the everyday experience of chronic microaggressions and discrimination. Effectively, it may hinder health-seeking behaviors, serving as a barrier to the detection and treatment of early cardiovascular toxicity and related CVD after cancer care in under-represented groups.²¹ Furthermore, structural racism has been established as a key component of persistent health disparities and adverse CVD outcomes (Table 1). For example, NHB and Hispanic/Latinx patients are more likely to delay preventive medical care, in part because of long-standing policies resulting from structural racism that limit access to education, employment, and health insurance.²¹ As such, this can potentially increase the burden of both cardiovascular and oncologic diseases. Compared to White individuals, more advanced staging at the time of diagnosis among NHB and Hispanic/Latinx individuals with adult-onset cancers is known to contribute to disparities in cancer-related mortality, although earlier detection may not fully eliminate those disparities.²²

Furthermore, Hispanic/Latinx, Asian American, and Pacific Islander individuals residing in communities with high social vulnerability experience higher rates of age-adjusted mortality because of comorbid CVD and cancer compared to those of the same racial and ethnic groups residing in communities with low social vulnerability.¹³ The social vulnerability index is a composite measure of 4 main themes (ie, neighborhood-level SES,²³ household composition and disability, transportation barriers, and minority status and language),²³ some of which are markers of existing structural racism.²⁴ Prior research illustrates that NHB women who experienced perceived racism or discrimination are at a significantly greater risk for low-grade chronic inflammation and subsequent CVD development,^25,26 both of which could contribute to disparate cardio-oncology outcomes. Similarly, Indigenous Americans face a disproportionate burden of disease driven by long-standing racial and cultural divides, including the lack of accessible medical specialists (ie, cardio-oncologists).²⁷ In parallel, despite limited data, disparities in cardio-oncology care and outcomes are inherent between sex and gender minorities along with immigrant populations within the United States. These are partially influenced by stigma faced in health care and hesitancy to pursue care because of limited trust in medical providers.^21,27 More research using diverse populations is critically needed among cardio-oncology patients. Representative population samples will allow for the examination of both patient experiences of structural racism and discrimination as well as the impact of provider-level implicit bias on health care delivery and CVD outcomes. Additionally, clinical trials in oncology and cardiovascular medicine often use nonrepresentative samples, thus limiting trial access for and recruitment of diverse populations.^27,28 Consequently, clinical trials may underestimate any effects of inherent structural racism and discrimination within cardio-oncology populations. Hence, special attention to equitable clinical trial enrollment is especially important to comprehensively understand and address structural factors in relation to cardio-oncologic outcomes.

Education and health care access

Lower educational attainment and lack of access to quality health care may further drive inequities within cardio-oncology populations. Several studies have shown that lower educational attainment is associated with a higher risk of CVD events, such as acute myocardial infarction, stroke, and heart failure,²⁹ and others found no clear trends in the associations between educational attainment and cancer mortality.³⁰ Prior research also shows that although the rates of attainment of an associate degree or higher increased from 2010 to 2022 across almost all racial and ethnic groups, the percentage of NHB or Hispanic/Latinx individuals with that degree remained significantly lower than NHW individuals (36% and 34% vs 56%).³¹ Evidently, although the effect that a patient’s educational attainment has on clinician bias, clinical care, and health outcomes requires further investigation, particularly in minoritized populations, educational level may shape the ability to recognize and describe symptoms or engage and advocate for quality medical care. This, in turn, may result in challenges navigating the health care system; delayed health screenings; limited access to medical care; and, overall, worse short- and long-term outcomes.³² Taken together, this evidence illustrates that marginalized and/or minoritized populations may be disproportionately affected by the adverse effects of a lower educational level.

Despite the exponential expansion of the cardio-oncology field globally, the availability of trained specialists remains limited. Within the United States, access to cardio-oncologists is mainly limited to the urban, coastal areas. These geographic limitations create a disparity in access to specialized cardio-oncology care for a large segment of the population. Rural populations are particularly disadvantaged by geographically inaccessible care, leading to suboptimal cardio-oncologic support. Several studies have established that increased travel time for health care and reduced geographic accessibility are linked to worse cancer and CVD outcomes.²⁷ Conversely, in childhood cancer survivors, residence in high-income or high–physician density communities is associated with increased cardio-oncology referrals and echocardiographic screening.³³ Additionally, patients within lower SES strata, those with transportation limitations, or those with medical insurance coverage barriers may not be able to access care even if geographically near specialists.³⁴ Although there are few studies specifically examining these determinants within the cardio-oncology population, the current literature suggests that education and health care access have multilevel effects on quality of life and mortality.

Socioeconomic status

Both childhood and adult cancer patients living in poverty experience higher rates of relapse and death.35, 36, 37 Racial and ethnic inequalities in mortality are influenced by relative SES, including education and job attainment levels, as demonstrated by investigators who have found that racial and ethnic differences in outcomes are associated with the unequal distribution of resources and SES across racial and ethnic groups.^21,38 In studies specifically evaluating childhood cancer survivors, NHB and Hispanic/Latinx individuals with lower household income and education were less likely to have health insurance and more likely to have obesity or diabetes,¹⁵ both risks for CVD. Among adolescent and young adult (AYA) cancer survivors, living in lower SES neighborhoods was associated with increased CVD events and mortality compared to living in higher SES neighborhoods.³⁹ An even larger retrospective cohort study from the Surveillance, Epidemiology, and End Results registry data (242,940 AYA women and 158,347 AYA men with a broad spectrum of primary malignancies) found that after adjusting for ethnicity and race, increasingly severe degrees of poverty were linked to an increased risk of CVD death.³⁰ Evidently, SES contributes to health inequities within cardio-oncology care and delivery, possibly through its associations with health literacy, resources, and accessibility.

Neighborhood built environment

Environmental SDOH are external factors in an individual’s physical surroundings that can significantly impact their health outcomes and overall well-being. These determinants include access to clean air and water, exposure to environmental toxins, and the built environment. Components of the built environment include access to pedestrian-friendly roads, green space, residential or recreation facility density, and public transportation that provide accessibility and proximity to health care and other social services. Increased rates of cardiovascular risk factors and pre-existing CVD among populations historically under-represented in biomedical research are influenced by these environmental determinants and contribute to increased cardiotoxicity incidence and mortality.³⁴ Similarly, the St. Jude Lifetime Cohort Study, a cohort study of childhood cancer survivors, found that living in a disadvantaged (high ADI) U.S. Census–block group was associated with significant increases in all-cause and health-related late mortality as opposed to living in more advantaged (low ADI) areas.¹⁷ Additionally, individuals living in lower SES neighborhoods have increased levels of sedentary behavior and physical inactivity. Thus, neighborhood characteristics are important contributors to cardio-oncologic disparities.²² More work is needed to examine the effects of environmental toxins and natural environment features, particularly in the context of climate change, on CVD outcomes for patients with cancer.

Community context and social risk

Multiple factors contribute to an individual’s social and community context including the food environment, social cohesion, and material circumstances (ie, food security, housing stability, and financial strain).⁴⁰ In regard to the food environment, access to nutritious food and overall dietary intake have established implications in biological and psychological mechanisms related to an individual’s cardiovascular health, including immune and stress responses.⁴¹ Previous literature using a comparative risk assessment model of nationally representative data found that poor dietary factors contributed to about one-half of cardiometabolic deaths.⁴² Unfortunately, food insecurity disproportionally impacts individuals from socioeconomically, ethnically, and racially disadvantaged backgrounds, which further widens the divide in health outcomes.⁴¹ Recent research indicates that NHB and Hispanic/Latinx patients experience a greater health care burden because of a lack of access to nutritious food.⁴³ Particularly, U.S. counties with the greatest amount of food insecurity were found to have not only increased cancer and CVD incidences but also increased mortality rates for both.^44,45 Sedentary behavior, which can be partially attributed to the lack of availability and accessibility of recreational facilities, also markedly increases CVD risk in patients with and without cancer.²⁹ In essence, limited access to high-quality food, community-tailored health care resources, and their intersection with other adverse SDOH can lead to delayed diagnoses, inadequate treatment, and poorer outcomes while further widening disparities within cardio-oncology care.

Psychosocial stressors

Factors that impact individuals psychologically may also influence cardiovascular health outcomes in patients with cancer. Longitudinal studies have revealed psychosocial determinants that increase the likelihood of poor cardiovascular health such as adverse childhood experiences,⁴⁶ chronic psychological stress,47, 48, 49 and depression.⁵⁰ Numerous studies have also shown that interpersonal connections and a sense of community play a protective role in medical conditions including CVD and cancer.²⁹ Survivors of childhood cancer also report better health-related quality of life scores when there is greater lifetime adherence to cardiovascular health behaviors (lifestyle factors), such as being physically active and choosing a healthy diet.⁵¹ Similarly, factors such as cultural values and beliefs, social norms, and faith also influence the self-care, monitoring, and maintenance behaviors of cancer survivors.⁵² Evidently, several SDOH domains influence not only baseline cardiovascular health factors (ie, body mass index, blood pressure, and cholesterol) but also a cancer survivor’s adherence to and adaptation of healthy lifestyle behaviors (ie, diet, exercise, avoiding smoking or vaping, and quality sleep).⁵³ Although this evidence indicates that the cardio-oncology population experiences the intersectional effects of multiple adverse SDOH, it also illustrates that psychosocial stressors may be a pathway linking SDOH to disparities in cardio-oncologic outcomes.

SDOH and Biological Pathways in Cardio-Oncology

Chronic exposure to adverse SDOH and associated stressors promote the development of CVD by known signaling mechanisms. Few studies have examined the biologic effects of adverse SDOH in cardio-oncology patients; however, there are common signaling pathways related to chronic stress responses relevant in CVD outcomes for patients treated for oncologic conditions.

Signaling mechanisms involved in chronic stress responses, CVD, and cardio-oncology

Chronic psychosocial and environmental stressors (PSES) related to adverse SDOH lead to activation of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system as well as the sympatho-adrenomedullary axis.^2,54 As summarized in prior reviews, the consequences of activation of the body’s stress response results in an increased release of cortisol and catecholamines such as epinephrine, norepinephrine, and dopamine.²

Although increased circulating levels of cortisol could initially be an anti-inflammatory mechanism, a proinflammatory response can also be observed in the setting of chronic stress.⁵⁵ This response can occur because of glucocorticoid resistance, which is present in individuals experiencing chronic PSES.^2,56 Glucocorticoid resistance leads to a decreased anti-inflammatory function of cortisol and a subsequent increase in proinflammatory cytokine release by immune cells.⁵⁷ When increasing catecholamine levels activate their respective receptors, intracellular signaling can switch to a noncanonical proinflammatory response, further accelerating inflammation.^58,59 A common feature involved in pathways that further accelerates proinflammatory cytokine production is the activation of nuclear factor kappa B. This pathway has been linked to chronic stress,⁶⁰ CVD,⁶¹ and various cancers.⁶²

Proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha are upregulated in individuals with adverse SDOH and chronic PSES. These cytokines are also upregulated in individuals who develop cancer therapy–related cardiovascular toxicities (CTR-CVTs) from select cancer therapeutics including anthracyclines, T-cell therapies, and immune checkpoint inhibitors.^1,2,63, 64, 65 Similarly, chronic inflammation plays a role in both CVD and cancer risk.⁶⁶ In the CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) trial, a randomized, double-blinded, placebo-controlled trial of the IL-1β inhibitor canakinumab, treatment significantly reduced recurrent cardiovascular events in patients with high CVD risk and lung cancer incidence and mortality.⁶⁷

Additionally, mitochondrial dysfunction, related DNA alterations, and cellular apoptosis are most commonly associated with anthracycline-induced cardiomyopathies, along with other CTR-CVTs, such as vascular and cardiac dysfunction from vascular epidermal growth factor receptor tyrosine kinase inhibitors.^64,68,69 Mitochondrial DNA (mtDNA)⁷⁰ is a biomarker of mitochondrial dysfunction measurable in peripheral blood; it has been altered in a variety of diseases⁷¹ including CVD⁷² and cancer.⁷³ In a recent cross-sectional study of 391 adults (183 NHW, 110 Black, and 98 Hispanic), the associations between mitochondrial DNA copy numbers (mtDNAcns) with behavioral factors and depression were investigated; moderation of these associations by sex, race and ethnicity, and age was also studied.⁷⁴ Although no associations were found between mtDNAcns and depression, a significant relationship between mtDNAcns and smoking was evident, which was more apparent in men and Black study participants.⁷⁴ mtDNAcn levels in leukocytes have been associated with increasing household density and markers of the built environment in a cohort of Mexican American adults.⁷⁵ A potential pathway impacting mtDNA release because of increased inflammation involves the activation of nuclear factor kappa B, which was found to actively bind to mtDNA itself and may regulate mitochondrial dynamics.^76,77

Clonal hematopoiesis as a common pathway in cancer, adverse cardiovascular outcomes, and chronic PSES

Clonal hematopoiesis (CH) (ie, hematopoietic stem cell clonal expansion) can be the consequence of chronic inflammation, subsequently creating a proinflammatory life cycle for all immune cells. CH may affect immune cells intergenerationally.⁷⁸ CH is a risk factor for acute myeloid leukemia, chronic lymphocytic leukemia, breast cancer, and myelodysplastic syndromes, among others,79, 80, 81 as well as coronary artery disease and heart failure.81, 82, 83, 84, 85

Somatic sequence variations in 3 epigenetic regulator genes (DNMT3A, TET2, and ASXL1), also known as DTA genes, are frequent genetic sequence variation associated with hematologic cancers and CVD.^81,86 Although much of CH can be related to aging and independent of cancer therapies, therapy-related clonal hematopoiesis (t-CH) is commonly found in cancer survivors, highlighting potential mechanisms for CTR-CVTs.⁸⁷ In an analysis of the DTA genes, as well as JAK2, TP53, SRSF2, and SF3B1, among 393 patients who underwent anthracycline-based acute myeloid leukemia treatment, those with t-CH sequence variants had a 74% increased risk of an adverse cardiovascular event compared to those without t-CH alterations.⁸⁸ Furthermore, 1 study assessing >30,000 patients diagnosed with solid tumor malignancies found associations between t-CH sequence variants with the use of pyrimidine analogs, tubulin binding agents, and immunotherapy, whereas sequence variants in genes associated with DNA damage response and repair were associated with the use of poly (adenosine phosphatase–ribose) polymerase inhibitor, platinum agents, and anthracyclines.⁸⁹ TP53, PPM1D (a gene within the damage response and repair pathway), and TET2 have been implicated as possible t-CH sequence variant sites important in the development of cancer therapy–related cardiomyopathy after anthracycline-based therapies (Figure 2).90, 91, 92

Figure 2.

Commonalities in Signaling Pathways Between SDOH and Cancer Therapeutics in CVD

All pathways mentioned in this figure, but especially the ones common for social determinants of health (SDOH) and cancer therapeutics, have been shown to be crucial for cardiovascular disease (CVD) development along with progression. BCR-ABL1 = breakpoint cluster region-Abelson leukemia gene 1; CHIP = clonal hematopoiesis of indeterminate potential; DNMT = DNA methyltransferase; HER2 = human epidermal growth factor receptor 2; IL = interleukin; MAPK = mitogen-activated protein kinase; mtDNAcn = mitochondrial DNA copy number; NF-κB = nuclear factor kappa-light-chain-enhancer of activated B cells; PPM1D = protein phosphatase, Mg2+/Mn2+ dependent 1D; ROS = reactive oxygen species; TET2 = ten-eleven translocation 2; TOP2β = topoisomerase; TNF = tumor necrosis factor; TP53 = tumor protein 53; VEGF = vascular endothelial growth factor.

To our knowledge, very limited research has examined CH among populations chronically exposed to adverse SDOH. Studies have evaluated the association of healthy weight,⁹³ nutritious diet and eating habits,⁹⁴ and smoking⁹⁵ with CH. However, individuals residing in more deprived neighborhoods or individuals of lower SES disproportionally experience obesity,⁹⁶ exposure to food deserts,⁹⁷ and nicotine.⁹⁸ Therefore, it is critical to understand the existence and association of CH in individuals chronically exposed to adverse SDOH. It is important to investigate the underlying mechanisms of CH in adults, particularly in the context of intergenerational trauma, which ultimately affects children and their response to childhood cancer and its therapy.

Gene expression and DNA modification-related mechanisms in chronic stress and cardio-oncology

Whole genome sequencing for genetic variants provides a potential role for predicting cardiac dysfunction postchemo/radiotherapy. Although associations exist between single-nucleotide variation (SNV) and an increased risk of CVD postchemo/radiotherapy, there are no conclusive findings to distinguish low- vs high-risk patients. Specifically, retinoic acid receptor-y SNVs rs2229774 and rs17863833 have been associated with an increased risk of heart failure in childhood cancer survivors who were treated with anthracycline-based therapies.⁹⁹ It is hypothesized that retinoic acid receptor-y variants influence cardiotoxicity by the suppression of cardioprotective enzymes and mechanism activation post–anthracycline therapy.¹⁰⁰ Additionally, studies have shown that truncating variants in the titin gene are highly expressed in patients with cancer therapy–associated cardiomyopathy.¹⁰¹ Individuals with truncating variants in the titin gene and cancer therapy–associated cardiomyopathy were found to be more likely to experience atrial fibrillation, heart failure, and diminished recovery of cardiac function.¹⁰² Neither of these studies describe if any differences existed by ancestry, a marker of genetic origin of a population, rather than the social constructs of race or ethnicity.¹⁰³ Few studies have described differences in European vs African ancestry with chemotherapy-induced cardiomyopathy. Specifically, patients with European ancestry with SNV rs1786814 on the CELF4 gene (a gene regulating messenger ribonucleic acid expression) have a genotype distribution of GG (66%), GA (29%), and AA (4%). GG genotype confers a 10-fold risk for anthracycline-induced cardiomyopathy compared with GA or AA.¹⁰⁴ These observed effects are speculated to at least in part be related to the impact of CELF4 loss on the neuronal sodium channel Nav1.6,¹⁰⁵ which has been shown to impact heart function.¹⁰⁶ In a study using genotype determination of ancestry, survivors of childhood cancer with African ancestry demonstrate a 2.5-fold higher rate of chemotherapy-induced cardiomyopathy compared with those of European descent. This is postulated to be secondary to hypomethylation of the putative homeodomain transcription factor 1. Additionally, the SNV rs6689879∗C variant conferred a 4.2% ejection fraction reduction in survivors of African ancestry and a 5.4-fold cardiomyopathy risk vs those with European ancestry (ejection fraction reduction = 0.4%, 1.31-fold risk).¹⁰⁷

Epigenetic mechanisms, which are crucial in transcriptional control of gene expression and implicated in adverse cardio-oncology outcomes, are largely understudied in the context of chronic PSES among cardio-oncology patients.¹⁰⁸ At present, most evidence is available on the epigenetic effects of doxorubicin in relation to cardiovascular outcomes.^108,109 Recently, a study suggested epigenetic memory after anthracycline therapy may lead to CVD.¹¹⁰ Therefore, it is important to establish overlapping epigenetic pathways related to the effects of cancer therapy, experiences caused by adverse SDOH, and CVD outcomes to identify specific predictors and therapeutic targets for populations at highest risk for cardiotoxicity after cancer treatment. This is particularly critical because therapies targeting epigenetic alterations are under investigation in both cardiovascular and oncologic medicine. Collectively, these findings support the need for the enrollment of diverse patient populations into cancer therapeutic clinical trials that involve sequencing to identify SNVs, genetic variations, and epigenetic markers predictive of CVD outcomes after cancer treatment. Ultimately, one might speculate that common signaling pathways related to both chronic exposure to adverse SDOH and poor CVD outcomes in oncologic patients promote inflammation or immune cell dysfunction; however, data from diverse cohorts of patients with cancer are needed to test these hypotheses.

Integration of SDOH Into Cardio-Oncology Intervention Development

Integrating SDOH into the prevention and management of cardio-oncology outcomes is crucial for comprehensive patient care. The integration of SDOH into cardio-oncology care acknowledges that individuals with cancer and those who experience the cardiac side effects of cancer therapeutics are affected by a complex interplay of factors beyond medical conditions. Multilevel interventions are needed to mitigate the effects of adverse SDOH, improve health outcomes, and enhance equity. An effective approach often involves a combination of individual, community, and health care system–level interventions tailored to the specific social needs and challenges of each patient and community.¹ Emphasis should be placed on implementing interventions that promote and facilitate sustainable community engagement. Multilevel approaches must be grounded in cultural humility and patient advocacy to facilitate access to health care, quality health insurance, and improved patient-provider ratios in minoritized and underserved populations (Central Illustration).

Central Illustration.

Social Determinants of Health and Cardio-Oncology

These social determinants of health (SDOH) domains have been shown to be integral to the development and progression of cardio-oncologic outcomes. Moreover, clonal hematopoiesis, as well as epigenetic (related to mitochondrial DNA copy number and DNA alterations) and cell signaling mechanistic pathways, which influence catecholamines and inflammatory cytokines, further link SDOH to cardio-oncology. It is imperative to consider the integration of SDOH into targeted interventions that encourage health equity within the field of cardio-oncology. The rightward arrow indicates the influence of adverse SDOH on biological pathways. The upward arrow indicates the integration of SDOH into cardio-oncologic care to impact cardio-oncology outcomes. CHIP = clonal hematopoiesis of indeterminate potential; ROS = reactive oxygen species.

Cultural humility and competency

Cultural humility and competence reflect congruent behaviors, attitudes, beliefs, and policies that facilitate effective cross-cultural collaboration.¹¹¹ Cultural competency includes 4 tenets: 1) awareness (insight into ones’ personal biases, prejudice, and stereotypes toward others); 2) knowledge (of personal cultural norms and beliefs and that of others); 3) attitudes (of respect and acceptance of difference); and 4) skills (that promote interaction with diverse cultures).¹¹² These 4 tenets must permeate all levels of interventions aimed at mitigating the adverse effects of SDOH. Training health care providers to be culturally sensitive and aware of diverse backgrounds can facilitate patient-provider communication and promote trust.^113,114 Cultural competency can also include making SDOH training a core competency within the cardio-oncology field.¹¹⁵

Additionally, being aware of the impact of structural racism within communities and how it contributes to health disparities is crucial.¹² Structural racism leads to “differential access to the goods, services, and opportunities of society by race,”¹¹⁶ determining societal values and power hierarchies, all of which underlie persistent health disparities in the United States. The presidential advisory statement for the American Heart Association acknowledged and emphasized that a society free from structural racism results in considerable social, economic, and health benefits for all those living in the United States, including those who are direct beneficiaries of the status quo and historically marginalized populations.¹¹⁷ Structural racism contributes to higher rates of CVD and risk factors, under-representation in research, socioeconomic and cultural barriers, and lack of access to specialty care. Efforts to dismantle structural racism include but are not limited to increasing diversity in the health care workforce and leadership, incorporating patient cultural values into treatment plans, and increasing antiracism and cultural competency training through well-developed cultural immersion programs.²¹

Community engagement

With the increasing awareness of the importance of incorporating SDOH into patient care frameworks, emerging models must identify and address barriers to care at the individual, population, and policy levels. To accomplish this, it is imperative that frameworks be designed leveraging feedback from those with greatest insight into the specific multilevel needs (ie, the cardio-oncology patients and communities most impacted by health inequities driven by adverse SDOH). By recognizing the voices of these communities, medical care recommendations and advocacy policies can be systematically tailored to design impactful, standardized interventions. Furthermore, through active and continuous engagement of community stakeholders, medical providers will not only be able to actively foster trust within the diverse populations they serve but also gain a more nuanced perspective into the difficulties their patients face in obtaining and receiving quality care. Involvement of community advisory boards has been shown to increase the participation of a more diverse group of participants in clinical trials. A study investigating the health and needs related to cardiovascular health and obesity within a cohort of patients in Washington, DC, effectively used a community advisory board to better inform their comprehensive understanding of this community’s needs.¹¹⁸ Thus, community engagement is needed to provide more equitable cardio-oncology care.

Interdisciplinary care teams

Bringing together health care professionals from different disciplines such as clinicians, social workers, psychologists, and nutritionists can provide holistic care addressing both medical and social needs. Clinicians can make patients aware of within-system resources (ie, clinic food pantry and produce prescriptions) and refer to social workers or case managers for other local resources along with eligibility for government food programs (ie, the Special Supplemental Nutrition Program for Women, Infants, and Children). Ideally, each cardio-oncology patient should have access to a multidisciplinary team invested in their well-being. Moreover, “compassionate surveillance” is the “process of working to identify individuals who have been negatively impacted by trauma and other SDOH in order to connect families to necessary resources and supports.” In doing so, providers can identify resource-related barriers to health promotion among cancer survivors and connect patients along with their families to community- based resources.¹¹⁹ Addressing psychosocial trauma related to poverty and community-level stressors is vital.

Addressing social needs and access to health care through policy and advocacy

Collaborating with and investing in community organizations to address social needs such as quality housing, food security and access to high-produce supply stores (stores with healthy food options), insurance options, accessible primary care, employment opportunities, and raising awareness of disparities will contribute to overall well-being and improved treatment outcomes.¹²⁰ Similar multilevel systems and supports have been proposed for patients with cardiovascular-kidney-metabolic syndrome, underscoring the need to provide consistent and equitable care across all variety of medical specialties.^121,122 Moreover, implementing standardized education platforms aimed at not only increasing awareness of cardio-oncology but also improving outcomes within the field is crucial.¹¹⁵

Ensuring equitable access to medical care, including screenings, treatment, and timely follow-up, is critical across the life course. This may include improving transportation options, reducing financial barriers, and offering language assistance services. Financial assistance programs to access insurance or medical expense supplements can alleviate financial stressors that might hinder cardiovascular care for oncology patients. Insurance status was identified as a key determinant of subsequent cardiovascular risk in long-term outcomes after cancer treatment.¹²³ The quality of health insurance has also been found to influence self-care behaviors of community-dwelling individuals with heart failure,¹²⁴ a possible cardiac complication of cancer therapeutics. This indicates that policy interventions aimed at addressing access to quality health care must also target both insurance type and the quality of insurance to adequately address the health care needs of cardio-oncology patients from historically under-represented groups. Overall, policy interventions that consider and mitigate social needs and health care access may enhance equitable care and improve health outcomes for all cardio-oncology patients.

Screening and management of social needs

Expansion of SDOH to children’s hospitals in the U.S. News and World Report Rankings (USNWR) may encourage hospitals to implement screening of SDOH among childhood cancer survivors. USNWR publishes annual rankings of hospitals and specialties.^125,126 For instance, pediatric oncology programs are ranked based on a variety of factors that include survival rates, patient volume, prevention of specific adverse events, quality improvement efforts, and patient supports. In 2022, USNWR published information on the plan to include health equity in rankings. Three new domains were created: access, outcomes, and SDOH. Per Binger et al,¹²⁷ “the social determinants of health domain examine ways in which hospitals address social conditions that create and exacerbate health inequalities.” These domains were included in the 2022 to 2023 best hospital rankings, although this was only applied to adult hospitals. A reported goal of ranking in these domains was to “incentivize hospitals to compete on measures of equity.”¹²⁸ An expansion of these health equity ratings to children’s hospitals could incentivize research and spending to address SDOH not only for childhood cancer survivors but for all children. By improving identification of these SDOH, interventions could be designed that would hopefully mitigate disparate cardiac outcomes for childhood cancer survivors experiencing these SDOH.

A second broad approach is to encourage increased adoption of value-based care or alternative payment models for reimbursement. In traditional fee-for-service payment models, both measurement of and interventions to address SDOH are not traditionally reimbursed. However, value-based care and alternative payment models typically have built-in reimbursement related to quality or health outcome.¹²⁹ A recent cross-sectional study of over 2,800 U.S. hospitals found that hospitals using value-based care models were more likely to implement additional SDOH screening strategies and potentially more efforts to address SDOH.¹³⁰ Although no payment strategy is perfect, continued advocacy for new reimbursement models that reward those addressing SDOH could reduce barriers to care faced by both childhood and adult cancer survivors.

Health technology for expanding access to cardio-oncologic care

Implementing telehealth services can improve access to care, especially for those in remote or underserved areas, as well as enhance patient monitoring. Incorporating screening tools into electronic health records (EHRs) and using resource navigators are also effective approaches in using health technology to bridge the gaps in care. Furthermore, machine learning can be used to create mortality risk assessments using a composite of risk factors through the EHR. As an example, the classification and regression tree has been used to assess the predictors of mortality among cancer survivors using 56 sociodemographic variables. Analyzing data from 987,009 patients within 2717 U.S. counties, factors such as teen birth, pre-1960 housing (lead paint indicator), ADI, medical factors, household income, number of hospitals, and exposure to particulate matter were determined to be the most important contributors to cardio-oncology mortality.¹³¹ With the expanding landscape of technological advancements, integration of such tools into clinical care may increase the efficiency and effectiveness of CVD surveillance and management among cancer survivors.

Future directions in integrating SDOH into cardio-oncology

Moving forward there are many ways to further incorporate SDOH into the field of cardio-oncology (Table 2). Given the well-known limitations in the existing evidence on SDOH-related epidemiologic research (nonrepresentative samples and low-powered studies), the development and validation of SDOH-informed cardio-oncology tools that reflect a diverse population is vital in tailoring interventions that ensure all patients and populations receive equitable care. Subsequently, these standardized measures can be included in artificial intelligence medical tools along with EHRs. In doing so, it may potentially increase awareness of both the direct and indirect impact of SDOH at the individual, community, and policy levels. Health care systems should also allocate resources toward training practitioners and researchers in identifying and addressing barriers to quality care. By expanding knowledge on SDOH, health care providers can better recognize and prioritize specific needs of their patients. In a similar vein, institutions should continue to engage in community partnerships not only to encourage increased participation in research activities but also to gain insight and amplify respective needs. Finally, well-curated data also provide evidence to advocate for policy changes and resource allocation at local, regional, or national levels as well as demonstrate the value for systemic improvements to support population health. Thus, emphasis on SDOH in future patient and community-centered interventions is key in addressing cardio-oncologic health disparities.

Table 2.

Recommendations for Patient and Community-Centered Interventions to Address Cardio-Oncologic Health Disparities

•Develop and validate measurement tools for specific SDOH domains salient to under-represented populations with CVD secondary to cancer therapeutics. Moreover, SDOH measurement tools should be linked with electronic medical records to identify patient and community-tailored targets for intervention.

•Funding priorities should target the use of SDOH measures in multimethod research (qualitative/quantitative [mixed methods] and community-based participatory research) to highlight the voices of under-represented populations when creating community data for social risk stratification in the cardio-oncology populations.

•Clinical researchers should leverage existent data from longitudinal cohort studies to investigate the intersectional impact of adverse SDOH on comorbid CVD and cancer health disparities to identify intervention targets along the signaling pathways linking SDOH to outcomes disparities.

•Interdisciplinary care training should be grounded in SDOH to educate clinical teams as change agents and health equity advocates throughout the care transition continuum for cardio-oncology patients and their families.

•Policy interventions must target sustainable community-informed social resources and services that empower patients in the setting of comorbid CVD and cancer.

Abbreviations as in Table 1.

Conclusions

Providing more equitable access to cardio-oncology care in the United States is needed.¹³² Disparities exist in cardio-oncology prevention and outcomes, especially among minoritized populations and those with adverse SDOH. Complex SDOH domains intersect to influence CVD among patients with cancer and cardiotoxicity. Additionally, mechanisms of adverse SDOH, cancer, and CVD are similar in cell signaling and genetic expression. A comprehensive approach encompassing cultural humility, community engagement, SDOH screening and management, emerging health technology, and interdisciplinary team-based care is needed to decrease disparities in cardio-oncology outcomes.

Funding Support and Author Disclosures

The Powell-Wiley Lab is funded by the Division of Intramural Research of the National, Heart, Lung, and Blood Institute of the National Institutes of Health and the Intramural Research Program of the National Institute on Minority Health and Health Disparities. This research was made possible through the National Institutes of Health Medical Research Scholars Program, a public-private partnership supported jointly by the National Institutes of Health and generous contributions to the Foundation for the National Institutes of Health from the Doris Duke Charitable Foundation, Genentech, the American Association for Dental Research, the Colgate-Palmolive Company, Elsevier, alumni of student research programs, and other individual supporters via contributions to the Foundation for the National Institutes of Health. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.