Atrial fibrillation in cancer, anticancer therapies, and underlying mechanisms.

Atrial fibrillation (AF) is a common arrhythmic complication in cancer patients and can be exacerbated by traditional cytotoxic and targeted anticancer therapies. Increased incidence of AF in cancer patients is independent of confounding factors, including preexisting myocardial arrhythmogenic substrates, type of cancer, or cancer stage. Mechanistically, AF is characterized by fast unsynchronized atrial contractions with rapid ventricular response, which impairs ventricular filling and results in various symptoms such as fatigue, chest pain, and shortness of breath. Due to increased blood stasis, a consequence of both cancer and AF, concern for stroke increases in this patient population. To compound matters, cardiotoxic anticancer therapies themselves promote AF; thereby exacerbating AF morbidity and mortality in cancer patients. In this review, we examine the relationship between AF, cancer, and anticancer therapies with a focus on the shared molecular and electrophysiological mechanisms linking these disease processes. We also explore the potential role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the management of anticancer-therapy induced AF.

Advance Care Planning (ACP) in Medicare Beneficiaries with Heart Failure.

BACKGROUND: Heart failure is a leading cause of death in the USA, contributing to high expenditures near the end of life. Evidence remains lacking on whether billed advance care planning changes patterns of end-of-life healthcare utilization among patients with heart failure. Large-scale claims evaluation assessing billed advance care planning and end-of-life hospitalizations among patients with heart failure can fill evidence gaps to inform health policy and clinical practice. OBJECTIVE: Assess the association between billed advance care planning delivered and Medicare beneficiaries with heart failure upon the type and quantity of healthcare utilization in the last 30 days of life. DESIGN: This retrospective cross-sectional cohort study used Medicare fee-for-service claims from 2016 to 2020. PARTICIPANTS: A total of 48,466 deceased patients diagnosed with heart failure on Medicare. MAIN MEASURES: Billed advance care planning services between the last 12 months and last 30 days of life will serve as the exposure. The outcomes are end-of-life healthcare utilization and total expenditure in inpatient, outpatient, hospice, skilled nursing facility, and home healthcare services. KEY RESULTS: In the final cohort of 48,466 patients (median [IQR] age, 83 [76-89] years; 24,838 [51.2%] women; median [IQR] Charlson Comorbidity Index score, 4 [2-5]), 4406 patients had an advance care planning encounter. Total end-of-life expenditure among patients with billed advance care planning encounters was 19% lower (95% CI, 0.77-0.84) compared to patients without. Patients with billed advance care planning encounters had 2.65 times higher odds (95% CI, 2.47-2.83) of end-of-life outpatient utilization with a 33% higher expected total outpatient expenditure (95% CI, 1.24-1.42) compared with patients without a billed advance care planning encounter. CONCLUSIONS: Billed advance care planning delivery to individuals with heart failure occurs infrequently. Prioritizing billed advance care planning delivery to these individuals may reduce total end-of-life expenditures and end-of-life inpatient expenditures through promoting use of outpatient end-of-life services, including home healthcare and hospice.

Targeting OCT3 attenuates doxorubicin-induced cardiac injury.

Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies offer only modest protection. Using stem-cell-derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified organic cation transporter 3 (OCT3) (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin. Functional validation studies in heterologous overexpression models confirmed that doxorubicin is transported into cardiomyocytes by OCT3 and that deficiency of OCT3 protected mice from acute and chronic doxorubicin-related changes in cardiovascular function and genetic pathways associated with cardiac damage. To provide proof-of-principle and demonstrate translational relevance of this transport mechanism, we identified several pharmacological inhibitors of OCT3, including nilotinib, and found that pharmacological targeting of OCT3 can also preserve cardiovascular function following treatment with doxorubicin without affecting its plasma levels or antitumor effects in multiple models of leukemia and breast cancer. Finally, we identified a previously unrecognized, OCT3-dependent pathway of doxorubicin-induced cardiotoxicity that results in a downstream signaling cascade involving the calcium-binding proteins S100A8 and S100A9. These collective findings not only shed light on the etiology of doxorubicin-induced cardiotoxicity, but also are of potential translational relevance and provide a rationale for the implementation of a targeted intervention strategy to prevent this debilitating side effect.

Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease.

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MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia.

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window.

Intracellular Signaling Pathways Mediating Tyrosine Kinase Inhibitor Cardiotoxicity.

Tyrosine kinase inhibitors (TKIs) are used to treat several cancers; however, a myriad of adverse cardiotoxic effects remain a primary concern. Although hypertension (HTN) is the most common adverse effect reported with TKI therapy, incidents of arrhythmias (eg, QT prolongation, atrial fibrillation) and heart failure are also prevalent. These complications warrant further research toward understanding the mechanisms of TKI-induced cardiotoxicity. Recent literature has given some insight into the intracellular signaling pathways that may mediate TKI-induced cardiac dysfunction. In this article, we discuss the cardiotoxic effects of TKIs on cardiomyocyte function, signaling, and possible treatments.

Disparities in heart transplantation.

PURPOSE OF REVIEW: Heart transplantation remains the gold standard therapy for end stage heart failure, but barriers remain, preventing equitable access to and affecting outcomes following transplantation. The objective of this review is to summarize current and historical literature on the disparities that persist, and to highlight the gaps in evidence for further investigation. RECENT FINDINGS: Although progress has been made to increase the rates of advanced heart failure therapies to racial/ethnic minority populations and those with lower socioeconomic status, differential access and outcomes remain. The disparities that persist are categorized by patient demographics, social influences, geopolitical factors, and provider bias. SUMMARY: Disparities in heart transplantation exist, which span a wide spectrum. Healthcare professionals need to be cognizant of these disparities that patients face in terms of access to and outcomes for heart transplantation. Further research and system changes are needed to make heart transplantation a fairer option for patients of varying backgrounds with end stage heart failure.

Worsening Renal Function in Cardiac Mechanical Support.

BACKGROUND: Venous congestion in heart failure (HF) may lead to worsening renal failure (WRF). We hypothesised that WRF in patients hospitalised for left ventricular assist device (LVAD) implantation is associated with increased 1-year mortality. There is limited data regarding WRF in HF patients with mechanical support. The objective of this paper is to determine whether WRF in HF patients hospitalised for LVAD implantation is associated with increased 1-year mortality and to identify risk factors for WRF. METHODS: We performed a single centre retrospective chart analysis of 162 patients who received an LVAD between August 2006 and December 2014 with pre-LVAD right heart catheterisation data. We stratified patients to those who demonstrated WRF and the use of haemodialysis (HD) or ultrafiltration (UF). RESULTS: Patients with a higher central venous pressure (CVP) >16 mmHg (17-24 mmHg range) developed WRF (29.7% vs. 14.1%, p=0.019). A CVP ≥16 and glomerular filtration rate (GFR) <30 ml/min/1.74m2 increased the odds of WRF. Worsening renal failure and HD/UF use were associated with increased 1-year mortality. Furthermore GFR <30, atherosclerosis, and right ventricular failure were independent predictors for increased 1-year mortality. A GFR <30 increased the odds of developing WRF five-fold (OR 4.14, CI [1.95-8.78], p<0.0001), and GFR <30 and central venous pressure (CVP) >16 increased the odds of requiring HD/UF. CONCLUSIONS: Worsening renal failure is associated with a higher CVP at the time of LVAD implantation and increases the risk of 1-year mortality and the odds of requiring HD/UF. Careful evaluation of renal function and comorbid conditions during LVAD implantation is critical to reduce mortality and for risk stratification.

Etiology-dependent impairment of relaxation kinetics in right ventricular end-stage failing human myocardium.

BACKGROUND: In patients with end-stage heart failure, the primary etiology often originates in the left ventricle, and eventually the contractile function of the right ventricle (RV) also becomes compromised. RV tissue-level deficits in contractile force and/or kinetics need quantification to understand involvement in ischemic and non-ischemic failing human myocardium. METHODS AND RESULTS: The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis. From 2009-present we assessed live tissue-level contractile force and kinetics in isolated myocardial RV trabeculae from 44 non-failing and 41 failing human hearts. At 1 Hz stimulation rate (in vivo resting state) the developed active force was not different in non-failing compared to failing ischemic nor non-ischemic failing trabeculae. In sharp contrast, the kinetics of relaxation were significantly impacted by disease, with 50% relaxation time being significantly shorter in non-failing vs. non-ischemic failing, while the latter was still significantly shorter than ischemic failing. Gender did not significantly impact kinetics. Length-dependent activation was not impacted. Although baseline force was not impacted, contractile reserve was critically blunted. The force-frequency relation was positive in non-failing myocardium, but negative in both ischemic and non-ischemic myocardium, while the ß-adrenergic response to isoproterenol was depressed in both pathologies. CONCLUSIONS: Force development at resting heart rate is not impacted by cardiac pathology, but kinetics are impaired and the magnitude of the impairment depends on the underlying etiology. Focusing on restoration of myocardial kinetics will likely have greater therapeutic potential than targeting force of contraction.

Pazopanib for renal cell carcinoma leads to elevated mean arterial pressures in a murine model.

BACKGROUND: In the setting of metastatic RCC (mRCC), pazopanib is approved as first line therapy. Unfortunately treatment may lead to cardiotoxicity such as hypertension, heart failure, and myocardial ischemia. OBJECTIVE: Define the in vivo role of pazopanib in the development of cardiotoxicity. METHODS: Wild type mice were dosed for 42 days via oral gavage, and separated into control and treatment (pazopanib) groups. Baseline ECG's, echocardiograms, and blood pressures were recorded. At the conclusion of the study functional parameters were again recorded, and animals were used for pathological, histological, and protein analysis. RESULTS: After 2 weeks of dosing with pazopanib, the treatment group exhibited a statistically significant increase in mean arterial pressure compared to control mice (119 ± 11.7 mmHg versus 108 ± 8.2 mmHg, p = 0.049). Treatment with pazopanib led to a significant reduction in the cardiac output of mice. CONCLUSION: Our findings in mice clearly demonstrate that treatment with pazopanib leads to a significant elevation in blood pressure after 2 weeks of dosing and this persists for the duration of dosing. The continued development of the cardio-oncology field will be paramount in providing optimal oncologic care while simultaneously improving cardiac outcomes through further investigation into the mechanisms of CV toxicity.

County socioeconomic characteristics and heart transplant outcomes in the United States.

BACKGROUND: Geographic disparities in survival after heart transplantation have received mixed support in prior studies, and specific geographic characteristics that might be responsible for these differences are unclear. We tested for differences in heart transplant outcomes across United States (US) counties after adjustment for individual-level covariates. Our secondary aim was to evaluate whether specific county-level socioeconomic characteristics explained geographic disparities in survival. METHODS: Data on patients aged ≥18 years undergoing a first-time heart transplant between July 2006 and December 2014 were obtained from the United Network for Organ Sharing. Residents of counties represented by <5 patients were excluded. Patient survival (censored in March 2016) was analyzed using multivariable Cox regression. Shared frailty models were used to test for residual differences in overall all-cause mortality across counties after adjusting for recipient and donor characteristics. Measures of county economic disadvantage, inequality, and racial segregation were obtained from US Census data and coded into quintiles. A likelihood ratio test determined whether adjusting for each county measure improved the fit of the Cox model. RESULTS: Multivariable analysis of 10,879 heart transplant recipients found that, adjusting for individual-level characteristics, there remained statistically significant variation in mortality hazard across US counties (P=.004). Adjusting for quintiles of community disadvantage, economic inequality, or racial segregation did not significantly improve model fit (likelihood ratio test P=.092, P=.273, and P=.107, respectively) and did not explain residual differences in patient survival across counties. CONCLUSIONS: Heart transplantation outcomes vary by county, but this difference is not attributable to county-level socioeconomic disadvantage.

Impact of insurance status on heart transplant wait-list mortality for patients with left ventricular assist devices.

OBJECTIVES: To test the hypotheses that receipt of Medicaid or Medicare (versus private insurance or self-pay) and low socioeconomic status (SES) leads to increased mortality and lower chances of transplantation among heart transplant (HTx) candidates with bridge to transplant left ventricular assist devices (BTT LVADs). BACKGROUND: Survival while awaiting HTx has improved with the use of BTT LVADs. However, it is unknown whether benefits extend uniformly across patient groups based on insurance status. METHODS: Data from the United Network of Organ Sharing (UNOS) registry between 2006 and 2015 were examined for first-time HTx candidates ≥18 and <65 years who had LVAD support while wait-listed. Multivariable survival analysis was conducted on competing outcomes of mortality and time to transplant stratified by insurance source at the time of listing. Additional covariates included demographic information and SES. RESULTS: A total of 4626 patients met inclusion criteria, with 3353 being used for multivariable analysis. A majority of patients (68%) underwent HTx during the study period. BTT LVAD wait-list mortality was found to be greater among Medicaid beneficiaries vs. private insurance (SHR 1.57, P<.05) and did not diminish with the inclusion of neighborhood SES. Transplantation as an outcome demonstrated no difference by insurance status. CONCLUSION: Medicaid insurance status is associated with worse survival on the HTx wait-list among patients with BTT LVADs, although access to transplant was not different among insurance groups. The disparity is not reflective of SES in general and therefore points to other barriers inherent to Medicaid beneficiaries.

Dysfunction in the ßII spectrin-dependent cytoskeleton underlies human arrhythmia.

BACKGROUND: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked to cardiac pathologies, including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction and cardiac electric activity is not well understood and often overlooked in the cardiac arrhythmia field. METHODS AND RESULTS: Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that ßII spectrin, an actin-associated molecule, is essential for the posttranslational targeting and localization of critical membrane proteins in heart. ßII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/ßII spectrin interaction, leading to severe human arrhythmia phenotypes. Mice lacking cardiac ßII spectrin display lethal arrhythmias, aberrant electric and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, ßII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes, including the Na/Ca exchanger, ryanodine receptor 2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in ßII spectrin-deficient mice. CONCLUSIONS: Our findings identify ßII spectrin as critical for normal myocyte electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.

Dysfunction of the ß2-spectrin-based pathway in human heart failure.

ß2-Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of ß2-spectrin for vertebrate function is illustrated by dysfunction of ß2-spectrin-based pathways in disease. Recently, defects in ß2-spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of ß2-spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that ß2-spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, ß2-spectrin levels were decreased in atrial samples of patients with atrial fibrillation compared with tissue from patients in sinus rhythm. Furthermore, compared with left ventricular samples from nonfailing hearts, ß2-spectrin levels were significantly decreased in left ventricle of ischemic- and nonischemic heart failure patients. Left ventricle samples of canine and murine heart failure models confirm reduced ß2-spectrin protein levels. Mechanistically, we identify that ß2-spectrin levels are tightly regulated by posttranslational mechanisms, namely Ca(2+)- and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca(2+)- and calpain-dependent loss of ß2-spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that ß2-spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca(2+)- and calpain-dependent proteolysis.

Ankyrin-G coordinates intercalated disc signaling platform to regulate cardiac excitability in vivo.

RATIONALE: Nav1.5 (SCN5A) is the primary cardiac voltage-gated Nav channel. Nav1.5 is critical for cardiac excitability and conduction, and human SCN5A mutations cause sinus node dysfunction, atrial fibrillation, conductional abnormalities, and ventricular arrhythmias. Further, defects in Nav1.5 regulation are linked with malignant arrhythmias associated with human heart failure. Consequently, therapies to target select Nav1.5 properties have remained at the forefront of cardiovascular medicine. However, despite years of investigation, the fundamental pathways governing Nav1.5 membrane targeting, assembly, and regulation are still largely undefined. OBJECTIVE: Define the in vivo mechanisms underlying Nav1.5 membrane regulation. METHODS AND RESULTS: Here, we define the molecular basis of an Nav channel regulatory platform in heart. Using new cardiac-selective ankyrin-G(-/-) mice (conditional knock-out mouse), we report that ankyrin-G targets Nav1.5 and its regulatory protein calcium/calmodulin-dependent kinase II to the intercalated disc. Mechanistically, ßIV-spectrin is requisite for ankyrin-dependent targeting of calcium/calmodulin-dependent kinase II-δ; however, ßIV-spectrin is not essential for ankyrin-G expression. Ankyrin-G conditional knock-out mouse myocytes display decreased Nav1.5 expression/membrane localization and reduced INa associated with pronounced bradycardia, conduction abnormalities, and ventricular arrhythmia in response to Nav channel antagonists. Moreover, we report that ankyrin-G links Nav channels with broader intercalated disc signaling/structural nodes, as ankyrin-G loss results in reorganization of plakophilin-2 and lethal arrhythmias in response to ß-adrenergic stimulation. CONCLUSIONS: Our findings provide the first in vivo data for the molecular pathway required for intercalated disc Nav1.5 targeting/regulation in heart. Further, these new data identify the basis of an in vivo cellular platform critical for membrane recruitment and regulation of Nav1.5.

The impact of insurance and socioeconomic status on outcomes for patients with left ventricular assist devices.

BACKGROUND: There has been a steady increase of patients living in the community with Left Ventricular Assist Devices (LVADs). There is a significant gap in our fund of knowledge with respect to the impact that insurance and socioeconomic status has on outcomes for LVAD patients. We thus hypothesize that low neighborhood socioeconomic status and receipt of Medicaid, respectively, lead to earlier readmissions, earlier death, as well as longer time to transplantation among LVAD patients. METHODS: This was a retrospective review of 101 patients using existing data in the medical information warehouse database at The Ohio State University Medical Center. Primary outcomes measured included time to first event (first readmission or death), death, and time to rehospitalization. Our secondary outcome of interest included time from LVAD implantation to cardiac transplantation. RESULTS: Recipients of Medicaid did not have an increased risk of adverse events compared with patients without Medicaid coverage. Low Median Household Income (MHI) was associated with an increased risk of readmission (log-rank P = 0.0069) and time to first event (log-rank P = 0.0088). Bridge to transplantation was the only independent predictor of time to death (Hazard Ratio 2.1, [95% confidence interval = 1.03-4.37]). Low MHI and a history of atherosclerosis were both significant predictors for readmission and time to first event. Aldosterone antagonist use decreased the risk of readmission or time to first event by 46%. CONCLUSIONS: LVAD recipients with a low MHI were more likely to be readmitted to the hospital after LVAD implantation. Whether these patients are adequately monitored on an outpatient basis remains unclear.

Chemotherapy-induced takotsubo cardiomyopathy.

Stress cardiomyopathy, also known as takotsubo cardiomyopathy, is a rapidly reversible form of acute heart failure classically triggered by stressful events. It is associated with a distinctive left ventricular contraction pattern described as apical akinesis/ballooning with hyperdynamic contraction of the basal segments in the absence of obstructive coronary artery disease. The traditional paradigm has expanded to include other causes, in particular chemotherapeutic drugs. The literature increasingly suggests an association between cancer, chemotherapeutic drugs, and stress cardiomyopathy. Chemotherapy-induced takotsubo cardiomyopathy is a relatively new phenomenon, but one that merits detailed attention to the elucidation of possible mechanistic links.

Donor and Recipient Hepatitis C Status Does Not Affect Rejection in Thoracic Transplantation.

BACKGROUND: Donors with hepatitis C virus (HCV) have expanded the donor pool for heart and lung transplantation, but concerns have arisen about rejection. We examined the incidence of rejection after heart and lung transplantation in recipients of HCV-positive donors as well as HCV-positive recipients. METHODS: Adults undergoing heart and lung transplantation from March 31, 2015 to December 31, 2019 were identified in the United Network for Organ Sharing/Organ Transplantation and Procurement Network Standard Transplant Analysis and Research file. Patients were stratified as donor-recipient HCV negative, donor positive, and recipient positive. Comparative statistics and a multilevel logistic regression model were used. RESULTS: Meeting the criteria were 10 624 heart transplant recipients. Donor-positive recipients were significantly associated with older age, blood group O, and shorter waitlist time. No significant differences existed with regards to treatment for rejection in the first year (negative, 19.5%; donor positive, 22.3%; recipient positive, 19.5%; P = .45) or other outcomes. On regression analysis HCV status was not associated with treated rejection; however center variability was significantly associated with treated rejection (median odds ratio, 2.18). Similarly, 9917 lung transplant recipients were identified. Donor-positive recipients were more commonly White and had obstructive disease and lower lung allocation scores. Both unadjusted (negative, 22.1%; donor positive, 23.0%; recipient positive, 18.6%; P = .43) and adjusted analyses failed to demonstrate a significant association between HCV status and treatment for rejection, whereas center variability remained significantly associated with treatment for rejection (median odds ratio, 2.41). CONCLUSIONS: Use of HCV donors has expanded the donor pool for heart and lung transplantation. HCV donor status was not associated with treatment for rejection in the first year, but center variability played a role in the incidence and treatment of rejection.

The Modifying Role of Resilience on Allostatic Load and Cardiovascular Disease Risk in the Jackson Heart Study.

We examined whether resilience modified associations between allostatic load (AL), a physiological indicator of coping with repeated stressors, and cardiovascular disease (CVD) among 2758 African Americans in the Jackson Heart Study. Baseline AL was quantified using biological measures of metabolic, cardiovascular, and immune markers. We constructed a multidimensional resilience measure using validated questionnaires for social support, social networks, religious experiences, and optimism. Participants were followed until 2016 for stroke, coronary heart disease (CHD), and heart failure (HF). We used multivariable-adjusted, sex-stratified Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between dichotomous AL and CVD. High AL was associated with CHD among women (HR = 1.73, 95% CI = 1.00, 2.99) and HF among women (HR = 1.52, 95% CI = 0.98, 2.37) and men (HR = 2.17, 95% CI = 1.28, 3.68). Among women, resilience did not modify the AL-CVD relationship. Among men, we observed higher stroke risk among men with low resilience (HR = 2.21, 95% CI = 0.94, 5.22) and no association among those with high resilience. Counterintuitively, high AL was associated with greater HF (HR = 5.80, 95% CI = 2.32, 14.47) in the subgroup of men with high resilience. Future studies addressing different facets of resilience are needed to elucidate underlying mechanisms for CVD prevention among African Americans.