Distribution of cardiovascular health by individual- and neighborhood-level socioeconomic status: Findings from the Jackson Heart Study

BACKGROUND: Data demonstrate a positive relationship between socioeconomic status (SES) and cardiovascular health (CVH). OBJECTIVE: To assess the association between individual- and neighborhood-level SES and CVH among participants of the JHS (Jackson Heart Study), a community-based cohort of African Americans in Jackson, Mississippi. METHODS: We included all JHS participants with complete SES and CVH information at the baseline study visit (n = 3,667). We characterized individual- and neighborhood-level SES according to income (primary analysis) and education (secondary analysis), respectively. The outcome of interest for these analyses was a CVH score, based on 7 modifiable behaviors and factors, summed to a total of 0 (worst) to 14 (best) points. We utilized generalized estimating equations to account for the clustering of participants within the same residential areas to estimate the linear association between SES and CVH. RESULTS: The median age of the participants was 55 years, and 64% were women. Nearly one-third of eligible participants had individual incomes \u3c$20,000 and close to 40$25,480). Adjusted for age, sex, and neighborhood SES, there was an average increase in CVH score of 0.31 points associated with each 1-category increase in individual income. Similarly, each 1-category increase in neighborhood SES was associated with a 0.19-point increase in CVH score. These patterns held for our secondary analyses, which used educational attainment in place of income. These data did not suggest a synergistic effect of individual- and neighborhood-level SES on CVH. CONCLUSIONS: Our findings suggest a potential causal pathway for disparities in CVH among vulnerable populations. These data can be useful to the JHS community to empower public health and clinical interventions and policies for the improvement of CVH

Dysfunction in the βII 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 with cardiac pathologies including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction in cardiac electrical 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 βII spectrin, an actin-associated molecule, is essential for the post-translational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electrical and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes that include the Na/Ca exchanger, RyR2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice. Conclusions: Our findings identify βII spectrin as critical for normal myocyte electrical activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology

Defects in Cytoskeletal Signaling Pathways, Arrhythmia, and Sudden Cardiac Death

Ankyrin polypeptides are cellular adapter proteins that tether integral membrane proteins to the cytoskeleton in a host of human organs. Initially identified as integral components of the cytoskeleton in erythrocytes, a recent explosion in ankyrin research has demonstrated that these proteins play prominent roles in cytoskeletal signaling pathways and membrane protein trafficking/regulation in a variety of excitable and non-excitable cells including heart and brain. Importantly, ankyrin research has translated from bench to bedside with the discovery of human gene variants associated with ventricular arrhythmias that alter ankyrin–based pathways. Ankyrin polypeptides have also been found to play an instrumental role in various forms of sinus node disease and atrial fibrillation. Mouse models of ankyrin deficiency have played fundamental roles in the translation of ankyrin-based research to new clinical understanding of human sinus node disease, atrial fibrillation, and ventricular tachycardia

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

Altered regulation of cardiac ankyrin repeat protein in heart failure

Background: Left ventricular assist devices (LVADs) have revolutionized and improved the care of the sickest heart failure (HF) patients, and it is imperative that they receive appropriate ventricular unloading. Assessing this critical parameter with current methodologies (labs, imaging) is usually suboptimal in this patient population. Hence it is imperative to elucidate the molecular underpinnings involved in ventricular unloading. We have previously identified the cytoskeletal protein βII spectrin as an essential nodal protein involved in post-translational targeting and βII spectrin protein levels are significantly altered in multiple forms of human and animal HF. We therefore hypothesized that the βII spectrin pathway would play a critical role in LVAD remodeling. Methods: Human heart failure samples were obtained from patients undergoing heart transplantation. Wild type (WT) mice and our previously validated βII spectrin conditional knock out (βII cKO) mice were used for animal experiments. Transaortic constriction (TAC) was performed on WT mice. Protein expression was assessed via immunoblots, and protein interactions were assessed with co-immunoprecipitation. Transcriptome analysis was performed using isolated whole hearts from control adult WT mice (n = 3) compared to βII cKO spectrin mice (n = 3). Results: We report that hearts from mice selectively lacking βII spectrin expression in cardiomyocytes displayed altered transcriptional regulation of cardiac ankyrin repeat protein (CARP). Notably, CARP protein expression is increased after TAC. Additionally, our findings illustrate that prior to LVAD support, CARP levels are elevated in HF patients compared to normal healthy controls. Further, for the first time in a LVAD population, we show that elevated CARP levels in HF patients return to normal following LVAD support. Conclusion: Our findings illustrate that CARP is a dynamic molecule that responds to reduced afterload and stress, and has the potential to serve as a prognostic biomarker to assess for an adequate response to LVAD therapy

Tumor-Induced Cardiac Dysfunction: A Potential Role of ROS

Cancer and heart diseases are the two leading causes of mortality and morbidity worldwide. Many cancer patients undergo heart-related complications resulting in high incidences of mortality. It is generally hypothesized that cardiac dysfunction in cancer patients occurs due to cardiotoxicity induced by therapeutic agents, used to treat cancers and/or cancer-induced cachexia. However, it is not known if localized tumors or unregulated cell growth systemically affect heart function before treatment, and/or prior to the onset of cachexia, hence, making the heart vulnerable to structural or functional abnormalities in later stages of the disease. We incorporated complementary mouse and Drosophila models to establish if tumor induction indeed causes cardiac defects even before intervention with chemotherapy or onset of cachexia. We focused on one of the key pathways involved in irregular cell growth, the Hippo–Yorkie (Yki), pathway. We used overexpression of the transcriptional co-activator of the Yki signaling pathway to induce cellular overgrowth, and show that Yki overexpression in the eye tissue of Drosophila results in compromised cardiac function. We rescue these cardiac phenotypes using antioxidant treatment, with which we conclude that the Yki induced tumorigenesis causes a systemic increase in ROS affecting cardiac function. Our results show that systemic cardiac dysfunction occurs due to abnormal cellular overgrowth or cancer elsewhere in the body; identification of specific cardiac defects associated with oncogenic pathways can facilitate the possible early diagnosis of cardiac dysfunction

Dysfunction of the β 2 -spectrin-based pathway in human heart failure

β 2 -Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of β 2 -spectrin for vertebrate function is illustrated by dysfunction of β 2 -spectrin-based pathways in disease. Recently, defects in β 2 -spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of β 2 -spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that β 2 -spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, β 2 -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, β 2 -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 β 2 -spectrin protein levels. Mechanistically, we identify that β 2 -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 β 2 -spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that β 2 -spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca 2+ - and calpain-dependent proteolysis.β 2 -Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of β 2 -spectrin for vertebrate function is illustrated by dysfunction of β 2 -spectrin-based pathways in disease. Recently, defects in β 2 -spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of β 2 -spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that β 2 -spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, β 2 -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, β 2 -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 β 2 -spectrin protein levels. Mechanistically, we identify that β 2 -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 β 2 -spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that β 2 -spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca 2+ - and calpain-dependent proteolysis

Lung transplantation following prior cardiac surgical procedures

Background: As lung transplant candidates are older with increased comorbidities, we sought to examine the prevalence and outcomes of lung transplant recipients after prior cardiac surgery. Methods: Lung transplants were identified from the United Network for Organ Sharing/Organ Procurement and Transplantation Network Database. Patients were stratified based on prior cardiac surgery (no surgery [NS], prior coronary artery bypass grafting [CABG], prior valve [Valve]). Unadjusted comparisons were performed among all groups, and propensity matching was utilized for adjusted comparisons. Survival was examined with Kaplan-Meier methods. Results: A total of 28,710 patients were identified, 467 (1.6%) had prior CABG and 84 (0.3%) had prior valvular surgery. Before matching, the NS group was significantly younger, less commonly male, and had lower lung allocation scores. There were significantly fewer bilateral lung transplants in the CABG and Valve groups. Length of stay was shortest in the CABG group, but there were no significant differences in postoperative stroke, dialysis, or in-hospital mortality. There was an increased incidence of cardiac/cerebrovascular cause of death in CABG recipients (18.3%) and malignancy death in Valve recipients (23.3%). Following matching, CABG 5-year survival was lower than NS (p < 0.01), while there was no significant difference between NS and Valve groups (p = 0.4). Conclusions: CABG and Valve recipients had decreased survival, however not at levels prohibitive to transplantation. Due to potentially increased risk of cardiovascular mortality, providers should evaluate the burden of vascular disease in potential recipients with prior CABG to improve patient selection and maximize post-transplant survival

Trends in survival after heart transplantation based on Social Vulnerability Index in the United States

Background: The association of social vulnerability (SV) and cardiac transplant survival remains poorly defined, particularly related to long-term outcomes. The purpose of this study was to define the impact of SV on survival among heart transplant recipients with at least 1 year of survival post-transplant. Methods: Heart transplant recipients were identified using the United Network for Organ Sharing database between June 1, 2006, and December 31, 2020. The Center for Disease Control’s Social Vulnerability Index (SVI) database was used to stratify patients based on SVI into 3 groups: low: <25; average: 26 to 74; high: 75+. The groups were analyzed with comparative statistics, and unadjusted survival was assessed using Kaplan-Meier methods. To determine the independent association between SVI and survival, a multivariable Cox proportional hazard model was created. Results: There were 27,740 recipients identified. High SVI patients more commonly identified as Black individuals and had a higher incidence of diabetes, pretransplant intensive care unit admission, and need for concomitant kidney transplant (p < 0.05 for all). Additionally, high SVI patients had the longest length of stay post-transplant (21.4 days) (p < 0.05). High and average SVI patients had inferior 3-year, 5-year, and 10-year survival vs low SVI patients (p < 0.05). After adjustment, average (hazard ratio [HR]: 1.12) and high (HR: 1.16) SVI were independently associated with an increased risk of mortality on multivariable analysis (both p < 0.001). Conclusion: High or average SVI is independently associated with increased mortality following heart transplantation in patients with 1-year conditional survival. These findings demonstrate that disparities persist among heart transplant recipients during long-term follow-up