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

Contribution of MATE1 to 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 predisposes 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 an efflux 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 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