Assessment of the impact of race and proxies of socioeconomic status on the prevalence and health outcome of peripartum cardiomyopathy (PPCM) using the “All of Us” Databank

Background: Peripartum Cardiomyopathy (PPCM) is a form of cardiomyopathy occurring during the last month of pregnancy or within months after giving birth in women with previously normal hearts. PPCM is an idiopathic systolic dysfunction that causes a reduced left ventricle ejection fraction. The estimated incidence of PPCM worldwide is 1 diagnosis out of 2,000 live births, and the causes of PPCM remain unknown. A retrospective cohort study conducted at the University of Pennsylvania Health System by Getz et al. showed that black race and socioeconomic proxies (like neighborhood disadvantage index (NDI)) were independently associated with sustained cardiac dysfunction (Getz et al., Am Heart J 2021). This study also showed that from all the components of NDI (education, high rental occupied housing, annual income below poverty line, female headed household, adults unemployed, adults on public assistance), low education and high rental occupied housing were significantly associated with sustained cardiac dysfunction. The central aim of the present project is to assess the effect of socioeconomic proxies (including NDI, lack of access to health care and food insecurity) on the prevalence of sustained cardiac dysfunction from PPCM across the US using the “All of Us” databank. A secondary aim is to test the compliance of the All of Us database capacity to interrogate this potential association. Lastly, we aim to compare the results obtained from the All of Us database with the UK Biobank. Methods: The All of Us databank (Ramirez et al., Patterns 2022; The All of US Research Program, NEJM 2019) will be used to conduct a retrospective cohort study to assess how proxies of socioeconomic status may affect the incidence and prevalence of sustained cardiac dysfunction from PPCM across different ethnicities in the US. The All of Us database focuses on enrolling people in the US from diverse groups that have historically been underrepresented in medical research. Therefore, it includes a more diverse population than the population targeted in the retrospective study conducted at the University of Pennsylvania in which only black women from Philadelphia, PA, were included. To further interrogate the impact that geographic location and population ethnicity may have on the prevalence of sustained cardiac dysfunction from PPCM, the results obtained from the “All of Us” database will be compared against data obtained from the UK Biobank. Expected Results: We expect that the socioeconomic proxies interrogated in this study will have a significant impact on the prevalence of sustained cardiac dysfunction from PPCM. Current knowledge is limited on how socioeconomic status affects sustained cardiac dysfunction resulting from PPCM. Previous studies have been done on populations restricted to small geographic areas and did not analyze factors such as food security, access to care, or disability status. Understanding how these factors affect the incidence and prevalence of sustained cardiac dysfunction from PPCM may be used to improve prevention, early diagnosis, and management of PPCM

Mechanisms of cardiac arrhythmias.

This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.joa.2015.11.003Blood circulation is the result of the beating of the heart, which provides the mechanical force to pump oxygenated blood to, and deoxygenated blood away from, the peripheral tissues. This depends critically on the preceding electrical activation. Disruptions in the orderly pattern of this propagating cardiac excitation wave can lead to arrhythmias. Understanding of the mechanisms underlying their generation and maintenance requires knowledge of the ionic contributions to the cardiac action potential, which is discussed in the first part of this review. A brief outline of the different classification systems for arrhythmogenesis is then provided, followed by a detailed discussion for each mechanism in turn, highlighting recent advances in this area.The author received a BBSRC Doctoral CASE Studentship at the Department of Biochemistry, University of Cambridge, in conjunction with Xention Discovery, for his PhD studies

Caveolae in Rabbit Ventricular Myocytes: Distribution and Dynamic Diminution after Cell Isolation

Caveolae are signal transduction centers, yet their subcellular distribution and preservation in cardiac myocytes after cell isolation are not well documented. Here, we quantify caveolae located within 100 nm of the outer cell surface membrane in rabbit single-ventricular cardiomyocytes over 8 h post-isolation and relate this to the presence of caveolae in intact tissue. Hearts from New Zealand white rabbits were either chemically fixed by coronary perfusion or enzymatically digested to isolate ventricular myocytes, which were subsequently fixed at 0, 3, and 8 h post-isolation. In live cells, the patch-clamp technique was used to measure whole-cell plasma membrane capacitance, and in fixed cells, caveolae were quantified by transmission electron microscopy. Changes in cell-surface topology were assessed using scanning electron microscopy. In fixed ventricular myocardium, dual-axis electron tomography was used for three-dimensional reconstruction and analysis of caveolae in situ. The presence and distribution of surface-sarcolemmal caveolae in freshly isolated cells matches that of intact myocardium. With time, the number of surface-sarcolemmal caveolae decreases in isolated cardiomyocytes. This is associated with a gradual increase in whole-cell membrane capacitance. Concurrently, there is a significant increase in area, diameter, and circularity of sub-sarcolemmal mitochondria, indicative of swelling. In addition, electron tomography data from intact heart illustrate the regular presence of caveolae not only at the surface sarcolemma, but also on transverse-tubular membranes in ventricular myocardium. Thus, caveolae are dynamic structures, present both at surface-sarcolemmal and transverse-tubular membranes. After cell isolation, the number of surface-sarcolemmal caveolae decreases significantly within a time frame relevant for single-cell research. The concurrent increase in cell capacitance suggests that membrane incorporation of surface-sarcolemmal caveolae underlies this, but internalization and/or micro-vesicle loss to the extracellular space may also contribute. Given that much of the research into cardiac caveolae-dependent signaling utilizes isolated cells, and since caveolae-dependent pathways matter for a wide range of other study targets, analysis of isolated cell data should take the time post-isolation into account

Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

Transverse (t)-tubules are invaginations of the plasma membrane that form a complex network of ducts, 200–400 nm in diameter depending on the animal species, that penetrates deep within the cardiac myocyte, where they facilitate a fast and synchronous contraction across the entire cell volume. There is now a large body of evidence in animal models and humans demonstrating that pathological distortion of the t-tubule structure has a causative role in the loss of myocyte contractility that underpins many forms of heart failure. Investigations into the molecular mechanisms of pathological t-tubule remodelling to date have focused on proteins residing in the intracellular aspect of t-tubule membrane that form linkages between the membrane and myocyte cytoskeleton. In this review, we shed light on the mechanisms of t-tubule remodelling which are not limited to the intracellular side. Our recent data have demonstrated that collagen is an integral part of the t-tubule network and that it increases within the tubules in heart failure, suggesting that a fibrotic mechanism could drive cardiac junctional remodelling. We examine the evidence that the linkages between the extracellular matrix, t-tubule membrane and cellular cytoskeleton should be considered as a whole when investigating the mechanisms of t-tubule pathology in the failing heart

Channel Activity of Cardiac Ryanodine Receptors (RyR2) Determines Potency and Efficacy of Flecainide and R-Propafenone against Arrhythmogenic Calcium Waves in Ventricular Cardiomyocytes.

Flecainide blocks ryanodine receptor type 2 (RyR2) channels in the open state, suppresses arrhythmogenic Ca2+ waves and prevents catecholaminergic polymorphic ventricular tachycardia (CPVT) in mice and humans. We hypothesized that differences in RyR2 activity induced by CPVT mutations determines the potency of open-state RyR2 blockers like flecainide (FLEC) and R-propafenone (RPROP) against Ca2+ waves in cardiomyocytes. Using confocal microscopy, we studied Ca2+ sparks and waves in isolated saponin-permeabilized ventricular myocytes from two CPVT mouse models (Casq2-/-, RyR2-R4496C+/-), wild-type (c57bl/6, WT) mice, and WT rabbits (New Zealand white rabbits). Consistent with increased RyR2 activity, Ca2+ spark and wave frequencies were significantly higher in CPVT compared to WT mouse myocytes. We next obtained concentration-response curves of Ca2+ wave inhibition for FLEC, RPROP (another open-state RyR2 blocker), and tetracaine (TET) (a state-independent RyR2 blocker). Both FLEC and RPROP inhibited Ca2+ waves with significantly higher potency (lower IC50) and efficacy in CPVT compared to WT. In contrast, TET had similar potency in all groups studied. Increasing RyR2 activity of permeabilized WT myocytes by exposure to caffeine (150 µM) increased the potency of FLEC and RPROP but not of TET. RPROP and FLEC were also significantly more potent in rabbit ventricular myocytes that intrinsically exhibit higher Ca2+ spark rates than WT mouse ventricular myocytes. In conclusion, RyR2 activity determines the potency of open-state blockers FLEC and RPROP for suppressing arrhythmogenic Ca2+ waves in cardiomyocytes, a mechanism likely relevant to antiarrhythmic drug efficacy in CPVT

Comparison of Ca²⁺ spark frequency in WT, caffeine (CAFF) treated WT and Casq2^-/- myocytes.

<p>A. Average spark frequency, N = 25–70 cells/group, ***<i>P</i><0.001. B. Representative LS showing sparks registered in permeabilized WT myocytes, CAFF-treated permeabilized WT myocytes, and Casq2^<b>-/-</b> myocytes in internal solution (IS) containing Fluo 4 pentapotassium salt ([EGTA]_IS = 0.4 mM, nominal [Ca^<b>2+</b>]_IS = 0.06 mM, estimated free [Ca^<b>2+</b>]_IS = 0.04 μM (Maxchelator)).</p

Potency (IC₅₀, expressed in μM) and efficacy (defined as maximum drug effect measured at 100 μM) of all the drugs tested in the different mouse groups.

<p>N = 20–25 cells/condition tested. All measurements are relative to measurements obtained in cells exposed to VEH.</p><p>Potency (IC₅₀, expressed in μM) and efficacy (defined as maximum drug effect measured at 100 μM) of all the drugs tested in the different mouse groups.</p