[Show abstract][Hide abstract] ABSTRACT: Aims:
In atrial fibrillation (AF), abnormalities in Ca(2+) release contribute to arrhythmia generation and contractile dysfunction. We explore whether RyR cluster ultrastructure is altered and is associated with functional abnormalities in AF.
Methods and results:
Using high resolution confocal microscopy (STED) we examined RyR cluster morphology in fixed atrial myocytes from sheep with persistent AF (N=6) and control (Ctrl; N=6) animals. RyR clusters on average contained 15 contiguous RyRs; this did not differ between AF and Ctrl. However, the distance between clusters was significantly reduced in AF (288±12 nm vs. 376±17 nm). When RyR clusters were grouped into Ca(2+) release units (CRUs), i.e. clusters separated by <150 nm), CRUs in AF had more clusters (3.43±0.10 vs. 2.95±0.02 in Ctrl), which were more dispersed. Furthermore, in AF cells, more RyR clusters were found between Z lines.In parallel experiments, Ca(2+) sparks were monitored in live permeabilized myocytes. In AF, myocytes had: (i) >50% higher spark frequency with (ii) increased spark time-to-peak (TTP) and duration and (iii) a higher incidence of macrosparks.A computational model of the CRU was used to simulate the morphological alterations observed in AF cells. Increasing cluster fragmentation to the level observed in AF cells caused the observed changes i.e. higher spark frequency, increased TTP and duration; RyR clusters dispersed between Z-lines increased the occurrence of macrosparks.
In persistent AF, ultrastructural reorganization of RyR clusters within CRUs is associated with overactive Ca(2+) release, increasing the likelihood of propagating Ca(2+) release.
Full-text · Article · Oct 2015 · Cardiovascular Research
[Show abstract][Hide abstract] ABSTRACT: Beat-to-beat variability of ventricular repolarization (BVR) has been proposed as a strong predictor of Torsades de Pointes (TdP). BVR is also observed at the myocyte level, and a number of studies have shown the importance of calcium handling in influencing this parameter. The chronic AV block (CAVB) dog is a model of TdP arrhythmia in cardiac hypertrophy, and myocytes from these animals show extensive remodeling, including of Ca(2+) handling. This remodeling process also leads to increased BVR. We aimed to determine the role that (local) Ca(2+) handling plays in BVR. In isolated LV myocytes an exponential relationship was observed between BVR magnitude and action potential duration (APD) at baseline. Inhibition of Ca(2+) release from sarcoplasmic reticulum (SR) with thapsigargin resulted in a reduction of [Ca(2+)]i, and of both BVR and APD. Increasing ICaL in the presence of thapsigargin restored APD but BVR remained low. In contrast, increasing ICaL with preserved Ca(2+) release increased both APD and BVR. Inhibition of Ca(2+) release with caffeine, as with thapsigargin, reduced BVR despite maintained APD. Simultaneous inhibition of Na(+)/Ca(2+) exchange and ICaL decreased APD and BVR to similar degrees, whilst increasing diastolic Ca(2+). Buffering of Ca(2+) transients with BAPTA reduced BVR for a given APD to a greater extent than buffering with EGTA, suggesting subsarcolemmal Ca(2+) transients modulated BVR to a larger extent than the cytosolic Ca(2+) transient. In conclusion, BVR in hypertrophied dog myocytes, at any APD, is strongly dependent on SR Ca(2+) release, which may act through modulation of the l-type Ca(2+) current in a subsarcolemmal microdomain.
Preview · Article · Oct 2015 · Journal of Molecular and Cellular Cardiology
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to investigate the relationship between T-wave alternans (TWA), infarct size and microvascular obstruction (MVO) and recurrent cardiac morbidity after ST elevation myocardial infarction (STEMI). One hundred six patients underwent TWA testing 1-12 months and 57 patients underwent cardiac magnetic resonance imaging (MRI) in the first 2-4 days after STEMI. During follow-up (3.5 ± 0.5 years), death (n = 2), ventricular tachycardia (n = 3), supraventricular tachycardia (n = 4), heart failure (n = 3) and recurrent coronary ischemia (n = 25) were observed. After multivariate analysis, positive TWA (HR2.59, CI1.10-6.11, p0.024) and larger MVO (HR1.08, CI1.01-1.16, p0.034) were associated with recurrent angina or ACS. Presence of MVO was correlated with TWA (Spearman rho 0.404, p0.002) and the impairment of LVEF (-0.524, p < 0.001). Patients after STEMI remain at a high risk of symptoms of coronary ischemia. The presence of MVO and TWA 1-12 months after STEMI is related to each other and to recurrent angina or ACS.
No preview · Article · Sep 2015 · Journal of Cardiovascular Translational Research
[Show abstract][Hide abstract] ABSTRACT: A hybrid search strategy, using lexical and citation based methods, is presented in this paper as a robust method to delineate the broad field of cardiovascular research. Overall, this study aims to provide scientifically reliable and accurate data driven evidence about cardiovascular research by establishing a dataset of published research in this field. A workflow is presented that outlines the methods carried out to establish a core dataset based on a core set of journals, to identify and use search terms to detect a broader dataset, and then to apply measures of similarities between the citations of these two datasets to ensure relevance of the final dataset. The final core set of journals established comprises of 120 unique journals covered in Thomson Reuters Web of Science Core Collection (WoS) database including a total of 320,647 documents from 1991 to 2013. The search terms utilised include 107 cardio-specific terms that initially identify 1.8 million unique documents when searching the title, abstract and keywords. Upon application of the citation-based similarity measures the final combined dataset consists of 845,071 publications. Overall, establishing a relevant dataset of cardiovascular research means placing a greater emphasis on having a precise dataset, reducing recall in the process.
[Show abstract][Hide abstract] ABSTRACT: This paper is the third in a series of reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation–contraction coupling and arrhythmias: Na+ channel and Na+ transport. The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on cardiac Na+/Ca2+ exchange (NCX) and Na+/K+-ATPase (NKA). While the relevance of Ca2+ homeostasis in cardiac function has been extensively investigated, the role of Na+ regulation in shaping heart function is often overlooked. Small changes in the cytoplasmic Na+ content have multiple effects on the heart by influencing intracellular Ca2+ and pH levels thereby modulating heart contractility. Therefore it is essential for heart cells to maintain Na+ homeostasis. Among the proteins that accomplish this task are the Na+/Ca2+ exchanger (NCX) and the Na+/K+ pump (NKA). By transporting three Na+ ions into the cytoplasm in exchange for one Ca2+ moved out, NCX is one of the main Na+ influx mechanisms in cardiomyocytes. Acting in the opposite direction, NKA moves Na+ ions from the cytoplasm to the extracellular space against their gradient by utilizing the energy released from ATP hydrolysis. A fine balance between these two processes controls the net amount of intracellular Na+ and aberrations in either of these two systems can have a large impact on cardiac contractility. Due to the relevant role of these two proteins in Na+ homeostasis, the emphasis of this review is on recent developments regarding the cardiac Na+/Ca2+ exchanger (NCX1) and Na+/K+ pump and the controversies that still persist in the field.
No preview · Article · Mar 2015 · The Journal of Physiology
[Show abstract][Hide abstract] ABSTRACT: Postconditioning and cyclosporine A prevent mitochondrial permeability transition pore opening providing cardioprotection during ischemia/reperfusion. Whether microvascular obstruction is affected by these interventions is largely unknown. Pigs subjected to coronary occlusion for 1 h followed by 3 h of reperfusion were assigned to control (n = 8), postconditioning (n = 9) or cyclosporine A intravenous infusion 10–15 min before the end of ischemia (n = 8). Postconditioning was induced by 8 cycles of repeated 30-s balloon inflation and deflation. After 3 h of reperfusion magnetic resonance imaging, triphenyltetrazolium chloride/Evans blue staining and histopathology were performed. Microvascular obstruction (MVO, percentage of gadolinium-hyperenhanced area) was measured early (3 min) and late (12 min) after contrast injection. Infarct size with double staining was smaller in cyclosporine (46.2 ± 3.1 %, P = 0.016) and postconditioning pigs (47.6 ± 3.9 %, P = 0.008) versus controls (53.8 ± 4.1 %). Late MVO was significantly reduced by cyclosporine (13.9 ± 9.6 %, P = 0.047) but not postconditioning (23.6 ± 11.7 %, P = 0.66) when compared with controls (32.0 ± 16.9 %). Myocardial blood flow in the late MVO was improved with cyclosporine versus controls (0.30 ± 0.06 vs 0.21 ± 0.03 ml/g/min, P = 0.002) and was inversely correlated with late-MVO extent (R
= 0.93, P < 0.0001). Deterioration of left ventricular ejection fraction (LVEF) between baseline and 3 h of reperfusion was smaller with cyclosporine (−7.9 ± 2.4 %, P = 0.008) but not postconditioning (−12.0 ± 5.5 %, P = 0.22) when compared with controls (−16.4 ± 5.5 %). In the three groups, infarct size (β = −0.69, P < 0.001) and late MVO (β = −0.33, P = 0.02) were independent predictors of LVEF deterioration following ischemia/reperfusion (R
= 0.73, P < 0.001). Despite both cyclosporine A and postconditioning reduce infarct size, only cyclosporine A infusion had a beneficial effect on microvascular damage and was associated with better preserved LV function when compared with controls.
Full-text · Article · Mar 2015 · Archiv für Kreislaufforschung
[Show abstract][Hide abstract] ABSTRACT: There is strong need to develop the current stratified practice of CVD management into a better personalized cardiovascular medicine, within a broad framework of global patient care. Clinical information obtained from history and physical examination, functional and imaging studies, biochemical biomarkers, genetic/epigenetic data, and pathophysiological insights into disease-driving processes need to be integrated into a new taxonomy of CVDs to allow personalized disease management. This has the potential for major health benefits for the population suffering from cardiovascular diseases.
No preview · Article · Dec 2014 · European Heart Journal