Tpeak-Tend, Tpeak-Tend/QT ratio and Tpeak-Tend dispersion for risk stratification in Brugada Syndrome:A systematic review and meta-analysis

Background: Brugada syndrome is an ion channelopathy that predisposes affected subjects to ventricular tachycardia/fibrillation (VT/VF), potentially leading to sudden cardiac death (SCD). Tpeak-Tend intervals, (Tpeak-Tend)/QT ratio and Tpeak-Tend dispersion have been proposed for risk stratification, but their predictive values in Brugada syndrome have been challenged recently. Methods: A systematic review and meta-analysis was conducted to examine their values in predicting arrhythmic and mortality outcomes in Brugada Syndrome. PubMed and Embase databases were searched until 1 May 2018, identifying 29 and 57 studies. Results: Nine studies involving 1740 subjects (mean age 45 years old, 80% male, mean follow-up duration was 68 ± 27 months) were included. The mean Tpeak-Tend interval was 98.9 ms (95% CI: 90.5-107.2 ms) for patients with adverse events (ventricular arrhythmias or SCD) compared to 87.7 ms (95% CI: 80.5-94.9 ms) for those without such events, with a mean difference of 11.9 ms (95% CI: 3.6-20.2 ms, P = 0.005; I2 = 86%). Higher (Tpeak-Tend)/QT ratios (mean difference = 0.019, 95% CI: 0.003-0.036, P = 0.024; I2 = 74%) and Tpeak-Tend dispersion (mean difference = 7.8 ms, 95% CI: 2.1-13.4 ms, P = 0.007; I2 = 80%) were observed for the event-positive group. Conclusion: Tpeak-Tend interval, (Tpeak-Tend)/QT ratio and Tpeak-Tend dispersion were higher in high-risk than low-risk Brugada subjects, and thus offer incremental value for risk stratification

Lack of Cardiac Nerve Sprouting after Intramyocardial Transplantation of Bone Marrow-Derived Stem Cells in a Swine Model of Chronic Ischemic Myocardium

Previous experimental studies suggested that mesenchymal stem cell transplantation causes cardiac nerve sprouting; however, whether bone marrow (BM)-derived mononuclear cells (MNC) and endothelial progenitor cells (EPC) can also lead to cardiac nerve sprouting and alter gap junction expression remains unclear. We investigated the effect of electroanatomical mapping-guided direct intramyocardial transplantation of BM-MNC (n = 8) and CD31+EPC (n = 8) compared with saline control (n = 8) on cardiac nerve sprouting and gap junction expression in a swine model of chronic ischemic myocardium. At 12 weeks after transplantation, the distribution and density of cardiac nerve sprouting were determined by staining of tyrosine hydroxylase (TH) and growth associated protein 43(GAP-43) and expression of connexin 43 in the targeted ischemic and remote normal myocardium. After 12 weeks, no animal developed sudden death after the transplantation. There were no significant differences in the number of cells with positive staining of TH and GAP-43 in the ischemic and normal myocardium between three groups. Furthermore, expression of connexin 43 was also similar in the ischemic and normal myocardia in each group of animals (P > 0.05). The results of this study demonstrated that intramyocardial BM-derived MNC or EPC transplantation in a large animal model of chronic myocardial ischemia was not associated with increased cardiac nerve sprouting over the ischemic myocardium

Effects of pharmacological gap junction and sodium channel blockade on S1S2 restitution properties in Langendorff-perfused mouse hearts

Gap junctions and sodium channels are the major molecular determinants of normal and abnormal electrical conduction through the myocardium, however, their exact contributions to arrhythmogenesis are unclear. We examined conduction and recovery properties of regular (S1) and extrasystolic (S2) action potentials (APs), S1S2 restitution and ventricular arrhythmogenicity using the gap junction and sodium channel inhibitor heptanol (2 mM) in Langendorff-perfused mouse hearts (n=10). Monophasic action potential recordings obtained during S1S2 pacing showed that heptanol increased the proportion of hearts showing inducible ventricular tachycardia (0/10 vs. 5/8 hearts (Fisher’s exact test, P < 0.05), prolonged activation latencies of S1 and S2 APs, thereby decreasing S2/S1 activation latency ratio (ANOVA, P < 0.05) despite prolonged ventricular effective refractory period (VERP). It did not alter S1 action potential duration at 90% repolarization (APD90) but prolonged S2 APD90 (P < 0.05), thereby increasing S2/S1 APD90 ratio (P < 0.05). It did not alter maximum conduction velocity (CV) restitution gradient or maximum CV reductions but decreased the restitution time constant (P < 0.05). It increased maximal APD90 restitution gradient (P < 0.05) without altering critical diastolic interval or maximum APD90 reductions. Pro-arrhythmic effects of 2 mM heptanol are explicable by delayed conduction and abnormal electrical restitution. We concluded that gap junctions modulated via heptanol (0.05 mM) increased arrhythmogenicity through a delay in conduction, while sodium channel inhibition by a higher concentration of heptanol (2 mM) increased arrhythmogenicity via additional mechanisms, such as abnormalities in APDs and CV restitution.GT received research funding from the BBSRC for this research and is currently supported by a Clinical Assistant Professorship from the Croucher Foundation of Hong Kong. WTW is supported by the Direct Grant for Research from the Research Committee of the Chinese University of Hong Kong, China

Effects of pharmacological gap junction and sodium channel blockade on S1S2 restitution properties in Langendorff-perfused mouse hearts

Gap junctions and sodium channels are the major molecular determinants of normal and abnormal electrical conduction through the myocardium, however, their exact contributions to arrhythmogenesis are unclear. We examined conduction and recovery properties of regular (S1) and extrasystolic (S2) action potentials (APs), S1S2 restitution and ventricular arrhythmogenicity using the gap junction and sodium channel inhibitor heptanol (2 mM) in Langendorff-perfused mouse hearts (n=10). Monophasic action potential recordings obtained during S1S2 pacing showed that heptanol increased the proportion of hearts showing inducible ventricular tachycardia (0/10 vs. 5/8 hearts (Fisher’s exact test, P < 0.05), prolonged activation latencies of S1 and S2 APs, thereby decreasing S2/S1 activation latency ratio (ANOVA, P < 0.05) despite prolonged ventricular effective refractory period (VERP). It did not alter S1 action potential duration at 90% repolarization (APD90) but prolonged S2 APD90 (P < 0.05), thereby increasing S2/S1 APD90 ratio (P < 0.05). It did not alter maximum conduction velocity (CV) restitution gradient or maximum CV reductions but decreased the restitution time constant (P < 0.05). It increased maximal APD90 restitution gradient (P < 0.05) without altering critical diastolic interval or maximum APD90 reductions. Pro-arrhythmic effects of 2 mM heptanol are explicable by delayed conduction and abnormal electrical restitution. We concluded that gap junctions modulated via heptanol (0.05 mM) increased arrhythmogenicity through a delay in conduction, while sodium channel inhibition by a higher concentration of heptanol (2 mM) increased arrhythmogenicity via additional mechanisms, such as abnormalities in APDs and CV restitution.GT received research funding from the BBSRC for this research and is currently supported by a Clinical Assistant Professorship from the Croucher Foundation of Hong Kong. WTW is supported by the Direct Grant for Research from the Research Committee of the Chinese University of Hong Kong, China

Effects of implantation of bone marrow cells on cytokine levels in the ischemic heart tissue. An experimental study

<p>Abstract</p> <p>Background</p> <p>In order to achieve a safe and persistent angiogenic effect, we investigated the potential of bone marrow cells implantation to enhance angiogenesis of ischemic hearts in a rat model, and also we have investigated growth factors accompanying and intermediating the angiogenesis, and the changes occurring in the levels of cytokines and their relations with angiogenesis.</p> <p>Methods</p> <p>30 adult male Wistar albino rats from the same colony were used. After anterior myocardial infarction induced by occlusion of the left anterior descending artery, they were divided into two groups (Group I and Group II). 2 × 10⁷bone marrow cells suspended in 0.1 ml phosphate-buffered saline solution and 0.1 ml phosphate-buffered saline solution were injected at six points in the infarcted area in Group I and Group II respectively. Changes in the vascular density and, vascular endothelial growth factor, vascular cell adhesion molecule and cytokine levels in the infarcted myocardium after bone marrow cells implantation were examined.</p> <p>Results</p> <p>The implantation assay showed that bone marrow cells induced angiogenesis. Light microscopic analysis of the vascular density in the ischemic area showed that, angiogenesis had been induced to higher in Group I than Group II. Levels of vascular endothelial growth factor, vascular cell adhesion molecule and the inflammatory cytokines such as interleukin-1 and tumor necrosis factor-α in Group I were significantly elevated compared with those in Group II.</p> <p>Conclusion</p> <p>Bone marrow cells implantation induced angiogenesis in a rat ischemic heart model as a result of increase of the levels of vascular endothelial growth factor, vascular cell adhesion molecule, interleukin-1, and tumor necrosis factor-α.</p

Attack Resilience of the Evolving Scientific Collaboration Network

Stationary complex networks have been extensively studied in the last ten years. However, many natural systems are known to be continuously evolving at the local (“microscopic”) level. Understanding the response to targeted attacks of an evolving network may shed light on both how to design robust systems and finding effective attack strategies. In this paper we study empirically the response to targeted attacks of the scientific collaboration networks. First we show that scientific collaboration network is a complex system which evolves intensively at the local level – fewer than 20% of scientific collaborations last more than one year. Then, we investigate the impact of the sudden death of eminent scientists on the evolution of the collaboration networks of their former collaborators. We observe in particular that the sudden death, which is equivalent to the removal of the center of the egocentric network of the eminent scientist, does not affect the topological evolution of the residual network. Nonetheless, removal of the eminent hub node is exactly the strategy one would adopt for an effective targeted attack on a stationary network. Hence, we use this evolving collaboration network as an experimental model for attack on an evolving complex network. We find that such attacks are ineffectual, and infer that the scientific collaboration network is the trace of knowledge propagation on a larger underlying social network. The redundancy of the underlying structure in fact acts as a protection mechanism against such network attacks

Differences in genotype and virulence among four multidrug-resistant <i>Streptococcus pneumoniae</i> isolates belonging to the PMEN1 clone

We report on the comparative genomics and characterization of the virulence phenotypes of four &lt;i&gt;S. pneumoniae&lt;/i&gt; strains that belong to the multidrug resistant clone PMEN1 (Spain&lt;sup&gt;23F&lt;/sup&gt; ST81). Strains SV35-T23 and SV36-T3 were recovered in 1996 from the nasopharynx of patients at an AIDS hospice in New York. Strain SV36-T3 expressed capsule type 3 which is unusual for this clone and represents the product of an in vivo capsular switch event. A third PMEN1 isolate - PN4595-T23 - was recovered in 1996 from the nasopharynx of a child attending day care in Portugal, and a fourth strain - ATCC700669 - was originally isolated from a patient with pneumococcal disease in Spain in 1984. We compared the genomes among four PMEN1 strains and 47 previously sequenced pneumococcal isolates for gene possession differences and allelic variations within core genes. In contrast to the 47 strains - representing a variety of clonal types - the four PMEN1 strains grouped closely together, demonstrating high genomic conservation within this lineage relative to the rest of the species. In the four PMEN1 strains allelic and gene possession differences were clustered into 18 genomic regions including the capsule, the blp bacteriocins, erythromycin resistance, the MM1-2008 prophage and multiple cell wall anchored proteins. In spite of their genomic similarity, the high resolution chinchilla model was able to detect variations in virulence properties of the PMEN1 strains highlighting how small genic or allelic variation can lead to significant changes in pathogenicity and making this set of strains ideal for the identification of novel virulence determinant