The Catecholaminergic Polymorphic Ventricular Tachycardia Mutation R33Q Disrupts the N-terminal Structural Motif That Regulates Reversible Calsequestrin Polymerization

Calsequestrin undergoes dynamic polymerization with increasing calcium concentration by front-to-front dimerization and back-to-back packing, forming wire-shaped structures. A recent finding that point mutation R33Q leads to lethal catecholaminergic polymorphic ventricular tachycardia (CPVT) implies a crucial role for the N terminus. In this study, we demonstrate that this mutation resides in a highly conserved alternately charged residue cluster (DGKDR; cluster 1) in the N-terminal end of calsequestrin. We further show that this cluster configures itself as a ring system and that the dipolar arrangement within the cluster brings about a critical conformational flip of Lys³¹-Asp³² essential for dimer stabilization by formation of a H-bond network. We additionally show that Ca²⁺-induced calsequestrin aggregation is nonlinear and reversible and can regain the native conformation by Ca²⁺ chelation with EGTA. This study suggests that cluster 1 works as a molecular switch and governs the bidirectional transition between the CASQ2 monomer and dimer. We further demonstrate that mutations disrupting the alternating charge pattern of the cluster, including R33Q, impair Ca²⁺-CASQ2 interaction, leading to altered polymerization-depolymerization dynamics. This study provides new mechanistic insight into the functional effects of the R33Q mutation and its potential role in CPVT.     

动态心电图在小儿心律失常与心率变异性诊断中的意义

目的：研究动态心电图（DCG）诊断小儿心律失常及心率变异性（HVR）的临床价值。方法：560 例患者均进行常规心电图和动 态心电图的检查,由两组专业人员分别对心电图（ECG）和动态心电图（DCG）的检查结果进行（评价）,比较两种检查手段的不同 类型的心律失常的诊出率;评价不同类型心律失常的HVR。结果：ECG对各型心律失常的总诊出率为25.00%,对不同类型心率失 常的诊出率分别为5.71%、1.43%、9.29%、6.43%和2.14%;DCG 总诊出率为62.85%,对不同类型心率失常的诊出率分别为 16.43%、6.43%、17.86%、14.29%和7.86%,二者具有统计学差异（P＜0.05）。不同类型的心律失常的HVR不同,其中室性心动过速 和室性期前收缩的各项指标均明显低于其他类型（P＜0.05）。结论：DCG对不同心律失常的诊出率明显高于ECG,并能有效反应 不同类型心率失常的HVR,在小儿心律失常的诊断中具有一定的临床价值。     

New-onset atrial fibrillation in sepsis is associated with increased morbidity and mortality

BackgroundThe development of new-onset atrial fibrillation in sepsis has been associated with adverse outcomes.MethodsA systematic literature search was conducted to retrieve articles that investigated the association of new-onset atrial fibrillation in patients diagnosed with sepsis. The primary outcome of interest was the pooled risk ratio (RR) of in-hospital mortality in patients with new-onset atrial fibrillation and sepsis.ResultsSix studies included 3100 patients with new-onset atrial fibrillation in sepsis and 36,900 patients without new-onset atrial fibrillation in sepsis. The pooled RR for in-hospital mortality was 1.45 (95 % CI 1.32–1.60, p < 0.00001, I^2 =24 %). New-onset atrial fibrillation was also associated with increased ICU mortality, ICU and in-hospital length of stay and stroke. New-onset atrial fibrillation occurred more in the elderly, those with a prior history of cardiovascular and respiratory disease, and those with increased severity of illness.ConclusionProspective randomised trials are needed to clarify the significance of new-onset atrial fibrillation in sepsis, optimal treatment strategies for these patients, and the benefit of systemic anticoagulation. Physicians should be aware that new-onset atrial fibrillation in sepsis is not merely an observed temporary arrhythmia but a marker of poor prognosis and should be managed accordingly.     

Serum Galectin-3 level and recurrence of atrial fibrillation post-ablation – Systematic review and meta-analysis

BackgroundSerum galectin-3, a circulating biomarker of fibrosis, has been associated with atrial remodelling. Recent studies investigating serum galectin-3 and AF recurrence post-ablation have shown mixed results. We aimed to analyze the latest evidence on the association between serum galectin-3 and AF recurrence after catheter ablation.MethodsWe performed a comprehensive search on topics that assesses serum galectin-3 and AF recurrence post-ablation up until August 2019.ResultsThere were 597 patients from seven studies. The mean difference of serum galectin-3 was similar in both AF recurrence and non AF recurrence group (mean difference 0.78 ng/mL [-0.56, 2.13]; p = 0.25; I²: 69%. Upon removal of a study in sensitivity analysis, the serum galectin-3 became higher in AF recurrence group (mean difference 1.41 ng/mL [0.47, 2.34], p = 0.003; I²: 17%). Serum galectin-3 was associated with a higher risk for AF recurrence (HR 1.25 [1.01, 1.55]; p = 0.04; I²: 76%). Upon removal of a study in sensitivity analysis, HR became 1.45 [1.07, 1.96], p = 0.02; I²: 47%. Meta-analysis of adjusted HR demonstrated that high serum galectin-3 independently predicts AF recurrence (HR 1.15 [1.02, 1.29], p < 0.02; I²: 57%, p = 0.10)ConclusionSerum galectin-3 is associated with an increased risk of AF recurrence post-ablation. Further studies are required, especially emphasis on the cut-off point should be given, before integrating it in routine risk stratification for AF ablation.     

Comparison of arrhythmia detection by conventional Holter and a novel ambulatory ECG system using patch and Android App,over 24 h period

BackgroundAmbulatory electrocardiogram (AECG) is done for evaluation of arrhythmia. Commonly used AECG system is 24 h Holter. Patch based second generation AECG monitoring devices, which can record for longer periods, are now available.ObjectiveAndroid App based WebCardio using WiPatch is a new AECG system which records ECG in two leads for 72 h. Our study compared the arrhythmia detection by WebCardio and conventional Holter by simultaneously connecting both for 24 h in patients having indication for AECG.MethodsThe AECG of patients who had simultaneous recording with WebCardio and conventional Holter, in the department of Cardiology, Medical College, Thrissur were evaluated. Ability to detect any of the 6 arrhythmias :1) atrial fibrillation (AF), 2) atrioventricular (AV) block, 3) sinus pause of ≥3 s (SP), 4) supraventricular tachycardia (SVT), 5) premature ventricular complex (PVC) and 6) ventricular tachycardia (VT)/ventricular fibrillation (VF) was compared. Detection of each arrhythmia was also compared.Results141 patients had simultaneous recordings by both systems of AECG. The WebCardio picked up at least one of the 6 arrhythmias; AF, AV block, SP, SVT, PVC or VT/VF in 98 cases compared to 88 in the Holter (McNemars test, two tail P = 0.006). In eleven cases WebCardio detected an arrhythmia where Holter could not. In one case Holter identified an arrhythmia and WebCardio could not. Individual arrhythmias; AF, SP, SVT and VT/VF were detected equally by both systems. AV block (23 Vs 18, p = 0.0625) and PVCs (83 Vs 74, p = 0.0636) were detected in more number of cases in WebCardio. In the five cases where WebCardio alone identified AV block, four had poor quality of P wave in the Holter.ConclusionArrhythmia was picked up in more number of patients by the WebCardio compared to Holter. This was due to higher pickup of AV block and PVCs by WebCardio. Difference in AV block identification was due to better quality of P in WebCardio. WebCardio is a good alternative to Holter for AECG.     

Reexcitation mechanisms in epicardial tissue: Role of Ito density heterogeneities and INa inactivation kinetics

Dispersion of action potential repolarization is known to be an important arrhythmogenic factor in cardiopathies such as Brugada syndrome. In this work, we analyze the effect of a variation in sodium current (I_Na) inactivation and a heterogeneous rise of transient outward current (I_to) in the probability of reentry in epicardial tissue. We use the Luo-Rudy model of epicardial ventricular action potential to study wave propagation in a one-dimensional fiber. Spatial dispersion in repolarization is introduced by splitting the fiber into zones with different strength of I_to. We then analyze the pro-arrhythmic effect of a variation in the relaxation time and steady-state of the sodium channel fast inactivating gate h. We quantify the probability of reentry measuring the percentage of reexcitations that occurs in 200 beats. We find that, for high stimulation rates, this percentage is negligible, but increases notably for pacing periods above 700 ms. Surprisingly, with decreasing I_Na inactivation time, the percentage of reexcitations does not grow monotonically, but presents vulnerable windows, separated by values of the I_Na inactivation speed-up where reexcitation does not occur. By increasing the strength of L-type calcium current I_CaL above a certain threshold, reexcitation disappears. Finally, we show the formation of reentry in stimulated two-dimensional epicardial tissue with modified I_Na kinetics and I_to heterogeneity. Thus, we confirm that while I_to dispersion is necessary for phase-2 reentry, altered sodium inactivation kinetics influences the probability of reexcitation in a highly nonlinear fashion.     

Inhibition of the Cardiac Na+ Channel Nav1.5 by Carbon Monoxide

Sublethal carbon monoxide (CO) exposure is frequently associated with myocardial arrhythmias, and our recent studies have demonstrated that these may be attributable to modulation of cardiac Na⁺ channels, causing an increase in the late current and an inhibition of the peak current. Using a recombinant expression system, we demonstrate that CO inhibits peak human Nav1.5 current amplitude without activation of the late Na⁺ current observed in native tissue. Inhibition was associated with a hyperpolarizing shift in the steady-state inactivation properties of the channels and was unaffected by modification of channel gating induced by anemone toxin (rATX-II). Systematic pharmacological assessment indicated that no recognized CO-sensitive intracellular signaling pathways appeared to mediate CO inhibition of Nav1.5. Inhibition was, however, markedly suppressed by inhibition of NO formation, but NO donors did not mimic or occlude channel inhibition by CO, indicating that NO alone did not account for the actions of CO. Exposure of cells to DTT immediately before CO exposure also dramatically reduced the magnitude of current inhibition. Similarly, l-cysteine and N-ethylmaleimide significantly attenuated the inhibition caused by CO. In the presence of DTT and the NO inhibitor N^ω-nitro-l-arginine methyl ester hydrochloride, the ability of CO to inhibit Nav1.5 was almost fully prevented. Our data indicate that inhibition of peak Na⁺ current (which can lead to Brugada syndrome-like arrhythmias) occurs via a mechanism distinct from induction of the late current, requires NO formation, and is dependent on channel redox state.     

葛根素对大鼠心室肌细胞动作电位的影响

目的:从电生理角度探讨葛根素抗心律失常的可能机制。方法:采用膜片钳技术记录大鼠心室肌细胞动作电位(AP)、转染的人胚胎肾细胞缓慢延迟整流钾电流(IKs),观察加药前、后葛根素对AP和IKs的影响。结果:0.01、0.1、1 mmol/L葛根素可浓度依赖性地延长动作电位时程,分别使APD50从(71.8±11.8)ms延长至(86.9±10.7)ms、(100.5±14.1)ms和(123.6±25.4)ms;使APD90从(164.6±21.4)ms延长至(188.3±11.5)ms、(221.6±25.7)ms和(278.7±38.2)ms(n=6,均P0.05),而对RMP、APA和APD20无显著影响。此外,0.01、0.1、1 mmol/L葛根素对IKs抑制率分别为(17.8±2.5)%、(40.4±1.9)%和(60.9±3.2)%(n=6,均P0.05)。结论:葛根素可能通过抑制IKs来延长动作电位时程,发挥抗心律失常作用。     

Design,synthesis and cardiovascular evaluation of some aminoisopropanoloxy derivatives of xanthone

A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α₁-(compound 2 and 8), β-(compounds 1, 3, 4, 7), α₁/β-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.