山羊心房颤动进展过程中心房电图形态的演变

目的利用山羊模型研究心房颤动(简称房颤)在由阵发性向持续性转变过程中,心房/肺静脉外膜电图形态的演变。方法在山羊的左房(LA)游离壁外膜和左上肺静脉(LSPV)根部缝合电极片,利用自制的房颤刺激器于体外发放50Hz的刺激,刺激左房,刺激时程1s,每次间隔2s,诱发出自发维持时间超过24h的持续性房颤。将心房/肺静脉外膜电图形态分为单电位(SP)、双电位(DP)和碎裂电位(FP)。分析在基础状态下和房颤维持不同时间时各电位在所有激动中所占比例和动态变化。结果在窦性心律时LA和LSPV全为SP,随着房颤持续时间的延长,两部位的SP比例逐渐减少,DP和FP的比例逐渐增加。房颤刚开始和持续24h后SP的比例在LA分别为94.2%±5.0%和68.4%±6.0%(P<0.01),在LSPV则分别为74.2%±3.3%和40.1%±7.3%(P<0.01)。在房颤自发持续24h后,LA各种形态的电位交替出现,而LSPV可见连续的反复快速激动。结论心房和肺静脉外膜电图的碎裂程度增加,以及肺静脉出现连续的反复快速激动与房颤的持续有关。     

C-reactive protein and microalbuminuria are associated with atrial fibrillation

BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk for cardiovascular disease. It is important to detect AF at an early stage and to search for new pathophysiological pathways to intervene. We hypothesized that microalbuminuria and C-reactive protein (CRP), a marker of generalized vascular damage and inflammation, respectively, are associated with AF. METHODS: Standard 12-lead electrocardiograms were recorded in 7546 subjects (mean age 49+/-13 years, 51% male). AF was defined according to Minnesota codes. The urinary albumin excretion rate was measured as the mean of two 24-h urine collections and microalbuminuria was defined as an albumin excretion rate between 30 and 300 mg per 24 h. High-sensitive CRP was dichotomized (low: three lowest quartiles, CRP<2.87 mg/l vs. high: highest quartile, CRP>2.87 mg/l). Data are expressed as odds ratios (95% confidence intervals). RESULTS: AF was present in 75 (1.0%) subjects. In multivariate analysis, an age >60 years, the presence of ischemic heart disease, left ventricular hypertrophy, elevated CRP level (1.79 [1.07-2.97], p=0.03) and microalbuminuria (1.93 [1.10-3.37], p=0.02) were significantly associated with AF. Surprisingly, the combination of elevated CRP and the presence of microalbuminuria showed an even higher association with AF after adjusting for all cardiovascular risk factors (3.80 [1.89-7.63], p<0.001). CONCLUSIONS: An elevated CRP level and microalbuminuria are associated with AF. Moreover, the combination of both indicates a fourfold higher association with the presence of AF in a population at large.     

自发性高血压大鼠不同G蛋白信号调节因子的变化

目的通过检测自发性高血压大鼠(spontaneously hypertensive rats,SHR)不同组织G蛋白信号调节因子(regulator of G protein signaling,RGS)包括RGS2、RGS3和RGS4 mRNA的变化及其与心血管系统生理学表型的相关性,探讨其在高血压中的作用及机制。方法SHR与正常血压对照组Wistar大鼠经颈动脉插管测量血流动力学指标,同时测定心重指数(heart weight/body mass,HW/BM)和左室质量指数(left ventricular mass index,LVMI)。提取主动脉和心肌组织总RNA,逆转录后采用实时定量聚合酶链式反应方法检测RGS2、RGS3和RGS4 mRNA水平。结果SHR组收缩压(229.2±30.6mm Hg比121.2±12.8mm Hg,P<0.01),HW/BM(0.34±0.01比0.26±0.01,P<0.01)和LVMI(0.28±0.01比0.21±0.01,P<0.01)均显著高于对照组。SHR组RGS2 mRNA水平与对照组相比,在主动脉中降低41.5%(0.69±0.14比1.18±0.26,P<0.05),心肌中升高3.3倍(0.20±0.04比0.06±0.01,P<0.05);SHR组主动脉和心肌中RGS3 mRNA水平分别较对照组升高4.2倍(1.51±0.20比0.36±0.06,P<0.01)和4.6倍(3.16±0.36比0.68±0.09,P<0.05)。SHR与对照组主动脉和心肌RGS4 mRNA水平差异无统计学意义。大鼠主动脉RGS2 mRNA水平与收缩压呈负相关(Y=-0.003X 0.89,P<0.05);心肌RGS2 mRNA水平与HW/BM(Y=1.56X-0.35,P<0.05)呈正相关。大鼠主动脉和心肌组织RGS3 mRNA水平呈正相关(P<0.05),并分别与收缩压(Y=0.01X-0.65,P<0.05)和LVM I(Y=23.8X-4.2,P<0.05)呈正相关。结论SHR大鼠主动脉选择性RGS2降低和RGS3升高可能参与了SHR高血压的发病,心脏RGS2和RGS3 mRNA水平升高与心肌肥厚和心脏收缩功能改变相关,提示RGS2和RGS3可能成为高血压及其心脏并发症药物治疗的新靶点。     

Changes in the indices of the atrial complex on a differentially amplified ECG in atrial infarct

The atrial complex of differentially amplified ECG was examined in 19 patients with atrial infarction. The diagnosis of atrial infarction was based on the electrocardiographic features, and in 7 cases it was confirmed by postmortem examination. The electrocardiographic pattern was characterized by P-Q segment shift. Atrial infarction resulted in a decrease in the amplitude, the prolongation of atrial conduction time and the appearance of additional fragments in the atrial complex of differentially amplified ECG.     

Members of the KCTD family are major regulators of cAMP signaling

Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger with an essential role in neuronal function. cAMP synthesis by adenylyl cyclases (AC) is controlled by G protein–coupled receptor (GPCR) signaling systems. However, the network of molecular players involved in the process is incompletely defined. Here, we used CRISPR/Cas9–based screening to identify that members of the potassium channel tetradimerization domain (KCTD) family are major regulators of cAMP signaling. Focusing on striatal neurons, we show that the dominant isoform KCTD5 exerts its effects through an unusual mechanism that modulates the influx of Zn²⁺ via the Zip14 transporter to exert unique allosteric effects on AC. We further show that KCTD5 controls the amplitude and sensitivity of stimulatory GPCR inputs to cAMP production by Gβγ-mediated AC regulation. Finally, we report that KCTD5 haploinsufficiency in mice leads to motor deficits that can be reversed by chelating Zn²⁺. Together, our findings uncover KCTD proteins as major regulators of neuronal cAMP signaling via diverse mechanisms.

Cyclic adenosine monophosphate (cAMP) is the key second messenger that mediates a vast number of cellular reactions to oncoming stimuli (1). Accordingly, it is involved in regulating a myriad of physiological processes including, among many others, proliferation, differentiation, synaptic plasticity, and actions of hormones and neurotransmitters (2–4).The homeostasis of cAMP is tightly controlled by the elaborate yet incompletely established network of players. cAMP is enzymatically synthesized from ATP by adenylyl cyclases (ACs) and degraded by phosphodiesterases. In mammals, there are nine transmembrane AC isoforms that show exquisite and differential regulation by a variety of mechanisms that include macromolecular scaffolding, binding of proteins and cofactors. Moreover, activity of ACs is also controlled by heavy metals (5, 6), calcium (7), and by a natural product forskolin, which acts through a distinct allosteric site (8, 9).Perhaps the best characterized modulatory input into the AC system controlling cAMP dynamics is provided by G protein–coupled receptors (GPCRs), the largest family of cell surface receptors with prominent roles in cellular communication, physiology, and disease (10, 11). Most, if not all, canonical GPCRs signal by activating heterotrimeric G proteins, which entails their dissociation into Gα and Gβγ subunits. Most AC isoforms are activated by direct interaction with Gαs and Gαolf and are inhibited by binding to Gαi1, Gαi2, Gαi3, and Gαz (12, 13). In addition, ACs are regulated by the Gβγ subunits, which provide inhibition of some ACs while conditionally stimulating other isoforms (14). However, the mechanisms of AC regulation are not fully elucidated with a growing appreciation that there are a significant number of players with pivotal roles in cAMP regulation yet to be discovered.Gβγ subunits have recently been identified to form a complex with members of the K⁺ channel tetradimerization domain (KCTD) family of proteins (15, 16). KCTD oligomers have been identified as adapters that enable Cul3-mediated ubiquitin degradation of substrate proteins (17), including Gβγ dimers (16, 18). Interaction of certain KCTD members with Gβγ have also been shown to regulate Gβγ availability for engagement with some effectors (19–21). Although KCTD proteins have ties to GPCR signaling (15, 18), the action of KCTDs on cellular signaling and the mechanisms of their effects remain poorly understood. In this study, we report a previously unknown role of KCTD members in regulating AC with a major impact on neuronal cAMP dynamics and movement control in rodents.     

Changes in P-wave dispersion and P-wave duration after open heart surgery are associated with the peak incidence of atrial fibrillation

Background: Increased P-wave dispersion (P-disp) and maximum P-wave duration (P-max) predict the development of atrial fibrillation (AF) in the general population. The present study evaluates the time-dependent relationship of P-disp and P-max after open heart surgery. Methods And Results: P-disp and P-max were measured in the perioperative period of open heart surgery (one day before surgery through postoperative day 4). Compared with the baseline, P-max decreased immediately after open heart surgery (112.63 +/- 7.4 ms vs 106.9 +/- 8.2 ms, P =.005). An increase in P-disp was observed between postoperative days 1 and 2 (37.5 +/- 6.8 ms vs 43.1 +/- 4.5 ms, P <.05), and postoperative days 1 and 3 (37.5 +/- 6.8 ms vs 44.1 +/- 6.6 ms, P <.05). There was also an increase in the P-max between postoperative day 1 and 3 (103 +/- 8.3 ms vs 110 +/- 7.7 ms, P <.05). Conclusions: Nonuniform atrial conduction (P-disp) is greatest on days 2 and 3 after open heart surgery, and the longest atrial conduction time (P-max) is greatest on day 3 after open heart surgery, findings that coincide with the time of greatest risk for AF. (Heart Lung((R)) 2001;30:466-71.)     

Double atrial potentials in left‐sided accessory pathways are associated with paroxysmal atrial fibrillation

1 Introduction

Muscular connections between the coronary sinus (CS) and left atrium probably impact distribution of electrical activity. Double atrial potentials (DP) may be their presentation. The aim was to investigate the presence of DP in CS recordings during atrioventricular reentrant tachycardia (AVRT) and its contribution to the occurrence of paroxysmal atrial fibrillation (AF).

2 Methods

A group of 247 patients with accessory pathways (AP) were screened for DP. The patients with DP during AVRT were compared to those without DP.

3 Results

DP during AVRT were found only among the left‐sided AP (AP‐L). Patients with AP‐L were divided into Group 1 (n  =  17) with DP during AVRT and Group 2 (n  =  108) without DP. Patients in Group 1 had higher incidence of AF in history (47.1% vs. 23.1%; P  =  0.0376), AF induced during electrophysiological (EP) study (70.6% vs. 25%; P  =  0.0002). Group 1 had higher heart rate (HR) during AVRT in the EP study (197.2 ± 27 vs. 175.1 ± 26.3 bpm; P  =  0.0019), but HR of clinical AVRT (208.5 ± 30.8 vs. 191.6 ± 27.8 bpm) was not significant different (P  =  ns). Additionally, electrical alternans of QRS amplitude during AVRT in the EP study was more frequent in Group 1 (52.9 vs. 20.4 %; P  =  0.0048).

4 Conclusion

Patients with DP and AP‐L were more prone to develop AF. The presence of DP was associated with faster AVRT rate. The direction of atrium depolarization during AVRT may be different in the presence of DP and probably plays a role in development of AF in this group of patients.     

Decreased beating rate variability of spontaneously contracting cardiomyocytes after co-incubation with endotoxin

Decreased heart rate variability (HRV) in critically ill patients indicates a poor prognosis. In heart failure patients, there is an elevated sympathetic tone, reflected by a dominance of sympathetic parameters in HRV, whereas in critically ill patients sympathetic and parasympathetic modulation of heart rate is attenuated despite increased catecholamine blood levels. Thus, autonomic dysfunction in the critically ill cannot be causally related to an impairment at the level of neural transmission, but may be due to a derangement of signal transduction at the effector cell level. On the basis of our working hypothesis that endotoxin may be involved in this blunting of effector cell response to nerval input, we studied the spontaneous beating of cardiomyocytes under the influence of endotoxin. Applying the clinically established indices of HRV to the analysis of beating rate variability (BRV) of neonatal rat cardiomyocytes in serum-free medium, a narrowing of their BRV by endotoxin is demonstrated. We propose that the narrowing of HRV in critically ill patients does not only reflect the altered input from the central or peripheral neurons, but rather a remodeling of the cardiac pacemaker cells by endotoxin and inflammatory mediators.     

The novel left atrial appendage strain parameters are associated with thrombosis risk in patients with non-valvular atrial fibrillation

Objectives

We sought to explore a novel left atrial appendage (LAA) strain parameter which could represent the cumulative adverse impact of chronic Atrial fibrillation (AF) on the LAA function, and the relationship between the LAA strain parameter and thrombosis risk in patients with non-valvular AF.

Methods

We enrolled 268 patients with non-valvular AF and 58 sinus rhythm subjects who underwent transesophageal echocardiography in the study. LAA longitudinal strain amplitude (LAA LSA) was defined as the sum of the value of the maximum positive peak strain (LAA PLS) and the absolute value of the minimum negative peak strain (LAA NLS). Dense spontaneous echo contrast (SEC) was defined as grade 3 or 4 SEC.

Results

Compared to sinus rhythm group, the global LAA strain parameters were significantly lower in paroxysmal AF (n = 148), and the lowest of them were found in persistent AF (n = 120), which suggested that the global LAA strain parameters could evaluate LAA function in sinus rhythm, paroxysmal AF and persistent AF. Compared with patients in AF without SEC/thrombus (n = 113), the regional and global LAA strain parameters were significantly depressed in AF with SEC/thrombus (n = 155). Multivariate logistic regression analyses showed that LAA global LSA (OR 0.768; 95% CI:0.569, 0.970; p = 0.027) was an independent predicter of the SEC/thrombus. Compared with patients in AF without dense SEC or thrombus (n = 210), the regional and global LAA strain parameters were significantly impaired in the patients with dense SEC/thrombus(n = 58). LAA global LSA (AUC 0.884) had the best predictable accuracy for dense SEC or thrombus, and outperformed LAA PLS, LAA NLS, CHA2DS2-VASc score and conventional LAA functional parameters that have been used in the evaluation blood flow stasis in LAA. LAA LSA showed excellent interobserver and intra-observer agreement beyond LAA PLS and LAA NLS.

Conclusion

The novel LAA strain parameters, which were feasible and reproducible parameters for evaluation LAA mechanic function, had good predictive accuracy for blood flow stasis in LAA beyond conventional LAA functional parameters.     

Total and interatrial epicardial adipose tissues are independently associated with left atrial remodeling in patients with atrial fibrillation

Epicardial Adipose Tissue in Atrial Fibrillation. Introduction: As epicardial adipose tissue (EAT) is a metabolically active visceral fat, potential interaction between EAT and myocardium is strongly suggested. The aims of this study were to determine whether the amount and regional distribution of EAT are related to the chronicity of atrial fibrillation (AF) and left atrial (LA) remodeling. Methods and Results: This study consisted of 40 subjects with paroxysmal AF (PAF) and 40 with persistent AF (PeAF). Eighty subjects with no history of AF were enrolled as controls. Total volume of EAT (EAT_total), regional thickness of EAT, and LA volume (LAV) were measured by multislice computed tomography. In the AF group, blood samples were drawn from coronary sinus for analysis of inflammatory cytokines including adiponectin. Results: Compared with controls, AF subjects had larger LAV, EAT_total, and the thicknesses of periatrial EAT including interatrial septum (IAS). However, the thicknesses of periventricular EAT were not different between the groups. The PeAF subjects had larger LAV, EAT_total, and periatrial EAT thicknesses, higher levels of inflammatory cytokines, and lower level of adiponectin than did the PAF subjects. Adiponection level was significantly associated with EAT_total and IAS thickness. Multivariate analysis revealed that EAT_total (P = 0.004) and IAS thickness (P = 0.016) were independently associated with LAV. Conclusion: EAT_total and thickness of periatrial EAT were significantly larger in AF subjects compared to those of the matched controls and were closely related to the chronicity of AF. Moreover, EAT_total and IAS thickness were independently associated with LAV in subjects with AF . (J Cardiovasc Electrophysiol, Vol. 22, pp. 647‐655, June 2011)     

Ceramides are associated with inflammatory processes in human mediastinal adipose tissue

Background and AimCeramides are poorly characterized in human adipose tissue. The aim of this study was to investigate concentrations of different ceramide species in human subcutaneous and visceral adipose tissue depots and to determine associations between ceramides and global gene expression profiles.Methods and ResultsConcentrations of six ceramide species were determined in plasma and in subcutaneous and mediastinal adipose tissue from 10 overweight subjects (BMI 29.4 ± 4.9 kg/m²). In the adipose tissue biopsies gene expression arrays were performed and relationships between ceramides and gene expression analyzed. Immunostaining of the two adipose tissue depots was performed in an independent group of 10 patients. Mediastinal adipose tissue contained significantly higher concentrations (p < 0.05) of all six ceramide species than the subcutaneous depot. Of the six ceramides in plasma, concentrations of only two (Cer d18:1/18:0 and Cer d18:1/22:0) correlated significantly (p < 0.05) with the corresponding species in mediastinal adipose tissue, but there were no significant correlations between ceramides in plasma and subcutaneous adipose tissue. Multivariate analysis identified significant correlations between the total ceramide concentration and global gene expression within mediastinal, but not subcutaneous adipose tissue, according to cross-validation. Gene ontology analysis of genes related to ceramides in the mediastinal depot revealed that genes positively correlated with ceramides were associated mainly with immune and inflammatory categories, while genes negatively correlated with ceramides were associated mainly with lipid and carbohydrate metabolism.ConclusionsCeramides in human mediastinal adipose tissue may be involved in inflammation and lipid and carbohydrate metabolism.