The mechanical effects of CRT promoting autophagy via mitochondrial calcium uniporter down-regulation and mitochondrial dynamics alteration.

The mechanism of cardiac resynchronization therapy (CRT) remains unclear. In this study, mitochondria calcium uniporter (MCU), dynamin-related protein-1 (DNM1L/Drp1) and their relationship with autophagy in heart failure (HF) and CRT are investigated. Thirteen male beagle's dogs were divided into three groups (sham, HF, CRT). Animals received left bundle branch (LBB) ablation followed by either 8-week rapid atrial pacing or 4-week rapid atrial pacing and 4-week biventricular pacing. Cardiac function was evaluated by echocardiography. Differentially expressed genes (DEGs) were detected by microarray analysis. General morphological changes, mitochondrial ultrastructure, autophagosomes and mitophagosomes were investigated. The cardiomyocyte stretching was adopted to imitate the mechanical effect of CRT. Cells were divided into three groups (control, angiotensin-II and angiotensin-II + stretching). MCU, DNM1L/Drp1 and autophagy markers were detected by western blots or immunofluorescence. In the present study, CRT could correct cardiac dysfunction, decrease cardiomyocyte's size, alleviate cardiac fibrosis, promote the formation of autophagosome and mitigate mitochondrial injury. CRT significantly influenced gene expression profile, especially down-regulating MCU and up-regulating DNM1L/Drp1. Cell stretching reversed the angiotensin-II induced changes of MCU and DNM1L/Drp1 and partly restored autophagy. CRT's mechanical effects down-regulated MCU, up-regulated DNM1L/Drp1 and subsequently enhanced autophagy. Besides, the mechanical stretching prevented the angiotensin-II-induced cellular enlargement.

"Pacing Bigeminal".

A rapid pacing-induced heart failure model is commonly used in developing dilated cardiomyopathy (DCM). Traditionally, the right ventricular lead was connected with a single chamber pacemaker specific for animals that had a high frequency. However, the pacemaker used in this model is commercially unavailable. We developed a "pacing bigeminal" method using a commercially available dual-chamber (DDD) pacemaker to achieve high-frequency pacing. Twenty beagles were assigned to group A (n = 10) (pacing bigeminal method) and group B (n = 10) (traditional method). Echocardiographic measurements and electrocardiograms were obtained at baseline, at two weeks of pacing, and at 4 weeks of end pacing. LV anterior wall cardiac samples were obtained at 2 weeks of pacing and 4 weeks of end pacing for myocardial microscopic evaluation. Clinical manifestation and exposure time were also observed. After pacing for 10.5 ± 2.3 (714) days, the beagles in group B experienced heart failure, whereas in group A, only 7.9 ± 2.5 (5-12) days (P < 0.05) were needed to reach heart failure. Both methods could induce wide QRS duration, heart rate elevation, and myocardial microscopic changes (P > 0.05). In conclusion, this pacing bigeminal-induced heart failure method is feasible and can induce heart failure faster than the traditional method, which makes it a promising alternative method.

Reappraisal and New Observations on Idiopathic Ventricular Arrhythmias Ablated From the Noncoronary Aortic Sinus.

BACKGROUND: The electrophysiological characteristics of idiopathic ventricular arrhythmias (VAs) from the noncoronary sinus (NCS) have not been fully described. OBJECTIVES: This study sought to investigate electrophysiological characteristics and catheter ablation in patients with idiopathic NCS-VA. METHODS: This study comprised 11 patients undergoing radiofrequency (RF) catheter ablation for idiopathic NCS-VA. Angiography was performed to confirm the origin in the aortic sinus before RF ablation. RESULTS: Clinical arrhythmias presented left bundle block/inferior axis morphology in all patients. QRS morphology of R' and R/s' pattern was dominantly found in lead III. Mapping in the right ventricle demonstrated the earliest ventricular activation (EVA) site at the His Bundle region, whereas mapping in the NCS demonstrated that the EVA preceded the activation at the His Bundle region by 12.1 ± 7.9 milliseconds. All VAs were successfully ablated in <2.5 seconds within the NCS with 1 RF application. The successful ablation site was at the nadir of NCS in 10 patients, and near the junction of NCS and the right coronary sinus in the remaining one. A discrete potential can be observed at the EVA site within the NCS in 10 patients (91%); however, an excellent pace mapping at the EVA site was obtained in only 2 patients. Junctional beats did not occur during RF application in all 11 patients. There were no complications or clinical recurrence during a mean follow-up of 26.0 ± 9.8 months. CONCLUSIONS: NCS-VA presents a peculiar electrocardiogram. A discrete potential can be mapped within the NCS during VA and sinus rhythm, and can be used in guiding ablation.

Inferior Vena Cava as a Trigger for Paroxysmal Atrial Fibrillation: Incidence, Characteristics, and Implications.

BACKGROUND: Identifying nonpulmonary vein triggers during atrial fibrillation (AF) ablation is of great importance. Currently, there are limited data on AF triggered by the inferior vena cava (IVC). OBJECTIVES: This study was performed to investigate the incidence, characteristics, and implications of IVC triggers for AF. METHODS: A total of 661 patients who underwent initial paroxysmal AF ablation were included. After pulmonary vein isolation, ectopic beats that triggered AF were further studied. Activation mapping and angiography were performed to confirm the location of ectopic origin. Electrocardiographic analysis of the ectopic P-wave (P'-wave) was performed. RESULTS: Six patients (0.91%) with AF triggered by the IVC were confirmed. The mean distance from the earliest activation site to the IVC ostium was 6.8 ± 2.5 mm (5.2 to 11.2 mm). Furthermore, the arrhythmogenic foci within the IVC were all located at the apical hemisphere of the IVC (3 at the septal side and 3 at the anterior side). A total of 2.3 ± 0.5 applications of radiofrequency energy were delivered to eliminate IVC triggers. The mean duration of the P' wave was 91.2 ± 11.2 milliseconds (81 to 108 milliseconds), which was narrower than that of the sinus P-wave (115.2 ± 19.3 milliseconds [87 to 139 milliseconds]; P = 0.002). Moreover, the configuration of all P' waves in the inferior leads was negative. During a mean follow-up period of 25.5 ± 7.3 months, all 6 patients remained arrhythmia free without antiarrhythmic drugs. CONCLUSIONS: IVC trigger, a rare but latent source of paroxysmal AF, could be identified and safely eliminated by focal radiofrequency ablation. Ectopic beats originating from the IVC presented with narrow P'-wave duration and negative P' waves in all inferior leads.

Blockade of NaV1.8 Increases the Susceptibility to Ventricular Arrhythmias During Acute Myocardial Infarction.

SCN10A/NaV1.8 may be associated with a lower risk of ventricular fibrillation in the setting of acute myocardial infarction (AMI), but if and by which mechanism NaV1.8 impacts on ventricular electrophysiology is still a matter of debate. The purpose of this study was to elucidate the contribution of NaV1.8 in ganglionated plexi (GP) to ventricular arrhythmias in the AMI model. Twenty beagles were randomized to either the A-803467 group (n = 10) or the control group (n = 10). NaV1.8 blocker (A-803467, 1 µmol/0.5 mL per GP) or DMSO (0.5 mL per GP) was injected into four major GPs. Ventricular effective refractory period, APD90, ventricular fibrillation threshold, and the incidence of ventricular arrhythmias were measured 1 h after left anterior descending coronary artery occlusion. A-803467 significantly shortened ventricular effective refractory period, APD90, and ventricular fibrillation threshold compared to control. In the A-803467 group, the incidence of ventricular arrhythmias was significantly higher compared to control. A-803467 suppressed the slowing of heart rate response to high-frequency electrical stimulation of the anterior right GP, suggesting that A-803467 could inhibit GP activity. SCN10A/NaV1.8 was readily detected in GPs, but was not validated in ventricles by quantitative RT-PCR, western blot and immunohistochemistry. While SCN10A/NaV1.8 is detectible in canine GPs but not in ventricles, blockade of NaV1.8 in GP increases the incidence of ventricular arrhythmias in AMI hearts. Our study shows for the first time an influence of SCN10A/NaV1.8 on the regulation of ventricular arrhythmogenesis via modulating GP activity in the AMI model.

Locally overexpressing hepatocyte growth factor prevents post-ischemic heart failure by inhibition of apoptosis via calcineurin-mediated pathway and angiogenesis.

BACKGROUND: Myocardial infarction is a significant cause of heart failure. Currently, therapies are limited and novel revascularization methods may play a role. We investigated the effects of hepatocyte growth factor (HGF) expressed by bone marrow-derived mesenchymal stem cells (MSCs) on post-ischemic heart failure. METHODS: Four weeks after myocardial infarction (MI), Sprague Dawley rats were randomly divided into saline control group, MSC-GFP group, MSC-HGF group, and MSC-HGF+CsA group. After another 4 weeks, hearts were analyzed for ventricular geometry, myocardial function, angiogenesis and endothelial cell density, apoptosis and the expression of calcineurin, Akt, and Bcl-2 protein. RESULTS: In MSC-HGF group, rats exhibited better LV systolic and diastolic function compared with other groups after 8 weeks of MI. Angiogenesis was significantly enhanced by HGF through inducing proliferation of endothelial cells. The effects of HGF on apoptosis were associated with the expression level of calcineurin protein. CONCLUSIONS: Our findings suggest that overexpression of HGF improved ischemic cardiac function through angiogenesis and reduction of apoptosis partly mediated by upregulation of calcineurin.

Blockade of renin-angiotensin system: a supplementary treatment for circumferential pulmonary vein isolation in treating persistent atrial fibrillation.

The development of atrial fibrillation ablation has revolutionized the field of antiarrhythmic treatment by reducing the recurrence of atrial fibrillation (AF) significantly in patients with paroxysmal atrium fibrillation (PAF). However, the effect of ablation on the patients with persistent atrial fibrillation (PeAF) is not as good as it on PAF. Although doctors have created a series of ablation strategy, they still cannot treat PeAF effectively. This phenomenon is caused by structural remodeling and electrical remodeling of atrium during the long period of AF. Many experimental have demonstrated remodeling of atrium correlated with high level of angiotensin in atrial tissue, and blockade of renin-angiotensin system (RAS) through angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) can reverse atrial remodeling. Clinical studies also confirmed that blockade of RAS can prevent AF effectively. Thus, for the object of treating PeAF effectively, we can combine the circumferential pulmonary vein isolation with blockade of RAS treatment, this combined strategy eliminate the trigger (pulmonary vein potential ) of AF and reverse the atrial remodeling, may be have a good effect on PeAF.

C-reactive protein and atrial fibrillation in idiopathic dilated cardiomyopathy.

BACKGROUND: Previous studies have found elevated plasma C-reactive protein (CRP) levels in atrial fibrillation (AF) patients. Most of these studies included AF patients with various heart diseases, but few studies were designed to investigate CRP in idiopathic dilated cardiomyopathy (IDCM) patients with AF. METHOD AND RESULTS: CRP levels in 242 IDCM patients with AF were compared with CRP levels in 280 control IDCM patients. Among control patients, 70 had atrial premature beats or atrial tachycardia and 210 had normal sinus rhythm. CRP was higher in the AF group than in the control group (median, 4.59 versus 2.81 mg/L; p < 0.001). The prevalence of AF in IDCM patients increased as plasma CRP levels increased, and the patients with the highest plasma CRP levels had the highest probability of suffering from AF. Outcome of multivariate logistic regression analysis showed body mass index, AF, and white blood cell count significantly correlated with the plasma CRP levels. CONCLUSION: Our data demonstrated that the plasma CRP level in IDCM patients with AF was higher than in IDCM patients without AF, and an increase in plasma CRP levels was associated with an increased prevalence of AF in IDCM patients. Also, body mass index, AF, and white blood cell count correlate with plasma CRP levels in IDCM patients. These data suggest there is presence of inflammation in IDCM patients with AF.

Prognostic factors affecting the all-cause death and sudden cardiac death rates of post myocardial infarction patients with low left ventricular ejection fraction.

BACKGROUND: Post myocardial infarction (post-MI) patients with low left ventricular ejection fraction (LVEF) have been candidates for an implantable cardioverter-defibrillator (ICD) since the Multicenter Automatic Defibrillator Implantation Trail II (MADIT II). However, due to the high costs of ICDs, widespread usage has not been accepted. Therefore, further risk stratification for post-MI patients with low LVEF may aid in the selection of patients that will benefit most from ICD treatment. METHODS: Four hundred and seventeen post-MI patients with low LVEF (< or = 35%) were enrolled in the study. All the patients received standard examination and proper treatment and were followed up to observe the all-cause death rate and sudden cardiac death (SCD) rate. Then COX proportional-hazards regression model was used to investigate the clinical factors which affect the all-cause death rate and SCD rate. RESULTS: Of 55 patients who died during (32 +/- 24) months of follow-up, 37 (67%) died suddenly. After adjusting for baseline clinical characteristics, multivariate COX proportional-hazards regression model identified the following variables associated with death from all causes: New York Heart Association (NYHA) heart failure class > or = III (Hazard ratio: 2.361), LVEF < or = 20% (Hazard ratio: 2.514), sustained ventricular tachycardia (Hazard ratio: 6.453), and age > or = 70 years (Hazard ratio: 3.116). The presence of sustained ventricular tachycardia (Hazard ratio: 6.491) and age > or = 70 years (Hazard ratio: 2.694) were specifically associated with SCD. CONCLUSIONS: In the post-MI patients with low LVEF, factors as LVEF < or = 20%, age > or = 70 years, presence of ventricular tachycardia, and NYHA heart failure class > or = III predict an adverse outcome. The presence of sustained ventricular tachycardia and age > or = 70 years was associated with occurrence of SCD in these patients.