This study aimed to assess acute and chronic effects of right ventricular mid-septum (RVS) versus right ventricular apex (RVA) pacing on left ventricular (LV) mechanical dyssynchrony using phase analysis of gated single photon emission computed tomography myocardial perfusion imaging (MPI).Thirty-nine patients with complete atrioventricular (AV) block, who were indicated for permanent pacing, were recruited and randomized to receive RVA (n = 20) or RVS (n = 19) pacing. All patients underwent MPI at 1 week and 6 months after pacemaker implantation. LV dyssynchrony and cardiac function were assessed by MPI and compared between the two groups.There were no significant differences in baseline characteristics between the RVS and RVA groups. The paced QRS duration was significantly longer in the RVA group than in the RVS group. LV dyssynchrony parameters were not significantly different between the groups at the 1-week follow-up, but they were significantly smaller in the RVS group than in the RVA group at the 6-month follow-up. LV dyssynchrony parameters significantly decreased in the RVS group from the 1-week follow-up to the 6-month follow-up, but were unchanged in the RVA group. No differences in LV function parameters were observed between the groups at the 1-week and 6-month follow-ups.RVS pacing produces better electrical and mechanical synchrony than RVA pacing for patients with complete AV block.

Abnormal proliferation of vascular smooth muscle cells (VSMCs) is an important factor during the progression of atherosclerosis. In this study, we investigated the effects of resveratrol on atherosclerosis-associated proliferation of VSMCs. We utilized an oxidized phospholipid, 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphorylcholine (POVPC) to induce abnormal proliferation of VSMCs. Our results showed the treatments with resveratrol dose-dependently abolished POVPC-induced VSMC proliferation, as evidenced by the decreased [3H]thymidine incorporated into VSMCs and reduced percentage of 5-ethynyl-2′-deoxyuridine (EdU)-positive VSMCs. Cell cycle analysis demonstrated that resveratrol inhibited POVPC-induced increase in the S phase cell population and DNA synthesis. Our study further indicated that POVPC-induced VSMC proliferation was associated with a significant increase in the phosphorylation of Cx43, which was a consequence of activation of MAPK signaling. Interestingly, treatment with resveratrol abolished POVPC-induced phosphorylation of Cx43 as a result of inhibiting activation of Src, MEK, and ERK1/2. Our results provided a novel mechanism by which resveratrol may contribute to cardiovascular protection.

Cadherin-mediated adherens junctions is impaired concomitant with a decrease in connexin 43 (Cx43) in diseases or pathological processes. We have investigated the acute effects of adherens junction impairment in isolated rat hearts by introducing Ala-His-Ala-Val-Asp-NH2 (AHAVD, a synthetic peptide) as a specific inhibitor of N-cadherin. Effect of AHAVD on N-cadherin mediated adhension was analyzed by Cardiomy-ocyte aggregation assay. Laser confocal microscopy showed disrupted cell-cell contacts in cultured neonatal cardiomyocytes co-incubated with 0.2 mM AHAVD. In isolated adult rat hearts, Cx43 was redistributed along the bilateral of cardiomyocytes from the intercalated discs and significant dephosphorylation of Cx43 on serine368 occurred concomitantly with decreased gap junction (GJ) function in dose dependent manner after 1 h perfusion with AHAVD. These results indicate that impairing cad-herin-mediated adhesion by AHAVD rapidly results in Cx43 redistribution and dephosphorylation of serine368, thereby impairing GJ communication function.

Our previous studies showed that resveratrol could inhibit the proliferation of vascular smooth muscle cells (VSMCs) and repress mRNA and protein expression of quinone reductase 2 (NQO2). This study further explored the potential mechanisms whereby resveratrol inhibits the proliferation of rat VSMCs. Lentiviral vectors that incorporated NQO2 small interfering RNA (siRNA) were constructed and transduced into rat VSMCs. The cell proliferation was detected using the bromodeoxyuridine (BrdU) assay. Cultured rat VSMCs were stimulated with angiotensin II and the level of reactive oxygen species (ROS) was measured using a ROS assay kit. A real-time quantitative PCR was used to detect NQO2 mRNA levels. Extracellular signal-regulated kinase (ERK1/2) and NQO2 protein expression were determined by Western blotting analysis. The inhibitory effect of resveratrol (10 and 50 μmol/L) on the proliferation of rat VSMCs in the NQO2 siRNA group was significantly weaker than that in the normal and scrambled siRNA group (P < 0.01). The ROS level in the NQO2 siRNA and resveratrol (50 μmol/L) treatment groups were lower than that in the normal and scrambled siRNA groups (P < 0.01 in both). Compared with the normal and scrambled siRNA group, the phosphorylation of ERK1/2 was significantly decreased in the NQO2 siRNA and resveratrol (50 μmol/L) treatment group (P < 0.01 in both). In conclusion, high concentration of resveratrol inhibits angiotensin II-induced ERK1/2 phosphorylation and subsequent proliferation by down-regulation of NQO2 in cultured rat VSMCs.

ObjectiveTo evaluate the arrhythmogenic effects of dismantling cadherin-mediated adhesion by recombinant mouse aminopeptidase N (rmAPN) in murine hearts.MethodsrmAPN was incubated with cultured neonatal rat cardiomyocytes as well as being infused in adult mice. The cell-cell connections were immunolabelled and observed by laser confocal microscopy. Disruption of the N-terminal of N-cadherin (N-cad) was detected by western blot and quantitative immunofluorescence. The risk of inducible ventricular tachyarrhythmia was evaluated in mice by an electrophysiological study.ResultsDisrupted cell-cell contact was observed in cultured neonatal rat cardiomyocytes in response to 30-40 ng/μL rmAPN. Loss of the N-terminal in N-cad and altered distribution of connexin 43 (Cx43) were observed in hearts from rmAPN-infused mice. In addition, a reduction of phosphorylated Cx43 was also detected concomitant with redistribution of Cx43. Electrophysiological studies of rmAPN-infused mice showed prolonged QRS duration and increased inducibility of ventricular tachycardias.ConclusionDisruption of N-cad by rmAPN contributes to gap junction remodeling and may elicit arrhythmogenic effects. The disorder of adherent junctions by proteolytic enzymes may play an important role in arrhythmogenic mechanisms in correlated diseases.

ObjectivesThe aim of this study was to develop a 3-dimensional (3D) fusion tool kit to integrate left ventricular (LV) venous anatomy on fluoroscopy venograms with LV epicardial surface on single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) for guiding cardiac resynchronization therapy (CRT) LV lead placement.BackgroundLV lead position is important for CRT response. For LV lead placement into viable regions with late activation, it is important to visualize both LV venous anatomy and myocardium.MethodsMajor LV veins were manually identified on fluoroscopic venograms and automatically reconstructed into a 3D anatomy. 3D LV epicardial surface was extracted from SPECT MPI. SPECT-vein fusion that consisted of geometric alignment, landmark-based registration, and vessel-surface overlay was developed to fuse the 3D venous anatomy with the epicardial surface. The accuracy of this tool was evaluated using computed tomography (CT) venograms. LV epicardial surfaces and veins were manually identified on the CT images and registered with the SPECT image by an independent operator. The locations of the fluoroscopic and CT veins on the SPECT epicardial surfaces were compared using absolute distances on SPECT short-axis slice and the 17-segment model.ResultsTen CRT patients were enrolled. The distance between the corresponding fluoroscopic and CT veins on the short-axis epicardial surfaces was 4.6 ± 3.6 mm (range 0 to 16.9 mm). The presence of the corresponding fluoroscopic and CT veins in the 17-segment model agreed well with a kappa value of 0.87 (95% confidence interval: 0.82 to 0.93). The tool kit was used to guide LV lead placement in a catheter laboratory and showed clinical feasibility and benefit to the patient.ConclusionsA tool kit has been developed to reconstruct 3D LV venous anatomy from dual-view fluoroscopic venograms and to fuse it with LV epicardial surface on SPECT MPI. It is technically accurate for guiding LV lead placement by the 17-segment model and is feasible for clinical use in the catheterization laboratory.