The Release of Cyclophilin A from Rapamycin-Stimulated Vascular Smooth Muscle Cells Mediated by Myosin II Activation: Involvement of Apoptosis but Not Autophagy.

INTRODUCTION: The exocytosis of cyclophilin A (CyPA) by a vesicular pathway in response to reactive oxygen species has been determined. However, other sources of extracellular CyPA remain obscure. OBJECTIVE: The aim of this study was to determine the role of autophagy in the secretion of CyPA. METHODS AND RESULTS: Rapamycin induced the activation of autophagy and release of CyPA from primary cultured rat aortic smooth muscle cells (RASMCs). However, inhibition of autophagy by knockdown of Atg7 or chloroquine did not affect the rapamycin-induced release of CyPA. With the exception of myosin II activity, rho-associated coiled-coil kinase (ROCK), actin remodelling, and synaptic vesicles were not implicated in the release of rapamycin-induced CyPA. Finally, we confirmed that rapamycin-induced extracellular CyPA originated from apoptotic RASMCs. Furthermore, the decreased activation of myosin II by blebbistatin blocked the release of CyPA from apoptotic RASMCs induced by rapamycin. CONCLUSIONS: Rapamycin induced the release of CyPA from apoptotic RASMCs but did not affect exocytosis through autophagosomes. ROCK, actin remodelling, and synaptic vesicles were not involved in the apoptosis-related release of CyPA. Myosin II activation modulated the apoptosis of vascular smooth muscle cells and the release of CyPA from rapamycin-induced apoptotic cell death.

Long-term efficacy and safety of statin treatment beyond six years: a meta-analysis of randomized controlled trials with extended follow-up.

Large-scale randomized controlled trials (RCTs) have well demonstrated the beneficial effects of cholesterol-lowering treatment with statins in patients at high risk of vascular disease. However, large statin RCTs were usually restricted to the typical 5-6 years. Moreover, non-cardiovascular events, especially the risk of cancer, probably failed to emerge within a restricted period of 6 years. The aim of this study was to evaluate the long-term efficacy and safety of statin treatment by performing a meta-analysis of statin RCTs with extended follow-up beyond 6 years. Six RCTs with post-trial follow-up were eligible for inclusion, involving 47,296 patients with total follow-up ranging from 6.7 to 14.7 years. During the post-trial period, all the surviving participants were advised to take a statin and the cholesterol level were almost identical between the original statin group and the original placebo group. Over the entire 6.7-14.7 years of follow-up, a significant reduction in the rates of all-cause mortality (relative risk 0.90, 95% confidence interval 0.85-0.96; P=0.0009), cardiovascular mortality (0.87, 0.81-0.93; P<0.0001) and major coronary events (0.79, 0.72-0.86; P<0.00001) was observed in favour of the original statin group. During 2-year post-trial period, further reduction in all-cause mortality (0.83, 0.74-0.93; P=0.001), cardiovascular mortality (0.81, 0.69-0.95; P=0.01) and major coronary events (0.77, 0.63-0.95; P=0.01) was observed among initially statin-treated patients. Over the entire follow-up period, statin treatment did not increase the incidence of cancers (0.99, 0.95-1.04; P=0.79), deaths from cancers (1.00, 0.93-1.07; P=0.98) and non-cardiovascular mortality (0.95, 0.90-1.00; P=0.07). In conclusion, statin treatment beyond 6 years is effective and safe in patients at high risk of vascular events. Moreover, earlier treatment with statin may not only preserve the initial benefit but also have further survival benefit for additional 2 years. Further studies are called for to explore the underlying mechanisms.

Global and regional myocardial function assessment in symptomatic patients with chronic coronary syndrome using longitudinal strain and noninvasive myocardial work.

Speckle tracking echocardiography (STE) derived longitudinal strain (LS) and noninvasive pressure-strain loop (PSL) derived myocardial work (MW) are more sensitive than conventional echocardiographic parameters in quantitative assessment of early myocardial dysfunction. The aim of this study was to assess left ventricular (LV) global and regional myocardial function in symptomatic chronic coronary syndrome (CCS) patients using the two promising methods. Transthoracic echocardiography was performed on patients with angina or equivalent symptoms before coronary angiography. STE-based LS and PSL-based MW analysis were carried out on each patient for global and regional myocardial function assessment. A total of 102 patients were classified into significant and nonsignificant coronary artery stenosis (CAS) groups. Among global myocardial function parameters, LS had the biggest area under the curve (AUC) of 0.735, with cutoff value of 18.4% (sensitivity, 79.6%; specificity, 72.9%), but remained statistically alike with all MW indices in predicting significant CAS (P>0.05 for all). Among regional myocardial function parameters, both LS and MW indices had predictive value for significant left anterior descending artery (LAD) or left circumflex artery (LCX) stenosis, while only myocardial work efficiency (MWE) for right coronary artery (RCA) stenosis. Both global and regional LS and MW have predictive value for significant CAS, but their value of regionalized assessment varies with specific coronary artery involvement.

Left bundle branch pacing on mechanical synchrony and myocardial work in bradycardia patients.

Left bundle branch pacing (LBBP) has emerged as a novel physiological pacing method to produce narrower QRS duration, but whether it could restore mechanical synchrony and improve myocardial work still lacks sufficient evidence. Therefore, the goal of this study was to evaluate mechanical synchrony and myocardial work in LBBP. We collected 20 patients with LBBP due to symptomatic bradycardia and another 29 age-matched patients with right ventricular pacing (RVP). For LBBP patients, cardiac electro-mechanical synchrony and myocardial work were measured at baseline and 7 days after implantation and compared with the RVP patients. In the LBBP group, paced QRS duration and mechanical synchrony were not significantly different from baseline(all P > 0.05), but significantly smaller than that in the RVP group (all P<0.05). Meanwhile, global longitudinal strain (GLS) in LBBP was greater than that in the RVP group (17.7 ± 3.5% vs. 14.8 ± 3.1%, P < 0.05). Global myocardial work index and global constructive work were also better than that in the RVP group(all P<0.05). Global work efficiency was 91.9 ± 3.1%, which was greater when compared with RVP (P < 0.05). LBBP provides better cardiac electro-mechanical synchrony and more effective myocardial work than that in RVP, thus improving global heart function.

3D transesophageal echocardiography assists in evaluating the morphology, function, and presence of thrombi of left atrial appendage in patients with atrial fibrillation.

BACKGROUND: Left atrial appendage (LAA) is significantly more likely to form thrombi in patients with atrial fibrillation (AFib). Two-dimensional transesophageal echocardiography (2D TEE) is considered the gold standard for assessing and studying LAA morphology and anatomy. However, 2D TEE can only visualize one plane at any given time. Real-time three-dimensional echocardiography (RT-3D TEE) imaging can preserve spatial and temporal resolution, which is a safe, accurate, and reproducible imaging modality. There are few reports of the usage of RT-3D TEE to study LAA in AFib patients. In our research, RT-3D TEE helps to provide detailed LAA information and identifying the presence or absence of thrombi from pectinate muscles in paroxysmal and long-standing AFib patients. METHODS: LAA morphology was analyzed in detail by 2D TEE and RT-3D TEE in 320 patients with paroxysmal or long-standing AFib. The LAA flow pattern, as maximal LAA emptying flow velocity (LAAeV), was retrieved from 2D and 3D TEE imaging. LAA morphological parameters, spontaneous echo contrast (SEC), and thrombi were also detected by 2D and 3D TEE in all patients. In addition, LAA lobes and types were classified according to the morphology by 3D TEE, and the relationship between LAA types and the incidence of thrombi was evaluated. RESULTS: Long-standing AFib had greater enlargement of LAAs (orifice diameters and area), significantly more severe SEC, and a higher thrombi clot incidence rate by 3D-TEE compared with paroxysmal AFib patients (P<0.05). In addition, cauliflower morphology in long-standing AFib patients was associated with a higher LAA thrombus (OR 2.1, 95% CI: 1.1-8.5, P=0.031) and increased prevalence of SEC. Moreover, the uncertainty of thrombi detection was significantly decreased by 3D TEE compared with 2D TEE (P<0.001), and the certainty of thrombi detection by 3D TEE also decreased slightly (P=0.06). CONCLUSIONS: RT-3D TEE is a safe and real-time option for the evaluation of LAA morphology and function. Long-standing AFib has greater LAA and SEC, as well as a higher incidence of thrombi than the paroxysmal group. Cauliflower LAA type was associated with a higher prevalence of SEC and thrombi.

Assessment of atrial septal defect using 2D or real-time 3D transesophageal echocardiography and outcomes following transcatheter closure.

BACKGROUND: The assessment of interatrial septum (IAS) requires a standardized, systematic approach, including two-dimensional transthoracic echocardiography (2D TTE), 2D transesophageal echocardiography (2D TEE), and three-dimensional (3D) TEE. Although 2D TEE has been widely used for the preoperative assessment of atrial septal defect (ASD), its ability to provide reliable information is often limited due to the structural characteristics of IAS. The introduction of 3D TEE provides a unique "en face" view of IAS, which allows the visualization and accurate measurements of diameters, area, and rims of ASD. Hence, appropriate ASD imaging information is particularly important in successful transcatheter closure. METHODS: In this retrospective study, 2D TTE/TEE, and 3D TEE were performed before ASD closure, with 2D minimal and maximal diameters, areas, and residual rims being recorded. Adequate 3D TEE imaging data sets were collected and then analyzed. ASD related parameters were compared using different echocardiography. Patients who underwent ASD closure completed a clinical follow-up. RESULTS: The mean defect maximal diameter and aperture area by 3D TEE was significantly larger than that of the corresponding 2D TEE (P<0.05). There was no statistical difference in the minimal and maximal diameter or area by TEE for circular-shaped ASDs. For oval ASDs, mean minimal diameter on 2D TEE was larger than that on 3D TEE. The mean maximal diameter measured using 2D TEE was smaller than the 3D TEE measurement (16.0±7.1 vs. 19.8±8.6; P<0.05). For complex-shaped defects, there were statistical differences in minimal and maximal diameter between TEEs. Furthermore, 2D and 3D TEE had a longer superior vena cava (SVC) residual rim than did 2D TTE (P<0.05). The 3D TEE residual rims of the inferior vena cava (IVC) was significantly larger than the corresponding 2D TEE. There was a very strong correlation between the residual rim measurements using 3D and 2D TEE. However, the limits of agreement between 2D and real-time 3D TEE measurements were more apparent in the IVC rim group than in the other groups. CONCLUSIONS: Our study confirms the value of 3D TEE in assessing ASD shape and size reported by previous studies, and is also the first to accurately and systematically characterize ASD residual rim in complex ASDs.