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.

An electrographic AV optimization for the maximum integrative atrioventricular and ventricular resynchronization in CRT.

BACKGROUND: Atrioventricular (AV) delay could affect AV and ventricular synchrony in cardiac resynchronization therapy (CRT). Strategies to optimize AV delay according to optimal AV synchrony (AVopt-AV) or ventricular synchrony (AVopt-V) would potentially be discordant. This study aimed to explore a new AV delay optimization algorithm guided by electrograms to obtain the maximum integrative effects of AV and ventricular resynchronization (opt-AV). METHODS: Forty-nine patients with CRT were enrolled. AVopt-AV was measured through the Ritter method. AVopt-V was obtained by yielding the narrowest QRS. The opt-AV was considered to be AVopt-AV or AVopt-V when their difference was < 20 ms, and to be the AV delay with the maximal aortic velocity-time integral between AVopt-AV and AVopt-V when their difference was > 20 ms. RESULTS: The results showed that sensing/pacing AVopt-AV (SAVopt-AV/PAVopt-AV) were correlated with atrial activation time (Pend-As/Pend-Ap) (P < 0.05). Sensing/pacing AVopt-V (SAVopt-V/PAVopt-V) was correlated with the intrinsic AV conduction time (As-Vs/Ap-Vs) (P < 0.01). The percentages of patients with more than 20 ms differences between SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V were 62.9% and 57.1%, respectively. Among them, opt-AV was linearly correlated with SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V. The sensing opt-AV (opt-SAV) = 0.1 × SAVopt-AV + 0.4 × SAVopt-V + 70 ms (R2 = 0.665, P < 0.01) and the pacing opt-AV (opt-PAV) = 0.25 × PAVopt-AV + 0.5 × PAVopt-V + 30 ms (R2 = 0.560, P < 0.01). CONCLUSION: The SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V were correlated with the atrial activation time and the intrinsic AV conduction interval respectively. Almost half of the patients had a > 20 ms difference between SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V. The opt-AV could be estimated based on electrogram parameters.

Effect of C reactive protein on the sodium-calcium exchanger 1 in cardiomyocytes.

Numerous previous studies have found that C-reactive protein (CRP) is associated with cardiac arrhythmia and cardiac remodeling. However, the underlying mechanisms of this association remain unclear. Sodium-calcium exchanger 1 (NCX1) serves an important role in the regulation of intracellular calcium concentration, which is closely related with cardiac arrhythmia and cardiac remodeling. The present study aimed to evaluate the effects of CRP on NCX1 and intracellular calcium concentration in cardiomyocytes. Primary neonatal mouse ventricular cardiomyocytes were cultured and treated with varying concentrations of CRP (0, 5, 10, 20 and 40 µg/ml). The cardiomyocytes were also treated with NF-κB-specific inhibitor PTDC and a specific inhibitor of the reverse NCX1 KB-R7943 before their intracellular calcium concentrations were measured. mRNA and protein expression levels of NCX1 were detected by reverse transcription-quantitative PCR and western blotting, respectively and intracellular calcium concentration was evaluated by flow cytometry. CRP treatment significantly increased mRNA and protein expression levels of NCX1 in myocytes (P=0.024), as well as intracellular calcium concentration (P=0.01). These results were significantly attenuated by the NF-κB-specific inhibitor PDTC and a specific inhibitor of the reverse NCX1, KB-R7943. CRP significantly upregulated NCX1 expression and increased intracellular calcium concentration in cardiomyocytes via the NF-κB pathway, suggesting that CRP may serve a pro-arrhythmia role via direct influence on the calcium homeostasis of cardiomyocytes.

LncRNA H19 governs mitophagy and restores mitochondrial respiration in the heart through Pink1/Parkin signaling during obesity.

Maintaining proper mitochondrial respiratory function is crucial for alleviating cardiac metabolic disorders during obesity, and mitophagy is critically involved in this process. Long non-coding RNA H19 (H19) is crucial for metabolic regulation, but its roles in cardiac disorders, mitochondrial respiratory function, and mitophagy during obesity are largely unknown. In this study, palmitic acid (PA)-treated H9c2 cell and Lep-/- mice were used to investigate cardiac metabolic disorders in vitro and in vivo, respectively. The effects of H19 on metabolic disorders, mitochondrial respiratory function, and mitophagy were investigated. Moreover, the regulatory mechanisms of PA, H19, mitophagy, and respiratory function were examined. The models tested displayed a reduction in H19 expression, respiratory function and mitochondrial number and volume, while the expression of mitophagy- and Pink1/Parkin signaling-related proteins was upregulated, as indicated using quantitative real-time PCR, Seahorse mitochondrial stress test analyzer, transmission electron microscopy, fluorescence indicators and western blotting. Forced expression of H19 helped to the recoveries of respiratory capacity and mitochondrial number while inhibited the levels of mitophagy- and Pink1/Parkin signaling-related proteins. Pink1 knockdown also attenuated PA-induced mitophagy and increased respiratory capacity. Mechanistically, RNA pull-down, mass spectrometry, and RNA-binding protein immunoprecipitation assays showed that H19 could hinder the binding of eukaryotic translation initiation factor 4A, isoform 2 (eIF4A2) with Pink1 mRNA, thus inhibiting the translation of Pink1 and attenuation of mitophagy. PA significantly increased the methylation levels of the H19 promoter region by upregulation Dnmt3b methylase levels, thereby inhibiting H19 transcription. Collectively, these findings suggest that DNA methylation-mediated the downregulation of H19 expression plays a crucial role in cardiomyocyte or H9c2 cells metabolic disorders and induces cardiac respiratory dysfunction by promoting mitophagy. H19 inhibits excessive mitophagy by limiting Pink1 mRNA translation, thus alleviating this cardiac defect that occurs during obesity.

Non-coding RNAs modulate autophagy in myocardial ischemia-reperfusion injury: a systematic review.

The myocardial infarction is the main cause of morbidity and mortality in cardiovascular diseases around the world. Although the timely and complete reperfusion via Percutaneous Coronary Intervention (PCI) or thrombolysis have distinctly decreased the mortality of myocardial infarction, reperfusion itself may lead to supererogatory irreversible myocardial injury and heart function disorders, namely ischemia-reperfusion (I/R) injury. Extensive studies have indicated that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), play important roles in the progress of myocardial I/R injury, which is closely correlative with cardiomyocytes autophagy. Moreover, autophagy plays an important role in maintaining homeostasis and protecting cells in the myocardial ischemia reperfusion and cardiomyocyte hypoxia-reoxygenation (H/R) progress. In this review, we first introduced the biogenesis and functions of ncRNAs, and subsequently summarized the roles and relevant molecular mechanisms of ncRNAs regulating autophagy in myocardial I/R injury. We hope that this review in addition to develop a better understanding of the physiological and pathological roles of ncRNAs, can also lay a foundation for the therapies of myocardial I/R injury, and even for other related cardiovascular diseases.

Minimum heart rate and mortality in critically ill myocardial infarction patients: an analysis of the MIMIC-III database.

BACKGROUND: Low minimum heart rate (MHR) is common in critically ill myocardial infarction (MI) patients. However, the association between MHR and the mortality of critically ill MI patients remains unclear. METHODS: In this retrospective cohort study, a total of 2,031 critically ill MI patients were enrolled from the Medical Information Mart for Intensive Care (MIMIC)-III database. Patients were divided into a low MHR group [MHR <60 beats per minute (bpm)] and a high MHR group (MHR ≥60 bpm). A Cox proportional hazard model was used to elucidate the association between these two groups and the mortality of MI patients. The association between mortality and MHR as a continuous variable was analyzed non-parametrically using restricted cubic splines. Sensitivity analyses were conducted to determine the impact of different admission heart rate, hypertension, atrial fibrillation, and vasopressor use on our results. RESULTS: MI patients in the low MHR group had higher 30-day and 1-year mortality than those in the high MHR group (20.59% vs. 10.91%, P<0.001 and 29.76% vs. 19.31%, P<0.001, respectively). After adjustment, the low MHR group was significantly correlated with 30-day mortality [hazard ratio, 1.779, 95% confidence interval (CI), 1.400-2.261, P<0.001] and 1-year mortality (hazard ratio, 1.537, 95% CI, 1.272-1.859, P<0.001). This correlation remained remarkable in patients with low or high admission heart rate, with or without hypertension, and with or without atrial fibrillation. An apparent L-curve relationship was observed between the 30-day mortality or 1-year mortality and MHR as a continuous variable. CONCLUSIONS: MHR under 60 bpm may be associated with a higher risk for both 30-day and 1-year mortality in critically ill MI patients. These findings highlight the possibility of MHR as an early risk indicator and potential therapeutic target for mortality in critically ill MI patients, which warrants further investigation.

Long non-coding RNA Linc00092 inhibits cardiac fibroblast activation by altering glycolysis in an ERK-dependent manner.

AIMS: Cardiac fibroblast (CF) activation is the key event for cardiac fibrosis. The role of glycolysis and the glycolysis-related lncRNAs in CF activation are unknown. Thus, we aimed to investigate the role of glycolysis in CF activation and to identify the glycolysis-related lncRNAs involved. MAIN METHODS: Glycolysis-related lncRNAs were searched and their expression profiles were validated in activated human CF (HCF) and human failing heart tissues. Expression of the target lncRNA was manipulated to determine its effects on HCF activation and glycolysis. The underlying mechanisms of lncRNA-dependent glycolysis regulation were also addressed. KEY FINDINGS: HCF activation induced by transforming growth factor-ß1 was accompanied by an enhanced glycolysis, and 2-Deoxy-d-glucose, a specific glycolysis inhibitor, dramatically attenuated HCF activation. Twenty-eight glycolysis-related lncRNAs were identified and Linc00092 expression was changed mostly upon HCF activation. In human heart tissue, Linc00092 is primarily expressed in cardiac fibroblasts. Linc00092 knockdown activated HCFs with enhanced glycolysis, while its overexpression rescued the activated phenotype of HCFs and down-regulated glycolysis. Restoration of glycolysis abolished the anti-fibrotic effects conferred by Linc00092. Linc00092 inhibited ERK activation in activated HCFs, and ERK inhibition counteracted the fibrotic phenotype in Linc00092 knockdown HCFs. SIGNIFICANCE: These results revealed that Linc00092 could attenuate HCF activation by suppressing glycolysis. The inhibition of ERK by Linc00092 may play an important role in this process. Together, this provides a better understanding of the mechanism of CF activation and may serve as a novel target for cardiac fibrosis treatment.

Construction and Analysis of a ceRNA Network in Cardiac Fibroblast During Fibrosis Based on in vivo and in vitro Data.

AIMS: Activation of cardiac fibroblasts (CF) is crucial to cardiac fibrosis. We constructed a cardiac fibroblast-related competing endogenous RNA (ceRNA) network. Potential functions related to fibrosis of "hub genes" in this ceRNA network were explored. MATERIALS AND METHODS: The Gene Expression Omnibus database was searched for eligible datasets. Differentially expressed messenger (m)RNA (DE-mRNA) and long non-coding (lnc)RNA (DE-lncRNA) were identified. microRNA was predicted and validated. A predicted ceRNA network was constructed and visualized by Cytoscape, and ceRNA crosstalk was validated. A Single Gene Set Enrichment Analysis (SGSEA) was done, and the Comparative Toxicogenomics Database (CTD) was employed to analyze the most closely associated pathways and diseases of DE-mRNA in the ceRNA network. The functions of DE-mRNA and DE-lncRNA in the ceRNA network were validated by small interfering (si)RNA depletion. RESULTS: The GSE97358 and GSE116250 datasets (which described differentially expressed genes in human cardiac fibroblasts and failing ventricles, respectively) were used for analyses. Four-hundred-and-twenty DE-mRNA and 39 DE-lncRNA, and 369 DE-mRNA and 93 DE-lncRNA were identified, respectively, in the GSE97358 and GSE116250 datasets. Most of the genes were related to signal transduction, cytokine activity, and cell proliferation. Thirteen DE-mRNA with the same expression tendency were overlapped in the two datasets. Twenty-three candidate microRNAs were predicted and the expression of 11 were different. Only two DE-lncRNA were paired to any one of 11 microRNA. Finally, two mRNA [ADAM metallopeptidase domain 19, (ADAM19) and transforming growth factor beta induced, (TGFBI)], three microRNA (miR-9-5p, miR-124-3p, and miR-153-3p) and two lncRNA (LINC00511 and SNHG15) constituted our ceRNA network. siRNA against LINC00511 increased miR-124-3p and miR-9-5p expression, and decreased ADAM19 and TGFBI expression, whereas siRNA against SNHG15 increased miR-153-3p and decreased ADAM19 expression. ADAM19 and TGFBI were closely related to the TGF-ß1 pathway and cardiac fibrosis, as shown by SGSEA and CTD, respectively. Depletion of two mRNA or two lncRNA could alleviate CF activation. CONCLUSIONS: The CF-specific ceRNA network, including two lncRNA, three miRNA, and two mRNA, played a crucial role during cardiac fibrosis, which provided potential target genes in this field.

The atheroprotective role of lipoxin A4 prevents oxLDL-induced apoptotic signaling in macrophages via JNK pathway.

BACKGROUND AND AIMS: We examined whether the inflammation resolution mediator lipoxin A4 (LXA4) inhibits foam cell formation and oxidized low-density lipoprotein (oxLDL)-induced apoptotic signaling in macrophages and the role of circulating/local LXA4 biosynthesis in atherogenesis. METHODS: LXA4 levels were measured by enzyme-linked immunosorbent assay. Dil-oxLDL and Dil-acLDL binding to and uptake by macrophages were evaluated by flow cytometry. Apoptosis was evaluated by TUNEL and Annexin V/PI assays. RESULTS: Circulating LXA4 levels in patients with coronary artery disease were much higher than those in respective controls. Local LXA4 levels were much lower in rabbit atherosclerotic vessel walls. Interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) were elevated in atherosclerotic vessels. After the inflammatory stimulus (IFN-γ, TNF-α, and C-reactive protein), LXA4 synthesis decreased significantly in foam cells. LXA4 dose-dependently suppressed the expression of the cholesterol uptake genes CD36 and SR-A in macrophages, which was blocked by the LXA4 receptor antagonist BOC-2. LXA4 also inhibited oxLDL-induced CD36 upregulation, Dil-oxLDL uptake, and foam cell formation. Furthermore, LXA4 inhibited the oxLDL-activated c-Jun N-terminal kinase pathway and reduced oxLDL-induced macrophage apoptosis by inhibiting caspase-3 activation and restoring the mitochondrial membrane potential. CONCLUSIONS: We found that LXA4 inhibited foam cell formation, oxLDL-induced inflammation, and apoptotic signaling in macrophages. Insufficient levels of the anti-inflammatory pro-resolution molecule LXA4 were found in rabbit atherosclerotic arteries, which might contribute to preventing inflammation resolution during atherogenesis.

Distinct Anti-Fibrotic Effects of Exosomes Derived from Endothelial Colony-Forming Cells Cultured Under Normoxia and Hypoxia.

BACKGROUND The therapeutic potential of endothelial colony-forming cells (ECFCs) may be impaired in an ischemic environment. Direct injection of ECFCs is not an effective method of rescuing the ischemic heart, but exosomes derived from these cells may be a promising therapeutic tool. However, exosomes produced under normoxia and hypoxia may not be identical. Therefore, the purpose of this study was to investigate alterations in the anti-fibrotic effects of hypoxia-treated ECFC-derived exosomes and the underlying mechanism involved. MATERIAL AND METHODS ECFCs were isolated from peripheral blood and exosomes were collected from ECFCs treated with normoxia (nor-exo) or hypoxia (hyp-exo). Effects of exosomes on cardiac fibroblast activation were evaluated in vitro. MicroRNAs (miRNAs) inside the exosomes were extracted and compared using next-generation RNA sequencing. Predicted target mRNAs of miR-10b-5p were validated using a dual-luciferase reporter gene assay method. RESULTS Nor-exo significantly ameliorated cardiac fibroblast activation in vitro. These effects were attenuated in the hyp-exo-treated group. miR-10b-5p was enriched in nor-exo but not in hyp-exo. Dual-luciferase reporter gene assay found that both SMAD-specific E3 ubiquitin protein ligase 1 (Smurf1) and histone deacetylase 4 (HDAC4) mRNAs were inhibited by miR-10b-5p. The expression of neutral sphingomyelinase 2 (N-SMase2) was decreased in hypoxia ECFCs, and this result was consistent with the changes in miR-10b-5p in hyp-exo. CONCLUSIONS Due to a reduction of miR-10b-5p, which targets the fibrotic genes Smurf1 and HDAC4, the anti-fibrotic effects of hyp-exo were abolished.

Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4.

Recently, endothelial-mesenchymal transition (EndMT) has been demonstrated to play an important role in the development of atherosclerosis, the molecular mechanisms of which remain unclear. In the present study, scanning electron microscopy directly revealed a widened endothelial space and immunohistofluorescence demonstrated that EndMT was increased in human aorta atherosclerotic plaques. M1 macrophage-derived foam cell (M1-FC) supernatants, but not M2 macrophage-derived foam cell (M2-FC) supernatants, induced EndMT. A protein array and enzyme-linked immunosorbent assay identified that the levels of several cytokines, including C-C motif chemokine ligand 4 (CCL-4) were increased in M1-FC supernatants, in which EndMT was promoted, accompanied by increased endothelial permeability and monocyte adhesion. Furthermore, anti-CCL-4 antibody abolished the effects of M1-FC supernatants on EndMT. At the same time, CCL-4 activated its receptor, C-C motif chemokine receptor-5 (CCR-5), and upregulated transforming growth factor-ß (TGF-ß) expression. Further experiments revealed that EndMT induced by CCL-4 was reversed by treatment with CCR-5 antagonist and the RNA-mediated knockdown of TGF-ß. On the whole, the data of the present study suggest that M1-FCs induce EndMT by upregulating CCL-4, and increase endothelial permeability and monocyte adhesion. These data may help to elucidate the important role of EndMT in the development of atherosclerosis.

Clinical effectiveness of telemedicine for chronic heart failure: a systematic review and meta-analysis.

Telemedicine interventions may be associated with reductions in hospital admission rate and mortality in patients with heart failure (HF). The present study is an updated analysis (as of June 30, 2016) of randomized controlled trials, where patients with HF underwent telemedicine care or the usual standard care. Data were extracted from 39 eligible studies for all-cause and HF-related hospital admission rate, length of stay, and mortality. The overall all-cause mortality (pooled OR=0.80, 95% CI 0.71 to 0.91, p<0.001), HF-related admission rate (pooled OR=0.63, 95% CI 0.53 to 0.76, p<0.001), and HF-related length of stay (pooled standardized difference in means=-0.37, 95% CI -0.72 to -0.02, p=0.041) were significantly lower in the telemedicine group (teletransmission and telephone-supported care), as compared with the control group. In subgroup analysis, all-cause mortality (pooled OR=0.69, 95% CI 0.56 to 0.86, p=0.001), HF-related admission rate (OR=0.61, 95% CI 0.42 to 0.88, p=0.008), HF-related length of stay (pooled standardized difference in means=-0.96, 95% CI -1.88 to -0.05, p=0.039) and HF-related mortality (OR=0.68, 95% CI 0.54 to 0.85, p=0.001) were significantly lower in the teletransmission group, as opposed to the standard care group, whereas only HF-related admission rate (OR=0.64, 95% CI 0.52 to 0.79, p<0.001) was lower in the telephone-supported care group. Overall, telemedicine was shown to be beneficial, with home-based teletransmission effectively reducing all-cause mortality and HF-related hospital admission, length of stay and mortality in patients with HF.

Acute Effects of Multisite Biventricular Pacing on Dyssynchrony and Hemodynamics in Canines With Heart Failure.

BACKGROUND: Multisite biventricular pacing (MSP) has been proposed as an alternative strategy to improve the efficiency of conventional biventricular pacing (BVP), but its utility remains unclear. This study sought to investigate whether MSP induced better synchrony and hemodynamic effects in canines with heart failure. METHODS AND RESULTS: After 3 weeks' rapid right ventricular pacing, 7 canines were sutured with 4 left ventricular (LV) leads on the anterior, lateral, posterior, and apical walls and followed by MSP and BVP. Hemodynamic, electrocardiographic, and echocardiographic parameters were measured. Dyssynchrony was assessed by tissue Doppler imaging for Yu-index (longitudinal direction) and speckle tracking imaging for the standard deviation of time to peak radial strains (SDε, radial direction). Compared with BVP, mean MSP reduced QRS width (P < .05), Yu-index (25.3 ± 1.9 ms vs 31.6 ± 4.3 ms, P = .008), SDε (32.8 ± 5.9 ms vs 37.3 ± 7.9 ms, P = .032), and LV end-diastolic pressure (P < .05). The optimal pacing site combination improved QRS width, Yu-index, SDε, LV end-diastolic pressure, and the maximum derivative of LV pressure (dP/dtmax) significantly (all P < .05), but the worst MSP (with the smallest dP/dtmax) did not show any improvement to BVP. CONCLUSIONS: MSP is superior to BVP in reducing dyssynchrony and improving hemodynamics. The pacing site combination has a potential effect on MSP response.

Hydrogen sulfide suppresses endoplasmic reticulum stress-induced endothelial-to-mesenchymal transition through Src pathway.

AIMS: Hydrogen sulfide (H2S) ameliorates cardiac fibrosis in several models by suppressing endoplasmic reticulum (ER) stress. Endothelial-to-mesenchymal transition (EndMT) is implicated in the development of cardiac fibrosis. Therefore, we investigated whether H2S could attenuate EndMT by suppressing ER stress. MAIN METHODS: ER stress was induced by tunicamycin (TM) and thapsigargin (TG) and inhibited by 4-phenylbutyrate (4-PBA) in human umbilical vein endothelial cells (HUVECs). ER stress and EndMT were measured by Western blot, Real-Time PCR and immunofluorescence staining. Inhibition Smad2 and Src pathway were performed by specific inhibitors and siRNA. Ultrastructural examination was detected by transmission electron microscope. The functions of HUVECs were investigated by cell migration assay and tube formation in vitro. KEY FINDINGS: Under ER stress, the expression of endothelial marker CD31 significantly decreased while mesenchymal markers α-SMA, vimentin and collagen 1 increased which could be inhibited by 4-PBA. Moreover, HUVECs changed into a fibroblast-like appearance with the activation of Smad2 and Src kinase pathway. After inhibiting Src pathway, EndMT would be significantly inhibited. TM reduced H2S levels in cell lysate and H2S pretreatment could preserve endothelial cell appearance with decreased ER stress and ameliorated dilation of ER. H2S could also downregulate the mesenchymal marker expression, and upregulate the endothelial markers expression, accompanied with the suppression of Src pathway. Moreover, H2S partially restored the capacity of migration and tube formation in HUVECs. SIGNIFICANCE: These results revealed that H2S could protect against ER stress-induced EndMT through Src pathway, which may be a novel role for the cardioprotection of H2S.

Tachycardia pacing induces myocardial neovascularization and mobilizes circulating endothelial progenitor cells partly via SDF-1 pathway in canines.

Neovascularization plays pivotal role in ischemic heart failure; however, it is unclear in non-ischemic heart failure. Non-ischemic heart failure was induced by chronic rapid right ventricular pacing at 200 beats/min, respectively, for 3 and 6 weeks in 12 dogs. Sham-operation was performed in another 6 dogs as control. Three-week tachycardia pacing could induce mild/moderate heart failure and 6-week pacing could induce severe heart failure. Pan-microvessel density (MVD) was assessed by CD31 and neovascularization density was assessed by CD105. Mean CD31-MVD and CD105-MVD were significantly increased after 3-week pacing. However, CD105-MVD was significantly decreased by 80 % in 6-week pacing group compared with 3-week pacing group, whereas CD31-MVD was only decreased slightly (15 %; P < 0.05). Myocardial proangiogenic factor stromal cell-derived factor 1 (SDF-1), hypoxia-inducible factors 1α (HIF-1α, a transcription factor which could regulate SDF-1 expression), serum SDF-1 levels and circulating EPC mobilization were greatly elevated after 3-week pacing but nearly returned to baseline level after 6-week pacing, which were in accordance with the changes of neovascularization levels assessed by CD105. Angiogenesis and migrating ability of EPCs were enhanced after stimulation of SDF-1, which could be abolished by pretreatment with SDF-1 receptor antagonist AMD3100. In addition, angiogenesis and migrating functions of EPCs were significantly enhanced by the serum from 3-week pacing dogs, but had much weaker response to the serum from 6-week pacing dogs. In conclusion, tachycardia pacing-induced non-ischemic heart failure, promoted myocardial neovascularization and mobilized circulating EPCs, which might be mediated partly through SDF-1 pathway.

Effects of C-reactive protein on K(+) channel interaction protein 2 in cardiomyocytes.

Several studies have found that C-reactive protein (CRP) was associated with QTc interval prolongation and ventricular arrhythmia. However, little is known about the mechanisms involved. K(+) channel interaction protein 2 (KChIP2) is a necessary subunit for the formation of transient outward potassium current (Ito.f) which plays a critical role in early repolarization and QTc interval of heart. In this study, we aimed to evaluate the effects of CRP on KChIP2 and Ito.f in cardiomyocytes and to explore the potential mechanism. The neonatal mice ventricular cardiomyocytes were cultured and treated with CRP at different concentrations. The expression of KChIP2 was detected by real time quantitative PCR and Western blot. In addition, Ito.f current density was evaluated by whole cell patch clamp techniques. Our results showed that CRP significantly decreased the mRNA and protein expression of KChIP2 in time and doses dependent manners (P < 0.05), and also reduced the current density of Ito.f (P < 0.05). In addition, CRP increased the expression of NF-κB and decreased IκBα expression without significant influence on the expression of ERK1/2 and JNK. Meanwhile, the NF-κB inhibitor PDTC significantly attenuated the effects of CRP on KChIP2 and Ito.f current density. In conclusion, CRP could significantly down-regulate KChIP2 expression and reduce current density of Ito.f partly through NF-κB pathway, suggesting that CRP may directly or indirectly influence QTc interval and arrhythmia via influencing KChIP2 expression and Ito.f current density of cardiomyocytes.

Effects of cardiac resynchronization therapy on left ventricular remodeling and dyssynchrony in patients with left ventricular noncompaction and heart failure.

Left ventricular noncompaction (LVNC) is a rare cardiomyopathy with high incidence of heart failure (HF). It is unclear whether LVNC patients with desynchronized HF would benefit from cardiac resynchronization therapy (CRT). In order to evaluate the effect of CRT on LVNC, this study explored left ventricular (LV) remodeling and mechanical synchronicity before and after CRT in LVNC patients, and compare with that in idiopathic dilated cardiomyopathy (DCM) patients. We collected 15 LVNC and 30 matched DCM patients. All the patients underwent clinical evaluation,electrocardiogram and echocardiography before CRT and ≥6 months later. LV response was defined as ≥15 % decrease in LV end-systolic volume (LVESV). Longitudinal synchronicity was quantified by YU-index using tissue Doppler imaging. The time delay of peak radial strain from anteroseptal to posterior wall, which derived from speckle tracking imaging, was used to quantify radial synchronicity. In LVNC group, LV ejection fraction increased from 27.6 ± 5.5 to 39.1 ± 7.0 % (P < 0.01) during follow-up, but LV volumes did not change significantly (both P > 0.05). Five LVNC patients (33.3 %) responded to CRT, and all of them were super-responders (reduction in LVESV > 30 %). In addition, the number of noncompacted segments and the thickness ratio of noncompacted to compacted myocardium decreased (both P < 0.05). Inter-ventricular, longitudinal and radial intra-ventricular dyssynchrony also reduced significantly (all P < 0.05). Compared with DCM group, there was no significant difference in LV response rate (33.3 vs. 60.0 %, P = 0.092), improvement of LV function and dyssynchrony index (all P < 0.05). In conclusion, CRT improved heart function, morphology and mechanical dyssynchrony in LVNC patients.

Dyssynchronous pacing triggers endothelial-mesenchymal transition through heterogeneity of mechanical stretch in a canine model.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) plays a pivotal role in cardiac fibrosis. However, it is unclear whether EndMT is involved in dyssynchronous heart failure (DHF). METHODS AND RESULTS: Twelve dogs received 3-week rapid right ventricular pacing (RVP) to develop DHF and then were randomly divided into a RVP group (n=6; RVP for another 3 weeks) and a biventricular pacing (BiVP) group (n=6; BiVP for 3 weeks), and another 6 dogs were in the control group. Contractile function in BiVP group was a little better than that in RVP group (P<0.05), but significant heart failure remained in 2 groups. RVP induced more significant cardiac fibrosis and higher collagen 1A2 expression in the left ventricular lateral wall (late-contracting and high-stress) than that in the anterior wall, and for those in the BiVP group, it was much lower. CD31, S100A4, α-smooth muscle actin and collagen 1A2 were used to evaluate EndMT. EndMT levels, transforming growth factor-ß (TGF-ß)/snail signaling, collagen 1A2 and integrin ß1 expression were much higher in the endothelial cells from the RVP lateral wall than that from BiVP. In this in vitro study, cyclic stretch could independently induce EndMT and enhance the pro-EndMT effect of TGF-ß in HUVECs, which could be partly blocked by integrin ß1 siRNA. CONCLUSIONS: RVP-induced DHF could aggravate fibrosis due to regional heterogeneity of mechanical stress, and it was better in the BiVP group where mechanical stress-induced EndMT might play a pivotal role through the integrin ß1 pathway.

Angiotensin II-derived reactive oxygen species promote angiogenesis in human late endothelial progenitor cells through heme oxygenase-1 via ERK1/2 and AKT/PI3K pathways.

Angiotensin II (Ang II), the main component of renin-angiotensin system, could mediate pathogenic angiogenesis in cardiovascular disorders. Late endothelial progenitor cells (EPCs) possess potent self-renewal and angiogenic potency superior to early EPCs, but few study focused on the cross-talk between Ang II and late EPCs. We observed that Ang II could increase reactive oxygen species (ROS) and promote capillary formation in late EPCs. Ang II-derived ROS could also upregulate heme oxygenase-1 (HO-1) expression, and treating late EPCs with HO-1 small interfering RNA or heme oxygenase inhibitor (HO inhibitor) could inhibit Ang II-induced tube formation and increase ROS level and apoptosis rate. In addition, PD98059 and LY294002 pretreatment attenuated Ang II-induced HO-1 expression. Accordingly, Ang II-derived ROS could promote angiogenesis in late EPCs by inducing HO-1 expression via ERK1/2 and AKT/PI3K pathways, and we believe HO-1 might be a promising intervention target in EPCs due to its potent proangiogenic, antioxidant, and antiapoptosis potentials.

C-reactive protein promotes vascular endothelial dysfunction partly via activating adipose tissue inflammation in hyperlipidemic rabbits.

BACKGROUND: Endothelial dysfunction is the basic and original sign of atherogenesis. Some evidences show that C-reactive protein (CRP) and perivascular adipose tissue (PVAT) play a pivotal role in atherosclerosis. However, the effects of CRP on atherosclerosis and the related mechanisms require elucidation. METHODS: The levels of basic total cholesterol, low-density lipoprotein cholesterol, triglyceride, CRP, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), nitric oxide (NO) and endothelin-1 (ET-1) were respectively measured in rabbits, endothelium-dependent vasorelaxation function was also evaluated. Animals were randomly divided into two groups: PVAT(-) and PVAT(+) group (removing or keeping pericarotid adipose tissue (PCAT)). Both of the two groups were exposed to a high-fat diet for six-week, and then sustained CRP treatment was performed for a week, at this time point all the above parameters were remeasured. In addition, mRNA and protein expression of TNF-α, IL-6, and macrophage chemoattractant protein-1 (MCP-1) were respectively evaluated by Polymerase Chain Reaction and immunoblotting in PCAT and cultured adipocytes treated by CRP. RESULTS: High-fat diet greatly increased the serum lipids and inflammatory markers, induced endothelial dysfunction and imbalance between NO and ET-1, increased mRNA and protein expression of TNF-α, IL-6, MCP-1 and enhanced macrophage infiltration of PCAT. CRP treatment could further promote macrophage infiltration of PVAT, induce the imbalance between NO and ET-1, aggravate endothelial dysfunction especially in PVAT(+) arteries, and could also enhance the above-mentioned mRNA and protein expression in PCAT and cultured adipocytes. CONCLUSIONS: CRP could significantly promote endothelial dysfunction in high-fat diet rabbits especially in PVAT(+) groups, which may be partly mediated by activating inflammatory reaction of adipose tissue.