TAX1BP1 downregulation by STAT3 in cardiac fibroblasts contributes to diabetes-induced heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is now the most common form of HF and has been reported to be closely related to diabetes. Accumulating evidence suggests that HFpEF patients exhibit cardiac fibrosis. This study investigates whether direct targeted inhibition of the activation of cardiac fibroblasts (CFs), the main effector cells in cardiac fibrosis, improves diabetes-induced HFpEF and elucidates the underlying mechanisms. Twenty-week-old db/db mice exhibited HFpEF, as confirmed by echocardiography and hemodynamic measurements. Proteomics was performed on CFs isolated from the hearts of 20-week-old C57BL/6 and db/db mice. Bioinformatic prediction was used to identify target proteins. Experimental validation was performed in both high glucose (HG)-treated neonatal mouse CFs (NMCFs) and diabetic hearts. TAX1 binding protein 1 (TAX1BP1) was identified as the most significantly differentially expressed protein between 20-week-old C57BL/6 and db/db mice. TAX1BP1 mRNA and protein were markedly downregulated in CFs from diabetic hearts and HG-cultured NMCFs. Overexpression of TAX1BP1 profoundly inhibited HG/diabetes-induced NF-κB nuclear translocation and collagen synthesis in CFs, improved cardiac fibrosis, hypertrophy, inflammation and HFpEF in diabetic mice. Mechanistically, signal transducer and activator of transcription 3 (STAT3), which is phosphorylated and translocated from the cytoplasm into the nucleus under hyperglycemic conditions, bound to TAX1BP1 promoter and blocked TAX1BP1 transcriptional activity, consequently promoting NF-κB nuclear translocation and collagen synthesis in CFs, aggravating cardiac fibrosis, hypertrophy and inflammation, leading to HFpEF in db/db mice. Taken together, our findings demonstrate that targeting regulation of STAT3-TAX1BP1-NF-κB signaling in CFs may be a promising therapeutic approach for diabetes-induced HFpEF.

Ivabradine Ameliorates Cardiac Diastolic Dysfunction in Diabetic Mice Independent of Heart Rate Reduction.

Cardiac fibroblast (CF) proliferation and activation play important roles in cardiac fibrosis and diastolic dysfunction (DD), which are involved in fibrosis-associated cardiovascular diseases. A previous study showed that ivabradine, a specific heart rate (HR)-lowering agent, significantly ameliorated DD in diabetic db/db mice by reducing HR. Herein, we attempted to determine whether ivabradine has antifibrotic and cardioprotective effects in diabetic mice by directly suppressing CF proliferation and activation, independent of a reduction in HR. We found that knockdown of c-Jun N-terminal kinase (JNK) or p38 mitogen-activated protein kinase (MAPK), or treatment with ivabradine, reduced JNK and p38 MAPK phosphorylation and the protein expression of proliferating cell nuclear antigen, collagen I, collagen III, tissue inhibitor of matrix metalloproteinase 2, and α-smooth muscle actin, accompanied with upregulation of matrix metalloproteinase 2 both in high glucose-treated neonatal rat CFs and left ventricular CFs isolated from db/db mice. However, zatebradine (a HR-lowering agent) did not have these effects in vitro or in vivo. In addition, cardiac fibrosis and DD were ameliorated in db/db mice that were intravenously administered lentiviruses carrying short hairpin RNAs targeting JNK and p38 MAPK or administered ivabradine. Taken together, these findings demonstrate that the ivabradine-induced amelioration of cardiac fibrosis, and DD in db/db mice may be at least in part attributable to the suppression of CF proliferation and activation, through the inhibition of JNK and p38 MAPK.

LCZ696, an Angiotensin Receptor-Neprilysin Inhibitor, Improves Cardiac Hypertrophy and Fibrosis and Cardiac Lymphatic Remodeling in Transverse Aortic Constriction Model Mice.

Cardiac hypertrophy and ventricular remodeling following heart failure are important causes of high mortality in heart disease patients. The cardiac lymphatic system has been associated with limited research, but it plays an important role in the improvement of myocardial edema and the promotion of fluid balance. LCZ696 is a novel combination of angiotensin and neprilysin inhibitors. Here, we studied the role played by LCZ696 during transverse aortic constriction (TAC) induced cardiac hypertrophy and changes in the lymphatic system. Mice undergoing aortic coarctation were constructed to represent a cardiac hypertrophy model and then divided into random groups that either received treatment with LCZ696 (60 mg/kg/d) or no treatment. Cardiac ultrasonography was used to detect cardiac function, and hematoxylin and eosin (H&E) and Masson staining were used to detect myocardial hypertrophy and fibrosis. The proinflammatory factors interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α) were detected in the blood and heart tissues of mice. The protein expression levels of lymphatic-specific markers, such as vascular endothelial growth factor C (VEGF-C), VEGF receptor 3 (VEGFR3), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) were detected in mouse heart tissues. We also examined the colocalization of lymphatic vessels and macrophages by immunofluorescence. The results showed that LCZ696 significantly improved heart dysfunction, cardiac hypertrophy, and fibrosis and inhibited the expression of proinflammatory factors IL-6, IL-1ß, and TNF-α in the circulating blood and heart tissues of mice. LCZ696 also decreased the protein expression levels of VEGF-C, VEGFR3, and LYVE-1 in mouse heart tissues, ameliorated the transport load of lymphatic vessels to macrophages, and improved the remodeling of the lymphatic system in the hypertrophic cardiomyopathy model induced by TAC.

Activation of the PP2A catalytic subunit by ivabradine attenuates the development of diabetic cardiomyopathy.

Hyperglycemia-induced apoptosis plays a critical role in the pathogenesis of diabetic cardiomyopathy (DCM). Our previous study demonstrated that ivabradine, a selective If current antagonist, significantly attenuated myocardial apoptosis in diabetic mice, but the underlying mechanisms remained unknown. This study investigated the underlying mechanisms by which ivabradine exerts anti-apoptotic effects in experimental DCM. Pretreatment with ivabradine, but not ZD7288 (an established If current blocker), profoundly inhibited high glucose-induced apoptosis via inactivation of nuclear factor (NF)-κB signaling in neonatal rat cardiomyocytes. The effect was abolished by transfection of an siRNA targeting protein phosphatase 2A catalytic subunit (PP2Ac). In streptozotocin-induced diabetic mice, ivabradine treatment significantly inhibited left ventricular hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) and HCN4 (major components of the If current), activated PP2Ac, and attenuated NF-κB signaling activation and apoptosis, in line with improved histological abnormalities, fibrosis, and cardiac dysfunction without affecting hyperglycemia. These effects were not observed in diabetic mice with virus-mediated knockdown of HCN2 or HCN4 after myocardial injection, but were alleviated by knockdown of PP2Acα. Molecular docking and phosphatase activity assay confirmed direct binding of ivabradine to, and activation of, PP2Ac. In conclusion, ivabradine may directly activate PP2Ac, leading to inhibition of NF-κB signaling activation, myocardial apoptosis, and fibrosis, and eventually improving cardiac function in experimental DCM. Taken together, the present findings suggest that ivabradine may be a promising drug for treatment of DCM.

Ivabradine improved left ventricular function and pressure overload-induced cardiomyocyte apoptosis in a transverse aortic constriction mouse model.

This study aimed to investigate the effects and molecular mechanisms of ivabradine in preventing cardiac hypertrophy in an established transverse aortic constriction (TAC) mouse model. A total of 56 male C57BL/6 mice were randomly assigned into the following seven groups (8 mice per group): sham, TAC model, Iva-10 (10 mg/kg/day ivabradine), Iva-20 (20 mg/kg/day ivabradine), Iva-40 (40 mg/kg/day ivabradine), Iva-80 (80 mg/kg/day ivabradine), and Rap (rapamycin, a positive control). Echocardiography and left ventricular hemodynamics were performed. Hematoxylin-eosin (H&E), Masson's trichome staining, and TUNEL assays were conducted to evaluate cardiac hypertrophy, fibrosis, and apoptosis, respectively. Western blotting was performed to detect the expression of proteins related to the PI3K/Akt/mTOR/p70S6K pathway. Ivabradine could effectively improve left ventricular dysfunction and hypertrophy induced by TAC in a dose-independent manner. Moreover, no obvious change in heart rate (HR) was observed in the TAC and Rap groups, whereas a significant decrease in HR was found after ivabradine treatment (P < 0.05). Cardiac hypertrophy, fibrosis, and apoptosis induced by TAC were notably suppressed after either rapamycin or ivabradine treatment (P < 0.05). Ivabradine and rapamycin also decreased the expression of PI3K/Akt and mTOR induced by TAC. Ivabradine improved cardiac hypertrophy and fibrosis as well as reduced cardiomyocyte apoptosis via the PI3K/Akt/mTOR/p70S6K pathway in TAC model mice.

Layer-specific strain analysis of left ventricular myocardium after alcohol septal ablation for hypertrophic obstructive cardiomyopathy.

INTRODUCTION: We aimed to explore the layer-specific systolic strain of left ventricular (LV) myocardium in patients with hypertrophic obstructive cardiomyopathy (HOCM) before and after alcohol septal ablation (ASA).The routine 2D (frame rate: >50 Hz) data sets were acquired using GE Vivi7 system for 44 consecutive HOCM patients and 21 matched normal subjects. Fifteen of HOCM patients had serial echocardiograms available for speckle tracking analyses before and 1 year after ASA. 2D strain was analyzed by EchoPAC software.The layer strain from inner to mid-myocardial and outer layers in basal and middle segments in HOCM patients continuously declined. The absolute values of peak systolic strains from the endocardium to mid-myocardium and epicardium in the basal septum of the HOCM group were significantly lower than those of the normal group (P <.01). Meanwhile, the layer systolic strain of LV endocardium in the basal septum increased significantly during a 1-year follow-up (P <.05). CONCLUSIONS: The layer-specific strains of HOCM patients measured by tissue Doppler echocardiography decreased significantly compared to those of normal individuals. The increased specific layer strain of LV endocardium in the basal septum may be a valid marker of echocardiographic improvement in HOCM patients receiving ASA.

Antithrombotic Strategies in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

The optimal strategy of antithrombotic therapy for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention remains to be a question to be answered. The major challenge in such population is the balance between the benefit of reduced stroke and coronary ischemic events, against the risk of increased bleeding complications. Thus, both thrombotic and bleeding risk assessments should be included into clinical decision-making process for such patients. Currently, there is limited evidence based on randomized trials with adequate power to show the superiority of any strategy in the beneficial profile of safety and efficacy, thus limited recommendations are provided by clinical guidelines. Given the recent advancement in this field, our review provided an overview of the available risk stratification schemes for stroke and bleeding risk for AF patients, discussed the multiple questions in the optimal regimens of oral antiplatelet and anticoagulation therapy, and summarized evidence and recommendations related to long-term antithrombotic therapy for AF patients receiving stent implications.

Atorvastatin Alleviates Experimental Diabetic Cardiomyopathy by Regulating the GSK-3ß-PP2Ac-NF-κB Signaling Axis.

Recent studies reported that atorvastatin (ATOR) alleviated progression of experimental diabetic cardiomyopathy (DCM), possibly by protecting against apoptosis. However, the underlying mechanisms of this protective effect remain unclear. Therefore, our study investigated the role of the glycogen synthase kinase (GSK)-3ß-protein phosphatase 2A(PP2A)-NF-κB signaling pathway in the anti-apoptotic and cardioprotective effects of ATOR on cardiomyocytes cultured in high glucose (HG) and in DCM. Our results showed that, in HG-cultured cardiomyocytes, phosphorylation of GSK-3ß was decreased, while that of the PP2A catalytic subunit C (PP2Ac) and IKK/IкBα was increased, followed by NF-кB nuclear translocation and apoptosis. IKK/IкBα phosphorylation and NF-кB nuclear translocation were also increased by treatment of cells with okadaic acid (OA), a selective PP2A inhibitor, or by silencing PP2Ac expression. The opposite results were obtained by silencing GSK-3ß expression, which resulted in PP2Ac activation. Furthermore, IKK/IкBα phosphorylation and NF-кB nuclear translocation were markedly inhibited and apoptosis attenuated in cells treated with ATOR. These effects occurred through inactivation of GSK-3ß and subsequent activation of PP2Ac. They were abolished by treatment of cells with OA or PP2Ac siRNA. In mice with type 1 diabetes mellitus, treatment with ATOR, at 10 mg-kg-1-d-1, significantly suppressed GSK-3ß activation, IKK/IкBα phosphorylation, NF-кB nuclear translocation and caspase-3 activation, while also activating PP2Ac. Finally, improvements in histological abnormalities, fibrosis, apoptosis and cardiac dysfunction were observed in diabetic mice treated with ATOR. These findings demonstrated that ATOR protected against HG-induced apoptosis in cardiomyocytes and alleviated experimental DCM by regulating the GSK-3ß-PP2A-NF-κB signaling pathway.

Pulmonary artery denervation improves pulmonary arterial hypertension induced right ventricular dysfunction by modulating the local renin-angiotensin-aldosterone system.

BACKGROUND: Pulmonary arterial hypertension (PAH) is commonly accompanied with the activation of the renin-angiotensin-aldosterone system (RAAS). Renal sympathetic denervation (RSD) reduces PAH partly through the inhibition of RAAS. Analogically, we hypothesized that pulmonary artery denervation (PADN) could reverse PAH and PAH-induced right ventricular (RV) dysfunction by downregulating the local RAAS activity. METHODS: Twenty-five beagle dogs were randomized into two groups: control group (intra-atrial injection of N-dimethylacetamide, 3 mg/kg, n = 6) and test group (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg, n = 19). Eight weeks later, dogs in the test group with mean pulmonary arterial pressure (mPAP) ≥25 mmHg (n = 16) were reassigned into the sham (n = 8) and PADN groups (n = 8) by chance. After another 6 weeks, the hemodynamics, pulmonary tissue morphology and the local RAAS expression in lung and right heart tissue were measured. RESULTS: PADN reduced the mPAP (25.94 ± 3.67 mmHg vs 33.72 ± 5.76 mmHg, P < 0.05) and the percentage of medial wall thickness (%MWT) (31.0 ± 2.6 % vs 37.9 ± 2.8 %, P < 0.05) compared with the sham group. PADN attenuated RV dysfunction, marked with reduced atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ratio of right ventricular to left ventricular plus septum weight [RV/(LV + S)]. Moreover, the local RAAS expression was activated in PAH dogs while inhibited after PADN. CONCLUSIONS: PADN improves hemodynamics and relieves RV dysfunction in dogs with PAH, which can be associated with the downregulating RAAS activity in local tissue.

Olmesartan Reduces New-onset Atrial Fibrillation and Atrial Fibrillation Burden after Dual-chamber Pacemaker Implantation in Atrioventricular Block Patients.

BACKGROUND: Atrial fibrillation (AF) is the most frequent tachyarrhythmia in patients with a permanent pacemaker. Angiotensin II receptor antagonists have a protective effect against the occurrence of AF in patients with heart diseases. This study aimed to assess the effectiveness of olmesartan in the prevention of new-onset AF and AF burden in atrioventricular block (AVB) patients with dual-chamber (DDD) pacemaker implantation. METHODS: This was a single-center, prospective, randomized, single-blind, controlled clinical study. A total of 116 AVB patients, who received DDD pacemakers implantation with the percentage of ventricular pacing (VP%) ≥40% from April 22, 2011 to December 24, 2012, were prospectively randomized to olmesartan group (20 mg per day; n = 57) or control group (n = 59). Patients were followed up using pacemaker programming, 12-lead electrocardiography in the intrinsic sinus rhythm, laboratory examinations, and transthoracic echocardiography at 24 months. Atrial high rate events (AHREs) were defined as 180 beats/min over a minimum of 5 min. AF burden was calculated by the number of hours with AHREs divided by the number of measurement hours. RESULTS: Ten (17.5%) patients in the olmesartan group and 24 patients (40.7%) in the control group occurred new-onset AF, and the difference between two groups was statistically significant (P = 0.04). AF burden was lower in olmesartan group than that in control group (8.02 ± 3.10% vs. 13.66 ± 6.14%, P = 0.04). There were no significant differences in mean days to the first occurrence of AHREs and mean cumulative numbers of AHREs between two groups (P = 0.89 and P = 0.42, respectively). Moreover, olmesartan group had smaller values of maximal P-wave durations and P-wave dispersion (PD) after 24 months follow-up compared with the control group (109.5 ± 7.4 ms vs. 113.4 ± 7.1 ms, P = 0.00; and 40.6 ± 4.5 ms vs. 43.3 ± 4.4 ms, P = 0.02, respectively). Left ventricular end-diastolic diameter and left ventricular ejection fraction were not significantly different between two groups (both P > 0.05). CONCLUSION: This study suggested that 24-month of olmesartan therapy could reduce new-onset AF and AF burden in patients with DDD pacemakers. CLINICAL TRIAL REGISTRATION: ChiCTR-TRC-12004443; http://www.chictrdb.org.

Efficiencies and Complications of Dual Chamber versus Single Chamber Implantable Cardioverter Defibrillators in Secondary Sudden Cardiac Death Prevention: A Meta-analysis.

BACKGROUND: Dual chamber implantable cardioverter defibrillators (ICDs) are considered to have better clinical outcomes than single chamber ICDs, however, an individual trial may not have sufficient power to prove it. This meta-analysis aimed to compare clinical outcomes of dual chamber ICDs (DC-ICDs) with single chamber ICDs (SC-ICDs) in secondary sudden cardiac death (SCD) prevention. METHODS: We searched Medline, the Cochrane Library, and other internet sources, without language or date restrictions for articles comparing clinical outcomes between DC-ICDs and SC-ICDs. Studies were selected for inclusion based on the following criteria: Randomised controlled trial.; Controlled design was used to compare SC-ICDs and DC-ICDs; Retrospective study if the survival analysis was performed. Efficacy endpoints were mortality, appropriate therapy, inappropriate detection of SVT, inappropriate therapy. Safety endpoints were lead-related complication and all complications. Relative risk (RR) or odds ratios (ORs) with 95% confidence intervals (CI) were calculated, and a χ2-based test of homogeneity was performed. RESULTS: We identified nine trials (n=2594) with a weighted mean follow-up of 18.9 months. Compared with DC-ICDs, SC-ICDs were associated with a significant reduction in lead complications (RR:3.30; 95% CI: 1.17-9.30; p=0.02). However, both groups had similar rates of mortality (OR: 0.91; 95%CI: 0.91-1.51; p=0.73), appropriate therapy (RR: 0.90; 95%CI: 0.73-1.11; p=0.32), inappropriate detection of SVT (RR: 1.82; 95%CI: 0.71-4.62; p=0.21), inappropriate therapy (RR: 2.08; 95%CI: -0.22-0.19; p=0.86) and all complications (OR: 1.27; 95%CI: 0.19-8.67; p=0.81). CONCLUSIONS: Besides more lead-related complications, DC-ICDs had similar efficacy and all complications as SC-ICDs in secondary sudden cardiac death prevention.

Can Pulmonary Vascular Resistance Predict Response to Cardiac Resynchronization Therapy in Patients with Heart Failure?

BACKGROUND: To evaluate if pulmonary vascular resistance (PVR) calculated by echocardiography can be a novel criterion to predict the response to cardiac resynchronization therapy (CRT). METHODS: Forty-five patients with heart failure who underwent CRT were retrospectively analyzed. Based on CRT response, which was defined by a decrease of left ventricular end-systolic volume by at least 15% after 6 months, the patients were assigned to the responder or nonresponder groups. The peak tricuspid regurgitant velocity (TRV) and time velocity integral of the right ventricular outflow tract (TVIRVOT ) were obtained. The relation between TRV, PVR, and CRT response were analyzed using univariate and multivariate analyses. RESULTS: Twenty-seven patients (60%) were responders and 18 patients (40%) were nonresponders to CRT. At baseline, responders had lower PVR (3.57±1.65 vs 2.32 ± 1.28 wood; P = 0.01), or lower PVR1 (3.26 ± 1.32 vs 1.83 ± 0.79 wood; P = 0.01) compared with nonresponders. Multivariate analysis has shown that PVR and PVR1 were independent factors for CRT response. The optimal cutoff point of PVR to predict nonresponse to CRT was 2.39 wood, with a sensitivity of 0.78 and a specificity of 0.81 (95% confidence interval [CI]: 53.4-88.2). The optimal cutoff point of PVR1 calculated by the other model was 3.55 wood, determined at a sensitivity of 0.72 and a specificity of 0.82 (95%CI: 56.7-90.7). In nonresponders, patients demonstrated higher PVR, TVIA , and TVIRVOT , and decreased TRV. CONCLUSIONS: PVR could be used to predict response to CRT after 6 months as a novel criterion, and higher PVR may indicate nonresponse.

Cardiac hypertrophy is positively regulated by long non-coding RNA PVT1.

The aim of this study was to determine whether long non-coding RNA PVT1 can participate in the regulation of cardiac hypertrophy. A C57BL/6 mouse cardiac hypertrophic model was established using transverse aortic constriction (TAC). The animals subjected to sham operation were used as controls. Transcripts of PVT1 were analyzed in hearts of model and sham control groups after TAC for 4 weeks using quantitative real-time PCR (qRT-PCR). Additionally, to investigate whether PVT1 was involved in cardiac hypertrophy, 1 µM angiotensin II (Ang II) was used to induce hypertrophy and PVT1 siRNA was performed in the cultured neonatal mouse cardiac cardiomyocytes. Cell size was measured by cell surface area and total protein content analyses in response to Ang II treatment. Moreover, some hypertrophic markers including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and beta-myosin heavy chain (ß-MHC) were also quantified using qRT-PCR. As a result, PVT1 was up-regulated by 2.5-fold (P<0.05) in hypertrophic hearts after TAC for 4 weeks as compared to sham group. In addition, siRNA of endogenous PVT1 in cardiomyocytes significantly reduced (P<0.05) Ang II-induced increase of cell size in terms of cell surface area (by 5.6-fold) and total protein content (by 23.0%). PVT1 siRNA also obviously attenuated Ang II-induced ANP and ß-MHC expression by 40.9% and 41.5%, respectively (P<0.05), but had no effect on BNP mRNA expression. Our results demonstrated that PVT1 was essential for the maintenance of cell size of cardiomyocytes and might play a role in the regulation of cardiac hypertrophy.

I(f) current channel inhibitor (ivabradine) deserves cardioprotective effect via down-regulating the expression of matrix metalloproteinase (MMP)-2 and attenuating apoptosis in diabetic mice.

BACKGROUND: Ivabradine (IVBD), a novel I(f)-channel inhibitor and specific heart rate-lowering agent, is known to have anti-oxidative activity that promotes endothelial function. However, the molecular mechanism through which IVBD acts on cardiac function has yet to be elucidated, especially in experimental diabetic animals. METHODS: For this reason, twenty diabetic mice were randomly assigned to IVBD-treated (10 mg/kg/day) and control (saline) groups. After a 3-month treatment, microarray assay was performed to identify differentia expressed genes, and cardiac function was measured by echocardiography, with subsequent immunohistochemistry analysis and western blotting. RESULTS: Our results showed that ivabradine treatment attenuated the expression and staining score of matrix metalloproteinase (MMP)-2, induced the dephosphorylation of caspase 3, BAX and MMP-2, and enhanced the phosphorylation of NF-κB. Ivabradine treatment led to a significant improvement in cardiac function. CONCLUSION: Ivabradine significantly improved cardiac function by attenuating apoptosis and inhibiting the expression and activity of MMP-2 in diabetic mice, which underscored the novel clinical implications of ivabradine for diabetic patients.

The left ventricular lead electrical delay predicts response to cardiac resynchronisation therapy.

Up to one-third of patients who undergo cardiac resynchronisation therapy (CRT) are not responders. To identify potential responders to CRT may be sometimes difficult and time-consuming. Forty-five patients who had undergone CRT implantation for standard indications were evaluated. Electrical left ventricular (LV) lead location was assessed by left ventricular activation time (LVAT), LV lead electrical delay (LVLED), and RV-LV interlead electrical delay (RVsense-LVsense). Anatomic LV pacing location was assessed as basal or mid-ventricular between 3:00 to 5:00 (traditionally optimal site), and all the other positions (traditionally non-optimal site). CRT response was defined as a decrease in LV end-systolic volume (LVESV) exceeding 15% at six months. LVLED was larger in the responder group than that in the non-responder group (67.3 ± 8.5% vs. 55.3 ± 8.1%, P< 0.001). In the multivariate analysis, LVLED and cLBBB morphology were the two independent predictors of positive echocardiographic response to CRT (OR=1.180, P=0.003; OR=7.497, P=0.04, respectively). A cutoff value of LVLED> 54.82% predicted responders with 96.3% sensitivity and 75.2% specificity and the area under the receiver operating characteristic (ROC) curve was 0.844 for LVLED (P=0.002). No relationship was found between the anatomic LV pacing sites and response to CRT (P=0.188). The larger left ventricular lead electrical delay may predict response to cardiac resynchronisation therapy.

Interleukin-6, but not C-reactive protein, predicts the occurrence of cardiovascular events after drug-eluting stent for unstable angina.

BACKGROUND: Evidences concerning the predictive value of baseline inflammatory biomarkers after drug-eluting stent (DES) placement are controversial, mainly because the use of statin was not precisely defined. OBJECTIVES: The aim was to compare the differences between interleukin (IL)-6 and high-sensitivity C-reactive protein (hs-CRP) in predicting cardiovascular events 2 years after stenting in patients with unstable angina (UA) who had not received statin pretreatment. METHODS: There were 1,896 patients included in this study. The primary end-point was the occurrence of cardiac death or myocardial infarction (MI). Secondary endpoints included all-cause death, stent thrombosis (ST), target lesion revascularization (TLR), target vessel revascularization (TVR), or a composite of major adverse cardiac events (MACE) at 2 years after the procedure. RESULTS: During the median follow-up of 2.77 years, 96 patients experienced cardiac death (n = 37, 1.95%) or MIs (n = 70, 3.69%), 94 TLRs, 123 TVRs, 215 MACEs, and 21 definite or probable STs. In multivariable Cox proportional-hazards models and discrimination analysis, elevated IL-6 levels were superior to hs-CRP in predicting the occurrence not only of cardiac death or MI (HR 1.337, 95% CI 1.234-1.449, P < 0.001), but also of MACE and late-occurring definite/probable ST. Incorporation of IL-6 into conventional variables resulted in significantly increased c statistic for the prediction of end-points, with the exception of TLR and TVR. CONCLUSION: Elevated IL-6 levels were independent predictors of cardiac death or MI, MACE, and late ST in patients with UA who had not received statin pretreatment, suggesting a role for IL-6 in the inflammatory risk assessment. Pathological studies have confirmed that atherosclerosis is a chronic inflammatory disease. Serum levels of high-sensitivity C-reactive protein (hs-CRP), matrix metalloproteinase, plasminogen activator inhibitor-1, the complement components C3a or C5a, and interleukin(IL)-6 were reported to provide strong and independent indications of the risk for future cardiovascular (CV) events, even among individuals who are thought to be free of vascular disease.

Intravenous injection of nicardipine changed the distribution of coronary artery endothelial shear stress and fluid dynamics in patients with unstable angina.

BACKGROUND: Coronary endothelial shear stress (ESS) triggered the development of atherosclerosis. However, the effect of calcium channel antagonist on the distribution of ESS remained unclear. METHODS: Twenty consecutive patients with acute coronary syndrome (ACS) 48 hours after maximal medication with single left anterior descending artery stenosis < 50% were studied. Nicardipine was intravenously injected at 1 µg/kg after a bolus of 10 mg in order to achieve mean blood pressure (MBP) reduced by 10% or more, or the heart rate increased by 10 - 15 beats/min. Hemodynamic variables and angiogram at baseline and during injection of nicardipine were recorded, respectively. Coronary artery 3-D reconstruction was used for the analysis of ESS. RESULTS: Distal reference-vessel-diameter and minimal lumen diameter decreased significantly from (2.42 ± 0.41) mm and (1.47 ± 0.49) mm at baseline to (2.22 ± 0.35) mm and (1.35 ± 0.49) mm at maximal drug-dosage (P = 0.018 and 0.020, respectively). Nicardipine did not change blood velocity. Lowest mean shear stress at segments 2-mm distal to plaque increased significantly from (0.034 ± 0.519) Pa at baseline to (0.603 ± 0.728) Pa (P = 0.013) at peak effect of drug. CONCLUSIONS: Nicardipine was associated with the constriction of diseased vessel segment that adapted to the reduction of blood pressure, without dynamic change of blood velocity at each stage of whole cardiac cycle. Increased ESS value at segments distal to plaque reflected the cardioprotection by nicardipine (ChiCTR-TRC-10000964).

Three hours continuous injection of adenosine improved left ventricular function and infarct size in patients with ST-segment elevation myocardial infarction.

BACKGROUND: The definitive treatment for myocardial ischemia is reperfusion. However, reperfusion injury has the potential to cause additional reversible and irreversible damage to the myocardium. One likely candidate for a cardioprotection is adenosine. The present study aimed at investigating the effect of intravenous adenosine on clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS: Patients with STEMI within 12 hours from the onset of symptoms were randomized by 1:1:1 ratio to receive either adenosine 50 µg×kg(-1)×min(-1) (low-dose group, n = 31), or 70 µg×kg(-1)×min(-1) (high-dose group, n = 32), or saline 1 ml/min (control group, n = 27) for three hours. Drugs were given to the patients immediately after the guide wire crossed the culprit lesion. Recurrence of no-reflow, TIMI flow grade (TFG) and TIMI myocardial perfusion grade (TMPG), and collateral circulation were recorded. The postoperative and preoperative ST segment elevation sum of 18-lead electrocardiogram (ECG) and their ratio (STsum-post/STsum-pre) were recorded, as well as the peak time and peak value of CK-MB enzyme. Serial cardiac echo and myocardial perfusion imaging were performed at 24 hours and 6 months post-stenting. The primary endpoint was left ventricular function, and infarct size. The secondary end-point was the occurrence of cardiac and non-cardiac death, non-fatal myocardial infarction, and heart failure. RESULTS: A total of 90 STEMI patients were studied. No-reflow immediately after stent procedure was seen in 11 (35.5%) patients in the control group, significantly different from 6.3% in the low-dose group or 3.7% in the high-dose group (both P = 0.001). STsum-post/STsum-pre in the low-dose and high-dose groups was significantly different from the control group (low-dose group vs. control group, P = 0.003 and high-dose group vs. control group, P = 0.001), without a dose-dependent pattern (P = 0.238). The peak value of CK-MB enzyme was significantly reduced in the high-dose group compared to the control group (P = 0.024). Compared to the left ventricular ejection fraction (LVEF) in control group, LVEF in the low-dose group increased by 5.8% at 24 hours (P = 0.012) and by 10.9% at 6 months (P = 0.007), LVEF in the high-dose group increased by 9.5% at 24 hours (P = 0.001) and by 10.0% at 6 months (P = 0.001), respectively. Significant reduction of infarct size by 24.2% was detected in the high-dose group vs. low-dose or control groups (P = 0.008). There was no significant difference regarding secondary endpoints at 6 months among the treated groups. Cardiac function by NYHA classification in both the low-dose and the high-dose groups was improved significantly (P = 0.013, P = 0.016). CONCLUSION: Intravenous adenosine administration might significantly reduce the recurrence of no-reflow, with resultant improved left ventricular systolic function. High-dose adenosine was further associated with significant reduction of infarct size.