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.

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.

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.

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.

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.

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.

Angioscopy study from a large patient population comparing sirolimus-eluting stent with biodegradable versus durable polymer.

AIMS: This study aimed to compare the neointimal coverage (NIC), subclinical thrombus, color of plaque underneath the stent at 9-month after implantation of sirolimus-eluting stent (SES) either with durable or with biodegradable polymer (BDPM). METHODS: A total of 175 patients were assigned as Cypher (n = 81, 97 stents with durable polymer) and Excel (n = 94, 112 stents with BDPM) stent at 9-month after indexed procedure. NIC was classified from grade 0-3. Color of plaque was divided into white, light-yellow, yellow, and dark yellow. Thrombus was diagnosed as white or red material with cotton-like or ragged appearance. Incomplete NIC (grade 0/1) circled by a blush was termed by "inflaming." RESULTS: There were significant differences in unstable angina (90.5 vs. 52.4%, P = 0.015), previous myocardial infarction (33.3 vs. 4.0%, P = 0.045) and left ventricular eject fraction (55.2 ± 7.8 vs. 62.6 ± 6.3%, P = 0.021) between the Excel and Cypher groups. The minimal- and maximal-NIC grades in the Cypher group were 0.67 ± 0.58 and 2.29 ± 0.46, respectively, when compared with 1.45 ± 0.67 (P < 0.001) and 2.64 ± 0.49 (P = 0.023) in the Excel group. The percentage of yellow plaque, thrombus, "inflaming" and NIC grade of 0 in the Excel and Cypher groups, respectively, were as follows: 8.0 vs. 26.8% (P = 0.031), 9.8 vs. 32.9% (P = 0.024), 8.0 vs. 38.1% (P = 0.017), and 38.1 vs. 0% (P < 0.001). Of the stents with "inflaming," 63.6% had thrombus when compared with 20.1% of the non-erosion stents (P < 0.001). Overlapping segments had the lowest NIC grades and more "inflaming" demonstrating a significant difference between Cypher vs. Excel stents. NIC grade was positively correlated with thrombus. CONCLUSIONS: SES with BDPM has improved NIC resulting in less yellow plaque, thrombus, and "inflaming." Overlapping segments had the lowest NIC grade and more "inflaming."

Serial intravascular ultrasound analysis comparing double kissing and classical crush stenting for coronary bifurcation lesions.

BACKGROUND: Compared with the classical crush, double kissing (DK) crush improved outcomes in patients with coronary bifurcation lesions. However, there is no serial intravascular ultrasound (IVUS) comparisons between these two techniques. OBJECTIVES: This study aimed to analyze the mechanisms of the two crush stenting techniques using serial IVUS imaging. METHODS: A total of 54 patients with IVUS images at baseline, post-stenting and eight-month follow-up were classified into classical (n = 16) and DK (n = 38) groups. All patients underwent final kissing balloon inflation (FKBI). Unsatisfactory kissing (KUS) was defined as the presence of wrist or >20% stenosis during FKBI at the side branch (SB) ostium. The vessels at bifurcation lesions were divided into the proximal main vessel (MV) stent, the crushed segment, the distal MV stent, the SB ostium and the SB stent body. RESULTS: KUS and incomplete crushing were commonly observed in the classical group (62.5%, 81.3%), compared with DK group (18.0%, 39.5%, P < 0.001 and P = 0.004). The post-stenting stent symmetry in the classical group was 71.85 ± 7.69% relative to 85.93 ± 6.09% in DK group (P = 0.022), resulting in significant differences in neointimal hyperplasia (NIH, 1.60 ± 0.21 mm(2) vs. 0.85 ± 0.23 mm(2) , P = 0.005), late lumen loss (1.31 ± 0.81 mm(2) vs. 0.55 ± 0.70 mm(2) , P = 0.013), and minimal lumen area (MLA, 3.57 ± 1.52 mm(2) vs. 4.52 ± 1.40 mm(2,) P = 0.042) at the SB ostium between two groups. KUS was positively correlated with the incomplete crush and was the only predictor of in-stent-restenosis (ISR) at the SB ostium. CONCLUSION: DK crush was associated with improved quality of the FKBI and larger MLA. KUS predicted the occurrence of ISR.

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.

Prediction of clinical outcomes in patients with unprotected left main trifurcation lesions treated by drug-eluting stents: importance of 2-stent technique and SYNTAX score.

BACKGROUND: There were insufficient data on the prognosis of stenting for patients with trifurcated unprotected left main lesions (UPLMS). METHODS: From the SPEED (stents for percutaneous treatment of coronary artery disease) registry of all percutaneous coronary interventions (PCI) for all types of UPLMS, data of 44 patients with trifurcated UPLMS were selected and analyzed. RESULTS: Patients were divided into one-stent (N = 23) or 2-stent (N = 21) groups. Clinical follow-up was available for 100%, and angiographic follow-up at 8 month was available for 91.3%. There were no differences in myocardial infarction, cardiac death, and stent thrombosis between groups. However, the target lesion revascularization (TLR) and target vessel revascularization (TVR) in the 1-stent group was lower when compared to the 2-stent group (13.0% vs. 23.8%, P = 0.004; 13.0% vs. 28.6%, P = 0.003, respectively). Cumulative survival free from major adverse cardiovascular events (MACE) in the 1-stent group was higher than the 2-stent group (65.2% vs. 57.1%, P = 0.033). Analysis of the receiver operator curve (ROC) of the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score showed the area under the curve was 0.414 (standard error = 0.089, 95% CI 0.240-0.589, P = 0.348). CONCLUSIONS: In patients with trifurcated UPLMS, higher TLR/TVR and lower cumulative survival from MACE were seen in the 2-stent group when compared to the 1-stent group. The SYNTAX scoring system had no predictive value of outcomes for patients with stenting of trifurcated UPLMS.

Distribution and magnitude of shear stress after coronary bifurcation lesions stenting with the classical crush technique: a new predictor for in-stent restenosis.

BACKGROUND: Wall shear stress (SS) plays an important role in the initiation and proliferation of coronary atherosclerosis, especially for bifurcations. Stenting in the coronary artery will cause many different changes in velocity, flow, cross-sectional area, and especially the wall SS. However, it is still unknown how much wall SS distribution varies with stenting in coronary bifurcation. OBJECTIVE: The purpose of this study was to investigate the magnitude and distribution of wall SS after the classical crush stenting for bifurcation lesions. METHODS: Eleven patients with true coronary bifurcation stenting by the classical crush technique were included. We studied the difference of wall SS between restenosis and nonrestenosis groups in these patients. The differences in SS between preprocedure and postprocedure, as well as between immediately postprocedure and after an 8-month follow-up, were also analyzed. Diameter stenosis or minimal lumen diameter were measured by quantitative coronary analysis. The commercial CD STAR-CCM+ was used to calculate the SS. RESULTS: At baseline, the SS in all the segments of all patients was high. The baseline SS of the restenosis group was 50% lower than the nonrestenosis group. Immediately after percutaneous coronary intervention (PCI), the SS in both areas decreased; however, the SS of the nonrestenosis group decreased to its lowest level possible while the SS of the restenosis group decreased moderately. Eight months later, the SS of all the segments of the nonrestenosis group remained persistently low at the same level of right after PCI. In contrary, the SS in the restenosis group returned to near its baseline level. CONCLUSION: From our study, after a 2-stent crush technique using drug-eluting stents (DES), the degree of SS reduction appears to predict in-stent restenosis (ISR). A SS decrease to its lowest level and remaining homogenously low is a prime condition to prevent ISR. A baseline low SS, which decreases minimally after PCI and recovers to around its baseline level, appears to be the setting for restenosis. These conditions can be evaluated as predictors of lesions that may need surveillance angiography and proper IVUS evaluation to prevent future in-stent restenosis.

Contradictory shear stress distribution prevents restenosis after provisional stenting for bifurcation lesions.

BACKGROUND: Endothelial shear stress is one of the local hemodynamic factors suspected in the development of coronary atherosclerosis in bifurcation lesions. In patients with provisional stenting, the endothelial shear stress (SS) distribution is unknown. OBJECTIVE: The aim of this study was to investigate the magnitude and distribution of the SS of coronary bifurcation lesions stenting by the provisional approach. METHODS: Ten consecutive patients were included in this study. Quantitative coronary analysis, flow study, and three-dimensional computational analysis with the aid of the commercial software CD STAR-CCM+ were done before and after the provisional stenting procedure and also 8 months later. RESULTS: Clinical and angiographic follow-up were available in all patients. No patient had a side branch (SB) stent. At the 8-month follow-up, no major adverse cardiac event (MACE) occurred. There was also no clinical and angiographic restenosis. Before PCI, the distal main vessel (MV)-lateral, and the SB-lateral subsegments had relative nonsignificant lower SS value (4.08 +/- 2.78 Pa and 4.35 +/- 5.04 Pa, respectively) when compared to other segments. After 8-month follow-up, sustained decreased SS value was shown in the distal MV-lateral segment (4.08 +/- 2.78-1.68 +/- 1.65 Pa), when compared with significantly increased SS value in the SB-lateral subsegment 4.35 +/- 5.04-16.50 +/- 40.45 Pa). The explanation is that after stenting in the MV, the flow was redistributed immediately after percutaneous coronary intervention (PCI) and reversed back to its original 8 months later. However, the growth of the fibrous tissue causing in-stent restenosis (ISR) is prohibited by sirolimus on the stent struts. In contrast, in a branch opened up by plain old balloon angioplasty (POBA), the flow did not change much, the flow could even be worse because it is shifted to the MV after the cross-sectional area of the MV improved by stenting. However, thanks to POBA, there is increased fibrous tissue formation, enough to increase the SS and prevent further accumulation of cell and cholesterol needed for more restenosis. CONCLUSION: In the provisional approach, low endothelial SS correlated with no restenosis for patients who underwent stenting of the MV, while a contradictory combination of high SS and no restenosis was seen in the SB after only POBA. The mechanism of prevention of restenosis in the SB is by increasing the SS while in the MV, the mechanism of prevention of ISR is secondary to sirolimus on the stents struts.

Left ventricular endocardial pacing predicts the reduction of left ventricular outflow tract pressure gradient immediately after percutaneous transseptal myocardial ablation in patients with hypertrophic obstructive cardiomyopathy refractory to medication.

BACKGROUND: Hypertrophic obstructive cardiomyopathy (HOCM) carries an increased risk for sudden cardiac death. No data regarding the percutaneous transseptal myocardial ablation (PTSMA) and epicardial left ventricular pacing (LVP) were reported. METHODS: Seven patients with recurrent symptoms and increased resting left ventricular outflow tract pressure gradient (LVOTG) after PTSMA and another 14 patients with HOCM without history of PTSMA were studied. Both resting and dobutamine stress echocardiography, PTSMA and LVP were routinely performed. RESULTS: In patients without previous PTSMA procedure, mild reduction of resting LVOTG was detected at 5 minutes after left ventricular pacing, and this reduction became significant at 10 minutes. All patients were divided into successful and unsuccessful groups according to their response to LVP. In contrary to patients in unsuccessful group, resting and R-S2 stimuli-induced LVOTG during PTSMA procedure were decreased dramatically ((9 +/- 5) mmHg vs (58 +/- 12) mmHg, (12 +/- 2) mmHg vs (113 +/- 27) mmHg, P < 0.001). Analysis of Logistic regression demonstrated that only LVOTG level during left ventricular pacing was an independent factor predicting the reduction of LVOTG immediately after PTSMA (odds ratio (OR), 0.59; 95% CI 2.67 to 5.82; P = 0.0002). CONCLUSION: Left ventricular endocardial temporary pacing plays a critical role in predicting acute effect on the reduction of LVOTG immediately after PTSMA procedure.

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.

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.

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.

Hemodynamic change in wall shear stress in patients with coronary bifurcation lesions treated by double kissing crush or single-stent technique.

BACKGROUND: Fluid dynamic mechanisms attributed to coronary bifurcation lesions remain a subject of study. The present study aimed at investigating the hemodynamic change of wall shear stress (WSS) in patients with coronary bifurcation lesions treated by double kissing (DK) crush or one-stent with final kissing balloon inflation (FKBI). METHODS: Eighty-one patients with bifurcation lesions treated by stenting who had 3-D model reconstruction were studied. The bifurcation vessels were divided into main vessel (MV), main branch (MB), side branch (SB), and polygon of confluence (POC). MB and SB were classified by internal- and lateral-subsegments, respectively. RESULTS: The baseline magnitude of WSS in proximal MV, POC-MV, POC-MB, POC-SB and MB-internal segments increased significantly, compared to MB-lateral, SB-internal and SB-lateral. DK crush had the potential of uniformly reducing WSS, turbulent index and the WSS gradient. The WSS value at the POC-SB and SB in the one-stent group remained higher. The turbulent index and WSS gradient between the POC-SB minus the SB-lateral had equal predictive values for in-stent restenosis (ISR). CONCLUSION: Fluid dynamic results favor the use of DK crush over the one-stent technique.

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.

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).