The Role of Cardiac Fibrosis in Diabetic Cardiomyopathy: From Pathophysiology to Clinical Diagnostic Tools.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia due to inadequate insulin secretion, resistance, or both. The cardiovascular complications of DM are the leading cause of morbidity and mortality in diabetic patients. There are three major types of pathophysiologic cardiac remodeling including coronary artery atherosclerosis, cardiac autonomic neuropathy, and DM cardiomyopathy in patients with DM. DM cardiomyopathy is a distinct cardiomyopathy characterized by myocardial dysfunction in the absence of coronary artery disease, hypertension, and valvular heart disease. Cardiac fibrosis, defined as the excessive deposition of extracellular matrix (ECM) proteins, is a hallmark of DM cardiomyopathy. The pathophysiology of cardiac fibrosis in DM cardiomyopathy is complex and involves multiple cellular and molecular mechanisms. Cardiac fibrosis contributes to the development of heart failure with preserved ejection fraction (HFpEF), which increases mortality and the incidence of hospitalizations. As medical technology advances, the severity of cardiac fibrosis in DM cardiomyopathy can be evaluated by non-invasive imaging modalities such as echocardiography, heart computed tomography (CT), cardiac magnetic resonance imaging (MRI), and nuclear imaging. In this review article, we will discuss the pathophysiology of cardiac fibrosis in DM cardiomyopathy, non-invasive imaging modalities to evaluate the severity of cardiac fibrosis, and therapeutic strategies for DM cardiomyopathy.

Effect of the Ligation and Reperfusion Timeframe on Maximal Ischemia-Reperfusion Injury in Diverse Rat Models.

Background: Little is known about the effect that different time sequences for coronary ligation and reperfusion have on ischemic-reperfusion (IR) injury. Objective: To investigate the relationship between the extent of IR injury and the timeframe for coronary ligation/reperfusion in three animal models. Methods: Three rat models were used: normal Sprague-Dawley rats, diabetes mellitus (DM) rats, and fat rats. The rats in each model were divided into four groups based on the coronary ligation period (L): 30, 60, 120, and 180 min, and then divided into seven sub-groups based on the reperfusion period (R): 0, 30, 60, 120, 180, 270, and 360 min. R0 was the IR injury baseline for each sub-group. The hearts were harvested and stained with Evans blue and 2,3,5-triphenyl tetrazolium chloride dye to distinguish the different myocardial injury areas: area at risk (AAR) and myocardial necrosis. The difference between each subgroup and baseline (R0) for the necrotic area/AAR was calculated. Results: In the normal rats, the highest IR injury differences compared with the baseline group occurred at L120, with a reperfusion time of > 180 min. The highest IR injury difference compared to the baseline group occurred at L30, with a reperfusion time of > 180 min in the DM rats and at L60R270, L120R180 in the fat rats. Conclusions: IR injury, as induced by different coronary ligation and reperfusion time intervals, had diverse expression profiles in the different animal models. Optimal animal models with optimal coronary ligation/reperfusion protocols to achieve maximal IR injury will affect the results and interpretation of future studies.

Association between viral hepatitis and metabolic syndrome in lung function impairment: A Taiwan community-based study.

OBJECTIVES: Metabolic syndrome (MetS) and hepatitis C virus (HCV) are associated with a higher risk of impaired pulmonary function (iPF). This study aimed to investigate the relationships among MetS, iPF, and viral hepatitis. METHODS: This community-based study enrolled participants undergoing annual health check-ups in southern Taiwan between March and December 2019. We performed multivariable logistic regression analyses adjusted for demographics and characteristics to identify the factors associated with iPF. RESULTS: A total of 2337 participants completed examinations, of whom 928 (39.7%) had iPF. The participants with iPF were elderly (68.8 ± 12.8 years old) and predominately female (63%). MetS increased the risk of iPF (odds ratio (OR) 1.51, 95% confidence interval (CI) 1.27-1.81, p < 0.001). Beyond age (OR 1.03, 95% CI 1.02-1.04) and smoking (OR 1.309, 95% CI 1.004-1.705), female sex (OR 0.74, 95% CI 0.59-0.93) and high education level (OR 0.96, 95% CI 0.94-0.98, p < 0.001) protected against iPF. HCV was not significantly associated with iPF (OR 1.17, 95% CI 0.90-1.52, p = 0.235) in multivariable analysis. MetS was associated with a higher risk of iPF in the non-HBV/HCV group (OR 1.86, 95% CI 1.54-2.26) and HBV alone group (OR 3.44, 95% CI 1.89-6.28), but not in the HCV alone group (OR 1.02, 95% CI 0.64-1.62). DISCUSSION: MetS was an independent predictor of iPF, especially the restrictive type, and had different effects in the HBV/non-viral hepatitis and HCV groups. Female sex and education were inversely associated with iPF.

The Impact of Hepatitis C Virus, Metabolic Disturbance, and Unhealthy Behavior on Chronic Kidney Disease: A Secondary Cross-Sectional Analysis.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with a higher risk of chronic kidney disease (CKD). This study investigates the relationship among HCV, CKD, and understudied confounders, such as unhealthy behaviors and metabolic disturbances. METHODS: This cross-sectional study was conducted as part of a community health promotion program in an HCV endemic area of Taiwan from June to December 2019. Multivariable logistic regression analyses adjusted for demographic and clinical characteristics were performed to investigate the association between CKD and HCV seropositivity. RESULTS: Of 2387 participants who underwent health check-ups, the mean age was 64.1 years old; females predominated (63.2%), and 306 (12.8%) subjects were seropositive for HCV. CKD, defined as a lower estimated glomerular filtration rate (eGFR) was associated with unhealthy dietary habits, metabolic syndrome, and HCV. Less frequent exercise, higher waist circumference (WC) and HbA1c all affected risk of CKD; HCV increased risk of CKD by 44% compared to non-HCV (OR 1.44, 95% confidence interval (CI) 1.05-1.98) in the multivariable analysis. In the HCV group, lower eGFR was also significantly associated with the severity of metabolic syndrome (MetS) (median eGFR was 86.4, 77.1, and 64.5 mL/min/1.73 m2 for individuals with three and five MetS components, respectively). CONCLUSIONS: Beyond metabolic disturbance and irregular exercise, HCV seropositivity is independently associated with CKD in a community survey. Healthy lifestyle promotion might protect against renal function decline in HCV; however, the mechanisms underlying the association need further large-scale investigation.

Cardioselective Versus Nonselective ß-Blockers After Myocardial Infarction in Adults With Chronic Obstructive Pulmonary Disease.

OBJECTIVE: To investigate which types of ß-blockers have better efficacy and safety profiles in patients with concomitant chronic obstructive pulmonary disease (COPD) and myocardial infarction (MI) to address concerns about use of ß-blockers in COPD. METHODS: We identified 65,699 patients with COPD prescribed ß-blockers after first MI in the Taiwan National Health Insurance Research Database between January 1, 2001, and December 31, 2013. Comparisons were performed using the inverse probability of treatment weighting method. The primary outcome was all-cause mortality; secondary outcomes were heart failure hospitalization, major adverse cardiac and cerebrovascular event (MACCE), and major adverse pulmonary event (MAPE). RESULTS: A total of 14,789 patients prescribed ß-blockers were enrolled, of whom 7247 (49.0%) used cardioselective ß-blockers and 7542 (51.0%) used nonselective ß-blockers. The cardioselective group had lower incidence rates of mortality (hazard ratio [HR], 0.93; 95% CI, 0.89 to 0.96), MACCE (HR, 0.96; 95% CI, 0.93 to 0.998), heart failure hospitalization (subdistribution HR, 0.84; 95% CI, 0.78 to 0.91), and MAPE (HR, 0.94; 95% CI, 0.90 to 0.98) at the end of follow-up after weighting. Similar results were also found in subgroup analysis between those prescribed bisoprolol and those prescribed carvedilol. CONCLUSION: Patients prescribed a cardioselective ß-blocker may have a lower incidence of all-cause mortality, MACCE, heart failure hospitalization, and MAPE than those prescribed a nonselective ß-blocker. Cardioselective ß-blocker treatment during hospitalization and continuing after discharge appears to be superior to nonselective ß-blocker treatment in patients with COPD after MI.

Statins to prevent pacing-induced cardiomyopathy: Evidence from the bench applied to clinical studies.

BACKGROUND: Pacing-induced cardiomyopathy is an undesired outcome in patients with atrioventricular block (AVB), and our animal model showed lipotoxic cardiomyopathy after pacing. OBJECTIVES: The purpose of this study was to explore the mechanisms and clinical outcomes of statins in AVB patients receiving pacing. METHODS: Rat ventricular cardiomyocytes were treated with atorvastatin, liver X receptor (LXR) agonist, and LXR antagonist during pacing. Pigs were divided into 3 groups: right ventricular pacing, pacing with concomitant atorvastatin treatment, and sham control. Clinically, we enrolled 1717 AVB patients who had received a permanent pacemaker from Chang Gung Memorial Hospital Medical database. The primary outcome (cardiovascular death or heart failure [HF] hospitalization) and individual outcome were compared between statin and nonstatin groups after inverse probability of treatment weighting. RESULTS: Lipid accumulation in rat cardiomyocytes by pacing was significantly reduced by treatment with LXR agonist and atorvastatin, whereas LXR antagonist counteracted the atorvastatin effect on lipid expression. Left ventricular ejection fraction (LVEF) was significantly lower in the AVB pig pacing group compared to the group concomitantly treated with atorvastatin. Moreover, lipid accumulation and fibronectin expression were significantly ameliorated by concomitant treatment with atorvastatin. In the clinical study, the statin group had a significantly lower risk of the primary outcome event (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.56-0.84), less HF hospitalization (HR 0.45; 95% CI 0.30-0.67), and higher LVEF than the nonstatin group. CONCLUSION: In experimental models, atorvastatin ameliorated lipid accumulation in cardiomyocytes and fibrosis in left ventricular myocardium induced by pacing. Clinically, treatment with statins was associated with less HF hospitalization and cardiovascular death in AVB patients receiving pacemaker therapy.

Venous Thromboembolism and Critical Limb Events in Patients with Atrial Fibrillation: A Nationwide Population-Based Cohort Study.

Little is known about whether venous thromboembolism (VTE) causes worse critical limb events in populations with atrial fibrillation (AF). A retrospective cohort study using claims data from Taiwan's National Health Insurance program between 2001 and 2013 compared AF patients with or without VTE. Outcomes were percutaneous transluminal angioplasty (PTA), amputation, systemic thromboembolism, all-cause mortality, cardiovascular death, ischemic stroke, and acute myocardial infarction. Patients (n = 316,817) with newly diagnosed AF were analyzed; of those, 2514 (0.79%) had VTE history. After inverse probability of treatment weighting, a history of VTE was significantly associated with higher risks of PTA (3.3 vs 2.2%; subdistribution hazard ratio [SHR] 1.47; 95% confidence interval [CI] 1.17-1.84); above knee amputation (0.7 vs 0.3%; HR 2.15; 95% CI 1.10-4.21); systemic thromboembolism (5.8 vs 3.9%; SHR 1.48; 95% CI 1.21-1.80); all-cause mortality (53 vs 46.4%; HR 1.20, 95% CI 1.12-1.29); and cardiovascular death (34.8 vs 29.4%; HR 1.25, 95% CI 1.14-1.36). In conclusion, VTE might increase the risk of critical lower limb events (PTA and above-knee amputation), systemic thromboembolism, and mortality in the AF population. However, current data cannot confirm a causal relationship between VTE and clinical outcomes in this population.

Sarcomeres Morphology and Z-Line Arrangement Disarray Induced by Ventricular Premature Contractions through the Rac2/Cofilin Pathway.

The most common ventricular premature contractions (VPCs) originate from the right ventricular outflow tract (RVOT), but the molecular mechanisms of altered cytoskeletons of VPC-induced cardiomyopathy remain unexplored. We created a RVOT bigeminy VPC pig model (n = 6 in each group). Echocardiography was performed. The histopathological alternations in the LV myocardium were analyzed, and next generation sequencing (NGS) and functional enrichment analyses were employed to identify the differentially expressed genes (DEGs) responsible for the histopathological alternations. Finally, a cell silencing model was used to confirm the key regulatory gene and pathway. VPC pigs had increased LV diameters in the 6-month follow-up period. A histological study showed more actin cytoskeleton disorganization and actin accumulation over intercalated disc, Z-line arrangement disarray, increased ß-catenin expression, and cardiomyocyte enlargement in the LV myocardium of the VPC pigs compared to the control pigs. The NGS study showed actin cytoskeleton signaling, RhoGDI signaling, and signaling by Rho Family GTPases and ILK Signaling presented z-scores with same activation states. The expressions of Rac family small GTPase 2 (Rac2), the p-cofilin/cofilin ratio, and the F-actin/G-actin ratio were downregulated in the VPC group compared to the control group. Moreover, the intensity and number of actin filaments per cardiomyocyte were significantly decreased by Rac2 siRNA in the cell silencing model. Therefore, the Rac2/cofilin pathway was found to play a crucial role in the sarcomere morphology and Z-line arrangement disarray induced by RVOT bigeminy VPCs.

Usefulness of serial post-systolic shortening by speckle tracking echocardiography to predict major adverse cardiovascular events and segmental function improvement after acute myocardial infarction.

PURPOSE: The aim is to determine whether serial post-systolic shortening (PSS) using speckle tracking echocardiography (STE) could predict major adverse cardiovascular events (MACE), especially symptom-driven infarct-related artery (IRA) revascularization and improvement in segmental function in post-myocardial infarction patients. METHODS/RESULTS: Ninety-four patients (average age 61.1 ± 12.5 y, 84 [84.9%] male) with new-onset acute myocardial infarction were enrolled. Serial echocardiography was performed during the initial presentation, and at 3, 6 and 12 months after admission. PSS, strain and systolic strain rate were calculated using STE. Improvement in segmental function was defined as a decrease of ≧1 grade in wall motion score. During the follow-up (29.4 ± 12.7months), 22 patients (23.4%) had MACE and 17 patients had symptom-driven IRA revascularization. In multivariate model, PSS at 3 months was independently predictive for symptom-driven IRA revascularization (Hazard ratio (HR) = 0.5, 95% CI = 0.26-0.97) and for MACE (HR = 0.4, 95% CI = 0.24-0.67) (p < 0.05). Segmental function improvements were found in 255 segments (66.1%) and ROC curve analyses showed that AUC (95% CI) of the initial PSS was 0.7(0.65-0.77) (cut-off values = -1.08, sensitivity = 58%, specificity = 73% specificity). CONCLUSIONS: Post-systolic shortening at 3 months is an independent predictor for symptom-driven IRA revascularization and MACE. Regional wall motion recovery also could be predicted by initial PSS. Serial assessment of two-dimensional STE should be investigated in post-myocardial infarction patients in the future.

Inhibition of Notch Signaling Alleviated Diabetic Macrovasculopathy in an In Vitro Model.

BACKGROUND: Interactions between endothelial cells and vascular smooth muscle cells (VSMCs) through the Notch signal pathway causing diabetic microvasculopathy have been reported. OBJECTIVES: The purpose of this study was to investigate whether the effect of high glucose on VSMCs through the Notch-2 signaling pathway could induce extracellular matrix (ECM) accumulation, VSMC proliferation and migration and thus directly mediate diabetic macrovasculopathy. METHODS: Rat smooth muscle cells (SV40LT-SMC Clone HEP-SA cells) were cultured in different concentrations of D-glucose to evaluate the impact of high glucose on ECM accumulation including fibronectin and collagen I measured by Western blot analysis, and on VSMC proliferation and migration evaluated by MTT assay and wound healing assay. The expression of Notch-2 intra-cellular domain (Notch-2 ICD) protein was also checked in high glucose-stressed VSMCs. N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), an inhibitor of γ-secretase, was used to modulate the Notch-2 signaling pathway. RESULTS: High glucose (D-glucose 25 mM) induced fibronectin and collagen I expressions in VSMCs, promoted VSMC proliferation/migration, and enhanced the expression of Notch-2 ICD. DAPT inhibited Notch-2 signal to abolish the expressions of fibronectin and collagen I in VSMCs, and also prevented the proliferation/migration of VSMCs under high glucose (D-glucose 25 mM) stress. CONCLUSIONS: Our study suggests that high glucose can enhance the Notch-2 signaling pathway thereby directly mediating diabetic macrovasculopathy. Blocking the Notch-2 signaling pathway decreased fibronectin and collagen I expressions secreted by VSMCs, and reduced the proliferation and migration of VSMCs under high glucose stress. Inhibition of Notch-2 signaling represents a promising target for treating diabetic macrovasculopathy.

The implications of catheter ablation for solitary atrial flutter in preventing stroke risk: a nationwide population-based cohort study.

AIMS: The implications of ablation for atrial fibrillation in preventing stroke are controversial, and no studies have investigated whether ablation prevents ischaemic stroke (IS) in atrial flutter (AFL). METHODS AND RESULTS: This study analysed data contained in the Taiwan National Health Insurance Research Database for 16 765 patients with a first diagnosis of solitary AFL during 2001-2013. Eligible patients were divided into two groups according to whether or not they had received ablation. Propensity score matching (PSM) was performed to mitigate the effects of potential confounding factors. The primary outcome was occurrence of IS during follow-up. After 1:2 PSM, the analysis included 1037 patients in the ablation group and 2074 patients in the non-ablation group. The incidence of IS was lower in the ablation group compared to the non-ablation group [subdistribution hazard ratio (SHR) 0.61, 95% confidence interval (CI) 0.41-0.90] during the 2-year follow-up period but not thereafter (SHR 1.03, 95% CI 0.72-1.48). When grouping by stroke history, it revealed that ablation affected the incidence of stroke in patients without history of stroke (SHR 0.59, 95% CI 0.38-0.91) but not in patients with history of stroke. When each group was stratified by CHA2DS2-VASc score, ablation lowered the incidence of stroke in patients with CHA2DS2-VASc ≤3 (SHR 0.31, 95% CI 0.16-0.60) but not in patients with CHA2DS2-VASc ≥4 in the initial 2-year follow-up. CONCLUSION: The different incidence of IS in patients with/without ablation indicates that ablation reduces the risk of IS in AFL patients.

Effect of initiating statin therapy on long-term outcomes of patients with dyslipidemia after intracerebral hemorrhage.

BACKGROUND AND AIMS: Intracerebral hemorrhage (ICH) has a higher mortality than ischemic stroke. Statin is beneficial for stroke, but high potency statin treatment has been associated with the risk of hemorrhagic stroke. The aim of this study was to assess the impact of initiating statin therapy after ICH on cardiovascular outcomes. METHODS: Dyslipidemic patients were retrieved from the ICH population from the National Health Insurance Research Database in Taiwan. We retrospectively compared patients prescribed with and without statin treatment after ICH. Outcomes of interest were mortality, myocardial infarction, ischemic stroke, and hemorrhagic stroke during 5 years of follow-up. RESULTS: Of 17,980 adult patients with ICH and dyslipidemia, 8927 were eligible for analysis over the study period, including 1613 patients receiving statin therapy and 7314 patients not taking statins. After propensity score matching, the mean age was 61.2 ±â€¯12.2 years in the statin group and 61.6 ±â€¯13.0 years in the non-statin group. Hypertension was dominant, followed by diabetes mellitus, and the mean estimated NIHSS score was 12.9. The patients who received statin therapy were associated with lower risks of all-cause mortality (12.7% vs. 21.3%; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.45-0.65), cardiovascular death (4.0% vs. 7.1%; HR, 0.54; 95% CI, 0.39-0.75) and ICH (5.4% vs. 8.5%; HR, 0.62; 95% CI, 0.46-0.83) compared to those who did not receive statins. CONCLUSIONS: Initiating statin therapy after ICH was associated with a decreased risk of recurrent ICH and mortality for dyslipidemia patients.

Association between hepatitis C virus infection and osteoporotic fracture risk among postmenopausal women: a cross-sectional investigation in Taiwan.

PURPOSE: Early low bone mass is a risk factor for osteoporotic fractures associated with multiple factors, including menopause and chronic liver diseases. Hepatitis C virus (HCV) also plays a major role in chronic liver disease and has many extrahepatic consequences, such as decreased bone mineral density (BMD). This study aimed to examine the hypothesis that HCV seropositivity is independently associated with menopausal BMD loss. METHODS: This community-based, cross-sectional study was based in two rural townships in Yunlin County, Taiwan. A total of 636 menopausal women aged 45-80 years who underwent annual health checks were included. Viral markers of HCV, dual-energy X-ray absorptiometry and fracture risk assessment tool (FRAX) scores were measured. Logistic regression analysis was performed to assess the association between various predictors and the presence of low BMD. RESULTS: The participants (median age: 65 years) had a HCV seropositivity rate of 32.2%. BMD was significantly lower in the HCV-seropositive participants in different anatomic locations than in the seronegative individuals (lumbar spine: -1.5 vs -1.1; total hip: -0.9 vs -0.6; femoral neck: -1.2 vs -1.0; p<0.05). HCV-seropositive subjects had higher rates of major osteoporotic fractures (11.3%±7.6%vs 9.0±6.8%; p<0.001) and hip fractures (3.4%±4.7%vs 2.3±4.9%; p=0.006) and a higher risk of lower BMD (osteopenia and osteoporosis) based on a multivariable regression analysis (adjusted OR: 1.8; 95% CI 1.16 to 2.81; p=0.009). CONCLUSIONS: HCV infection may be an independent risk factor for menopausal BMD loss and fractures predicted by FRAX.

Liver X Receptor/Retinoid X Receptor Pathway Plays a Regulatory Role in Pacing-Induced Cardiomyopathy.

Background The molecular mechanisms through which high-demand pacing induce myocardial dysfunction remain unclear. Methods and Results We created atrioventricular block in pigs using dependent right ventricular septal pacing for 6 months. Echocardiography was performed to evaluate dyssynchrony between pacing (n=6) and sham control (n=6) groups. Microarray and enrichment analyses were used to identify differentially expressed genes ( DEG s) in the left ventricular ( LV ) myocardium between pacing and sham control groups. Histopathological and protein changes were also analyzed and an A cell pacing model was also performed. Pacing significantly increased mechanical dyssynchrony. Enrichment analysis using Ingenuity Pathway Analysis and the activation z-score analysis method demonstrated that there were 5 DEG s ( ABCA 1, APOD , CLU , LY 96, and SERPINF 1) in the LV septum (z-score=-0.447) and 5 DEG s ( APOD , CLU , LY 96, MSR 1, and SERPINF 1) in the LV free wall (z-score=-1.000) inhibited the liver X receptor/retinoid X receptor ( LXR / RXR ) pathway, and 4 DEG s ( ACTA 2, MYL 1, PPP 2R3A, and SNAI 2) activated the integrin-linked kinase ( ILK ) pathway in the LV septum (z-score=1.000). The pacing group had a larger cell size, higher degree of myolysis and fibrosis, and increased expression of intracellular lipid, inflammatory cytokines, and apoptotic markers than the sham control group. The causal relationships between pacing and DEG s related to LXR / RXR and ILK pathways, apoptosis, fibrosis, and lipid expression after pacing were confirmed in the cell pacing model. Luciferase reporter assay in the cell pacing model also supported inhibition of the LXR pathway by pacing. Conclusions Right ventricular septal-dependent pacing was associated with persistent LV dyssynchrony-induced cardiomyopathy through inhibition of the LXR / RXR pathway.

Discontinuing or continuing statin following intracerebral hemorrhage from the view of a national cohort study.

BACKGROUND AND AIMS: Statins improve clinical outcomes in patients with ischemic stroke but there is no evidence of the effect of continuing long-term statin therapy in patients with intracerebral hemorrhage (ICH). The aim of this study was to evaluate the impact of continuing statin after ICH. METHODS: Data on patients with ICH was retrieved from the National Health Insurance Research Database of Taiwan. The final population was separated into two groups according to those who continued and those who discontinued statin treatment. All-cause mortality and cardiovascular outcomes were analyzed after a 3 year follow-up after propensity score matching (PSM). RESULTS: Of the 114,101 patients with ICH, who were initially enrolled, 2468 patients with dyslipidemia and ICH were included. After PSM, the benefit of statin therapy on mortality appeared from 1 year to the end of the 3-year follow-up period after discharge (statin group versus non-statin group: 4.9% vs.12.3% at 1 year (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.26-0.57) and 12.9% vs. 25.3% at the end of the 3 year follow-up period (HR, 0.45; 95% CI, 0.35-0.58). Compared with the patients using lipophilic statins, those using hydrophilic statins had a significantly lower incidence of all-cause mortality (HR = 0.65, 95% CI = 0.43-0.99). There were no differences between those prescribed moderate-intensity statins and those prescribed high-intensity statins in terms of stroke and all-cause mortality (HR = 0.76; 95% CI = 0.40-1.46). CONCLUSIONS: There was a lower risk of all-cause mortality following ICH in patients who continued statin treatment compared with those without statin treatment, especially in those treated with hydrophilic statins.

Protein kinases are involved in the cardioprotective effects activated by platelet glycoprotein IIb/IIIa inhibitor tirofiban at reperfusion in rats in vivo.

The thrombolytic effect of platelet glycoprotein IIb/IIIa inhibitors (GP IIb/IIIa inhibitors) in myocardial infarction has been well established. Nevertheless, data on the mechanism of the cardioprotective effect of GP IIb/IIIa inhibitors in ischemic-reperfusion injury (IR) are lacking. Sprague-Dawley rats received 120 min of coronary ischemia and 180 min of reperfusion. A GP IIb/IIIa inhibitor was given via continuous intravenous infusion at a rate of 2 µg/kg/min 30 min prior to reperfusion with/without inhibitors of PKCε (chelerythrine), PI3 kinase and Akt (wortmannin), p38 MAPK (SB203582), p42/44 MAPK (PD98059) and ERK1/2 (u0126) 15 min prior to the GP IIb/IIIa inhibitor. Protein isolation and analysis were performed by Western blot analysis. The cardioprotective effects were measured as the ratio of myocardial necrotic area to the area at risk (AAR) and the apoptotic index (AI) calculated as the percentage of myocytes positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling of all myocytes stained by 4', 6-diamidino-2-phenylindole. The GP IIb/IIIa inhibitor reduced the ratio of myocardial necrotic area to AAR and AI, and also exerted an immediate cardioprotective effect by activating multiple signaling pathways including phosphorylation and activation of PKCε, PI3 kinase, Akt, p38 MAPK, p42/44 MAPK and ERK1/2. However, there were no significant increases in the phosphorylation of Raf and MEK1/2. We concluded that the GP IIb/IIIa inhibitor reduced the extent of cardiac IR and significantly ameliorate the apoptosis of myocytes in the rats. In addition, the cardioprotective effect was mediated through the activation of multiple signal transduction pathways.

The Unraveled Link Between Antiviral Therapy and Heart Failure Hospitalization in Chronic Hepatitis C Virus Infection　- A Nationwide Cohort Study.

BACKGROUND: Although hepatitis C virus (HCV) is a known risk factor for cardiovascular disease, whether antiviral therapy (AVT) can reduce heart failure (HF) hospitalizations is unknown.Methods and Results:In this population-based cohort study, we used data from the Taiwan National Health Insurance Research Database to evaluate the effect of interferon-based therapy (IBT) on cardiovascular events in patients with chronic HCV infection. Clinical outcomes evaluated included HF hospitalizations; a composite of acute myocardial infarction, ischemic stroke, and peripheral artery disease; all-cause death; and cardiovascular death. Of 83,229 eligible patients with chronic HCV infection, we compared 16,284 patients who received IBT with untreated subjects after propensity score matching. Patients who received IBT were less likely to be hospitalized for HF compared with untreated subjects (incidence density.ID, 0.9 vs. 1.5 events per 103person-years; hazard ratio.HR, 0.58; 95% confidence interval.CI, 0.42-0.79; P=0.001). Compared with untreated subjects, the treated group had significantly lower risk of composite vascular events (ID, 3.7 vs. 5.0 events per 103person-years; P<0.001), all-cause death (ID, 5.6 vs. 17.2 events per 103person-years; P<0.001), and cardiovascular death (ID, 0.2 vs. 0.6 events per 103person-years; P=0.001). CONCLUSIONS: AVT for chronic HCV infection might offer protection against HF hospitalizations, critical vascular events, and cardiovascular death beyond known beneficial effects.

Albuminuria and neck circumference are determinate factors of successful accurate estimation of glomerular filtration rate in high cardiovascular risk patients.

BACKGROUND: Estimated glomerular filtration rate (eGFR) is used for diagnosis of chronic kidney disease (CKD). The eGFR models based on serum creatinine or cystatin C are used more in clinical practice. Albuminuria and neck circumference are associated with CKD and may have correlations with eGFR. AIM: We explored the correlations and modelling formulates among various indicators such as serum creatinine, cystatin C, albuminuria, and neck circumference for eGFR. DESIGN: Cross-sectional study. METHODS: We reviewed the records of patients with high cardiovascular risk from 2010 to 2011 in Taiwan. 24-hour urine creatinine clearance was used as the standard. We utilized a decision tree to select for variables and adopted a stepwise regression method to generate five models. Model 1 was based on only serum creatinine and was adjusted for age and gender. Model 2 added serum cystatin C, models 3 and 4 added albuminuria and neck circumference, respectively. Model 5 simultaneously added both albuminuria and neck circumference. RESULTS: Total 177 patients were recruited in this study. In model 1, the bias was 2.01 and its precision was 14.04. In model 2, the bias was reduced to 1.86 with a precision of 13.48. The bias of model 3 was 1.49 with a precision of 12.89, and the bias for model 4 was 1.74 with a precision of 12.97. In model 5, the bias could be lower to 1.40 with a precision of 12.53. CONCLUSIONS: In this study, the predicting ability of eGFR was improved after the addition of serum cystatin C compared to serum creatinine alone. The bias was more significantly reduced by the calculation of albuminuria. Furthermore, the model generated by combined albuminuria and neck circumference could provide the best eGFR predictions among these five eGFR models. Neck circumference can be investigated potentially in the further studies.

Moderate to high intensity statin in dialysis patients after acute myocardial infarction: A national cohort study in Asia.

BACKGROUND AND AIMS: Statin is not beneficial for dialysis patients but moderate to high intensity statin is beneficial for patients after acute myocardial infarction (MI). The aim of this study was to evaluate the effect of moderate to high intensity statin on mortality, cardiovascular outcomes in dialysis patients after acute MI. METHODS: Data on dialysis patients were retrieved from the National Health Insurance Research Database in Taiwan. Dialysis patients admitted for MI were selected and divided into two groups according to statin prescription or not after MI. All-cause mortality and cardiovascular outcomes after a 4-year follow-up were analyzed after propensity score matching (PSM). RESULTS: We identified 790 patients who received moderate to high intensity statin therapy and 1788 patients who did not receive any statins after acute MI and clinical outcomes were analyzed after 1:1 PSM. The benefit of statin on mortality therapy appeared from 1 year to the end of the 4-year follow-up period after hospitalization (statin group versus non-statin group: 22.9% vs. 31.1% at 1 year (HR: 0.70; 95% CI: 0.58-0.85); 48.0% vs. 55.1% at the end of the 4 years (HR: 0.76; 95% CI: 0.67-0.88)). In addition, the impact of statin therapy was stronger in patients with shock at admission (p = 0.035). There were no differences in any individual cardiovascular outcome or adverse event. CONCLUSIONS: Moderate to high intensity statin therapy might lower all-cause mortality in dialysis patients after acute MI, especially those with shock, but not influence cardiovascular outcomes and any adverse events.

Effects of statin therapy on cerebrovascular and renal outcomes in patients with predialysis advanced chronic kidney disease and dyslipidemia.

BACKGROUND: Treatment with statin may be beneficial for patients with chronic kidney disease (CKD). However, the debate over the clinical importance of statin in patients with predialysis advanced CKD remains unresolved. OBJECTIVES: The objective of the article was to evaluate the effect of statin on mortality, cerebrovascular, and renal outcomes in patients with predialysis advanced CKD and dyslipidemia. METHODS: Data on predialysis advanced CKD patients were retrieved from the National Health Insurance Research Database based on the guidelines for prescribing regular erythropoietin-stimulating agent in CKD patients. Patients with dyslipidemia were further selected and divided into 2 groups by their statin use after the prescribed erythropoietin-stimulating agent. All-cause mortality and cerebrovascular and renal outcomes were analyzed after propensity score matching. RESULTS: There were 2016 and 14,412 patients in the statin and nonstatin groups. Their average follow-up periods were 3.7 and 3.0 years, respectively. After 1:2 propensity score matching, the annual all-cause mortality rate was higher in the nonstatin than in the statin group (143.99 vs 109.50 per 1000 person-years; P < .001; hazard ratio: 0.73; 95% confidence interval: 0.68-080). The annual risk of ischemic stroke (P = .186) and intracranial hemorrhage (P = .322) were not significantly different between the 2 groups. The nonstatin group had a higher risk of dialysis than the statin group (1269.45 vs 1095.00 per 1000 person-years; P = .002). Adverse events were not significant between the 2 groups. CONCLUSIONS: Statins may reduce the all-cause mortality and reduced the risk of dialysis in patients with predialysis advanced CKD and dyslipidemia. However, statins have no impact on ischemic-hemorrhage stroke.