Hsu-Lung Jen

Associations between Endothelin-1 and Adiponectin in Chronic Heart Failure

Objectives: Endothelin-1 (ET-1) induces cardiac hypertrophy, whereas adiponectin may elicit protective effects in the vasculature and myocardium. We therefore evaluated the relationship between plasma ET-1 and adiponectin levels in heart failure (HF) patients, and the association between adiponectin expression and ET-1-induced hypertrophy of human cardiomyocytes (HCM) in vitro. Methods: One hundred seventeen patients with chronic HF were enrolled into this study. A group of 7 patients with end-stage HF undergoing heart transplantation was included in the histopathological study. Baseline clinical evaluations and laboratory measurements were performed. HCM cultures were studied to investigate the effect of ET-1 on cell size and adiponectin expression. Results: Plasma ET-1, adiponectin, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) increased with the severity of HF. Higher New York Heart Association functional class, plasma ET-1, adiponectin, and NT-proBNP levels were significant predictors of adverse outcomes in these patients. The myocardial expression of adiponectin was significantly higher in the recipient hearts of patients undergoing emergency or urgent heart transplantation. In cell culture, ET-1 significantly increased cell size and adiponectin expression in HCM. Conclusions: Adiponectin was significantly elevated in HF and was significantly associated with ET-1. The study provides a basis for further investigation of ET-1 and adiponectin modulation as a therapeutic strategy for ventricular remodeling in HF.

Effects of moderate alcohol consumption on inflammatory biomarkers.

Objectives — Although light to moderate alcohol consumption has been associated with lower allcause and cardiovascular (CV) mortality, the underlying mechanisms are only partly understood. Evidence has emerged in recent years that atherosclerosis is an inflammatory disease.We hypothesize that beneficial effects of moderate alcohol consumption on CV mortality may be linked to antiinflammatory effects. Methods and results — The association between alcohol consumption and concentrations of high sensitivity C-reactive protein (hs-CRP) and fibrinogen were investigated. Six hundred and thirtysix eligible individuals apparently healthy were included. 393 (61.8%) were men and 243 (38.2%) were women.The mean ages for men and women were 51.5 ± 12.4 y and 50.8 ± 12.1 y, respectively. Daily alcohol intake showed an apparent U-shaped association with hs-CRP and fibrinogen values in men, with lowest levels at an alcohol intake of 20-70 g daily (0.139 ± 0.116 mg/dl for hs-CRP and 274 ± 51.7 mg/dl for fibrinogen). Proportional odds model analysis showed moderate alcohol consumption (20 to 70 g vs. no drinking per day, OR = 0.32, 95% CI: 0.14-0.74), and regular exercise (≥3 times/week vs. no, OR = 0.52, 95% CI: 0.35-0.77) were negatively correlated with elevated hs-CRP values. Conclusions — Our results parallel the demonstration of a U-shaped relationship between alcohol consumption and cardiovascular mortality, and suggest that anti-inflammatory effects of moderate alcohol intake may partly be linked to a low cardiovascular and overall mortality.

Transradial approach in myocardial infarction

Objective This study investigates the feasibility, effi cacy, and safety of routine primary percutaneous coronary intervention via transradial approach in patients with acute ST-elevation myocardial infarction. Methods and results From 2005 to 2007, 122 consecutive patients with acute ST-elevation myocardial infarction within 12 hours, including those experiencing cardiogenic shock, were eligible for primary transradial PCI if the radial artery pulse could be felt. Effi cacy, safety, and major adverse cardiac events regarding mortality, recurrent non-fatal myocardial infarction, and revascularization were recorded. Eighty-fi ve of 122 patients underwent transradial PCI, and 37 had transfemoral PCI. Older women, haemodynamic instability, and the presence of severe chronic kidney disease (stages 4 and 5) or end-stage renal disease were signifi cantly related to choice of transfemoral approach (P < 0.05). Glycoprotein IIb/IIIa inhibitors were used more often in patients who underwent transradial PCI than in those who underwent transfemoral PCI (37% vs 16%; P = 0.043). The incidence of major bleeding complications requiring blood transfusion was signifi cantly higher in the transfemoral group (P= 0.004). A similar procedural success rate was achieved in both groups (P = 0.737). During follow-up of 580 days, the total major adverse cardiac events were similar in both groups (P = 0.299). Conclusions Routine transradial primary PCI can be safely and successfully performed on up to 70% of acute ST-elevation myocardial infarction patients and, compared with transfemoral approach, is associated with a signifi cantly reduced rate of major bleeding complications.

Transradial versus transfemoral rotablation for heavily calcified coronary lesions in contemporary drug-eluting stent era

Background Although radial access for drug-eluting stent (DES) combined with rotational atherectomy (RA) in patients with calcified coronary lesions may be associated with a lower risk of major bleeding complications and obtain favorable clinical results compared with femoral access, the long-term outcome data of this approach were limited in contemporary DES era. Methods & Results This retrospective study sought to compare in-hospital and long-term outcomes for patients undergoing RA via the transradial (TR) and transfemoral (TF) route in 126 consecutive patients (59 radial, 67 femoral) from 2009 to 2014. TR RA procedures were performed in 44/62 (71%) by the three TR operators, compared with 15/64 (23%) by the four TF operators in the present study. Significantly smaller diameter guide catheters and burrs (1.39 ± 0.16 mm vs. 1.53 ± 0.24 mm, P = 0.001) were used in the TR group. Procedural success rates were similar in both TR and TF groups. There was a significantly less major access site bleeding complications in favor of radial artery access (2% vs. 16%, P = 0.012). The incidence of in-hospital death or myocardial infarction was low in both groups. Although a trend of lower adverse event rate was demonstrated in the TR group compared with the TF one, no statistical significance (21% vs. 27%, P = 0.135) was detected. Conclusions Radial access, a useful alternative to femoral access for RA and DES, can be safely and successfully performed on up to 71% of the patients with heavily calcified coronary lesions needing RA by experienced TR operators.

Circulating Soluble Tumor Necrosis Factor-α and Cell Adhesion Molecules in Patients with Acute Cardiogenic Pulmonary Edema

Background: Circulating soluble tumor necrosis factor-alpha (TNF-α) and cell adhesion molecules (CAMs) are elevated in patients with heart failure. Whether this elevation plays a role in heart failure or is merely a marker of inflammatory response remains to be determined. We hypothesized that TNF-α activated the vascular endothelium, resulting in endothelial dysfunction and permeability changes that may play a role in the development of acute cardiogenic pulmonary edema. Materials and Methods: We measured plasma levels of TNF-α and three CAMs [vascular cell adhesion molecule-1, (VCAM-1) intercellular adhesion molecule-1, (ICAM-1) and P-selectin] in 35 patients (mean age, 64±14 years) with acute myocardial infarction. Patients who had acute pulmonary edema (APE) were placed in the APE group, and those with no pulmonary edema were placed in the non-APE group. Univariate and multivariate comparisons of the clinical and hemodynamic characteristics and levels of TNF-α and CAMs between these two groups were performed. Results: The left ventricular ejection fraction was significantly lower (p=0.00l), the left ventricular end-diastolic pressure was significantly higher (p=0.005), and the levels of the TNF-ct and VCAM-1 were also significantly higher (p＜0.0001 and p=0.003, respectively) in the APE group than in the non-APE group. After adjustment for possible adverse baseline variables, circulating levels of TNF-α and VCAM-1 remain significant predictors of the development of APE [hazard ratio (HR) 32.7, p=0.015 and HR 27.6, p=0.048, respectively]. Conclusions: These findings indicated that inflammation and immune activation were associated with the development of acute cardiogenic pulmonary edema.

Circulating Adiponectin Levels Following Treatment Can Predict Late Clinical Outcomes in Chronic Heart Failure.

BACKGROUND Circulating adiponectin concentration increases in patients with chronic heart failure (HF). We sought to explore the prognostic value of temporal changes in adiponectin concentration following treatment for chronic HF. METHODS Serum adiponectin levels were measured at baseline and after a 3-month anti-failure treatment in 124 patients with symptomatic chronic systolic HF. Major adverse cardiac events (MACE) including death, heart transplantation, or hospitalization with worsening HF during a median follow-up period of 752 days were determined. RESULTS Univariate and multivariate analysis showed that high levels of adiponectin after a 3-month treatment were associated with a 3.8-fold increased risk of MACE (p = 0.03), independent of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Moreover, the combining of circulating levels of adiponectin with NT-proBNP provided independent and additional prognostic value in identifying high risk patients with MACE during follow-up. CONCLUSIONS Changes in adiponectin and NT-proBNP over time provide prognostic information. When adiponectin is used in conjunction with NT-proBNP in chronic HF, the prognostic value may be better than if each biomarker is used separately.

Peroxisome Proliferator-Activated Receptor α Reduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-κB and Adiponectin

Peroxisome proliferator-activated receptor α (PPARα) plays a role in the pathogenesis of cardiac hypertrophy, although its underlying mechanism remains unclear. The purpose of this study was to evaluate the effect of PPARα activation on endothelin-1- (ET-1-) caused cardiomyocyte hypertrophy and explore its underlying mechanisms. Human cardiomyocytes (HCMs) were cultured with or without ET-1, whereafter the inhibitory effects of fenofibrate, a PPARα activator, on cell size and adiponectin protein were tested. We examined the activation of extracellular signal-regulated kinase (ERK) and p38 proteins caused by ET-1 and the inhibition of the ERK and p38 pathways on ET-1-induced cell size and adiponectin expression. Moreover, we investigated the interaction of PPARα with adiponectin and nuclear factor-κB (NF-κB) by electrophoretic mobility shift assays and coimmunoprecipitation. ET-1 treatment significantly increased cell size, suppressed PPARα expression, and enhanced the expression of adiponectin. Pretreatment with fenofibrate inhibited the increase in cell size and enhancement of adiponectin expression. ET-1 significantly activated the ERK and p38 pathways, whereas PD98059 and SB205380, respectively, inhibited them. Our results suggest that activated PPARα can decrease activation of adiponectin and NF-κB and inhibit ET-1-induced cardiomyocyte hypertrophy.

Endothelin-1-Induced Cell Hypertrophy in Cardiomyocytes is Improved by Fenofibrate: Possible Roles of Adiponectin

Aim: Previous studies demonstrated that endothelin-1 (ET-1) can significantly increase the cell size and stimulate adiponectin expression in cultured human cardiomyocytes (HCM). The aim of the present study was to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor-α (PPARα) activator, on cell hypertrophy and adiponectin expression in vitro and in a rat model of daunorubicin-induced cardiomyopathy. Methods: The cultured human cardiomyocytes (HCM) were stimulated with or without ET-1. The cell size and the protein expressions of PPARα and adiponectin were tested by confocal Immunofluorescence study and Western blot, respectively. To study the effects of PPARα activation on ET-1-induced cell hypertrophy and adiponectin protein synthesis, HCM were pretreated with fenofibrate or small interfering RNA (siRNA) of PPARα. Echocardiographic parameters were measured and immunohistochemistry study of myocardial adiponectin expression was conducted in the in vivo study. Results: ET-1 significantly increased the cell size, dose-dependently suppressed the expression of PPARα, and enhanced the expression of adiponectin; whereas, such an increase of cell size and enhancement of adiponectin expression were inhibited by the pre-treatment with fenofibrate. Addition of siRNA of PPARα abolished the effects of fenofibrate. Moreover, we found that fenofibrate treatment can significantly improve the left ventricular function and reverse the myocardial expression of adiponectin. Conclusions: Our study shows that fenofibrate may protect against ET-1-induced cardiomyocyte hypertrophy and enhanced adiponectin expression through modulation of PPARα expression in vitro and limitation of daunorubicin cardiotoxicity in vivo, suggesting a novel mechanistic insight into the role of PPARα and adiponectin in cardiac hypertrophy and heart failure.

Statin Therapy is Associated with Improved Clinical Outcomes in Patients Undergoing Emergency Percutaneous Coronary Intervention

Purpose: Previous studies have suggested that the use of statins after percutaneous coronary intervention (PCI) is associated with better clinical outcomes. However, lipid-lowering treatment with statins is a neglected therapeutic approach in patients undergoing PCI in Taiwan. This study investigated the current status of statin use and the effect of statin treatment on clinical outcomes in patients with acute myocardial infarction (AMI) undergoing emergency PCI. Methods: Two hundred and forty patients (aged 61±13 years, M/F=192/48) with AMI were enrolled. All of them underwent emergency coronary angiography and PCI. Patients were classified into 2 groups, those who were receiving continuous statin therapy (n=149, 62%) and those who were not (n=91, 38%). Cox proportional hazards model was performed to determine if continuous statin therapy was independently associated with a reduction in the risk of adverse clinical outcomes. Results: Our data demonstrated that continuous statin therapy was independently associated with a significant reduction (~35%) in the risk of adverse events (55% versus 36%; P=0.019). The adjusted odds ratio for the development of adverse events in patients receiving continuous statin therapy compared with patients who were not was 0.60 (95% CI, 0.41 to 0.90, P=0.012). Conclusion: Continuous statin therapy may reduce the risk of adverse clinical outcomes after PCI for AMI patients. However, the low use of statins (62%) in the study patients indicates that there is substantial room for improvement in implementation of statin therapy in AMI patients undergoing PCI.

Brachial Artery Distensibility as a Cardiovascular Risk Marker in Asymptomatic Individuals

Previous studies have shown that brachial arterial distensibility (BD) is a measure of arterial stiffness and may be used in risk assessment for cardiovascular disease (CVD). The aim of this study was to explore the predictive value of BD for CVD risk levels and to seek cardiovascular risk factors influencing BD. In this study, BD data were obtained using the DynaPulse 2000A instrument (Pulse Metric, Inc, USA) in 300 asymptomatic, apparently healthy subjects (M/F=152/148; aged 52±13 years) who were admitted for routine physical check-up. Family history, serum lipids and lipoproteins, glucose levels and mercury sphygmomanometer blood pressure measurements were obtained. The risk for CVD in each individual was assessed using the Framingham Risk Score system. Significant correlations were found between unadjusted BD and age, measures of blood pressure, height, body mass index, total cholesterol levels, LDL-cholesterol levels, and glucose levels. Multivariate regression analyses showed that age, systolic and diastolic blood pressures and glucose levels independently predicted changes in BD. There was a significantly negative correlation between BD and the Framingham risk scores (r=-0.45, P＜0.0001). Subjects with a 10-year risk for a future coronary heart disease events of ＜10% had significantly higher BD than those whose risk for coronary heart disease was 10% (6.12±1.25%/mmHg vs. 4.94±1.2%/mmHg, P=0.0001). These findings indicate that non-invasive measures of BD are effective in assessing CVD risk.