Jiangui He

More Favorable Response to Cardiac Resynchronization Therapy in Women Than in Men

Background—Data on sex difference in response to cardiac resynchronization therapy (CRT) remain controversial. We conducted a meta-analysis to summarize all published studies to determine whether sex-based differences in response to CRT exist. Methods and Results—We performed a literature search using MEDLINE (source PubMed; January 1966 to March 2014) and EMBASE (January 1980 to March 2014) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Seventy-two studies involving 33 434 patients were identified. Overall, female patients had better outcomes from CRT compared with male patients, with a significant 33% reduction in the risk of death from any cause (hazard ratio, 0.67; 95% confidence interval, 0.61–0.74; P<0.001), 20% reduction in death or hospitalization for heart failure (hazard ratio, 0.80; 95% confidence interval, 0.71–0.90; P<0.001), 41% reduction in cardiac death (hazard ratio, 0.59; 95% confidence interval, 0.42–0.84; P<0.001), and 41% reduction in ventricular arrhythmias or sudden cardiac death (hazard ratio, 0.59; 95% confidence interval, 0.49–0.70; P<0.001). These more favorable responses to CRT in women were consistently associated with greater echocardiographic evidence of reverse cardiac remodeling in women than in men. Conclusions—Women obtained greater reductions in the risk of death from any cause, cardiac cause, death or hospitalization for heart failure, and ventricular arrhythmias or sudden cardiac death with CRT therapy compared with men, with consistently greater echocardiographic evidence of reverse cardiac remodeling in women than in men. Further studies are needed to investigate the exact reasons for these results and determine whether indications for CRT in women should be different from men.

B‐type natriuretic peptide attenuates cardiac hypertrophy via the transforming growth factor‐β1/smad7 pathway in vivo and in vitro

1. Previously, we showed that long‐term treatment of rats after myocardial infarction (MI) with B‐type natriuretic peptide (BNP) prevented ventricular remodelling. However, it is unclear whether long‐term BNP treatment affects cardiac hypertrophy and, if so, its mechanism of action. In the present study, we investigated the effects of long‐term BNP treatment on cardiac hypertrophy and the molecular mechanisms involved.

Cyclooxygenase mediates cardioprotection of angiotensin-(1-7) against ischemia/reperfusion-induced injury through the inhibition of oxidative stress

Angiotensin (Ang)-(1-7) exhibits cardioprotective effects in myocardial ischemia reperfusion (I/‌R)-induced injury. However, the roles of oxidation and cyclooxygenase (COX) in the cardioprotection of Ang-(1-7) remain unclear. This study was conducted to investigate whether oxidation and COX were involved in the cardioprotection of Ang-(1-7) against I/‌R-induced injury in isolated rat hearts. The hearts were subjected to 15 min regional ischemia followed by 30 min reperfusion. Myocardial I/‌R treatment induced significant cardiac dysfunction, including ventricular arrhythmia (VA) and a reduction of left ventricular systolic pressure (LVSP), cardiomyocyte apoptosis and oxidative stress, manifesting as an increase in malondialdehyde (MDA) production and a decrease in superoxide dismutase (SOD) activity. Pretreatment of the hearts with 1.0 nmol/‌l Ang-(1-7) for 30 min prior to ischemia considerably attenuated I/‌R-induced VA, apoptosis and MDA production, and enhanced LVSP and SOD activity. These cardioprotective effects of Ang-(1-7) were antagonized by the intraperitoneal injection of 5 mg/‌kg body weight indomethacin (IDM, a COX inhibitor), presenting as an enhancement of VA, apoptosis and MDA production as well as a reduction of LVSP and SOD activity. In conclusion, COX mediated Ang-(1-7)-induced cardioprotection via its antioxidative mechanism.

Exendin-4 attenuates cardiac hypertrophy via AMPK/mTOR signaling pathway activation

Diabetes mellitus is a prominent risk factor for cardiovascular diseases. Diabetic cardiomyopathy is an important complication of the heart independent of hypertension and coronary artery disease and is accompanied by cardiac hypertrophy. Cardiac hypertrophy easily leads to heart failure, which is a leading cause of morbidity and mortality. Glucagon-like peptide 1 (GLP-1) is an incretin hormone, which has various beneficial roles in the cardiovascular system, and exendin-4 is a highly potent glucagon-like peptide 1 receptor agonist. However, the role of GLP-1 in cardiac hypertrophy remains unknown. Our study revealed that exendin-4 treatment ameliorated phenylephrine (PE)-induced cardiac hypertrophy, which presented as decreased cardiac hypertrophic markers (ANP, BNP, and β-MHC) and cell surface area. This condition was significantly reversed upon treatment with the GLP-1 receptor antagonist exendin9-39. We also discovered that Erk1/2 and AMPK signaling pathways were involved in this process. Furthermore, our data demonstrate that the AMPK inhibitor compound C inhibited the anti-hypertrophic effect of exendin-4, which is associated with the mTOR/p70S6K/4-EBP1 signaling pathway. Finally, exendin-4 enhanced the anti-hypertrophic effect of rapamycin. In summary, our study disclosed that exedin-4 inhibits cardiac hypertrophy by upregulating GLP-1 receptor expression and activating the AMPK/mTOR signaling pathway.

Acute myocardial ischemia directly modulates the expression of brain natriuretic peptide at the transcriptional and translational levels via inflammatory cytokines

Cardiomyocyte stretching has been reported to be a major trigger for brain natriuretic peptide (BNP) release; however, an increase in circulating BNP is observed in patients with acute myocardial ischemia in the absence of increased left ventricular wall stress or cardiomyocyte stretching. In the present study, to investigate the direct and independent effects of acute myocardial ischemia on BNP expression and its mechanism, we established an in vitro glucose-free ischemia and hypoxia injured model of cultured rat cardiomyotes and proved hypoxia upregulated expressions of interleukin-6(il-6) and BNP. Further treatment with il-6 elicited dose- and time-dependent increases in BNP mRNA and protein expression as well as an upregulation in transforming growth factor-β1 (TGF-β1)/Smad2 expression, which was partially suppressed by a neutralizing antibody. In conclusion, our study showed that acute myocardial ischemia can directly upregulate BNP expression at the translational and transcriptional levels through the action of il-6, and this process is associated with the upregulation of TGF-β1/Smad2 signal path.

The nonpeptide AVE0991 attenuates myocardial hypertrophy as induced by angiotensin II through downregulation of transforming growth factor-β1/Smad2 expression

The nonpeptide AVE0991 is expected to be a putative new drug for cardiovascular diseases. However, the mechanisms for the cardioprotective actions of AVE0991 are still not fully understood. We planned to determine whether AVE0991 attenuates the angiotensin II (AngII)-induced myocardial hypertrophy and whether these AVE0991 effects involved transforming growth factor β1 (TGF-β1) and Smad2. A rat model of neonatal myocardial hypertrophy was induced by AngII. The AngII group significantly increased in protein content, surface area, and [3H]leucine incorporation efficiency by cardiomyocytes, compared to those of the control group (P < 0.01). The AngII group also had elevated TGF-β1 and Smad2 expression (P < 0.01). These AngII-induced changes were significantly attenuated by AVE0991 in a dose-dependent manner. In our study, these actions of AngII (10−6 mol/l) were significantly inhibited by both concentrations of AVE0991 (10−5 mol/l and 10−7 mol/l). Moreover, the high AVE0991 group had significantly better inhibition of myocardial hypertrophy than the low AVE0991 group. Meanwhile, the beneficial effects of AVE0991 were completely abolished when the cardiomyocytes were pretreated with Ang-(1–7) receptor antagonist A-779 (10−6 mol/l). These results suggested that AVE0991 prevented AngII-inducing myocardial hypertrophy in a dose-dependent fashion, a process that may be associated with the inhibition of TGF-β1/Smad2 signaling.

One-Year Clinical Outcome of Pulmonary Vein Isolation Using the Second-Generation Cryoballoon: A Meta-Analysis.

The second‐generation cryoballoon (CB‐2G) is a promising technique to treat atrial fibrillation (AF). It is necessary to summarize and analyze the available data on 1‐year clinical outcome of pulmonary vein isolation (PVI) with CB‐2G.

Ang-(1-7) offers cytoprotection against ischemia-reperfusion injury by restoring intracellular calcium homeostasis.

Abstract: Accumulating evidence indicates that angiotensin-(1–7) [Ang-(1–7)] offers protective effects against ischemia–reperfusion (I/R) induced arrhythmias and contractile dysfunction, which are related to disturbances of intracellular calcium homeostasis. However, whether or not Ang-(1–7) regulates intracellular calcium in I/R is not clear. To shed light on this issue, we carried out studies with a cellular model of simulated I/R in isolated rat ventricular myocytes and measured calcium transients using laser scanning confocal microscopy. Our results showed that Ang-(1–7) had no effects on the calcium transient in myocytes superfused with normal solution; however, in myocytes of simulated I/R, Ang-(1–7) significantly attenuated the increased diastolic intracellular Ca2+ during reperfusion, restored the decreased peak Ca2+ of calcium transient during ischemia, and reversed the decreased amplitude of calcium transient throughout the I/R periods. Additionally, Ang-(1–7) significantly suppressed the reactive oxygen species production in I/R, especially during the ischemic phase. These data indicated that Ang-(1–7) affords significant cytoprotective effects through directly improving calcium homeostasis independent of its anti-oxidative action. Most notably, the effects of Ang-(1–7) on intracellular Ca2+ dynamics manifests only in the diseased states, that is, I/R. This unique property suggests that upregulation of Ang-(1–7) expression and/or activation of the Ang-(1–7)/Mas signaling cascade is a highly desirable strategy for the treatment of myocardial impairment induced by I/R.

AMPK attenuates ventricular remodeling and dysfunction following aortic banding in mice via the Sirt3/Oxidative stress pathway

ABSTRACT Although recent findings have suggested that AMP‐activated protein kinase (AMPK) exerts inhibitory effects on cardiac remodeling secondary to hypertension, the mechanism and optimal duration of treatment remain unknown. Mice with descending aortic banding (AB) or subjected to sham operation received subcutaneous injection of either AICAR (0.5 mg g‐1 day‐1) or vehicle over 4 week periods. At the end of 4 week treatment, left ventricular (LV) remodeling and function were evaluated with histological analysis and echocardiography. Collagen deposition within the LV myocardium was detected with Massons trichrome staining. Collagen I, Collagen III, Smad 2, Smad 3, NOX2, NOX4 and Sirt3 (an important antioxidant factor) within the LV tissue were also evaluated. Compared with the sham group, the vehicle‐treated AB group exhibited significant elevations in cardiac remodeling and heart failure, characterized by an increase in LV weight relative to body weight, an increase in the area of collagen deposition, an increase in LV end‐diastolic diameter, an increase in mitral E inflow velocity to mitral A inflow velocity and increases in the gene expressions of the fibrosis markers Collagen I, III and Smad 2, 3 mRNA and decreases in EF and fractional shortening. AMPK attenuate the cardiac remodeling parameters and improve cardiac function. Moreover, the expressions of NOX2, NOX4 were significantly elevated in vehicle‐treated AB group. AMPK was able to significantly inhibit NOX2, NOX4 expression, while activate Sirt3 expression. AMPK significantly attenuated hypertension‐induced Ventricular remodeling and dysfunction, which may be mediated by the Sirt3/Oxidative stress signaling pathway.

AVE 3085, a novel endothelial nitric oxide synthase enhancer, attenuates cardiac remodeling in mice through the Smad signaling pathway.

AVE 3085 is a novel endothelial nitric oxide synthase enhancer. Although AVE 3085 treatment has been shown to be effective in spontaneously restoring endothelial function in hypertensive rats, little is known about the effects and mechanisms of AVE 3085 with respect to cardiac remodeling. The present study was designed to examine the effects of AVE 3085 on cardiac remodeling and the mechanisms underlying the effects of this compound. Mice were subjected to aortic banding to induce cardiac remodeling and were then administered AVE 3085 (10 mg kg day(-1), orally) for 4 weeks. At the end of the treatment, the aortic banding-treated mice exhibited significant elevations in cardiac remodeling, characterized by an increase in left ventricular weight relative to body weight, an increase in the area of collagen deposition, an increase in the mean myocyte diameter, and increases in the gene expressions of the hypertrophic markers atrial natriuretic peptide (ANP) and β-MHC. These indexes were significantly decreased in the AVE 3085-treated mice. Furthermore, AVE 3085 treatment reduced the expression and activation of the Smad signaling pathway in the aortic banding-treated mice. Our data showed that AVE 3085 attenuated cardiac remodeling, and this effect was possibly mediated through the inhibition of Smad signaling.