Epicardial Adipose Tissue-Derived Leptin Promotes Myocardial Injury in Metabolic Syndrome Rats Through PKC/NADPH Oxidase/ROS Pathway.

Background The epicardial adipose tissue (EAT) of metabolic syndrome (MetS) is abnormally accumulated with dysfunctional secretion of adipokines, closely relating to cardiac dysfunction. The current study was designed to identify the effects of EAT-derived leptin on the myocardium of MetS rats and explore the potential molecular mechanisms. Methods and Results A MetS rat model was established in 8-week-old Wistar rats by a 12-week high-fat diet. MetS rats exhibited increased leptin secretion from EAT, cardiac hypertrophy, and diastolic dysfunction with preserved systolic function. The myocardium of MetS rats had abnormal structure, increased oxidative stress injury, and higher inflammatory factor levels, especially the subepicardial myocardium, which was correlated with the EAT-derived leptin level but not the serum leptin. The EAT was separated from each group of rats to prepare EAT-conditioned medium. H9C2 rat cardiomyoblasts were treated with EAT-conditioned medium or leptin, plus various inhibitors. EAT-derived leptin from MetS rats promoted mitochondrial oxidative stress and dysfunction, induced mitochondrial pathway apoptosis, and inhibited cell viability in H9C2 cardiomyoblasts via the protein kinase C/reduced nicotinamide adenine dinucleotide phosphate oxidase/reactive oxygen species (PKC/NADPH oxidase/ROS) pathway. EAT-derived leptin from MetS rats stimulated inflammation in H9C2 cardiomyocytes by promoting activator protein 1 nuclear translocation via the PKC/NADPH oxidase/ROS pathway. Leptin promoted the interaction between p-p47phox and gp91phox in H9C2 cardiomyocytes via protein kinase C, activating nicotinamide adenine dinucleotide phosphate oxidase, increasing reactive oxygen species generation, and inhibiting cell viability. Conclusions EAT-derived leptin induces MetS-related myocardial injury through the following 2 cooperative ways via PKC/NADPH oxidase/ROS pathway: (1) inducing mitochondrial pathway apoptosis by promoting mitochondrial oxidative stress and dysfunction; and (2) stimulating inflammation by promoting activator protein 1 nuclear translocation.

Gender Differences in the Relationship of Waist Circumference to Coronary Artery Lesions and One-Year Re-Admission Among Coronary Artery Disease Patients with Normal Body Mass Index.

PURPOSE: The study explored the association of waist circumference (WC) with the severity of cardiovascular diseases and hospital readmission of coronary artery disease (CAD) patients with normal body mass index (BMI). PATIENTS AND METHODS: 213 female and 431 male normal-BMI CAD patients were enrolled and assigned in three groups based on their gender-specific WC tertiles. Their cardiovascular risk factors and coronary angiography characteristics were analyzed in a cross-sectional study, and the gender-specific relationship between WC and one-year re-admission rate was prospectively explored. RESULTS: The cross-sectional analysis showed that for male normal-BMI CAD patients, diabetes and dyslipidemia prevalence, Apo B/A1, hs-CRP, and uric acid levels triglycerides-glucose index, the incidence of left main disease, three vessel disease, calcification lesion, total occlusive lesion, and complex lesion, as well as Gensini score was in the order of WC tertile 3 > WC tertile 2 > WC tertile 1. In addition, male normal-BMI CAD patients in the highest WC tertile were at an increased risk of severe CAD (OR=2.21), and the correlation was still statistically significant even after adjusting for potential cardiovascular risk factors (OR=1.87). For female normal-BMI CAD patients, as the WC tertiles increased, uric acid level, the prevalence of three vessel disease, diffuse lesion, and complex lesion gradually increased (P <0.05), but no significant difference was found in the risk of severe CAD among different WC groups (all P >0.05). Prospective analyses showed that the higher the WC tertile was, the higher the one-year re-admission rate in men, but not in women, and after adjusting for other risk factors, men with the highest WC tertile showed more than twice the risk of patients with the lowest WC tertile. CONCLUSION: Male but not female, normal-BMI CAD patients with increased WC had more severe CAD and a higher risk of one-year re-admission rate.

Pericardial Adipose Tissue-Derived Leptin Promotes Myocardial Apoptosis in High-Fat Diet-Induced Obese Rats Through Janus Kinase 2/Reactive Oxygen Species/Na+/K+-ATPase Signaling Pathway.

Background Pathophysiologic mechanisms underlying cardiac structural and functional changes in obesity are complex and linked to adipocytokines released from pericardial adipose tissue (PAT) and cardiomyocyte apoptosis. Although leptin is involved in various pathological conditions, its role in paracrine action of pericardial adipose tissue on myocardial apoptosis remains unknown. This study was designed to investigate the role of PAT-derived leptin on myocardial apoptosis in high-fat diet-induced obese rats. Methods and Results Hearts were isolated from lean or high-fat diet-induced obese Wistar rats for myocardial remodeling studies. Obese rats had abnormal myocardial structure, diastolic dysfunction, greatly elevated cardiac apoptosis, enhanced cardiac fibrosis, and increased oxidative stress level. ELISA detected significantly higher than circulating leptin level in PAT of obese, but not lean, rats. Western blot and immunohistochemical analyses demonstrated increased leptin receptor density in obese hearts. H9c2 cardiomyoblasts, after being exposed to PAT-conditioned medium of obese rats, exhibited pronounced reactive oxygen species-mediated apoptosis, which was partially reversed by leptin antagonist. Moreover, leptin derived from PAT of obese rats inhibited Na+/K+-ATPase activity of H9c2 cells through stimulating reactive oxygen species, thereby activating calcium-dependent apoptosis. Pretreatment with specific inhibitors revealed that Janus kinase 2/signal transducer and activator of transcription 3 and phosphoinositide 3-kinase/protein kinase B signaling pathways were involved in leptin-induced myocardial apoptosis. Conclusions PAT-derived leptin induces myocardial apoptosis in high-fat diet-induced obese rats via activating Janus kinase 2/signal transducer and activator of transcription 3/reactive oxygen species signaling pathway and inhibiting its downstream Na+/K+-ATPase activity.

Elevated 1-h postload plasma glucose levels identify coronary heart disease patients with greater severity of coronary artery lesions and higher risk of 1-year re-admission.

OBJECTIVE: To investigate the relationship of 1-h postload plasma glucose during the oral glucose tolerance test with the severity of coronary artery lesions and risk of 1-year re-admission in coronary heart disease patients with normal glucose tolerance. METHODS: A total of 266 consecutive coronary heart disease patients who underwent coronary angiography and had normal glucose tolerance confirmed by oral glucose tolerance test during hospitalization were prospectively enrolled and followed in two groups according to the 1-h postload plasma glucose cut-off point (1-h postload plasma glucose <155 mg/dL, n = 149 and 1-h postload plasma glucose ⩾155 mg/dL, n = 117). Angiographic severity was assessed by number of diseased vessels, lesion morphology and Gensini score. The risk of 1-year re-admission with adverse cardiovascular events after discharge was analysed. RESULTS: Subjects with a 1-h postload plasma glucose ⩾155 mg/dL had higher incidence of multivessel disease and complex lesions, Gensini score and risk of 1-year re-admission than subjects with a 1-h postload plasma glucose <155 mg/dL (all p < 0.05). In the stepwise multivariate regression analysis, 1-h postload plasma glucose was the major determinant of the Gensini score. Subgroup analyses by sex showed that men with a 1-h postload plasma glucose ⩾155 mg/dL had higher incidence of complex lesions and risk of 1-year re-admission than men with a 1-h postload plasma glucose <155 mg/dL (all p < 0.05). CONCLUSION: Coronary heart disease patients with normal glucose tolerance and elevated 1-h postload plasma glucose levels had a greater severity of coronary artery lesions and an increased risk of re-admission with adverse cardiovascular events, particularly in men.

Monocyte/lymphocyte ratio is related to the severity of coronary artery disease and clinical outcome in patients with non-ST-elevation myocardial infarction.

Monocyte/lymphocyte ratio (MLR), a widely used inflammation maker for prognosis of cancer, tuberculosis, and autoimmune diseases, has attracted more and more attention for its application to cardiovascular disease. The aim of the present study was to investigate the relationship of MLR with the severity of coronary lesion and clinical outcomes in non-ST-elevation myocardial infarction (NSTEMI) patients.963 consecutive NSTEMI patients (mean age, 60.77 ±â€Š11.34; 758 male) undergoing coronary angiography were analyzed and followed in 3 groups according to the average MLR tertile (low MLR <0.23, n = 321; intermediate MLR 0.23-0.35, n = 322; high MLR >0.35, n = 320) in this study. The severity of coronary lesion was determined by Gensini score. Multiple linear regression analysis was used to examine the correlation between MLR and the severity of coronary lesion. Kaplan-Meier curve was performed to compare the long-term major adverse cardiac event (MACE)-free survival. Logistic regression analysis and Cox proportional hazard regression model were used to assess the independent predictors for in-hospital and long-term MACE.MLR (B: 0.281, 95% confidence interval [CI]: 0.130-0.432, P < .001) and high-sensitivity C-reactive protein (B: 0.017, 95% CI: 0.010-0.024, P < .001) were both independently correlated with the severity of coronary lesion, while neutrophil/lymphocyte ratio was not. The frequencies of in-hospital MACE (1.6%, 2.2%, 4.7%, P = .016) and long-term MACE (13.3%, 16.2%, 27.2%, P < .001) both increased among the 3 groups. Kaplan-Meier curve analysis indicated that patients in high MLR group had worse long-term MACE-free survival than the patients in low MLR group (P2 < .001) and intermediate MLR group (P3 = .004) during a median follow-up of 22 (12-35) months. MLR was an independent predictor for in-hospital MACE (adjusted odds ratio: 2.891, 95% CI: 1.265-8.354, P = .026) and long-term MACE (adjusted hazard ratio: 1.793, 95% CI: 1.169-2.515, P = .012) in NSTEMI patients.MLR is independently correlated with the severity of coronary lesion and has better performance to reflect the severity of coronary lesion than NLR. MLR is an independent predictor for the MACE in NSTEMI patients.

Effect of long-term lifestyle intervention on mild cognitive impairment in hypertensive occupational population in China.

BACKGROUND: The incidence of hypertension in China is high, which seriously affects people's health, including occupational population in mining areas. Cognitive dysfunction has a serious impact on the work and life of patients. Lifestyle intervention can improve diabetes and cardiovascular diseases. However, there are few studies on the effects of lifestyle interventions on cognitive function in hypertensive patients. So the aim of this study was to analyze the effect of long-term lifestyle intervention on mild cognitive impairment in hypertensive occupational population in China. METHODS: In September 2013, a cluster sampling was conducted for the workers in the Shaanxi Jinduicheng (intervention group) and Hancheng (control group) mining areas. In both groups, according to the blood pressure (BP) level, they were divided into hypertension stage 1 to 3 subgroups; according to their age, they were divided into between 45 and 59 and under 45 years subgroups; and according to whether or not taking medicine, they were divided into Lifestyle intervention, Lifestyle intervention plus medication, Medication, and No lifestyle intervention nor medication subgroups. The intervention group received regular lifestyle intervention for 2 years, which included diet, smoke, drink, and exercise intervention. Mild cognitive impairment was measured by the Montreal Cognitive Assessment (MoCA). The arterial stiffness was measured by Omron Automatic Atherosclerosis Tester. We conducted BP measurement and MoCA questionnaire at baseline, 6, 12, and 24 months. RESULTS: We analyzed a total of 510 mine workers, whose average age was 45.6 ±â€Š13.4 years old. With the increase of BP level, the MoCA scores decreased significantly both in control and lifestyle intervention groups (P < .05). There was no obvious difference between the hypertensive patients whose age was between 45 and 59 to those under 45 in MoCA scores (P > .05). After 2 years, the BP, total cholesterol, glucose, and brachial-ankle pulse wave velocity of the Lifestyle intervention subgroup and Lifestyle intervention plus medication subgroup decreased (P < .05), and the MoCA scores and ankle-brachial index increased (P < .05), and the latter improved more significantly. Compared with the No lifestyle intervention nor medication subgroup, the BP and MoCA scores had no obvious changes at 6 months (P > .05), but the BP decreased and the MoCA scores increased significantly in the Lifestyle intervention and Lifestyle intervention plus medication subgroups after 1 and 2 years of lifestyle intervention (P < .05). CONCLUSION: Long-term lifestyle intervention can be used as adjunctive therapy to improve the BP and cognitive function of hypertensive occupational population in China.

Family-based randomized trial to detect effects on blood pressure of a salt substitute containing potassium and calcium in hypertensive adolescents.

BACKGROUND: Potassium and calcium are important in blood pressure (BP) regulation. The aim of this study was to test the effects on BP of adding potassium and calcium to dietary salt. METHODS: A total of 325 adolescents selected with high BP (systolic BP (SBP) >or=90th percentile by age and sex) along with 978 family members. The adolescents were randomized into three groups by coin toss, and their families (300 total) were also allocated to the three groups: one in which 10 mmol of potassium and 10 mmol of calcium were added to the cooking salt, one encouraged to follow a salt-restricted diet, and a control group. In the salt-restricted group, salt intake was decreased gradually through health-behavior education to reach the goal of 50-100 mmol per person per day at 2 years. No intervention took place in for the control group. Salt sensitivity was determined by a volume expansion and contraction protocol at the beginning of the study. The three groups were followed up every 6 months for 2 years. RESULTS: At 2 years, systolic and diastolic blood pressure (SBP/DBP) had decreased by 5.9/2.8 mm Hg (4.7/3.6%) in the added-potassium-and-calcium group and by 5.8/1.0 mm Hg (4.8/1.4%) in the salt-restricted group; the values rose in the control group by 1.3/2.3 mm Hg (1.1/1.8%). There was no difference between the added-potassium-and-calcium group and the restricted-salt group (P = 0.24), but both differed significantly from the controls (P < 0.05). Similar changes in BP were found in family members. Subgroup analysis showed that the BP in salt-sensitive (SS) subjects decreased more than in the non-salt-sensitive (NSS) group (P < 0.05). CONCLUSION: A salt substitute containing potassium and calcium was as effective as sodium restriction in reducing BP in hypertensive adolescents and their families in a that rural Chinese community.

[Insulin resistance and effects of intravenous acute saline load on renal production of prostaglandin I2 and thromboxane A2 in salt-sensitive hypertensive patients].

OBJECTIVE: To investigate insulin resistance and the effects of intravenous acute saline load on renal production of prostaglandin I(2) (PGI(2)) and thromboxane A(2) (TXA(2)) in salt-sensitive hypertensive patients. METHODS: The 24-hour excretion of urinary 6-keto-prostaglandin F (PGF) 1alpha and thromboxane B(2) were measured before and after intravenous acute saline load in 53 hypertensive patients whose salt sensitivity had been determined. Oral glucose tolerance test and insulin release test were performed in all the subjects. RESULTS: after intravenous acute saline load, the 24-hour excretions of urinary 6-keto PGF 1alpha were significantly lower in salt-sensitive (SS) hypertensive patients than that in non-salt-sensitive (NSS) ones (316+/-57 pg/min vs 371+/-68 pg/min, P<0.01), and the decrease from baseline was much greater in SS group than that in NSS group (197+/-99 pg/min vs 136+/-101 pg/min, P<0.01). Both 24 hour urinary excretion of TXA(2) and the increase in urinary excretion of TXA(2) were significantly greater in SS hypertensive patients than those in NSS ones after salt loading (394+/-32 pg/min vs 359+/-44 pg/min, P<0.01, and 80+/-47 pg/min vs 47+/-45 pg/min, P<0.01, respectively). The plasma glucose and insulin concentrations in every time point were much higher in SS hypertensive subjects than that in NSS ones, and the former group had lower insulin sensitivity index than the latter (0.013+/-0.003 vs 0.018+/-0.004, P<0.01) CONCLUSION: Saline load produces significantly different effects on renal production of PGI(2) and TXA(2) in SS and NSS hypertensive patients, and these changes may be related to the pathophysiology of SS hypertensive patients after acute salt loading. Insulin resistance is greater in SS hypertensive patients than in NSS ones.