Sodium-glucose cotransporter 2 inhibitors, inflammation, and heart failure: a two-sample Mendelian randomization study.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are increasingly recognized for their role in reducing the risk and improving the prognosis of heart failure (HF). However, the precise mechanisms involved remain to be fully delineated. Evidence points to their potential anti-inflammatory pathway in mitigating the risk of HF. METHODS: A two-sample, two-step Mendelian Randomization (MR) approach was employed to assess the correlation between SGLT-2 inhibition and HF, along with the mediating effects of inflammatory biomarkers in this relationship. MR is an analytical methodology that leverages single nucleotide polymorphisms as instrumental variables to infer potential causal inferences between exposures and outcomes within observational data frameworks. Genetic variants correlated with the expression of the SLC5A2 gene and glycated hemoglobin levels (HbA1c) were selected using datasets from the Genotype-Tissue Expression project and the eQTLGen consortium. The Genome-wide association study (GWAS) data for 92 inflammatory biomarkers were obtained from two datasets, which included 14,824 and 575,531 individuals of European ancestry, respectively. GWAS data for HF was derived from a meta-analysis that combined 26 cohorts, including 47,309 HF cases and 930,014 controls. Odds ratios (ORs) and 95% confidence interval (CI) for HF were calculated per 1 unit change of HbA1c. RESULTS: Genetically predicted SGLT-2 inhibition was associated with a reduced risk of HF (OR 0.42 [95% CI 0.30-0.59], P < 0.0001). Of the 92 inflammatory biomarkers studied, two inflammatory biomarkers (C-X-C motif chemokine ligand 10 [CXCL10] and leukemia inhibitory factor) were associated with both SGLT-2 inhibition and HF. Multivariable MR analysis revealed that CXCL10 was the primary inflammatory cytokine related to HF (MIP = 0.861, MACE = 0.224, FDR-adjusted P = 0.0844). The effect of SGLT-2 inhibition on HF was mediated by CXCL10 by 17.85% of the total effect (95% CI [3.03%-32.68%], P = 0.0183). CONCLUSIONS: This study provides genetic evidence supporting the anti-inflammatory effects of SGLT-2 inhibitors and their beneficial impact in reducing the risk of HF. CXCL10 emerged as a potential mediator, offering a novel intervention pathway for HF treatment.

Analysis of physical activity and prescription opioid use among US adults: a cross-sectional study.

BACKGROUND: Opioid crisis has become a global concern, but whether physical activity (PA) can effectively reduce prescription opioid use remains unclear. The study aimed to examine the relationship of different domains of PA (e.g., occupation-related PA [OPA], transportation-related PA [TPA], leisure-time PA [LTPA]) with prescription opioid use and duration of prescription opioid use. METHODS: This cross-sectional study was conducted on 27,943 participants aged ≥ 18 years from National Health and Nutrition Examination Survey (NHANES, 2007- March 2020). We examined the relationship of different domains of PA with prescription opioid use and duration of prescription opioid use using multivariable logistic regression. Stratified analysis and a series of sensitivity analysis were used to elevate robustness. All analyses were conducted using appropriate sampling weights. RESULTS: Of the 27,943 participants, the mean age was 45.10 years, with 14,018 [weighted, 50.0%] females and 11,045 [weighted, 66.0%] non-Hispanic White. After multivariable adjustment, inverse associations between PA and prescription opioid use were observed for sufficient (≥ 150 min/week) total PA (OR,0.68 95%CI [0.56-0.81]), TPA (OR,0.73 95%CI [0.58-0.92]), and LTPA (OR,0.60 95%CI [0.48-0.75]) compared with insufficient PA(< 150 min/week), but not for sufficient OPA (OR,0.93 95%CI [0.79-1.10]). In addition, the associations were dose-responsive, participants had 22-40%, 27-36%, and 26-47% lower odds of using prescription opioids depending on the duration of total PA, TPA, and LTPA, respectively. Nevertheless, the impact of PA on prescription opioid use varied by duration of opioid use. Sufficient total PA was associated with elevated odds of short-term use of prescription opioids (< 90 days). Comparatively, sufficient total PA, TPA, and LTPA had different beneficial effects on reducing long-term use of prescription opioids (≥ 90 days) depending on the strength of opioids. CONCLUSIONS: This study demonstrated sufficient total PA, TPA, and LTPA were inversely associated with prescription opioid use and varied depending on the duration and strength of prescription opioid use. These findings highlight PA can provide policy guidance to address opioid crisis.

ß-hydroxybutyrate administered at reperfusion reduces infarct size and preserves cardiac function by improving mitochondrial function through autophagy in male mice.

Ischemia/reperfusion (I/R) injury after revascularization contributes ∼50% of infarct size and causes heart failure, for which no established clinical treatment exists. ß-hydroxybutyrate (ß-OHB), which serves as both an energy source and a signaling molecule, has recently been reported to be cardioprotective when administered immediately before I/R and continuously after reperfusion. This study aims to determine whether administering ß-OHB at the time of reperfusion with a single dose can alleviate I/R injury and, if so, to define the mechanisms involved. We found plasma ß-OHB levels were elevated during ischemia in STEMI patients, albeit not to myocardial protection level, and decreased after revascularization. In mice, compared with normal saline, ß-OHB administrated at reperfusion reduced infarct size (by 50%) and preserved cardiac function, as well as activated autophagy and preserved mtDNA levels in the border zone. Our treatment with one dose ß-OHB reached a level achievable with fasting and strenuous physical activity. In neonatal rat ventricular myocytes (NRVMs) subjected to I/R, ß-OHB at physiologic level reduced cell death, increased autophagy, preserved mitochondrial mass, function, and membrane potential, in addition to attenuating reactive oxygen species (ROS) levels. ATG7 knockdown/knockout abolished the protective effects of ß-OHB observed both in vitro and in vivo. Mechanistically, ß-OHB's cardioprotective effects were associated with inhibition of mTOR signaling. In conclusion, ß-OHB, when administered at reperfusion, reduces infarct size and maintains mitochondrial homeostasis by increasing autophagic flux (potentially through mTOR inhibition). Since ß-OHB has been safely tested in heart failure patients, it may be a viable therapeutic to reduce infarct size in STEMI patients.

Association between secondhand smoke exposure and severe headaches or migraine in never-smoking adults.

OBJECTIVE: The study aimed to examine the relationship between secondhand smoke (SHS) exposure and severe headaches or migraine in never-smoking adults verified by serum cotinine. BACKGROUND: Current evidence about the association between self-reported SHS exposure and headaches or migraine is limited and contradictory. An important issue lies in the lack of actual SHS exposure assessment through biomarkers. METHODS: We conducted a cross-sectional study on 4560 never-smoking adults from the National Health and Nutrition Examination Survey (NHANES), 1999-2004. The SHS exposure was evaluated by measuring serum cotinine concentrations. The information regarding severe headaches or migraine was based on self-reporting. RESULTS: The overall prevalence rate of severe headaches or migraine was 20% (919/4560). After adjusting for relevant covariates, we found that heavy SHS exposure (serum cotinine at 1 to 10 ng/mL) was positively associated with severe headaches or migraine (OR: 2.02, 95% CI [1.19, 3.43]); however, no significant association was found between low SHS exposure (serum cotinine at 0.05 to 0.99 ng/mL) and severe headaches or migraine (OR: 1.15, 95% CI [0.91, 1.47]). Restricted cubic spline analysis showed that the natural logarithm of serum cotinine had a linear relationship with severe headaches or migraine (p = 0.335 for nonlinearity). Stratified analysis indicated that individuals with a BMI of <25 (p < 0.001 for interaction) and sedentary activity (p = 0.016 for interaction) modified the relationship between SHS exposure and severe headaches and migraine. Even after altering the definition of SHS exposure, excluding drugs that might affect the metabolism of serum cotinine, and multiple imputation, our sensitivity analysis results remained stable. CONCLUSIONS: The study demonstrated that heavy SHS exposure (serum cotinine at 1 to 10 ng/mL) had a significant positive association with severe headaches or migraine in never-smoking adults. Prospective studies are necessary to verify this relationship in the future.

Development and Validation of a Prediction Model for Chronic Post-Surgical Pain After Thoracic Surgery in Elderly Patients: A Retrospective Cohort Study.

Purpose: Chronic post-surgical pain (CPSP) is one of the adverse outcomes after surgery, especially in thoracotomy. However, the prevalence of CPSP in elderly adults (≥65 years), is still limited. Therefore, the present study was undertaken to establish and validate the prediction model of CPSP in those patients after thoracic surgery, including thoracotomy and video-assisted thoracoscopic surgery. Patients and Methods: This retrospective, observational single-center cohort study was conducted in Nanfang Hospital, Southern Medical University, which randomly and consecutively collected 577 elderly patients who underwent thoracic surgery between January 1, 2017, and December 31, 2020. According to the Akaike information criterion, the prediction model was built based on all the data and was validated by calibration with 500 bootstrap samples. Results: The mean age of participants was 69.09±3.80 years old, and 63.1% were male. The prevalence of CPSP was 26.9%. Age more than 75 years, BMI, blood loss, longer length of hospital stays, and higher pre-operative neutrophil count were associated with CPSP. Except for these factors, we incorporated history of drinking to build up the prediction model. The areas under the curve (AUCs) of the prediction models were 0.66 (95% CI, 0.61-0.71) and 0.64 (95% CI, 0.59-0.69) in the observational and validation cohorts, respectively. And the calibration curve of the predictive model showed a good fit between the predicted risk of CPSP and observed outcomes in elderly patients. Conclusion: The present developed model may help clinicians to find high-risk elderly patients with CPSP after thoracic surgery and take corresponding measures in advance to reduce the incidence of CPSP and improve their life quality.

Association of spironolactone treatment and arterial stiffness and cardiovascular disease in hypertensive patients.

Introduction: The aim of the current study was to evaluate the association of spironolactone and arterial stiffness and composite cardiovascular disease (CVD, including coronary heart disease, congestive heart failure and ischemic stroke) in hypertensive patients. Material and methods: Baseline data were collected and arterial stiffness was presented by carotid-femoral pulse wave velocity (cf-PWV) using applanation tonometry. Serum levels of fasting plasma glucose, total cholesterol, C-reactive protein and creatinine were measured using an automatic biochemistry analyzer. Plasma aldosterone concentration and plasma renin activity were determined by radioimmunoassay. The associations of spironolactone and arterial stiffness and composite CVD were evaluated. Results: Compared to patients without spironolactone (n = 274), those with spironolactone (n = 170) were older and more likely to have diabetes and chronic heart failure. No differences in antihypertensive medications used were observed except for spironolactone. Mean number of antihypertensive medications used was significantly higher in the spironolactone group (2.6 ±0.8 vs. 2.2 ±0.6). Compared to patients without spironolactone, those with spironolactone had significantly lower cf-PWV (9.4 ±1.8 vs. 10.1 ±2.2 m/s). After adjustment for covariates, spironolactone was still associated with 10% lower risk of arterial stiffness, with a 95% confidence interval (CI) of 0.85-0.97. In patients without arterial stiffness, after adjustment for covariates, no significant association of spironolactone and composite CVD was observed. However, in patients with increased arterial stiffness, after adjustment for covariates, spironolactone was still independently associated with 11% lower risk of composite CVD (95% CI: 0.83-0.97). Conclusions: Spironolactone treatment is independently associated with lower cf-PWV and lower prevalence of composite CVD in patients with increased arterial stiffness.

Association between Education Attainment and Guideline-Directed Medication Therapy in Patients with Heart Failure and Reduced Ejection Fraction.

Objective: The aim of the current study was to evaluate association of education attainment and guideline-directed medications therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF). Method: HFrEF patients were enrolled, and baseline characteristics were recorded. Based on highest educational attainment, patients were divided into low and high education attainment groups. Data on GDMT use at admission, discharge and follow-up were collected and between-group differences were evaluated. Results: A total of 336 patients were recruited, and 59.8% (n = 201) were defined as low education attainment. Patients with low education attainment were older and more likely to be female, obese and smokers. In addition, they had a higher prevalence of hypertension and valvular heart disease. Patients with low education attainment also had lower physical and mental component scores (PCS, 50.5 ± 6.4 vs. 56.3 ± 7.8), (MSC, 48.4 ± 6.0 vs. 54.7 ± 5.6) but higher serum NT-proBNP levels (1148.6 ± 233.4 vs. 1050.8 ± 205.6 pg/mL). Significant differences in GDMT use at admission, discharge and follow-up were observed. In the unadjusted model, high education attainment was associated with 2-fold odds of GDMT use at discharge. With adjustment for covariates, the high education attainment group remained significantly associated with being 22% more likely to receive GMDT at discharge. Similar findings were observed in associations between high education attainment and GDMT use at follow-up. After adjustment for PCS and MCS, high education attainment was still significantly associated with GDMT use at follow-up, with odds ratio of 1.13 and a 95% confidence interval of 1.08-1.28. Conclusion: HFrEF patients are under-treated. Education attainment is significantly associated with GDMT use at discharge and follow-up.

Association between lipoprotein (a) and heart failure with reduced ejection fraction development.

BACKGROUND: The current study aimed to evaluate the relationship between baseline serum lipoprotein (a) [Lp(a)] level and heart failure with reduced ejection fraction (HFrEF) development. METHODS: This was a retrospective study, and participants were enrolled from the outpatient clinic. All data were extracted from the electronic health record of the outpatient clinic system. The follow-up was performed through reviewing the clinical notes at the outpatient clinic system, and study outcome of the current study was the first diagnosis of HFrEF. Participants were divided into low Lp(a) (<30 mg/dl, n = 336) and high Lp(a) (≥30 mg/dl, n = 584) groups. RESULTS: Individuals in the high Lp(a) group were more likely to be men and have diabetes mellitus (DM) and dyslipidemia. Increased Lp(a) at baseline was positively associated with serum N-terminal pro-B natriuretic peptide level while negatively associated with left ventricular ejection fraction (LVEF) at follow-up. After adjusting for covariates, per 10 mg/dl increase in baseline Lp(a) remained significantly associated with HFrEF, with odds ratio of 1.17 (95% confidence interval of 1.05, 1.46). The magnitude of association between baseline Lp(a) level and HFrEF was greater in men and in individuals with DM or coronary heart disease (CHD), while it was weaker in individuals treated with beta-blocker at baseline. CONCLUSION: Increased Lp(a) at baseline was associated with HFrEF development. The adverse effects of Lp(a) were greater on men and individuals with DM or CHD, which were mitigated by beta-blocker therapy. These findings together underscore the possibility and usefulness of Lp(a) as a new risk factor to predict HFrEF.

The value of lactate/albumin ratio for predicting the clinical outcomes of critically ill patients with heart failure.

BACKGROUND: Previous studies have shown that the lactate/albumin (L/A) ratio plays a role in predicting the outcomes of septic shock or severe sepsis. However, the role of the L/A ratio in predicting the outcomes of critically ill patients with heart failure remains unclear. We therefore performed a retrospective study to clarify this issue. METHODS: The study was based on the Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) database and included critically ill adult patients with heart failure. The primary endpoints were 28-day and 1-year all-cause mortality after admission at the intensive care unit. RESULTS: We analyzed 4,562 patients in this study. We divided the participants into five groups according to the L/A ratio: quintile (Q)1 (L/A ratio ≤0.40, n=913), Q2 (0.40< L/A ratio ≤0.51, n=912), Q3 (0.51< L/A ratio ≤0.66, n=912), Q4 (0.66< L/A ratio ≤0.92, n=912), and Q5 (L/A ratio >0.92, n=913). After stratifying by L/A ratio, the risk of 28-day and 1-year mortality were significantly different between the groups (log-rank P<0.001). Compared with the first quintile, the second, third, fourth, and fifth quintiles of the L/A ratio were associated with higher 28-day [hazard ratio (HR) 1.57, 95% confidence interval (CI): 1.21-2.03 for Q3, HR 1.72, 95% CI: 1.34-2.21 for Q4, and HR 3.15, 95% CI: 2.47-4.01 for Q5) and 1-year mortality (HR 1.19, 95% CI: 1.00-1.41 for Q2, HR 1.36, 95% CI: 1.15-1.60 for Q3, HR 1.42, 95% CI: 1.20-1.67 for Q4, and HR 2.46, 95% CI: 2.09-2.89 for Q5). The restricted cubic spline showed that the L/A ratio positively correlated with both 28-day and 1-year all-cause mortality. CONCLUSIONS: The L/A ratio could serve as a predictor of short and long-term mortality in critically ill patients with heart failure.

Association of lipoprotein (a) and in-hospital outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

Objective: The current study was to evaluate the association of Lipoprotein (a) [Lp(a)] and in-hospital outcomes in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).Methods: ACS patients undergoing PCI were retrospectively enrolled. Based on Lp(a) level, patients were divided into low (<30 mg/dL) and high (≥30 mg/dL) Lp(a) groups.Results: Compared to those with low Lp(a), patients with high Lp(a) had larger numbers of coronary arteries ≥70% stenosis and had longer coronary artery lesion (P < 0.05). After adjustment for covariates, high Lp(a) remained associated with higher odds of having coronary artery ≥70% stenosis, type C coronary lesion and pre-PCI TIMI flow grade 1/0. Patients with high Lp(a) had a higher unadjusted odds of acute stent thrombosis (odds ratio [OR] 1.10 and 95% confidence interval [CI] 1.01-2.27), congestive heart failure (OR 1.24 and 95% CI 1.15-2.38) and composite in-hospital outcomes (OR 1.28 and 95% CI 1.18-2.42). After adjustment for covariates, patients with high Lp(a) still had a higher odds of congestive heart failure (OR 1.08 and 95% CI 1.01-1.78) and composite in-hospital outcomes (OR 1.12 and 95% CI 1.04-1.81).Conclusion: In ACS patients undergoing PCI, compared to those with low Lp(a), patients with high Lp(a) had more severe coronary artery lesion, higher risk of congestive heart failure and composite in-hospital outcomes.

Association of trimethylamine N-oxide with coronary atherosclerotic burden in patients with non-ST-segment elevation myocardial infarction.

BACKGROUND: Recently, trimethylamine N-oxide (TMAO) unexplained gut microbe has been proposed as a promising risk factor for atherosclerotic cardiovascular disease (CVD) pathogenesis and adverse events. The relationship of TMAO with coronary atherosclerotic burden has been evaluated in patients with stable coronary artery disease and ST-segment elevation myocardial infarction, but still needs to be explored in newly diagnosed non-ST-segment elevation myocardial infarction (NSTEMI) patients. MATERIAL AND METHODS: A prospective, single-center, SZ-NSTEMI trial (ChiCTR1900022366) is underway to investigate the relationship of TMAO with the severity and prognosis of coronary atherosclerosis in newly diagnosed NSTEMI patients who will undergo coronary angiography with primary percutaneous coronary intervention (pPCI). The primary endpoint of the study will be assessed the association of TMAO with coronary atherosclerotic severity quantify by the number of diseased coronary arteries and SYNTAX score after the coronary angiography. The secondary endpoints will be identified the TMAO as a prognostic biomarker for the short (1 month) and long-term (12 months) major cardiovascular and cerebrovascular events (MACCEs) rate including myocardial infarction, target vessel revascularization, stroke, heart failure, all-cause rehospitalization, and all-cause mortality after the pPCI. The blood samples will be collected from each patient before the procedure to measure the TMAO by isotope dilution high-performance liquid chromatography. In conclusion, SZ-NSTEMI will be the first cohort that will be investigated the association of TMAO with the severity and prognosis of coronary atherosclerotic burden in NSTEMI patients, aiming to identify TMAO as a predictor and a prognostic biomarker.

Gender-specific cardiovascular outcomes in patients undergoing percutaneous coronary intervention in Chinese populations.

BACKGROUND: Data was limited on the rates of in-hospital and 30-days composite outcomes between male and female patients with coronary heart disease (CHD) undergoing percutaneous coronary intervention (PCI). METHODS: This was a retrospective study and CHD patients undergoing PCI between January and December of 2018 were screened and recruited. Baseline characteristics, in-hospital and 30-days composite outcomes were compared by gender. The factors influencing gender-outcome associations were evaluated. RESULTS: A total of 672 CHD patients undergoing PCI were included into current analysis. Compared to males, females were older (53.8 ± 12.7 years vs 50.6 ± 11.8 years), more likely to be obese (32.9% vs 29.4%) and had higher prevalence of hypertension (46.7% vs 41%). Females were less likely to be smoker (30.3% vs 1.1%), have prior history of CHD (4.4% vs 10.9%), and lower socioeconomic status [SES; full-time employment (64.4% vs 71.9%), education attainment ≥ college (29.6% vs 36.8%) and annual income ≥60,000 RMB (23.7% vs 27.1%)]. Hospitalized stay was longer in females (median 5.2 vs 4.0 days), and females were more likely to experience in-hospital bleeding (3.0% vs 1.2%) and 30-days non-fatal myocardial infarction (5.9% vs 2.9%). In unadjusted model, compared to males, females had a crude odds ratio (OR) of 2.05 (95% confidence interval [CI] 1.68-2.59) for in-hospital composite outcomes and 2.16 (95% CI 1.74-2.63) for 30-days post-PCI composite outcomes. After adjustment for potential covariates, female gender remains independently associated with in-hospital and 30-days post-PCI composite outcomes. OR change was the greatest with adjustment for SES when compared to other covariates. CONCLUSION: Compared to male patients, female patients had a higher risk of in-hospital and 30-days composite outcomes post-PCI treatment, which were mainly attributed to the differences in SES.

Association of anti-hyperuricemia treatment and prevalent cardiovascular disease in hypertensive patients.

INTRODUCTION: The current study aimed to evaluate the association of anti-hyperuricemia treatment and prevalent cardiovascular disease (CVD) in hypertensive patients. MATERIAL AND METHODS: Primary hypertensive patients with hyperuricemia were enrolled. All participants were separated into two groups: anti-hyperuricemia and control groups (without anti-hyperuricemia treatment). Comparisons of prevalent CVD including coronary heart disease, ischemic stroke and heart failure were made and the associations of anti-hyperuricemia treatment and prevalent CVD were analyzed. RESULTS: Compared to the anti-hyperuricemia group, patients in the control group had significantly higher serum C-reactive protein (10.6 ±2.8 vs. 7.4 ±1.2 mg/dl) and uric acid (UA) levels (438 ±33 vs. 379 ±64 µmol/l), and were more likely to receive ß-blockers (34.2% vs. 31.1%) and calcium channel blockers (49.2% vs. 43.4%). The prevalence of ischemic stroke was higher in the control group (15.8% vs. 11.3%). Compared to other groups, blood pressure was significantly higher in patients in the 4th quartile serum UA level group. In the unadjusted model, anti-hyperuricemia treatment was significantly associated with a reduced odds ratio (OR) of composite CVD. After adjusting for potential covariates, OR of anti-hyperuricemia treatment for composite CVD was 0.89 with a 95% confidence interval (IC) of 0.82-0.98. Associations of anti-hyperuricemia treatment and ischemic stroke were also significant with OR = 0.93 and 95% CI: 0.88-0.99, while associations of anti-hyperuricemia with coronary heart disease and heart failure attenuated into insignificance after adjusting for covariates. CONCLUSIONS: In hypertensive patients with hyperuricemia, anti-hyperuricemia treatment was associated with lower odds of prevalent CVD.

HDAC inhibition induces autophagy and mitochondrial biogenesis to maintain mitochondrial homeostasis during cardiac ischemia/reperfusion injury.

AIMS: The FDA-approved histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA, Vorinostat) has been shown to induce cardiomyocyte autophagy and blunt ischemia/reperfusion (I/R) injury when administered at the time of reperfusion. However, the precise mechanisms underlying the cardioprotective activity of SAHA are unknown. Mitochondrial dysfunction and oxidative damage are major contributors to myocardial apoptosis during I/R injury. We hypothesize that SAHA protects the myocardium by maintaining mitochondrial homeostasis and reducing reactive oxygen species (ROS) production during I/R injury. METHODS: Mouse and cultured cardiomyocytes (neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes) I/R models were used to investigate the effects of SAHA on mitochondria. ATG7 knockout mice, ATG7 knockdown by siRNA and PGC-1α knockdown by adenovirus in cardiomyocytes were used to test the dependency of autophagy and PGC-1α-mediated mitochondrial biogenesis respectively. RESULTS: Intact and total mitochondrial DNA (mtDNA) content and mitochondrial mass were significantly increased in cardiomyocytes by SAHA pretreatment before simulated I/R. In vivo, I/R induced >50% loss of mtDNA content in the border zones of mouse hearts, but SAHA pretreatment and reperfusion treatment alone reverted mtDNA content and mitochondrial mass to control levels. Moreover, pretreatment of cardiomyocytes with SAHA resulted in a 4-fold decrease in I/R-induced loss of mitochondrial membrane potential and a 25%-40% reduction in cytosolic ROS levels. However, loss-of-function of ATG7 in cardiomyocytes or mouse myocardium abolished the protective effects of SAHA on ROS levels, mitochondrial membrane potential, mtDNA levels, and mitochondrial mass. Lastly, PGC-1α gene expression was induced by SAHA in NRVMs and mouse heart subjected to I/R, and loss of PGC-1α abrogated SAHA's mitochondrial protective effects in cardiomyocytes. CONCLUSIONS: SAHA prevents I/R induced-mitochondrial dysfunction and loss, and reduces myocardial ROS production when given before or after the ischemia. The protective effects of SAHA on mitochondria are dependent on autophagy and PGC-1α-mediated mitochondrial biogenesis.

Effects and potential mechanism of atorvastatin treatment on Lp-PLA2 in rats with dyslipidemia.

INTRODUCTION: The effects of statins on lipoprotein-associated phospholipase A2 (Lp-PLA2) are controversial, and the present study aimed to investigate whether atorvastatin could reduce Lp-PLA2 in rats with dyslipidemia. MATERIAL AND METHODS: A high-fat and high-cholesterol diet was prescribed to produce a dyslipidemia model. Thereafter, low-dose atorvastatin (5 mg/kg/day), high-dose atorvastatin (20 mg/kg/day) or saline (without-treatment group) was prescribed for 14 days. At 6 weeks after dyslipidemia model establishment and 14 days of atorvastatin treatment, fasting venous blood was drawn for biochemical analysis. Between-group differences and Pearson correlation analysis were conducted. RESULTS: Compared to the normal-control group, fasting plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly increased in dyslipidemia groups, while plasma nitric oxide (NO) levels were significantly decreased with attendant elevation of plasma C-reactive protein (CRP) and rho-associated kinase 1 (ROCK1) levels (p < 0.05). At 14 days of atorvastatin treatment, compared to the without-treatment group, plasma levels of TC and LDL-C in the high-dose group were significantly reduced (p < 0.05); and compared to low-dose and without-treatment groups, NO up-regulation (1.8 ±1.1 µmol/l), and CRP (-0.8 ±0.4 ng/ml), ROCK1 (-124 ±65 mmol/l) and Lp-PLA2 (-3.8 ±1.2 ng/ml) reduction were more significant in the high-dose group (p < 0.05). Pearson correlation analysis showed that TC (r = 0.365), LDL-C (r = 0.472), CRP (r = 0.501) and ROCK1 (r = 0.675) were positively correlated with Lp-PLA2, while NO (r = -0.378) and atorvastatin (r = -0.511) were negatively correlated with Lp-PLA2. CONCLUSIONS: Atorvastatin treatment is beneficial for reducing the Lp-PLA2 level in rats with dyslipidemia, which may be related to reduced ROCK1 expression in a dose-dependent manner.

Prevalence, risk factors, and prognostic significance of masked hypertension in diabetic patients.

The aims of present study were to evaluate the prevalence, risk factors, and prognostic significance of masked hypertension in diabetic patients. Using a cross-sectional design, 266 patients with documented type 2 diabetes mellitus and clinic blood pressure (BP) <140/90 mm Hg without antihypertension treatment were enrolled; 24-hour ambulatory BP monitoring was applied to evaluate mean 24-hour systolic/diastolic BP. Demographics, medical histories, and medications usage were obtained using questionnaire. Fasting venous blood was drawn for biochemical analysis. Approximately 26.5% of participants were diagnosed as masked hypertension with mean 24-hour systolic BP >130 mm Hg and/or mean 24-hour diastolic BP >80 mm Hg. Compared with those without masked hypertension, other than significantly higher mean 24-hour systolic/diastolic BP, patients with masked hypertension were more elderly, had higher serum glycated hemoglobin (HbA1c) and C-reactive protein (CRP) levels and higher prevalence of coronary heart disease (CHD). Multivariate regression analysis showed that aging, increased HbA1c and CRP levels, and prevalent CHD were independently associated with masked hypertension. Logistic regression analysis revealed that after adjusted for traditional risk factors including age, male sex, smoking status, low-density lipoprotein-cholesterol, CRP, clinic systolic BP, and HbA1c, masked hypertension remained independently associated with prevalent cardiovascular disease (CVD), with odds ratio of 1.31 and 95% confidence interval of 1.11 to 1.85. In summary, in diabetic patients, concurrent masked hypertension increases the odds of having CVD. Future randomized controlled trials are warranted to investigate whether screening and managing masked hypertension could reduce cardiovascular events in diabetic patients.

Association of adiponectin level and obstructive sleep apnea prevalence in obese subjects.

Obstructive sleep apnea (OSA) is prevalent in obese subjects. Plasma adiponectin level in obese subjects is decreased. Whether reduced adiponectin level is associated with OSA is unknown. Participants without a previous diagnosis of OSA or who have not been treated with continuous positive airway pressure were enrolled and parameters of interest were collected. Polysomnography was performed to evaluate the presence of OSA and the severity of OSA as indexed by the apnea-hypopnea index (AHI). Between-group differences were analyzed. Pearson correlation analysis was used to evaluate the association between body mass index (BMI) with plasma levels of adiponectin and C-reactive protein (CRP) and AHI; and the association between plasma adiponectin level with CRP and AHI was also evaluated. Logistic regression analysis was conducted to evaluate the association between per 1-SD standardized decrease of plasma adiponectin level and the prevalence of OSA using stepwise adjustment models. A total of 486 participants were enrolled and the mean BMI was 26.9 ±â€Š6.2 kg/m with obesity prevalence of 28%; and the mean AHI was 12.6 ±â€Š8.9 per sleep hour with OSA prevalence of 42%. The mean adiponectin level was 18.4 ±â€Š10.6 µg/mL. Compared with the nonobese group, participants in the obese group had higher BMI, neck girth, waist circumference, and AHI (P < .05 for all comparisons). The prevalence of OSA (51% vs 37%) and the proportion of moderate OSA (49% vs 42%) were also significantly higher, while adiponectin level (14.6 ±â€Š8.7 µg/mL vs 20.7 ±â€Š10.5 µg/mL) was significantly lower. In the obese group, plasma adiponectin level was decreased gradually with the increasing severity of OSA, which was not observed in the nonobese group. BMI was negatively correlated with adiponectin while positively correlated with CRP and AHI; and adiponectin was negatively correlated with both CRP and AHI. After adjusted for covariates including BMI and waist circumference, adiponectin remained significantly associated with OSA prevalence with odds ratio of 1.20 (95% confidence interval 1.12-1.65). In summary, our preliminary study suggests that in obese subjects, plasma adiponectin level is associated with the prevalence of OSA.

Increased Lipoprotein-associated phospholipase A2 activity portends an increased risk of resistant hypertension.

BACKGROUND: To investigate the relationship between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and incidence of resistant hypertension (RH). METHODS: This was a cross-sectional research. In essential, it was an observational design and collecting data on a population at a single point in time to evaluate the associations of studied variables. Totally 208 patients with arterial hypertension were enrolled. Baseline characteristics were collected and fasting venous blood were drawn for plasma Lp-PLA2 activity assessment. Twenty-four hour ambulatory blood pressure ambulatory (ABPM) was performed to diagnose RH. Initially, based on ABPM examination, all participants were divided into two groups, namely RH group and without RH group. And thereafter, in order to evaluate the effects of Lp-PLA2 activity on blood pressure, all participants were divided into low (< 225 nm/min/ml) and high (≥ 225 nm/min/ml) Lp-PLA2 activity groups based on the cut-off value of Lp-PLA2 activity. Comparisons were conducted between groups. RESULTS: Forty two patients were diagnosed as RH. Compared to patients without RH, patients with RH were more elderly, had more males, smokers, longer duration of hypertension, higher plasma C-reactive protein (CRP) level and Lp-PLA2 activity (P < 0.05 for all comparisons). More RH patients treated with calcium channel blocker and diuretic, while less treated with angiotensin converting enzyme inhibitor, angiotensin receptor blocker and statins (P < 0.05 for all comparisons). Compared to low Lp-PLA2 group, the rate of RH was significantly higher in high Lp-PLA2 group (26.7 % versus 6.1 %, P < 0.05). Multivariate regression analysis revealed that after adjusted for age, gender, smoking, body mass index, hypertension duration, CRP, and anti-hypertensive drugs, association between Lp-PLA2 activity and RH remained significant, with odds ratio (OD) of 2.02 (95 % confidence interval, CI 1.85-2.06, P < 0.05). Nonetheless, the association was attenuated when further adjusted for statins, with OR of 1.81 (95 % CI 1.74-1.93, P < 0.05). CONCLUSION: Increased plasma Lp-PLA2 activity portends increased risk of RH, and statins may be beneficial to reduce incidence of RH in subjects with increased plasma Lp-PLA2 activity.

Atorvastatin protects endothelium by decreasing asymmetric dimethylarginine in dyslipidemia rats.

BACKGROUND: Asymmetric Dimethylarginine (ADMA) is an inhibitor of endogenous nitric oxide synthase, which is the key synthase for nitric oxide (NO) production. Whether statins could protect endothelium by reducing ADMA concentration is unclear, and whether this effect is associated with the dose of statins usage is also needed further studied. METHODS: Dyslipidemia rat model was produced by giving high-fat and high-cholesterol diet for 8 weeks. Thereafter, low-dose (5 mg/kg body weight/day) and high-dose (20 mg/kg body weight/day) atorvastatin were orally prescribed for 4 weeks. Parameters of interest including lipid profiles, inflammatory and oxidative markers, NO production and plasma levels of ADMA and ADMA concentration of myocardium were evaluated. Liver enzymes and creatinine kinase (CK) were also detected for safety concern. RESULTS: At baseline, all parameters were comparable between the sham and the dyslipidemia groups. At 8 weeks of dyslipidemia establishment, as compared to the sham group, body weight and lipid profiles were significantly elevated, and plasma levels of C-reactive protein (CRP), malondialdehyde (MDA) and ADMA were concomitantly increased in accompanying with NO reduction in the dyslipidemia groups. With 4 weeks of atorvastatin therapy, as compared to the control group, lipid disorders and NO production were improved, and plasma levels of CRP, MDA and ADMA were significantly decreased in the high-dose atorvastatin group. ADMA concentration of cardiac tissues was also significantly reduced in the high-dose atorvastatin group. Notably, there was a trend to similar effects which did not reach statistical significance in the low-dose atorvastatin group when compared to the control group. Liver enzyme and CK were comparable after 4 weeks of atorvastatin therapy between groups. CONCLUSION: In rats with dyslipidemia, atorvastatin therapy could reduce plasma level of ADMA and ADMA concentration in cardiac tissues, and these effects are associated with the dose of atorvastatin therapy.

Effects of rosuvastatin combined with fasudil therapy on rabbits with dyslipidemia.

BACKGROUND: Present study was conducted to investigate the effects of rosuvastatin combined with fasudil on rabbits with dyslipidemia. METHODS: Dyslipidemia model of rabbits were produced by prescribing atherogenic diet for 2 weeks. Thereafter, 40 rabbits with dyslipidemia were randomly and evenly divided into four groups as follow: untreated group (orally prescribed 3 ml of normal saline), rosuvastatin group (orally prescribed 3 mg/kg body weight daily, dissolved in 3 ml of normal saline), fasudil group (intravenously prescribed 0.5 mg/kg body weight daily, dissolved in 3 ml of normal saline), and combined group (the same doses of rosuvastatin and fasudil as aforementioned). At baseline, 2 weeks of dyslipidemia establishment and 2 weeks of medical therapy, fasting venous blood was drawn for laboratory examination. RESULTS: After 2 weeks' atherogenic diet treatment, lipid disorders and impaired fasting glucose were observed. Systemic inflammation and oxidation were also promoted as revealed by increased serum levels of high sensitive C-reactive protein (Hs-CRP) and malondialdehyde (MDA). Notably, endothelial function has been impaired significantly as reflected by decreased nitric oxide (NO) production and increased serum asymmetric dimethylarginine (ADMA) level. RhoA associated kinase (ROCK) activity was also profoundly enhanced (P < 0.05). Inter-group comparisons showed that when compared to untreated group, modest improvements of endothelial function, inflammation and oxidation were observed in rosuvastatin and fasudil groups (P > 0.05). These benefits were improved more prominently in combined group (P < 0.05). Intra-group comparisons also showed that when compared to 2 weeks of dyslipidemia, slight improvement of endothelial function, inflammation and oxidation in rosuvastatin and fasudil groups were observed (P > 0.05). The improvements were more prominent in the combined groups (P < 0.05). CONCLUSION: Rosuvastatin combined with fasudil conferred synergistic effects on endothelium-protection and inflammation- and oxidation-amelioration in the setting of early stage of dyslipidemia.