B-Type Natriuretic Peptide Inhibits the Expression and Function of SERCA2a in Heart Failure.

B-type natriuretic peptide (BNP) possesses protective cardiovascular properties; however, there has not been sufficient serious consideration of the side effects of BNP. As for sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), it was once considered a new target for the treatment of heart failure (HF). Nevertheless, clinical trials of SERCA2a gene therapy in HF have finally become unsuccessful. Research has found that elevated BNP levels and decreased SERCA2a expression are two important HF characteristics, which are always negatively correlated. We hypothesize that BNP inhibits SERCA2a expression and, therefore, exerts negative effects on SERCA2a expression and function.The effects of BNP on endogenous SERCA2a expression and function were tested in mice with HF induced by transverse aortic constriction and neonatal rat cardiomyocytes (NRCM). Furthermore, to verify the effects of BNP on exogenous SERCA2a gene transduction efficacy, BNP was added to the myocardium and cardiomyocytes infected with an adenovirus overexpressing SERCA2a.In vivo, BNP levels were increased, SERCA2a expression was reduced in both the BNP intervention and HF groups, and BNP reduced the overexpressed exogenous SERCA2a protein in the myocardium. Our in vitro data showed that BNP dose-dependently inhibited the total and exogenous SERCA2a expression in NRCM by activating the cGMP-dependent protein kinase G. BNP also inhibited the effects of SERCA2a overexpression on Ca2+ transience in NRCM.The expression and function of endogenous and exogenous SERCA2a are inhibited by BNP. The opposite relationship between BNP and SERCA2a should be given serious attention in the treatment of HF via BNP or SERCA2a gene therapy.

Direct comparison of coronary microvascular obstruction evaluation using CMR feature tracking and layer-specific speckle tracking echocardiography in STEMI patients.

PURPOSE: Layer-specific speckle tissue echocardiography (LS-STE) is a unique technique used to assess coronary microvascular obstruction (CMVO) that may offer more information on the myocardial anatomy of patients with ST-elevation myocardial infarction (STEMI). Cardiovascular magnetic resonance feature tracking (CMR-FT) has also been gaining popularity as a way to evaluate CMVO. The aim of the present study was to directly compare CMVO assessment in STEMI patients using CMR-FT and LS-STE. PATIENTS AND METHODS: A total of 105 STEMI patients with LS-STE, CMR-FT, and primary percutaneous coronary intervention (PPCI) were included in the study. Longitudinal peak systolic strain (LS), circumferential peak systolic strain (CS), and radial peak systolic strain (RS) were each used to evaluate CMVO using CMR-FT and LS-STE. RESULTS: Correlation coefficients were 0.56, 0.53, and 0.55 for CMR-FT CS vs. endocardial CS, midcardial CS, and epicardial CS comparisons, respectively, and 0.87, 0.51, and 0.32 for CMR-FT LS vs. endocardial LS, midcardial LS, and epicardial LS comparisons, respectively. Bland-Altman analysis revealed strong inter-modality agreement and little bias in endocardial LS, while the absolute of limited of agreement (LOA) value was 2.28 ± 4.48. The absolutes LOA values were 1.26 ± 11.16, -0.02 ± 12.21, and - 1.3 ± 10.27 for endocardial, midcardial, and epicardial respectively. Intraclass correlation coefficient value of 0.87 showed good reliability in endocardial LS, and moderate reliability with values of 0.71, 0.70, and 0.64 in endocardial, midcardial, and epicardial CS, respectively (all p < 0.001). CONCLUSIONS: CMR-FT is a viable technique for CMVO evaluation in STEMI patients. Endocardial LS showed good reliability for CMR-FT. STEMI patients can undergo LS-STE to assess the CMVO before PPCI.

Luteolin Pretreatment Ameliorates Myocardial Ischemia/Reperfusion Injury by lncRNA-JPX/miR-146b Axis.

Background: In the present study, we aimed to find out whether luteolin (Lut) pretreatment could ameliorate myocardial ischemia/reperfusion (I/R) injury by regulating the lncRNA just proximal to XIST (JPX)/microRNA-146b (miR-146b) axis. Methods: We established the models in vitro (HL-1 cells) and in vivo (C57BL/6J mice) to certify the protection mechanism of Lut pretreatment on myocardial I/R injury. Dual luciferase reporter gene assay was utilized for validating that JPX could bind to miR-146b. JPX and miR-146b expression levels were determined by RT-qPCR. Western blot was utilized to examine apoptosis-related protein expression levels, including cleaved caspase-9, caspase-9, cleaved caspase-3, caspase-3, Bcl-2, Bax, and BAG-1. Apoptosis was analyzed by Annexin V-APC/7-AAD dualstaining, Hoechst 33342 staining, as well as flow cytometry. Animal echocardiography was used to measure cardiac function (ejection fraction (EF) and fractional shortening (FS) indicators). Results: miR-146b was demonstrated to bind and recognize the JPX sequence site by dual luciferase reporter gene assay. The expression level of miR-146b was corroborated to be enhanced by H/R using RT-qPCR (P < 0.001 vs. Con). Moreover, JPX could reduce the expression of miR-146b, whereas inhibiting JPX could reverse the alteration (P < 0.001 vs. H/R, respectively). Western blot analysis demonstrated that Lut pretreatment increased BAG-1 expression level and Bcl-2/Bax ratio, but diminished the ratio of cleaved caspase 9/caspase 9 and cleaved caspase 3/caspase 3 (P < 0.001 vs. H/R, respectively). Moreover, the cell apoptosis change trend, measured by Annexin V-APC/7-AAD dualstaining, Hoechst 33342 staining, along with flow cytometry, was consistent with that of apoptosis-related proteins. Furthermore, pretreatment with Lut improved cardiac function (EF and FS) (P < 0.001 vs. I/R, respectively), as indicated in animal echocardiography. Conclusion: Our results demonstrated that in vitro and in vivo, Lut pretreatment inhibited apoptosis via the JPX/miR-146b axis, ultimately improving myocardial I/R injury.

Association of low-level lead exposure with all-cause and cardiovascular disease mortality in US adults with hypertension: evidence from the National Health and Nutrition Examination Survey 2003-2010.

BACKGROUND: To explore the association of low-level lead exposure with all-cause mortality and cardiovascular disease (CVD) mortality among hypertensive patients. METHODS: This cohort study enrolled 6453 adults with hypertension from the National Health and Nutrition Examination Survey 2003-2010 and followed mortality information through December 31, 2019. The baseline population were divided into four groups based on quartiles of blood lead levels (Q1: < 1.2 µg/dL, Q2: 1.2-1.6 µg/dL, Q3: 1.7-2.4 µg/dL, Q4: 2.5-4.9 µg/dL). The correlation of blood lead levels to mortality was investigated by Kaplan-Meier survival curves, restricted cubic spline (RCS), proportional hazard regression model, and subgroup analysis. RESULTS: During a median follow-up period of 136 (interquartile range 113, 164) months, a total of 1943 (30.1%) deaths were documented, among which 553 (28.5%) were due to CVD. Blood lead showed a linear dose-response relationship with all-cause and CVD mortality. After adequate adjusting for confounders, the risk of all-cause death rose by 23% for each unit increase in continuous variable blood lead (hazard ratio (HR): 1.23; 95% confidence interval (CI):1.16-1.30). When blood lead was a quartile group variable, participants in the Q 4 group had a 73% higher risk of death than those in the Q 1 group (HR:1.73; 95% CI: 1.43-2.10; P for trend < 0.001). The association for CVD mortality was analogous. The concordant results were achieved in the subgroup analysis. CONCLUSION: Elevated blood lead levels were strongly associated with an increased all-cause and CVD mortality in adults with hypertension, even at the reference range of blood lead.

LncRNA JPX targets SERCA2a to mitigate myocardial ischemia/reperfusion injury by binding to EZH2.

Long non-coding RNAs (lncRNAs) are pivotal regulators in heart disease, including myocardial ischemia/reperfusion (I/R) injury. LncRNA just proximal to XIST (JPX) is a molecular switch for X-chromosome inactivation. Enhancer of zeste homolog 2 (EZH2) is a core catalytic subunit of the polycomb repressive complex 2 (PRC2), which is involved in chromatin compaction and gene repression. This study aims to explore the mechanism of JPX regulating the expression of Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) by binding to EZH2 and preventing cardiomyocyte I/R damage in vivo and in vitro. First, we constructed mouse myocardial I/R and HL1 cell hypoxia/reoxygenation models, and found that JPX was low expressed in both models. JPX overexpression alleviated cardiomyocyte apoptosis in vivo and in vitro, reduced the I/R-induced infarct size in mouse hearts, lowered the serum cTnI concentration, and promoted mouse cardiac systolic function. The evidence implies that JPX can alleviate I/R-induced acute cardiac damage. Mechanistically, the FISH and RIP assays showed that JPX could bind to EZH2. The ChIP assay revealed EZH2 enrichment at the promoter region of SERCA2a. Both the EZH2 and H3K27me3 levels at the promoter region of SERCA2a were reduced in the JPX overexpression group compared to those in the Ad-EGFP group (P < 0.01). In summary, our results suggested that LncRNA JPX directly bound to EZH2 and reduced the EZH2-mediated H3K27me3 in the SERCA2a promoter region, protecting the heart from acute myocardial I/R injury. Therefore, JPX might be a potential therapeutic target for I/R injury.

The association between serum albumin and long length of stay of patients with acute heart failure: A retrospective study based on the MIMIC-IV database.

BACKGROUND: The purpose of this article is to assess the relationship between serum albumin level and long length of stay (LOS) of inpatients with acute heart failure (AHF) in the intensive care unit (ICU). METHODS: We retrospectively analyzed data of 2280 patients with AHF from the medical information mart for intensive care IV (the MIMIC-IV) database. Multivariate logistic regression was performed to evaluate the association between serum albumin and long LOS, and the development of the predictive model was based on independent predictors of long LOS. RESULTS: According to the statistical results, A negative linear relationship was presented between albumin and long LOS of AHF patients in the ICU (P for trend <0.001), and serum albumin could predict long LOS (AUC 0.649, 95%CI 0.616-0.683, P <0.001). Based on independent predictors, including respiratory failure (OR 1.672, 95%CI 1.289-2.169, P<0.001), WBC (OR 1.046, 95%CI 1.031-1.061, P<0.001), creatinine (OR 1.221, 95%CI 1.098-1.257, P<0.001), glucose (OR 1.010, 95%CI 1.007-1.012, P<0.001), lactic acid (OR 1.269, 95%CI 1.167-1.381, P<0.001), and albumin (OR 0.559, 95%CI 0.450-0.695, P<0.001), identified by multivariable logistic regression analysis, we developed the nomogram to predict the probability of long LOS of AHF patients in the ICU. The nomogram accurately predicted the probability of long LOS (AUC 0.740, 95%CI 0.712-0.768, P<0.001). The calibration suggested the predictive probability was highly consistent with the actual probability of long LOS. Decision curve analysis (DCA) also suggested that the nomogram was applicable in the clinic. CONCLUSION: Serum albumin level was negatively associated with LOS among AHF patients. The predictive model based on serum albumin has predictive value for evaluating the length of stay in AHF patients.

Triglyceride Glucose Index Increases Significantly Risk of Hypertension Development in Chinese Individuals Aged ≥45 Years Old: Analysis from the China Health and Retirement Longitudinal Study.

Objective: Our purpose was to explore the relationship between triglyceride glucose (TyG) index and the risk of new-onset hypertension in Chinese individuals aged ≥45 years. Methods: From 2011 to 2018, data from the China Health and Retirement Longitudinal Survey (CHARLS) were analyzed. The relationship between TyG index and hypertension was assessed utilizing Cox regression and restricted cubic spline (RCS) plot, and the importance of the TyG index in hypertension development was demonstrated by a random forest machine learning model. Finally, subgroup analysis was conducted to test for potential interactions on hypertension development between the TyG index and subgroups. Results: 19.7% of the 4755 individuals who were involved in this survey developed hypertension over an average follow-up period of 5.22 years. Compared with the first quartile of albumin, the multivariate HR (95% CI) for the risk of new-onset hypertension across the TyG index quartiles was 1.09 (0.89, 1.33), 1.09 (0.89, 1.33), and 1.29 (1.06, 1.58), respectively (P for trend <0.001). The RCS plot revealed a linear relationship (P for nonlinear = 0.322), and the random forest machine learning model illustrated that the TyG index was a significant hazard factor on hypertension development. There was no interaction between subgroups and the relationships of the TyG index with the prevalence of hypertension (all P-value >0.05). Conclusion: TyG index was an independent hazard indicator for new-onset hypertension, and routine measurement and control of TyG index level might be great for preventing hypertension development.

The evaluation of coronary microvascular obstruction in patients with STEMI by cardiac magnetic resonance T2-STIR image and layer-specific analysis of 2-dimensional speckle tracking echocardiography combined with low-dose dobutamine stress echocardiography.

This study was designed to assess coronary microvascular obstruction (MVO) in patients with acute ST-segment elevation myocardial infarction (STEMI) by cardiac magnetic resonance T2-weighted short tau inversion recovery (T2-STIR) image and layer-specific analysis of 2-dimensional speckle tracking echocardiography combined with low-dose dobutamine stress echocardiography (LDDSE-LS2D-STE). 32 patients were enrolled to perform cardiac magnetic resonance and echocardiography 5-7 days after primary percutaneous coronary intervention. Infarcted myocardium was categorized into MVO+ group and MVO- group by late gadolinium enhancement as gold standard. At T2-weighted image, the area of hyper-intense region and hypo-intense core inside were marked as A1, A2 and A2/A1 > 0 represented MVO. Strain parameters were composed of longitudinal strain (LS), circumferential strain and radial strain at rest and dobutamine stress. There were 94 MVO+ segments, 136 MVO- segments according to gold standard. 96 segments had hypo-intense core at T2-STIR image. The sensitivity and specificity of T2-STIR in detecting MVO were 91.49 and 92.65%. Endocardial LS was superior to other parameters, and stress endocardial LS was higher than that of resting endocardial LS (sensitivity: 77.11% vs 72.29%, specificity: 93.28% vs 83.19%, AUC: 0.87 vs 0.82, P < 0.05). The combination of T2-STIR and stress endocardial LS in parallel test could improve sensitivity significantly (98.05% vs 91.49%). T2-STIR has higher diagnostic value in detecting MVO with some limitations. However, LDDSE-LS2D-STE with cost-effective and handling may be a good alternative to T2-STIR. It provides additional and reliable diagnostic tools to identify MVO in STEMI patients after reperfusion.

Development and validation of a predictive model for adverse left ventricular remodeling in NSTEMI patients after primary percutaneous coronary intervention.

INTRODUCTION: To develop and validate clinical evaluators that predict adverse left ventricular remodeling (ALVR) in non-ST-elevation myocardial infarction (NSTEMI) patients after primary percutaneous coronary intervention (PCI). METHODS: The retrospective study analyzed the clinical data of 507 NSTEMI patients who were treated with primary PCI from the Affiliated Hospital of Xuzhou Medical University and the Second Affiliated Hospital of Xuzhou Medical University, between January 1, 2019 and September 31, 2021. The training cohort consisted of patients admitted before June 2020 (n = 287), and the remaining patients (n = 220) were assigned to an external validation cohort. The endpoint event was the occurrence of ALVR, which was described as an increase ≥ 20% in left ventricular end-diastolic volume (LVEDV) at 3-4 months follow-up CMR compared with baseline measurements. The occurrence probability of ALVR stemmed from the final model, which embodied independent predictors recommended by logistic regression analysis. The area under the receiver operating characteristic curve (AUC), Calibration plot, Hosmer-Lemeshow method, and decision curve analysis (DCA) were applied to quantify the performance. RESULTS: Independent predictors for ALVR included age (odds ratio (OR): 1.040; 95% confidence interval (CI): 1.009-1.073), the level of neutrophil to lymphocyte ratio (OR: 4.492; 95% CI: 1.906-10.582), the cardiac microvascular obstruction (OR: 3.416; 95% CI: 1.170-9.970), peak global longitudinal strain (OR: 1.131; 95% CI: 1.026-1.246), infarct size (OR: 1.082; 95% CI: 1.042-1.125) and left ventricular ejection fraction (OR: 0.925; 95% CI: 0.872-0.980), which were screened by regression analysis then merged into the nomogram model. Both internal validation (AUC: 0.805) and external validation (AUC: 0.867) revealed that the prediction model was capable of good discrimination. Calibration plot and Hosmer-Lemeshow method showed high consistency between the probabilities predicted by the nomogram (P = 0.514) and the validation set (P = 0.762) and the probabilities of actual occurrence. DCA corroborated the clinical utility of the nomogram. CONCLUSIONS: In this study, the proposed nomogram model enabled individualized prediction of ALVR in NSTEMI patients after reperfusion and conduced to guide clinical therapeutic schedules.

Comparison of Diagnostic Value Between STE+LDDSE and CMR-FT for Evaluating Coronary Microvascular Obstruction in Post-PCI Patients for STEMI.

Background: Coronary microvascular obstruction (CMVO) is closely associated with poor prognosis of ST-segment elevation myocardial infarction (STEMI) patients. However, data showing the comparison between cardiac magnetic resonance feature tracking (CMR-FT) and speckle tracking echocardiography (STE) combined with low-dose dobutamine stress echocardiography (LDDSE) in evaluating CMVO was scarcely available. We aimed to explore and compare the predictive value between CMR-FT and STE+LDDSE in detecting CMVO. Methods: Sixty-one STEMI patients were executed cardiac magnetic resonance and echocardiography within the first 5-7 days after primary percutaneous coronary intervention (PCI). The myocardial strain analysis was performed in STE, STE+LDDSE, and CMR-FT, and strain parameters included radial strain (RS), circumferential strain (CS), and longitudinal strain (LS). ROC curves were performed to predict infarcted myocardium segments with CMVO. Results: Finally, 324 infarcted myocardium segments were analyzed, including 100 infarcted segments with CMVO and 224 segments without CMVO by the gold standard assessment of late gadolinium-enhancement cardiac magnetic resonance imaging (LGE-CMR). The results showed that CS was generally superior to RS and LS in identifying CMVO. CS in CMR-FT facilitated the detection of CMVO, with a sensitivity, specificity, and accuracy of 78.00%, 81.25%, and 80.25%, respectively. The sensitivity, specificity, and accuracy of CS in STE combined with LDDSE were better than STE alone (76.00% vs 60.00%, 79.91% vs 64.29%, and 78.70% vs 62.96%, P < 0.05). In addition, CMR-FT is not superior to STE+LDDSE for detection of CMVO (P > 0.05). Conclusion: Low-dose dobutamine can improve the clinical value of STE for evaluating CMVO in STEMI patients. Compared with CMR-FT, STE+LDDSE might be a better choice for STEMI patients because of its safety, convenience, and low-cost.

Effects of angiotensin receptor neprilysin inhibitor on renal function in patients with heart failure: a systematic review and meta-analysis.

The angiotensin receptor neprilysin inhibitor (ARNI) has been recommended as a first-line treatment in patients with heart failure (HF). However, the effects of ARNI on renal function remain controversial.The PubMed, Embase, the Cochrane Library of Trials and Web of Science were searched in the period from inception to 31 January 2021. Randomised controlled trial, cohort studies and observational studies reporting at least one of renal function indicators were included.In patients with HF with reduced ejection fraction (HFrEF), ARNI did not lead to a significant decrease in estimated glomerular filtration rate (eGFR, p=0.87), and the risk of worsening renal function (WRF) dropped by 11% compared with control group. Though the level of serum creatinine (SCr) and serum potassium had a slight increase (p=0.01; p=0.02), in contrast to the baseline level, but without clinical significance. In patients with HF with preserved ejection fraction (HFpEF), the level of SCr and serum potassium did not have a significant change, and patients with HFpEF assigned to ARNI had a much lower rate of WRF (p=0.0007). In contrast to control group, both patients with HFrEF and HFpEF had a less decrease in eGFR and a lower rate of hyperkalaemia in ARNI group.ARNI did not lead to a significant decrease in eGFR in HFrEF. Compared with control group, ARNI could delay the progression of decrease in eGFR and result in less events of hyperkalaemia in patients with HF. Besides, patients with HFpEF had a lower rate in the events of WRF.

Combination pharmacotherapies for cardiac reverse remodeling in heart failure patients with reduced ejection fraction: A systematic review and network meta-analysis of randomized clinical trials.

Pharmacotherapies, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor II blockers (ARBs), ß-blockers (BBs), mineralocorticoid receptor antagonists (MRAs) and angiotensin receptor blocker-neprilysin inhibitor (ARNI), have played a pivotal role in reducing in-hospital and mortality in heart failure patients with reduced ejection fraction (HFrEF). However, effects of the five drug categories used alone or in combination for cardiac reverse remodeling (CRR) in these patients have not been systematically evaluated. A Bayesian network meta-analysis was conducted based on 55 randomized controlled trials published between 1989 and 2019 involving 12,727 patients from PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov. The study is registered with PROSPERO (CRD42020170457). Our primary outcomes were CRR indicators, including changes of left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV), indexed LVEDV (LVEDVI) and LVESV (LVESVI), and left ventricular end-diastolic dimension (LVEDD) and end-systolic dimension (LVESD); Secondary outcomes were functional capacity comprising New York Heart Association (NYHA) class and 6-min walking distance (6MWD); cardiac biomarkers involving B type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP). The effect sizes were presented as the mean difference with 95% credible intervals. According to the results, all dual-combination therapies except ACEI+ARB were significantly more associated with LVEF or NYHA improvement than placebo, ARB+BB and ARNI+BB were the top two effective dual-combinations in LVEF improvement (+7.59% [+4.27, +11.25] and +7.31% [+3.93, +10.97] respectively); ACEI+BB was shown to be superior to ACEI in reducing LVEDVI and LVESVI (-6.88 mL/m2 [-13.18, -1.89] and -10.64 mL/m2 [-18.73, -3.54] respectively); ARNI+BB showed superiority over ACEI+BB in decreasing the level of NT-proBNP (-240.11 pg/mL [-456.57, -6.73]). All tri-combinations were significantly more effective than placebo in LVEF improvement, and ARNI+BB+MRA ranked first (+21.13% [+14.34, +28.13]); ACEI+BB+MRA was significantly more associated with a decrease in LVEDD than ACEI (-6.57 mm [-13.10, -0.84]). A sensitivity analysis ignoring concomitant therapies for LVEF illustrated that all the five drug types except ARB were shown to be superior to placebo, and ARNI ranked first (+4.83% [+1.75, +7.99]). In conclusion, combination therapies exert more benefits on CRR for patients with HFrEF. Among them, ARNI+BB, ARB+BB, ARNI+BB+MRA and ARB+BB+MRA were the top two effective dual and triple combinations in LVEF improvement, respectively; The new "Golden Triangle" of ARNI+BB+MRA was shown to be superior to ACEI+BB+MRA or ARB+BB+MRA in LVEF improvement.

SERCA2a ameliorates cardiomyocyte T-tubule remodeling via the calpain/JPH2 pathway to improve cardiac function in myocardial ischemia/reperfusion mice.

Transverse-tubules (T-tubules) play pivotal roles in Ca2+-induced, Ca2+ release and excitation-contraction coupling in cardiomyocytes. The purpose of this study was to uncover mechanisms where sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a) improved cardiac function through T-tubule regulation during myocardial ischemia/reperfusion (I/R). SERCA2a protein expression, cytoplasmic [Ca2+]i, calpain activity, junctophilin-2 (JPH2) protein expression and intracellular localization, cardiomyocyte T-tubules, contractility and calcium transients in single cardiomyocytes and in vivo cardiac functions were all examined after SERCA2a knockout and overexpression, and Calpain inhibitor PD150606 (PD) pretreatment, following myocardial I/R. This comprehensive approach was adopted to clarify SERCA2a mechanisms in improving cardiac function in mice. Calpain was activated during myocardial I/R, and led to the proteolytic cleavage of JPH2. This altered the T-tubule network, the contraction function/calcium transients in cardiomyocytes and in vivo cardiac functions. During myocardial I/R, PD pretreatment upregulated JPH2 expression and restored it to its intracellular location, repaired the T-tubule network, and contraction function/calcium transients of cardiomyocytes and cardiac functions in vivo. SERCA2a suppressed calpain activity via [Ca2+]i, and ameliorated these key indices. Our results suggest that SERCA2a ameliorates cardiomyocyte T-tubule remodeling via the calpain/JPH2 pathway, thereby improving cardiac function in myocardial I/R mice.

Efficacy and safety of low dose ticagrelor in patients with acute coronary syndrome: a systematic review and meta-analysis.

Our aim was to examine clinical trials, provide guidance to practitioners and estimate the efficacy and safety of two agents by comparing low dose ticagrelor with standard dose clopidogrel in patients with acute coronary syndrome. We systematically looked through Pubmed, Embase, the Cochrane Library, Wanfang data and CNKI for trials comparing low dose ticagrelor with standard dose clopidogrel for the treatment of patients with ACS since the database was created. The primary endpoint for efficacy was the rate of major adverse cardiac events (MACEs). The primary endpoint for safety was the rate of major bleeding events. We also evaluated platelet function between low dose ticagrelor and standard dose clopidogrel in ACS patients. From 6744 articles, 16 studies including 1629 patients met the inclusion criteria. In contrast with standard dose clopidogrel, low dose ticagrelor significantly reduced MACEs (OR 0.39, 95% CI 0.26, 0.58) and the difference was statistically significant (p<0.01). No difference was noted for major bleeding events (OR 1.16, 95% CI 0.43, 3.08) between the two agents (p=0.77). In addition, low dose ticagrelor showed lower platelet aggregation rate than clopidogrel (standardised mean difference (SMD) -0.68, 95% CI -0.83 to 0.53) (p<0.01). Platelet reaction units for low dose ticagrelor were much lower than those for standard dose clopidogrel (SMD -2.46, 95% CI -2.85 to -2.07) (p<0.01). In comparison with standard dose clopidogrel, low dose ticagrelor significantly lowered the incidence of MACEs, improved left ventricular ejection fraction, decreased left ventricular end diastolic dimension and did not expand the risk of major bleeding events or minor or minimal bleeding events in ACS patients with a considerable safety and efficacy profile. In addition, low dose ticagrelor was associated with dramatically lower platelet aggregation compared with standard dose clopidogrel.

Luteolin Enhances Sarcoplasmic Reticulum Ca2+-ATPase Activity through p38 MAPK Signaling thus Improving Rat Cardiac Function after Ischemia/Reperfusion.

BACKGROUND/AIMS: A major challenge for current therapeutic strategies against ischemia/reperfusion (I/R) is the lack of effective drugs. Considering luteolin enhances the activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) to improve the systolic/diastolic function of rat hearts and cardiomyocytes during the I/R process, we studied the regulatory function of the p38 MAPK pathway in this protective mechanism. METHODS: Isolated cardiomyocytes and perfused hearts were separately divided into five groups and used to investigate I/R. The phosphorylation of p38 and phospholamban (p-PLB), the levels and activity of SERCA2a and the levels of proteins related to apoptosis were measured. Apoptotic cells were assessed using the TUNEL assay. Single-cell shortening, Ca2+ transients, and the decay of the mitochondrial membrane potential (Δψm) were detected. RESULTS: The p38 MAPK pathway was activated during the I/R process, and inhibiting it with SB203580 promoted p-PLB, which enhanced the activity of SERCA2a and relieved the calcium overload to promote the recovery of the Δψm and reduce cardiomyocyte apoptosis in I/R. Luteolin also suppressed the activation of the p38 MAPK pathway and showed cardioprotective effects during I/R injury. CONCLUSIONS: We conclude that luteolin enhances SERCA2a activity to improve systolic/diastolic function during I/R in rat hearts and cardiomyocytes by attenuating the inhibitive effects of the p38 pathway on p-PLB.

Luteolin Exerts Cardioprotective Effects through Improving Sarcoplasmic Reticulum Ca(2+)-ATPase Activity in Rats during Ischemia/Reperfusion In Vivo.

The flavonoid luteolin exists in many types of fruits, vegetables, and medicinal herbs. Our previous studies have demonstrated that luteolin reduced ischemia/reperfusion (I/R) injury in vitro, which was related with sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) activity. However, the effects of luteolin on SERCA2a activity during I/R in vivo remain unclear. To investigate whether luteolin exerts cardioprotective effects and to monitor changes in SERCA2a expression and activity levels in vivo during I/R, we created a myocardial I/R rat model by ligating the coronary artery. We demonstrated that luteolin could reduce the myocardial infarct size, lactate dehydrogenase release, and apoptosis during I/R injury in vivo. Furthermore, we found that luteolin inhibited the I/R-induced decrease in SERCA2a activity in vivo. However, neither I/R nor luteolin altered SERCA2a expression levels in myocardiocytes. Moreover, the PI3K/Akt signaling pathway played a vital role in this mechanism. In conclusion, the present study has confirmed for the first time that luteolin yields cardioprotective effects against I/R injury by inhibiting the I/R-induced decrease in SERCA2a activity partially via the PI3K/Akt signaling pathway in vivo, independent of SERCA2a protein level regulation. SERCA2a activity presents a novel biomarker to assess the progress of I/R injury in experimental research and clinical applications.