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Introduction and Objectives: Coronary microvascular dysfunction (CMD) is highly prevalent and is recognized as an important clinical entity in patients with coronary heart disease (CHD). Nevertheless, the association of CMD with adverse cardiovascular events in the spectrum of CHD has not been systemically quantified., Methods: We searched electronic databases for studies on patients with CHD in whom coronary microvascular function was measured invasively, and clinical events were recorded. The primary endpoint was major adverse cardiac events (MACE), and the secondary endpoint was all-cause death. Estimates of effect were calculated using a random-effects model from published risk ratios., Results: We included 27 studies with 11 404 patients. Patients with CMD assessed by invasive methods had a higher risk of MACE (RR, 2.18; 95%CI, 1.80-2.64; P<.01) and all-cause death (RR, 1.88; 95%CI, 1.55-2.27; P<.01) than those without CMD. There was no significant difference in the impact of CMD on MACE (interaction P value=.95) among different invasive measurement modalities. The magnitude of risk of CMD assessed by invasive measurements for MACE was greater in acute coronary syndrome patients (RR, 2.84, 95%CI, 2.26-3.57; P<.01) than in chronic coronary syndrome patients (RR, 1.77, 95%CI, 1.44-2.18; P<.01) (interaction P value<.01)., Conclusions: CMD based on invasive measurements was associated with a high incidence of MACE and all-cause death in patients with CHD. The magnitude of risk for cardiovascular events in CMD as assessed by invasive measurements was similar among different methods but varied among CHD populations., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: The CHA 2 DS 2 -VASc score, used to assess the risk of left atrial appendage thrombus (LAAT) formation in patients with atrial fibrillation (AF), has limited predictive value. Moreover, transesophageal echocardiography imaging, the gold standard diagnostic method to identify thrombi, is semi-invasive. Consequently, there is a need for alternative and noninvasive diagnostic methods for LAAT risk assessment., Methods: Deep proteomic analysis was conducted in plasma samples from 8 patients with nonvalvular AF, divided into thrombus and control groups (4 patients in each group) based on the presence or absence of LAAT. Biomarkers associated with LAAT were validated using an enzyme-linked immunosorbent assay in a cohort of 179 patients with available clinical, transthoracic, and transesophageal echocardiography data. Predictive models were developed to assess the improvement in LAAT identification., Results: The LAAT group had higher CHA 2 DS 2 -VASc scores, larger LA diameter, and lower LAA flow velocities. Deep proteomic analysis identified 30 differentially expressed proteins, including myosin light chain 4, prenylcysteine oxidase 1 (PCYOX1), and decorin as potential diagnostic biomarkers of LAAT. The model showed that PCYOX1 and decorin provided an area under the curve (AUC) of 0.970 for LAAT prediction compared with 0.672 in a model including the CHA 2 DS 2 -VASc score and LAA cauliflower morphology. The incremental value of proteomic biomarkers for LAAT in patients with nonvalvular AF was further confirmed with the net reclassification improvement and integrated discrimination improvement indices., Conclusions: Protein levels of PCYOX1 and decorin improve the predictive performance for LAAT in patients with nonvalvular AF., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: The aim of this study was to explore the potential of adhering to the American Heart Association's updated Life's Essential 8 (LE8) scores in delaying biological aging amid growing concerns about aging populations and related diseases., Methods: A total of 18 261 adults (≥ 20 years old) were examined using National Health and Nutrition Examination Survey data from 2005-2010 and 2015-2018. The LE8 includes 8 components, covering health behaviors and factors. Acceleration of biological aging was defined as an excess of biological/phenotypic age over chronological age, assessed by using clinical biomarkers. The association between LE8 score and biological aging was explored through regression analyses., Results: Each 10-point increase in LE8 scores was associated with a 1.19-year decrease in biological age and a 1.63-year decrease in phenotypic age. Individuals with high cardiovascular health (CVH) had a 90% reduction in their risk of accelerated aging based on biological age and an 81% reduction based on phenotypic age compared with individuals with low CVH. Bootstrap-based model estimates and weighted quantile sum regression suggested that health factors, particularly blood glucose, had strong impact on delaying aging. The association between smoking and biological aging seemed to differ depending on the definition of aging used. Among all subgroups, LE8 consistently correlated negatively with biological aging, despite observed interactions. Three sensitivity analyses confirmed the robustness of our conclusions., Conclusions: A higher CVH is associated with a lower risk of biological aging. Maintaining elevated LE8 levels across demographics, regardless of cardiovascular history, is recommended to delay aging and promote healthy aging, with significant implications for primary health care., (Copyright © 2024 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: A new computed tomography-derived fractional flow reserve (CT-FFR) technique with a "coarse-to-fine subpixel" algorithm has been developed to generate precise lumen contours. The aim of this study was to assess the diagnostic performance of this new CT-FFR algorithm for discriminating lesion-specific ischemia using wire-based FFR ≤ 0.80 as the reference standard in patients with coronary artery disease., Methods: This prospective, multicenter study screened 330 patients undergoing coronary CT angiography (CCTA) and invasive FFR (median interval 2 days) from 6 tertiary hospitals. CT-FFR was evaluated in a blinded fashion with a "coarse-to-fine subpixel" algorithm for lumen contour., Results: Between March 2019 and May 2020, we included 316 patients with 324 vessels. There was a good correlation between CT-FFR and invasive FFR (r=0.76, P<.001). The diagnostic sensitivity, specificity, and accuracy on a per-vessel level were 95.3%, 89.8%, and 92.0% for CT-FFR, and 96.4%, 26.4%, and 53.1% for CCTA>50% stenosis, respectively. CT-FFR showed improved discrimination of ischemia compared with CCTA alone overall (AUC, 0.95 vs 0.74, P<.001) and in intermediate (AUC, 0.96 vs 0.62, P<.001) and "gray zone" lesions (AUC, 0.88 vs 0.61, P<.001). The diagnostic specificity, accuracy, and AUC for CT-FFR (71.9%, 82.8%, and 0.84) outperformed CCTA (9.4%, 48.3%, and 0.66) in patients or in vessels with severe calcification (all P<.05)., Conclusions: CT-FFR with a new "coarse-to-fine subpixel" algorithm showed high performance in identifying hemodynamically significant stenosis. The diagnostic performance of CT-FFR was superior to that of CCTA in intermediate lesions, "gray zone" lesions, and severely calcified lesions. Clinical Trial Register: NCT04731285., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Patients with nephrotic syndrome are at high risk of venous thromboembolism (VTE), especially for primary membranous nephropathy (PMN). The phospholipase A2 receptor (PLA2R) is a marker of primary membranous nephropathy activity. This study investigated the predictive value of PLA2R antibodies in PMN for VTE., Methods: In this retrospective study, we included 97 PMN patients and evaluated the predictive value of serum PLA2R antibodies for VTE risk. Lower extremity venous ultrasound, renal vein ultrasound, or spiral computed tomography pulmonary arteriography were used to assess VTE events. Serum anti-PLA2R antibodies were detected by enzyme-linked immunosorbent assay (ELISA). The risk of VTE was stratified according to serum albumin levels., Results: Twenty PMN patients (21%) had thromboembolic events. Eight (15%) of patients with serum albumin >25g/l developed VTE, 6 of whom were positive for serum PLA2R antibodies. Positive serum PLA2R antibodies were significantly associated with VTE events in patients with serum albumin >25g/l (p=0.01). Age, sex, blood creatinine, serum albumin, and 24-h urine protein levels were not statistically different between the two groups. Kaplan-Meier analysis using the log-rank test revealed anti-PLA2R positive membranous nephropathy patients had more probability of VTE events than anti-PLA2R negative patients. Univariate Cox proportional hazards analysis revealed that lnPLA2R-Ab is an unfavorable predictor for VTE events in patients with serum albumin >25g/l (hazard ratio (HR) 2.1, p=0.01)., Conclusions: The PLA2R antibody was a risk predictor for thromboembolic events in patients with primary membranous nephropathy with serum albumin >25g/l., (Copyright © 2023 Elsevier España, S.L.U. All rights reserved.)

Background: Although patients with advanced liver disease have been included in studies evaluating fibrates for the treatment of primary biliary cholangitis (PBC), the frequency of biochemical responses and adverse effects for this group of patients was not reported separately and comprehensively., Aims: to evaluate the efficacy and safety of additional fenofibrate therapy in patients with advanced and ursodeoxycholic acid (UDCA)-refractory PBC., Methods: Patients were analyzed retrospectively to determine the clinical therapeutic effects of UDCA with additional fenofibrate therapy versus continued UDCA monotherapy. The liver transplantation (LT)-free survival and the alkaline phosphatase (ALP) normalization rates were estimated using Cox regression analyses and Kaplan-Meier plots with inverse probability of treatment weighting (IPTW)., Results: A total of 118 patients were included: 54 received UDCA alone and 64 received UDCA in combination with fenofibrate therapy. In the fenofibrate and UDCA groups, 37% and 11% of patients with advanced and UDCA-refractory PBC, respectively, achieved ALP normalization (P=0.001). Additional fenofibrate therapy improved both LT-free survival and ALP normalization rate after IPTW (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07-0.75, P=0.015; and HR: 11.66, 95% CI: 5.02-27.06, P=0.001, respectively). These effects were supported by parallel changes in the rates of liver decompensation and histologic progression, and the United Kingdom (UK)-PBC and Globe risk scores. During the follow-up period, serum levels of ALP and aminotransferase decreased significantly, while total bilirubin, albumin, platelet, serum creatinine, and estimated glomerular filtration rate remained stable in fenofibrate-treated participants. No fenofibrate-related significant adverse events were observed in our cohort., Conclusions: Additional fenofibrate therapy significantly improved LT-free survival and ALP normalization in patients with advanced and UDCA-refractory PBC. Furthermore, adding-on fenofibrate therapy appeared to be safe and well tolerated in this population., (Copyright © 2023 Elsevier España, S.L.U. All rights reserved.)

Purpose: To investigate the prognosis of patients with spontaneous remission (SR) of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN)., Patients and Methods: Patients diagnosed with MN were recruited after examining their renal biopsy in the Renal Department of China-Japan Friendship Hospital between January 2015 and September 2021. Among them, 24 patients with SR were included in this study and follow-up., Results: Twenty-four patients diagnosed with SR of PLA2R-associated MN were recruited; 11 were male, and 13 were female, with a mean age of 49.5±14.5 years (range, 30-77 years). The initial 24-hour urinary total protein and serum albumin levels were 0.29±0.14g/d and 37.5±4.4g/L, respectively, and the initial serum creatinine was 65.0±15.8μmol/L. During the follow-up of 33.9±19.1 months (range, 6-73 months), 22 (91.7%) patients maintained remission; however, one patient had impaired renal function due to acute coronary syndrome and coronary angiography findings, and one patient experienced a repeated relapse caused by respiratory tract infection, at 50 and 70 months. A systematic review of the relevant literature was conducted, and records of patients with SR of PLA2R-associated MN were retrieved from 16 case reports or case series with a total of 97 cases., Conclusions: Most patients with SR of MN had a promising long-term prognosis, with only a few cases of relapse., (Copyright © 2022 The Authors. Published by Elsevier España, S.L.U. All rights reserved.)

Background and Objective: Efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in combination with renin-angiotensin-system (RAS) blockers for CKD remains controversial. We conducted this meta-analysis to explore the effect of SGLT2 inhibitors combining with RAS blockers on cardiovascular outcomes in chronic kidney disease (CKD) patients., Methods: We searched Embase, PubMed, Web of Science, and Cochrane Library databases with the following keywords. "Renal Insufficiency, Chronic" or "Diabetic Nephropathies" and "Sodium-glucose cotransporter 2 inhibitors". We included randomized controlled trials (RCTs) based on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. The outcome events included cardiac and renal outcomes and other adverse events. This study is registered with PROSPERO: CRD42020218337., Results: Ten RCTs including 16,983 CKD patients met the inclusion criteria. Compared with placebo plus RAS blockers, SGLT2 inhibitors plus RAS blockers significantly reduced cardiovascular mortality and heart failure-related hospitalization rates (RR=0.78, 95% CI: 0.66-0.91, p=0.002; RR=0.7, 95% CI: 0.61-0.8, p=0.000). We also performed trials sequential analysis (TSA) and the results indicated that our results are reliable. Additionally, it significantly reduced the 24-h urinary albumin excretion rate (24hUAE) and the creatinine elevation rate (WMD=-0.19, 95% CI: -0.24 to -0.14; RR=0.61, 95% CI: 0.51-0.74, p=0.000), delayed progression to end-stage renal disease (ESRD) (RR=0.69, 95% CI: 0.59-0.81, p=0.000). Further, it had no significant effect on the incidence of renal-related adverse events or renal-related mortality. Although it decreased the estimated glomerular filtration rate (eGFR) (WMD=-5.4, 95% CI: -7.24 to -3.57), this effect was reversible., Conclusions: These data provide a well-document testimonial of the benefits of the combined use of SGLT2 inhibitors and RAS blockers for cardiovascular and renal outcomes in CKD patients., (Copyright © 2021 Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: Chronic kidney disease (CKD) is a risk factor for the development of acute kidney injury (AKI). Recent studies have revealed numerous biomarkers eligible for AKI prediction. However, the expression and performance of AKI biomarkers in acute injury superimposed on preexisting CKD (AonC) remain elusive. The aim of this study was to evaluate whether biomarkers which robustly expressed in acute kidney injury could predict acute injury based on CKD., Materials and Methods: Mice were classified into cohorts: AKI, CKD, AonC and sham. The AonC model mice were subjected to renal bilateral ischemia/reperfusion (I/R) injury fourteen days after intraperitoneally administrated with 20mg/kg aristolochic acid. Severity of acute ischemic injury was stratified by clamping the dissected bilateral renal arteries with non-traumatic microvascular clips for 20 or 35min. The AKI mice were induced with renal bilateral I/R injury and CKD mice were crafted with 20mg/kg aristolochic acid administrated intraperitoneally. Histology, genetic and protein expression of biomarkers were measured in three cohorts., Results: We found that serum creatinine dramatically increased in severe (sAonC) but not in moderate (mAonC) injury mice. Upregulation of Kidney injury molecule-1 (KIM-1) mRNA, tissue inhibitor of metalloproteinase-2 (TIMP-2), Syndecan-1 (SDC-1) mRNA and insulin-like growth factor binding protein-7 (IGFBP7) protein indicated the onset of mAonC. An increase in neutrophil gelatinase-associated lipocalin (NGAL), rhomboid-like protein 2 (RHBDL2), Syndecan-1 (SDC-1) mRNA and protein, and a decrease in IGFBP7 protein were associated with sAonC., Conclusions: Our study revealed the variational expression of AKI biomarkers in AonC kidneys, and uncovered IGFBP7 protein can be used as a sensitive biomarker to predict and differentiate AonC severity. The performance of RHBDL2 and SDC-1 in predicting severe AonC was promising, providing new biomarkers for predicting AonC., (Copyright © 2020 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: For patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI), it is unclear whether angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) are associated with reduced mortality, particularly with preserved left ventricular ejection fraction (LVEF). The goal of this study was to determine the association between ACEI/ARB and mortality in ACS patients undergoing PCI, with and without reduced LVEF., Methods: Data from the BleeMACS registry were used. The endpoint was 1-year all-cause mortality. The prognostic value of ACEI/ARB was tested after weighting by survival-time inverse probability and after adjustment by Cox regression, propensity score, and instrumental variable analysis., Results: Among 15 401 ACS patients who underwent PCI, ACEI/ARB were prescribed in 75.2%. There were 569 deaths (3.7%) during the first year after hospital discharge. After multivariable adjustment, ACEI/ARB were associated with lower 1-year mortality, ≤ 40% (HR, 0.62; 95%CI, 0.43-0.90; P=.012). The relative risk reduction of ACEI/ARB in mortality was 46.1% in patients with LVEF ≤ 40%, and 15.7% in patients with LVEF> 40% (P value for treatment-by-LVEF interaction=.008). For patients with LVEF> 40%, ACEI/ARB was associated with lower mortality only in ST-segment elevation myocardial infarction (HR, 0.44; 95%CI, 0.21-0.93; P=.031)., Conclusion: The benefit of ACEI/ARB in decreasing mortality after an ACS in patients undergoing PCI is concentrated in patients with LVEF ≤ 40%, and in those with LVEF> 40% and ST-segment elevation myocardial infarction. In non-ST-segment elevation-ACS patients with LVEF> 40%, further studies are needed to assess the prognostic impact of ACEI/ARB., (Copyright © 2019. Published by Elsevier España, S.L.U.)

Objectives: The aim of this study is to identify the clinical characteristics of primary Sjögren's syndrome (PSS) patients with pulmonary involvement and the associated factors for pulmonary involvement in PSS., Methods: We retrospectively reviewed clinical features, laboratory examinations, imaging tests, pathological results and therapeutic strategy of 367 PSS patients. Comparisons were made between two subgroups: PSS with pulmonary involvement and those without. Correlation between the pathology of minor salivary gland biopsy (MSGB) and diverse features with pulmonary involvement were detected by Pearson correlation analysis and associated factors were selected by multivariate logistic regression analysis., Results: The lung involved PSS patients had significantly higher level of inflammatory associated indexes (p<0.05). There is no significant correlation between pathology of MSGB and lung involvements. Age, elevated neutrophils level and hypoproteinemia are significantly associated with lung disease with in PSS cohort (p<0.05). As for therapeutic strategy, moderate dose prednisone (15-40mg/d) and cyclophosphamide (CTX) are mainly different between two subgroups., Conclusions: PSS patients with pulmonary involvements show enhanced inflammation. Age, elevated neutrophils level and hypoproteinemia are independent associated with pulmonary involvements in PSS patients. For those PSS with pulmonary involvement moderate dose of prednisone and CTX were still the mainstream., (Copyright © 2019 Elsevier España, S.L.U. All rights reserved.)

Background: The "secondary injury" theory of liver failure indicated that hyperammonaemia due to liver failure causes further deterioration of hepatocytes. Our previous studies have demonstrated that high blood ammonia levels may lead to hepatocyte apoptosis, as NH 4 Cl loading caused metabolic acidosis and an increase in sodium-hydrogen exchanger isoform 1 (NHE1). In this study, we established a hyperammonia hepatocyte model to determine the role of NHE1 in the regulation of hepatocyte apoptosis induced by NH 4 Cl., Materials and Methods: In current studies, intracellular pH (pHi) and NHE1 activity were analyzed using the pHi-sensitive dye BCECF-AM. The results showed that intracellular pH dropped and NHE1 activity increased in hepatocytes under NH 4 Cl treatment. As expected, decreased pHi induced by NH 4 Cl was associated with increased apoptosis, low cell proliferation and ATP depletion, which was exacerbated by exposure to the NHE1 inhibitor cariporide. We also found that NH 4 Cl treatment stimulated PI3K and Akt phosphorylation and this effect was considerably reduced by NHE1 inhibition., Conclusion: This study highlighted the significant role of NHE1 in the regulation of cell apoptosis induced by hyperammonaemia., (Copyright © 2018 Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: Recent studies have shown that rapid atrial pacing causes atrial electrical remodeling. However, the influence of the vagus nerve on atrial electrical remodeling is not clear., Methods: This study involved 24 dogs divided into three groups. In the control group, the inducibility of atrial fibrillation (AF) during vagal stimulation (VS(1)) was investigated. In the pacing group, the atrial effective refractory period (AERP) was determined before and after pacing in the left superior pulmonary vein (LSPV). In the vagal stimulation (VS) plus pacing group, the LSPV was subjected to rapid electrical pacing after vagal stimulation (VS(2)), and the AERP was measured both before VS(2) and after pacing. The I(KACh) density was measured in LSPV and atrial myocardial cells in the three groups using the patch-clamp technique., Results: The duration of induced AF was greater in the pacing group than in the control or VS-plus-pacing group. In the pacing group, the AERP was markedly shortened and the AERP dispersion (dAERP) was significantly increased (P< .05). However, there was no significant change in AERP in the VS-plus-pacing group, though the dAERP increased significantly (P< .05). The I(KACh) density was increased in LSPV and atrial myocardial cells after pacing. However, there was no significant change in I(KACh) density after VS(2) plus pacing., Conclusions: Although shortening of the AERP may play a fundamental role, it is not in itself responsible for cholinergically induced AF. Rapid pacing in the LSPV increased the I(KACh). However, VS before rapid pacing partly protected the atria against electrical remodeling.