ABSTRACT
Background: Ischaemia-reperfusion injury (IRI) is the damage that occurs when blood flow is restored to a tissue or organ after a period of ischaemia. Postconditioning is a therapeutic strategy aimed at reducing the tissue damage caused by IRI. Postconditioning in rodents is a useful tool to investigate the potential mechanisms of postconditioning. Currently, there is no convenient approach for postconditioning rodents. Methods: Rats were subjected to a balloon postconditioning procedure. A balloon was used to control the flow in the vessel. This allowed for easy and precise manipulation of perfusion. Evans blue and triphenyltetrazolium chloride (TTC) double staining were used to determine the infarct size. Apoptosis in the myocardium was visualised and quantified by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Western blotting was performed to assess the expression of key apoptotic proteins, i.e., B-cell lymphoma 2 (Bcl-2), Bcl-2 Associated X (Bax), and cleaved caspase-3. Results: The balloon control approach to postconditioning provided accurate control of coronary blood flow and simplified the postconditioning manipulation. Infarct size reduction was observed in IRI rats after post-conditioning. There was a decrease in cardiac apoptosis in IRI rats after conditioning, as detected by TUNEL staining. IRI rats showed increased Bcl-2 levels and decreased Bax and cleaved caspase-3 levels in the myocardium. Conclusions: Postconditioning was successfully applied in rats using this novel approach. Postconditioning with this approach reduced infarct size and apoptosis in the area at risk.
ABSTRACT
Long non-coding RNAs (lncRNAs) have been associated with atherosclerosis (AS), but the role of lncRNA PVT1 in this disease is still unknown. However, lncRNA PVT1 was found to be significantly upregulated in the serum of AS patients. In vitro experiments using human vascular endothelial cells (HUVECs) showed that oxidized low-density lipoprotein (ox-LDL) treatment enhanced PVT1 expression and impeded HUVEC proliferation, which could be reversed by PVT1 knockdown or miR-106b-5p mimics. Additionally, knockdown of PVT1 and overexpression of miR-106b-5p inhibited the increase of iron content, MDA level, lipid ROS, ACSL4, and PTGS2 in ox-LDL-induced HUVECs, as well as the decrease of GSH and GPX4. We also found that PVT1 knockdown reduced lipid deposition, atherosclerotic plaque number, and size in ApoE-/- mice. These results suggest that PVT1 plays a crucial role in AS progression by regulating the miR-106b-5p/ACSL4 axis in HUVECs, and may therefore be a potential therapeutic target for AS.
Subject(s)
Atherosclerosis , MicroRNAs , RNA, Long Noncoding , Animals , Humans , Mice , Apoptosis , Atherosclerosis/genetics , Atherosclerosis/metabolism , Cell Proliferation , Coenzyme A Ligases/metabolism , Endothelial Cells/metabolism , Lipoproteins, LDL/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , RNA, Long Noncoding/metabolismABSTRACT
OBJECTIVES: To report the 10-year survival rate and prognostic factors of pulmonary arterial hypertension associated with CTD (CTD-PAH) patients, to compare treatment and survival between patients enrolled before and after 2015, and to validate the discrimination of the recommended four-strata model in predicting 10-year survival at follow-up in Chinese CTD-PAH patients. METHODS: This study was derived from a Chinese national multicentre prospective registry study from 2009 to 2019. Medical records were collected at baseline and follow-up, including PAH-targeted therapy and binary therapy (both CTD and PAH-targeted therapy). RESULTS: A total of 266 CTD-PAH patients were enrolled and the 10-year survival rate was 59.9% (median follow-up time: 4.85 years). Underlying CTD (SSc), baseline 6-min walking distance and SaO2 were independent risk factors for 10-year survival. The proportion of patients receiving PAH-targeted combination therapy increased from 10.1% (2009-2014) to 26.5% (2015-2019) and that of binary therapy increased from 14.8% to 35%. The 1-year survival rate increased from 89.8% (2009-2014) to 93.9%, and the 3-year survival rate increased from 80.1% (2009-2014) to 86.5% (both P > 0.05). The four-strata strategy performed well in predicting 10-year survival at follow-up (C-index = 0.742). CONCLUSION: The 10-year survival rate of CTD-PAH patients was reported for the first time. The 10-year prognosis was poor, but there was a tendency for more standardized treatment and better survival in patients enrolled after 2015. The recommended four-strata model at follow-up can effectively predict 10-year survival in CTD-PAH patients.
Subject(s)
Connective Tissue Diseases , Hypertension, Pulmonary , Pulmonary Arterial Hypertension , Humans , Pulmonary Arterial Hypertension/etiology , Pulmonary Arterial Hypertension/complications , Connective Tissue Diseases/complications , Prognosis , Familial Primary Pulmonary Hypertension/complications , RegistriesABSTRACT
BACKGROUND: Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) belongs to Group 1 pulmonary hypertension. Pulmonary veno-occlusive disease (PVOD), which is characterized by venous system aberrations, has been previously reported in CTD-PAH; however, it has rarely been observed in Sjogren's syndrome (SS). CASE PRESENTATION: Our 28-year-old female patient was admitted to the hospital with recurrent shortness of breath even after minimal physical activity. Her chest high-resolution CT scan demonstrated pulmonary artery dilatation and bilateral ground-glass nodules. A subsequent right heart catheterization confirmed pulmonary hypertension because her mean pulmonary arterial pressure was 62 mmHg. Our inquisitive genomic assessment identified a novel EIF2AK4 mutation at c.1021 C > T (p. Gln341*), the dominant causal gene of PVOD. Histological examination demonstrated stenosis and occlusions in the pulmonary veins. Because she presented with features such as dry eyes and Raynaud's phenomenon, we performed a biopsy on the labial salivary gland, which confirmed SS. Her treatment regimen included PAH-targeted therapies (tadalafil and macitentan) in combination with hydroxychloroquine. Although she was hospitalized several times due to acute exacerbation of PAH, her disease progression was under control, and she did not demonstrate any signs of pulmonary edema even after a three-year treatment period. CONCLUSION: Here, we report the case of an SS-PAH patient with PVOD who carried a novel biallelic EIF2AK4 mutation, and PAH-targeted therapies were well tolerated by our patient.
Subject(s)
Hypertension, Pulmonary , Pulmonary Arterial Hypertension , Pulmonary Veno-Occlusive Disease , Sjogren's Syndrome , Humans , Female , Adult , Pulmonary Veno-Occlusive Disease/complications , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/genetics , Sjogren's Syndrome/complications , Sjogren's Syndrome/genetics , Lung , Familial Primary Pulmonary Hypertension , Protein Serine-Threonine Kinases/geneticsABSTRACT
Myocardial infarction is one of the most lethal diseases in cardiovascular diseases. In the present work, we aimed to elucidate the molecular and functional association long non-coding RNA (lncRNA) X-inactive specific transcript (XIST), microRNA (miR)-191-5p, and TNF receptor-associated factor 3 (TRAF3). Human cardiomyocyte primary cells (HCMs) were stimulated by hypoxia to establish a model of myocardial injury in vitro. The relative expressions of XIST, miR-191-5p, and TRAF3 were measured using quantitative real-time polymerase chain reaction (qRT-PCR) assay. The capabilities of proliferation and apoptosis were determined using cell counting kit (CCK-8) and flow cytometry assays, respectively. The molecular interactions were verified using dual luciferase assay. The protein contents of TRAF3, Bcl-2, and Bax were calculated using western blot assay. XIST was significantly increased, but miR-191-5p was reduced in hypoxia-treated HCMs compared to that in control group. Either downregulated XIST or enforced miR-191-5p markedly enhanced cell viability and restrained cell apoptotic rate in hypoxia-treated HCMs. Mechanistically, XIST directly interacted with miR-191-5p to competitive releasing TRAF3 expression. Importantly, overexpression of TRAF3 dramatically diminished the protective effects of XIST knockdown on hypoxia-triggered HCMs injury. Collectively, our data elucidated a novel "lncRNA XIST/miR-191-5p/TRAF3" molecular network in vitro, indicating that the reduced lncRNA XIST-protected HCMs from hypoxia-induced cell injury by regulating miR-191-5p/TRAF3 signaling, which might provide some convincing evidences for further understanding the influences of "lncRNA-miRNA-mRNA" network in the development of MI.
Subject(s)
MicroRNAs , RNA, Long Noncoding , Apoptosis/physiology , Cell Proliferation , Humans , Hypoxia/metabolism , MicroRNAs/metabolism , Myocytes, Cardiac/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , TNF Receptor-Associated Factor 3/genetics , TNF Receptor-Associated Factor 3/metabolismABSTRACT
BACKGROUND: There is no generally accepted comprehensive risk prediction model cooperating risk factors associated with heart failure and pulmonary hemodynamics for patients with pulmonary hypertension due to left heart disease (PH-LHD). We aimed to explore outcome correlates and evaluate incremental prognostic value of pulmonary hemodynamics for risk prediction in PH-LHD. METHODS: Consecutive patients with chronic heart failure undergoing right heart catheterization were prospectively enrolled. The primary endpoint was all-cause mortality. Individual variable selection was performed by machine learning methods. Cox proportional hazards models were conducted to identify the association between variables and mortality. Incremental value of hemodynamics was evaluated based on the Seattle heart failure model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) scores. RESULTS: A total of 276 PH-LHD patients were enrolled, with a median follow-up time of 34.7 months. By L1-penalized regression model and random forest approach, diastolic pressure gradient (DPG) and mixed venous oxygen saturation (SvO2) were the hemodynamic predictors most strongly associated with mortality (coefficient: 0.0255 and -0.0176, respectively), with consistent significance after adjusted for SHFM [DPG: HR 1.067, 95% CI 1.024-1.113, P = 0.022; SvO2: HR 0.969, 95% CI 0.953-0.985, P = 0.002] or MAGGIC (DPG: HR 1.069, 95% CI 1.026-1.114, P = 0.011; SvO2: HR 0.970, 95% CI 0.954-0.986, P = 0.004) scores. The inclusion of DPG and SvO2 improved risk prediction compared with using SHFM [net classification improvement (NRI): 0.468 (0.161-0.752); integrated discriminatory index (IDI): 0.092 (0.035-0.171); likelihood ratio test: P < 0.001] or MAGGIC [NRI: 0.298 (0.106-0.615); IDI: 0.084 (0.033-0.151); likelihood ratio: P < 0.001] scores alone. CONCLUSION: In PH-LHD, pulmonary hemodynamics can provide incremental prognostic value for risk prediction. CLINICAL TRIAL REGISTRATION: NCT02164526 at https://clinicaltrials.gov .
Subject(s)
Heart Failure/complications , Hemodynamics , Hypertension, Pulmonary/etiology , Pulmonary Circulation , Aged , Cardiac Catheterization , China , Chronic Disease , Female , Heart Failure/diagnosis , Heart Failure/mortality , Heart Failure/physiopathology , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/mortality , Hypertension, Pulmonary/physiopathology , Male , Middle Aged , Predictive Value of Tests , Prognosis , Prospective Studies , Registries , Risk Assessment , Risk Factors , Time FactorsABSTRACT
BACKGROUND AND OBJECTIVE: Nationally representative reports on the characteristics and long-term survival of pulmonary arterial hypertension (PAH) from developing countries are scarce. The applicability of the current main risk stratifications and the longitudinal changes in goal-oriented treatments have yet to be elucidated in real-world settings. Therefore, we aimed to provide insights into the characteristics, goal-oriented treatments and survival of PAH in China and to explore the applicability of the main risk stratifications in our independent cohort. METHODS: PAH patients were consecutively enrolled from a national prospective multicentre registry. Data on baseline, follow-up re-evaluation and therapeutic changes were collected. RESULTS: A total of 2031 patients were enrolled, with congenital heart disease (CHD)-PAH (45.2%) being the most common aetiology. The mean age was 35 ± 12 years, and 76.2% were females. At baseline, approximately 20% of the patients with intermediate or high risk received combination treatment. At follow-up, approximately half of the re-evaluated patients did not achieve low-risk profiles, and even among patients who received combination therapy at baseline, 4% of them still worsened. The rate of combination therapy increased significantly from 6.7% before 2015 to 35.5% thereafter. The main risk assessment tools demonstrated good performance for predicting survival both at baseline and at follow-up. CONCLUSION: Chinese PAH patients show both similar and distinct features compared to other countries. Current main risk stratifications can significantly discriminate patients at different risk levels. There were still many patients not achieving low-risk profiles at follow-up, indicating more aggressive treatment should be implemented to optimize the goal-oriented treatment strategy.
Subject(s)
Heart Defects, Congenital , Pulmonary Arterial Hypertension , Adult , Familial Primary Pulmonary Hypertension , Female , Goals , Humans , Male , Middle Aged , Registries , Young AdultABSTRACT
BACKGROUND AND OBJECTIVE: The purpose of this study was to report the characteristics and long-term survival of patients with CTEPH treated in three distinct ways: PEA, BPA and medical therapy. METHODS: Patients diagnosed with CTEPH were included in the registry that was set up in 18 centres from August 2009 to July 2018. The characteristics and survival of patients with CTEPH receiving the different treatments were reported. Prognostic factors were evaluated by Cox regression model. RESULTS: A total of 593 patients with CTEPH were included. Eighty-one patients were treated with PEA, 61 with BPA and 451 with drugs. The estimated survival rates at 1, 3, 5 and 8 years were, respectively, 95.2%, 84.6%, 73.4% and 66.6% in all patients; 92.6%, 89.6%, 87.5% and 80.2% in surgical patients; and 95.4%, 88.3%, 71.0% and 64.1% in medically treated patients. The estimated survival rates at 1, 3, 5 and 7 years in patients treated with BPA were 96.7%, 88.1%, 70.0% and 70.0%, respectively. For all patients, PEA was an independent predictor of survival. Other independent risk factors were CHD, cardiac index, PVR, big endothelin-1, APE and 6MWD. CONCLUSION: This is the first multicentre prospective registry reporting baseline characteristics and estimated survival of patients with CTEPH in China. The long-term survival rates are similar to those of patients in the international and Spanish registries. PEA is an independent predictor of survival.
Subject(s)
Hypertension, Pulmonary/complications , Hypertension, Pulmonary/mortality , Pulmonary Embolism/complications , Pulmonary Embolism/mortality , Angioplasty, Balloon , China , Chronic Disease , Endarterectomy , Endothelin-1/metabolism , Female , Humans , Hypertension, Pulmonary/diagnosis , Male , Middle Aged , Multivariate Analysis , Pulmonary Embolism/surgery , Registries , Risk Factors , Survival Analysis , Time Factors , Treatment OutcomeABSTRACT
Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).
Subject(s)
Antihypertensive Agents/therapeutic use , Epoprostenol/analogs & derivatives , Placebos/therapeutic use , Pulmonary Arterial Hypertension/drug therapy , Administration, Oral , Adolescent , Adult , Aged , Antihypertensive Agents/administration & dosage , Double-Blind Method , Epoprostenol/therapeutic use , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: At present, there is no generally accepted comprehensive prognostic risk prediction model for medically treated chronic thromboembolic pulmonary hypertension (CTEPH) patients. METHODS: Consecutive medically treated CTEPH patients were enrolled in a national multicenter prospective registry study from August 2009 to July 2018. A multivariable Cox proportional hazards model was utilized to derive the prognostic model, and a simplified risk score was created thereafter. Model performance was evaluated in terms of discrimination and calibration, and compared to the Swedish/COMPERA risk stratification method. Internal and external validation were conducted to validate the model performance. RESULTS: A total of 432 patients were enrolled. During a median follow-up time of 38.73 months (IQR: 20.79, 66.10), 94 patients (21.8%) died. The 1-, 3-, and 5-year survival estimates were 95.5%, 83.7%, and 70.9%, respectively. The final model included the following variables: the Swedish/COMPERA risk stratum (low-, intermediate- or high-risk stratum), pulmonary vascular resistance (PVR, ≤ or > 1600 dyn·s/cm5), total bilirubin (TBIL, ≤ or > 38 µmol/L) and chronic kidney disease (CKD, no or yes). Compared with the Swedish/COMPERA risk stratification method alone, both the derived model [C-index: 0.715; net reclassification improvement (NRI): 0.300; integrated discriminatory index (IDI): 0.095] and the risk score (C-index: 0.713; NRI: 0.300; IDI: 0.093) showed improved discriminatory power. The performance was validated in a validation cohort of 84 patients (C-index = 0.707 for the model and 0.721 for the risk score). CONCLUSIONS: A novel risk stratification strategy can serve as a useful tool for determining prognosis and guide management for medically treated CTEPH patients. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01417338).
Subject(s)
Hypertension, Pulmonary/mortality , Hypertension, Pulmonary/physiopathology , Renal Insufficiency, Chronic/complications , Risk Assessment/methods , Adult , Aged , China/epidemiology , Female , Humans , Hypertension, Pulmonary/therapy , Male , Middle Aged , Practice Guidelines as Topic , Prognosis , Prospective Studies , Registries , Survival Analysis , Vascular ResistanceABSTRACT
RNA-binding properties of nucleolin play a fundamental role in regulating cell growth and proliferation. We have previously shown that nucleolin plays an important regulatory role in the phenotypic transformation of vascular smooth muscle cells (VSMCs) induced by angiotensin II (Ang II). In the present study, we aimed to investigate the molecular mechanism of nucleolin-mediated phenotypic transformation of VSMCs induced by Ang II. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) inhibitors were used to observe the effect of Ang II on phenotypic transformation of VSMCs. The regulatory role of nucleolin in the phenotypic transformation of VSMCs was identified by nucleolin gene mutation, gene overexpression and RNA interference technology. Moreover, we elucidated the molecular mechanism underlying the regulatory effect of nucleolin on phenotypic transformation of VSMCs. EGF and PDGF-BB played an important role in the phenotypic transformation of VSMCs induced by Ang II. Nucleolin exerted a positive regulatory effect on the expression and secretion of EGF and PDGF-BB. In addition, nucleolin could bind to the 5' untranslated region (UTR) of EGF and PDGF-BB mRNA, and such binding up-regulated the stability and expression of EGF and PDGF-BB mRNA, promoting Ang II-induced phenotypic transformation of VSMCs.
Subject(s)
Angiotensin II/pharmacology , Becaplermin/metabolism , Epidermal Growth Factor/metabolism , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/metabolism , Phosphoproteins/metabolism , RNA-Binding Proteins/metabolism , 5' Untranslated Regions/genetics , Becaplermin/genetics , Cell Line , Cell Line, Transformed , Epidermal Growth Factor/genetics , Gene Expression Regulation , Genes, Reporter , Luciferases/metabolism , Phenotype , Protein Binding , RNA Stability , NucleolinABSTRACT
Few studies about nucleotide-oligomerization domain-like receptor subfamily C3 (NLRC3) in PASMCs have been conducted. This research aimed to investigate the role of NLRC3 on platelet-derived growth factor (PDGF)-induced proliferation of pulmonary artery smooth muscle cells (PASMCs) and its underlying mechanism. We found that the proliferation of PASMCs stimulated with PDGF decreased when phosphoinositide 3-kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitors pretreatment. Overexpression of NLRC3 inhibited the proliferation of PASMCs and the phosphorylation of PI3K and mTOR while knocking down NLRC3 reversed this effect. Targeted to PI3K or mTOR can also reverse the effect of NLRC3. Activation of PI3K increased the phosphorylation of mTOR while inhibition of PI3K reduced it. Our data suggest that PDGF can induce abnormal proliferation of PASMCs, and NLRC3 suppresses activation of the PI3K-mTOR signaling thus inhibits PASMCs proliferation. These findings unveiled the effect of NLRC3 as an inhibitor of the PI3K-mTOR pathway mediating protection against PASMCs proliferation.
Subject(s)
Intercellular Signaling Peptides and Proteins/genetics , Phosphatidylinositol 3-Kinases/genetics , Phosphoinositide-3 Kinase Inhibitors/pharmacology , TOR Serine-Threonine Kinases/genetics , Animals , Cell Proliferation/genetics , Gene Expression Regulation/drug effects , Gene Knockdown Techniques , Humans , Myocytes, Smooth Muscle/metabolism , Phosphatidylinositol 3-Kinases/pharmacology , Phosphorylation/drug effects , Platelet-Derived Growth Factor/pharmacology , Pulmonary Artery/growth & development , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Rats , TOR Serine-Threonine Kinases/antagonists & inhibitorsABSTRACT
OBJECTIVES: To analyze the 3-year outcomes of the biodegradable polymer cobalt-chromium sirolimus-eluting stent (EXCROSSAL) in CREDIT II AND III TRIALS. BACKGROUND: Though approved by CFDA, the long-term safety and efficacy of EXCROSSAL is still unknown. METHODS: CREDIT II was a randomized trial comparing the EXCROSSAL versus EXCEL stents in patients with up to two de novo coronary lesions, and CREDIT III was a prospective, single-arm study evaluating the efficacy and safety of EXCROSSAL in broad types of de novo coronary artery lesions. We pooled the 3-year follow-up data of the EXCROSSAL arm of the CREDIT II and CREDIT III Trials. The primary outcome was 3-year target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (TV-MI), and clinically indicated target lesion revascularization (CI-TLR). The patient-oriented composite endpoint (PoCE) (all-cause death, all MI, or any revascularization) and stent thrombosis (ST) were also analyzed. RESULTS: A total of 833 patients were included in this study. The incidence of TLF and PoCE in the 3-year follow-up were 7.6% and 12.5%, respectively. ST occurred in 0.6% of patients. In the subgroup analyses, TLF was significantly higher in small target vessels, multi-lesion PCI, and multi-vessel disease. CONCLUSIONS: The 3-year follow-up analysis confirmed low rates of TLF and ST in EXCROSSAL, which is similar to the most widely used new generation durable polymer drug-eluting stent.
Subject(s)
Absorbable Implants , Cardiovascular Agents/administration & dosage , Chromium Alloys , Coronary Artery Disease/therapy , Drug-Eluting Stents , Percutaneous Coronary Intervention/instrumentation , Polymers , Sirolimus/administration & dosage , Aged , Cardiovascular Agents/adverse effects , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/mortality , Female , Humans , Male , Middle Aged , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/mortality , Prosthesis Design , Randomized Controlled Trials as Topic , Recurrence , Risk Assessment , Risk Factors , Sirolimus/adverse effects , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVES: To report the clinical outcomes of the RESTORE drug-coated balloon (DCB; Cardionovum, Bonn, Germany) for treatment of de novo small vessel disease (SVD) beyond 1 year. BACKGROUND: Previous reports have demonstrated the noninferiority of the RESTORE DCB to the RESOLUTE Integrity drug-eluting stent (DES; Medtronic, Minneapolis, Minnesota) in terms of 9-month in-segment percent diameter stenosis. METHODS: In the prospective, multicenter, noninferiority RESTORE SVD China trial, 230 patients with visually-estimated reference vessel diameter (RVD) ≥2.25 and ≤2.75 mm were randomized to DCB or DES in a 1:1 ratio stratified by diabetes and number of lesions treated. Furthermore, 32 patients with RVD ≥2.00 and <2.25 mm were enrolled in a nested very small vessel (VSV) registry. Clinical follow-up were performed at 2 years to evaluate target lesion failure (TLF) in both groups and the VSV cohort. RESULTS: Overall, 256 (97.7%) patients (115 and 109 in the DCB and DES groups, respectively, and 32 in the VSV cohort) completed 2 years of follow-up. There was no significant difference in TLF between the DCB and DES groups (5.2 vs. 3.7%, p = .75). Target lesion revascularization was acceptable at 1 month, 1 year, and 2 years, and did not differ significantly with DCB from that in the DES group (0.9 vs. 0%, p = 1.0, 4.4 vs. 2.6%, p = .72, 5.2 vs. 2.8%, p = .50, respectively). CONCLUSIONS: Compared to the second-generation DES, the RESTORE DCB did not increase the risk of clinical outcomes. Late catch-up phenomen requiring revascularization was not significant in this study.
Subject(s)
Angioplasty, Balloon, Coronary/instrumentation , Cardiac Catheters , Coated Materials, Biocompatible , Coronary Artery Disease/therapy , Drug-Eluting Stents , Aged , Angioplasty, Balloon, Coronary/adverse effects , China , Coronary Artery Disease/diagnostic imaging , Female , Humans , Male , Middle Aged , Registries , Risk Assessment , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: The efficacy and safety of ambrisentan has been previously evaluated in Chinese patients with pulmonary arterial hypertension (PAH). This post-hoc analysis assessed the efficacy and safety of ambrisentan in a subgroup of connective tissue disease (CTD) patients with PAH. METHODS: In this open-label, single-arm study, patients received ambrisentan 5 mg once daily for 12 weeks, followed by 12-week dose titration period (dose up to 10 mg). Efficacy endpoints included change from baseline in exercise capacity (measured by 6-min walk test [6MWT]), N-terminal pro B type natriuretic peptide (NT-proBNP) plasma levels, WHO Functional Class (FC) and Borg Dyspnoea Index (BDI) scores from baseline to weeks 12 and 24. Safety endpoints included time to clinical worsening and incidence of adverse events (AEs). RESULTS: In total, 71 Chinese patients with CTD-PAH were included in this analysis. Ambrisentan treatment significantly improved exercise capacity (6MWT) from baseline (mean: 366.4 m) to week 12 (63.8 m, p < 0.001) and week 24 (73.2 m, p < 0.001). A significant reduction in NT-proBNP levels was observed from baseline (mean: 1837.5 ng/L) to week 12 (- 1156.8 ng/L, p < 0.001) and week 24 (- 1095.5 ng/L, p < 0.001). BDI scores decreased significantly at week 12 (- 0.6, p < 0.001) and week 24 (- 0.4, p = 0.002) from baseline (mean: 2.7). The WHO FC improved in 29 (40.8%) and 34 (47.9%) patients at weeks 12 and 24, respectively. Adverse events were reported in 52 (73.2%) patients. One patient (1.4%) experienced clinical worsening at week 24. CONCLUSION: Ambrisentan showed significant improvement in exercise capacity and no clinical worsening in the majority of Chinese patients with CTD-PAH in the 24-week treatment period. The AEs observed in the CTD-PAH subgroup were consistent with the known safety profile of ambrisentan in the overall Chinese PAH population. TRIAL REGISTRATION: ClinicalTrial.gov Identifier, https://clinicaltrials.gov/, NCT01808313 Registration date (first time): February 28, 2013.
Subject(s)
Antihypertensive Agents/therapeutic use , Connective Tissue Diseases/complications , Endothelin A Receptor Antagonists/therapeutic use , Phenylpropionates/therapeutic use , Pulmonary Arterial Hypertension/drug therapy , Pulmonary Arterial Hypertension/etiology , Pyridazines/therapeutic use , Adult , Antihypertensive Agents/adverse effects , Beijing , Biomarkers/blood , Connective Tissue Diseases/diagnosis , Endothelin A Receptor Antagonists/adverse effects , Exercise Tolerance/drug effects , Female , Humans , Male , Middle Aged , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Phenylpropionates/adverse effects , Pulmonary Arterial Hypertension/diagnosis , Pulmonary Arterial Hypertension/physiopathology , Pyridazines/adverse effects , Recovery of Function , Time Factors , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Pulmonary veno-occlusive disease (PVOD) and pulmonary arterial hypertension (PAH) share an overlapping disease phenotype. Hence it is necessary to distinguish them. CASE PRESENTATION: Our 14-year-old female patient admitted with progressive shortness of breath, dizziness, and fatigue even after minimal physical activity was clinically suspected for PAH, based on her previous history. Her chest computed tomography artery reported the presence of PVOD triad features - subpleural thickened septal lines, ground-glass nodules/opacities and mediastinal lymphadenopathy. Because of her weak physical stature, a lung biopsy was not performed; however, the genetic testing identified a novel heterozygous EIF2AK4 mutation at c.4833_4836dup (p.Q1613Kfs*10) - the dominant susceptible factor driving PVOD. Combination of genetic testing and computed tomography artery facilitated us to distinguish PVOD from PAH. Her disease symptoms advanced aggressively so that she died even before the lung transplantation, which was less than 6 months from the onset of disease symptoms. CONCLUSION: This case report highlights that novel EIF2AK4 mutation at [c.4833_4836dup (p.Q1613Kfs*10)] would predict an aggressive phenotype of PVOD. Hence, we conclude that a genetic test identifying EIF2AK4 mutation would serve as a tool for the early diagnosis of PVOD, circumventing lung biopsy.
Subject(s)
Protein Serine-Threonine Kinases/genetics , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/genetics , Adolescent , Diagnosis, Differential , Disease Progression , Fatal Outcome , Female , Humans , Mutation , Phenotype , Pulmonary Arterial Hypertension/diagnosis , Tomography, X-Ray ComputedABSTRACT
Phosphoinositide 3-kinase (PI3K) activation plays a critical role in the pulmonary vascular remodeling of pulmonary hypertension (PH). The nucleotide-oligomerization domain (NOD)-like receptor subfamily C3 (NLRC3) inhibits proliferation and inflammation via PI3K signaling in cancer. We previously showed NLRC3 was significantly reduced in PH patients, but the mechanism of function remains unclear. This study aimed to determine the potential role of NLRC3 in PH. We found that NLRC3 was downregulated in the pulmonary arteries of PH animal models and platelet-derived growth factor-BB (PDGF-BB) stimulated pulmonary arterial smooth muscle cells (PASMCs). NLRC3 pretreatment reduced right ventricular systolic pressure, attenuated pulmonary vascular remodeling and RVHI, and ameliorated proliferation, migration, and inflammation. Monocrotaline (MCT)- and PDGF-BB-mediated PI3K activation were suppressed by NLRC3 pretreatment. 740Y-P decreased the effect of NLRC3. Collectively, NLRC3 protected against MCT-induced rat PH and PDGF-BB-induced PASMC proliferation, migration, and inflammation through a mechanism involving PI3K inhibition. NLRC3 may have a therapeutic effect on PH and provide a promising therapeutic strategy for PH.
ABSTRACT
BACKGROUND: Hypertension is a highly prevalent disease and the leading cause of chronic kidney disease (CKD). Metabolic syndrome could also be the risk factor for CKD. We sought to study the association between metabolic syndrome components and the prevalence of CKD in patients with hypertension. METHODS: We carried out a multi-center cross-sectional study from Apr. 2017- Apr. 2018 in 15 cities in China. RESULTS: A total of 2484 patients with hypertension were enrolled. Among them, 56% were male and the average age was 65.12 ± 12.71 years. The systolic BP/diastolic BP was 142 ± 18/83 ± 12 mmHg. Metabolic syndrome components turned out to be highly prevalent in patients with hypertension, ranging from 40 to 58%. The prevalence of chronic kidney disease reached 22.0%. Multi-variate logistic analysis revealed that elevated triglyceride (TG) (OR = 1.81, 95% CI 1.28-2.57, p < 0.01), elevated fasting blood glucose (FBG) (OR = 1.43, 95% CI 1.00-2.07, p = 0.05) and hypertension grades (OR = 1.20, 95% CI 1.00-1.44, p = 0.05) were associated with the prevalence of CKD. In sub-group analysis, elevated TG remained strongly associated with CKD in both diabetes (OR = 2.10, 95%CI 1.22-3.61, p < 0.01) and non-diabetes (OR = 1.53, 95% CI 1.09-2.16, p = 0.01). In sub-group analysis of hypertension grades, there was also a graded trend between elevated TG and CKD from controlled blood pressure (BP) to hypertension grade 2 (OR = 1.81, 95%CI 1.06-3.11, p = 0.03; OR = 1.85, 95%CI 1.00-3.43, p = 0.05; OR = 2.81, 95% CI 1.09-7.28, p = 0.03, respectively). CONCLUSION: Elevated TG, elevated FBG and hypertension grades were significantly associated with the prevalence of CKD in patients with hypertension. Particularly, elevated TG was strongly associated with CKD, independent of diabetes and hypertension grades.
Subject(s)
Hypertension/blood , Metabolic Syndrome/blood , Renal Insufficiency, Chronic/blood , Triglycerides/blood , Aged , Blood Glucose , Blood Pressure , Diabetes Complications/blood , Diabetes Complications/pathology , Female , Humans , Hypertension/complications , Hypertension/epidemiology , Hypertension/pathology , Logistic Models , Male , Metabolic Syndrome/complications , Metabolic Syndrome/epidemiology , Metabolic Syndrome/pathology , Middle Aged , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/etiology , Renal Insufficiency, Chronic/pathology , Risk FactorsABSTRACT
AIMS: This study aimed to assess whether neutrophil gelatinase-associated lipocalin (NGAL) and fibroblast growth factor 23 (FGF23) could be reliable biomarkers for early diagnosis of contrast-induced nephropathy (CIN). METHODS: 202 patients who underwent percutaneous coronary intervention (PCI) were included in the research. All subjects were divided into CIN group and non-CIN group. Serum NGAL and FGF23 were evaluated before and 0, 1, and 2 days after PCI. Serum levels of these two markers were compared intra-group and among groups. Receiver-operating characteristic (ROC) analysis and logistic regression models were conducted to assess the diagnostic performance of NGAL and FGF23 in detecting CIN. RESULTS: When compared with baseline values, serum levels of both NGAL and FGF23 in all subjects increased after PCI, and the values peaked 1 day after PCI, but the changing was greater in CIN group. There were obvious differences between two groups in serum NGAL after 1, 2 days, and similar differences present in serum FGF23 after 1 day. ROC analysis showed that the area under the curve (AUC) of relative values (percent change from the baseline) in NGAL after 1 day was 0.899 (95% CI: 0.834-0.964, p = .000), the optimum cutoff was 49% (sensitivity = 80%, specificity = 92.4%). And the AUC in FGF23 was 0.814 (95% CI: 0.733-0.894, p = .000), the optimum cutoff was 20% (sensitivity = 73.3%, specificity = 87.6%). Both serum NGAL and serum FGF23 could improve the clinical models in identifying CIN. CONCLUSIONS: NGAL and FGF23 may have certain value in early diagnosis of CIN.
Subject(s)
Acute Kidney Injury/diagnosis , Contrast Media/adverse effects , Early Diagnosis , Fibroblast Growth Factor 2/blood , Lipocalin-2/blood , Acute Kidney Injury/blood , Acute Kidney Injury/chemically induced , Aged , Biomarkers/blood , China , Coronary Angiography/adverse effects , Female , Fibroblast Growth Factor-23 , Humans , Logistic Models , Male , Middle Aged , Percutaneous Coronary Intervention/adverse effects , ROC Curve , Sensitivity and SpecificityABSTRACT
BACKGROUND: The overproliferation of pulmonary vascular cells is noted in pulmonary hypertension. The role of exosomes from pulmonary artery endothelial cells (PAEC) in the proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMC) remains unclear. METHODS: Exosomes were isolated and purified from the culture medium of PAEC using a commercial kit. Lipopolysaccharide (LPS), hypoxia, and hydrogen peroxide were utilized to induce PAEC injury. Coculture of PAEC and PASMC was conducted using Transwell plates, and GW4869 was applied to inhibit exosome release. The proliferation and apoptosis level of PASMC was assayed by MTT assay, apoptosis staining, and cleaved caspase-3 immunoblotting. Plasma exosomes were isolated by differential ultracentrifugation. RESULTS: LPS or hypoxia enhance exosome release from PAEC. Release of PAEC-derived exosomes positively correlates with LPS concentration. The coculture of LPS-disposed PAEC with PASMC leads to overproliferation and apoptosis resistance in PASMC, and the exosome inhibitor GW4869 can partly cancel out this effect. Exosomes derived from PAEC could be internalized into PASMC, and thus promote proliferation and induce apoptosis resistance in PASMC. Idiopathic pulmonary arterial hypertension patients exhibit a higher circulation level of endothelium-derived exosomes. CONCLUSIONS: Inflammation and hypoxia could induce PAEC to release exosomes. PAEC- derived exosomes are involved in overproliferation and apoptosis resistance in PASMC, by which they may contribute to the pathogenesis of pulmonary hypertension.