ABSTRACT
BACKGROUND: Indobufen is widely used in patients with aspirin intolerance in East Asia. The OPTION trial launched by our cardiac center examined the performance of indobufen based dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). However, the vast majority of patients with acute coronary syndrome (ACS) and aspirin intolerance were excluded. We aimed to explore this question in a real-world population. METHODS: Patients enrolled in the ASPIRATION registry were grouped according to the DAPT strategy that they received after PCI. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) and Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. Propensity score matching (PSM) was adopted for confounder adjustment. RESULTS: A total of 7135 patients were reviewed. After one-year follow-up, the indobufen group was associated with the same risk of MACCE versus the aspirin group after PSM (6.5% vs. 6.5%, hazard ratio [HR] = 0.99, 95% confidence interval [CI] = 0.65 to 1.52, P = 0.978). However, BARC type 2, 3, or 5 bleeding was significantly reduced (3.0% vs. 11.9%, HR = 0.24, 95% CI = 0.15 to 0.40, P < 0.001). These results were generally consistent across different subgroups including aspirin intolerance, except that indobufen appeared to increase the risk of MACCE in patients with ACS. CONCLUSIONS: Indobufen shared the same risk of MACCE but a lower risk of bleeding after PCI versus aspirin from a real-world perspective. Due to the observational nature of the current analysis, future studies are still warranted to further evaluate the efficacy of indobufen based DAPT, especially in patients with ACS. TRIAL REGISTRATION: Chinese Clinical Trial Register ( https://www.chictr.org.cn ); Number: ChiCTR2300067274.
Subject(s)
Acute Coronary Syndrome , Isoindoles , Percutaneous Coronary Intervention , Phenylbutyrates , Humans , Acute Coronary Syndrome/drug therapy , Acute Coronary Syndrome/surgery , Aspirin/adverse effects , Drug Therapy, Combination , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/methods , Platelet Aggregation Inhibitors/adverse effects , Registries , Treatment OutcomeABSTRACT
Calcium overload is the key trigger in cardiac microvascular ischemia-reperfusion (I/R) injury, and calreticulin (CRT) is a calcium buffering protein located in the endoplasmic reticulum (ER). Additionally, the role of pinacidil, an antihypertensive drug, in protecting cardiac microcirculation against I/R injury has not been investigated. Hence, this study aimed to explore the benefits of pinacidil on cardiac microvascular I/R injury with a focus on endothelial calcium homeostasis and CRT signaling. Cardiac vascular perfusion and no-reflow area were assessed using FITC-lectin perfusion assay and Thioflavin-S staining. Endothelial calcium homeostasis, CRT-IP3Rs-MCU signaling expression, and apoptosis were assessed by real-time calcium signal reporter GCaMP8, western blotting, and fluorescence staining. Drug affinity-responsive target stability (DARTS) assay was adopted to detect proteins that directly bind to pinacidil. The present study found pinacidil treatment improved capillary density and perfusion, reduced no-reflow and infraction areas, and improved cardiac function and hemodynamics after I/R injury. These benefits were attributed to the ability of pinacidil to alleviate calcium overload and mitochondria-dependent apoptosis in cardiac microvascular endothelial cells (CMECs). Moreover, the DARTS assay showed that pinacidil directly binds to HSP90, through which it inhibits chaperone-mediated autophagy (CMA) degradation of CRT. CRT overexpression inhibited IP3Rs and MCU expression, reduced mitochondrial calcium inflow and mitochondrial injury, and suppressed endothelial apoptosis. Importantly, endothelial-specific overexpression of CRT shared similar benefits with pinacidil on cardiovascular protection against I/R injury. In conclusion, our data indicate that pinacidil attenuated microvascular I/R injury potentially through improving CRT degradation and endothelial calcium overload.
Subject(s)
Chaperone-Mediated Autophagy , Reperfusion Injury , Humans , Pinacidil/metabolism , Endothelial Cells/metabolism , Calreticulin/metabolism , Calcium/metabolism , Reperfusion Injury/metabolism , ApoptosisABSTRACT
Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial dysfunction, and DCM; however, its effects on ferroptosis and mitophagy remain unexplored. The present study aimed to assess the beneficial effects of nicorandil against endothelial ferroptosis in DCM and the underlying mechanisms. Cardiac microvascular perfusion was assessed using a lectin perfusion assay, while mitophagy was assessed via mt-Keima transfection and transmission electron microscopy. Ferroptosis was examined using mRNA sequencing, fluorescence staining, and western blotting. The mitochondrial localization of Parkin, ACSL4, and AMPK was determined via immunofluorescence staining. Following long-term diabetes, nicorandil treatment improved cardiac function and remodeling by alleviating cardiac microvascular injuries, as evidenced by the improved microvascular perfusion and structural integrity. mRNA-sequencing and biochemical analyses showed that ferroptosis occurred and Pink1/Parkin-dependent mitophagy was suppressed in cardiac microvascular endothelial cells after diabetes. Nicorandil treatment suppressed mitochondria-associated ferroptosis by promoting the Pink1/Parkin-dependent mitophagy. Moreover, nicorandil treatment increased the phosphorylation level of AMPKα1 and promoted its mitochondrial translocation, which further inhibited the mitochondrial translocation of ACSL4 via mitophagy and ultimately suppressed mitochondria-associated ferroptosis. Importantly, overexpression of mitochondria-localized AMPKα1 (mitoAα1) shared similar benefits with nicorandil on mitophagy, ferroptosis and cardiovascular protection against diabetic injury. In conclusion, the present study demonstrated the therapeutic effects of nicorandil against cardiac microvascular ferroptosis in DCM and revealed that the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway mediates mitochondria-associated ferroptosis and the development of cardiac microvascular dysfunction.
Subject(s)
Diabetes Mellitus , Diabetic Cardiomyopathies , Ferroptosis , Humans , Diabetic Cardiomyopathies/genetics , AMP-Activated Protein Kinases/metabolism , Nicorandil/pharmacology , Nicorandil/therapeutic use , Nicorandil/metabolism , Endothelial Cells/metabolism , Mitochondria/metabolism , Signal Transduction , Myocytes, Cardiac/metabolism , Ubiquitin-Protein Ligases/metabolism , RNA, Messenger/metabolism , Diabetes Mellitus/metabolismABSTRACT
Doxorubicin (DOX) as a chemotherapeutic agent can cause mitochondrial dysfunction and heart failure. COX5A has been described as an important regulator of mitochondrial energy metabolism. We investigate the roles of COX5A in DOX-induced cardiomyopathy and explore the underlying mechanisms. C57BL/6J mice and H9c2 cardiomyoblasts were treated with DOX, and the COX5A expression was assessed. An adeno-associated virus serum type 9 (AAV9) and lenti-virus system were used to upregulate COX5A expression. Echocardiographic parameters, morphological and histological analyses, transmission electron microscope and immunofluorescence assays were used to assess cardiac and mitochondrial function. In a human study, we found that cardiac COX5A expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to the control group. COX5A was significantly downregulated following DOX stimulation in the heart of mice and H9c2 cells. Reduced cardiac function, decreased myocardium glucose uptake, mitochondrial morphology disturbance, reduced activity of mitochondrial cytochrome c oxidase (COX) and lowered ATP content were detected after DOX stimulation in mice, which could be significantly improved by overexpression of COX5A. Overexpression of COX5A effectively protected against DOX-induced oxidative stress, mitochondrial dysfunction and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, the phosphorylation of Akt (Thr308) and Akt (Ser473) were also decreased following DOX treatment, which could be reserved by the upregulation of COX5A. Furthermore, PI3K inhibitors abrogated the protection effects of COX5A against DOX-induced cardiotoxicity in H9c2 cells. Thus, we identified that PI3K/Akt signaling was responsible for the COX5A-mediated protective role in DOX-induced cardiomyopathy. These results demonstrated the protective effect of COX5A in mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis, providing a potential therapeutic target in DOX-induced cardiomyopathy.
Subject(s)
Cardiomyopathies , Cardiotoxicity , Doxorubicin , Electron Transport Complex IV , Animals , Humans , Mice , Apoptosis , Cardiomyopathies/metabolism , Cardiotoxicity/metabolism , Doxorubicin/adverse effects , Electron Transport Complex IV/genetics , Electron Transport Complex IV/metabolism , Mice, Inbred C57BL , Mitochondria/metabolism , Myocytes, Cardiac/metabolism , Oxidative Stress , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
BACKGROUND: The perturbation of fatty acid metabolism in heart failure (HF) has been a critical issue. It is unclear whether the amounts of circulating carnitines will benefit primary etiology diagnosis and prognostic prediction in HF. This study was designed to assess the diagnostic and prognostic values of serum carnitine profiles between ischemic and non-ischemic derived heart failure. METHODS: HF patients (non-ischemic dilated cardiomyopathy: DCM-HF, n = 98; ischemic heart disease: IHD-HF, n = 63) and control individuals (n = 48) were enrolled consecutively. The serum carnitines were quantitatively measured using the UHPLC-MS/MS method. All patients underwent a median follow-up of 28.3 months. Multivariate Cox regression analysis was performed during the prognosis evaluation. RESULTS: Amongst 25 carnitines measured, all of them were increased in HF patients, and 20 acylcarnitines were associated with HF diagnosis independently. Seven acylcarnitines were confirmed to increase the probability of DCM diagnosis independently. The addition of isobutyryl-L-carnitine and stearoyl-L-carnitine to conventional clinical factors significantly improved the area under the receiver operating characteristic curve (ROC) from 0.771 to 0.832 (p = 0.023) for DCM-HF diagnosis (calibration test for the composite model: Hosmer-Lemeshow χ2 = 7.376, p = 0.497 > 0.05). Using a multivariate COX survival analysis adjusted with clinical factors simultaneously, oleoyl L-carnitine >300 nmol/L (HR = 2.364, 95% CI = 1.122-4.976, p = 0.024) and isovaleryl-L-carnitine <100 nmol/L (HR = 2.108, 95% CI = 1.091-4.074, p = 0.026) increased the prediction of all-cause mortality independently, while linoleoyl-L-carnitine >420 nmol/L, succinyl carnitine >60 nmol/L and isovaleryl-L-carnitine <100 nmol/L increased the risk of HF rehospitalization independently. CONCLUSIONS: Serum carnitines could not only serve as diagnostic and predictive biomarkers in HF but also benefit the identification of HF primary etiology and prognosis.
Subject(s)
Heart Failure , Tandem Mass Spectrometry , Humans , Heart Failure/diagnosis , Carnitine , Multivariate AnalysisABSTRACT
BACKGROUND: Aortic valve calcification (AVC) is associated with increased cardiovascular risk in the general population. We sought to investigate whether AVC identified by transthoracic echocardiography could be a predictor of long-term adverse events after primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction. METHODS: Patients undergoing primary PCI were consecutively enrolled in this cohort study between 1 January 2009 and 31 December 31 2018. The presence of AVC was identified by transthoracic echocardiography one to three days after PCI. The primary endpoint was major adverse cardiovascular and cerebral events (MACCE) during follow-up. Propensity score matching was adopted to adjust for the baseline differences between groups. RESULTS: Of 2117 patients enrolled in the study, 566 (26.7%) were found to have AVC. Patients with AVC were older, more likely to be women, and disposed to have comorbidities and complex lesions. During a median follow-up period of 6.1 years, 699 cases of MACCE occurred, including 243 (42.9%) cases in patients with AVC and 456 (29.4%) cases in patients without AVC. After 1:1 propensity score matching, the presence of AVC increased the risk of MACCE (adjusted hazard ratio: 1.442, 95% confidence interval: 1.186 to 1.754, p < 0.001). This difference persisted when sensitivity and subgroup analyses were made. CONCLUSIONS: AVC identified by transthoracic echocardiography independently increased the long-term risk of MACCE after primary PCI in patients with acute myocardial infarction. This imaging feature will contribute to better risk stratification in this population.
Subject(s)
Coronary Artery Disease , Myocardial Infarction , Percutaneous Coronary Intervention , Aortic Valve/diagnostic imaging , Aortic Valve/pathology , Aortic Valve/surgery , Aortic Valve Stenosis , Calcinosis , Cohort Studies , Coronary Artery Disease/etiology , Female , Humans , Male , Myocardial Infarction/epidemiology , Myocardial Infarction/etiology , Risk FactorsABSTRACT
BACKGROUND: Predictors of prognosis in patients with coronary chronic total occlusion (CTO) undergoing elective percutaneous coronary intervention (PCI) have remained lacking. Lipidomic profiling enables researchers to associate lipid species with disease progression and may improve the prediction of cardiovascular events. METHODS: In the present study, 781 lipids were measured by targeted lipidomic profiling in 350 individuals (50 healthy controls, 50 patients with coronary artery disease and 250 patients with CTO). L1-regularized logistic regression was used to identify lipid species associated with adverse cardiovascular events and create predicting models, which were verified by 10-fold cross-validation (200 repeats). Comparisons were made between a traditional model constructed with clinical characteristics alone and a combined model built with both lipidomic data and traditional factors. RESULTS: Twenty-four lipid species were dysregulated exclusively in patients with CTO, most of which belonged to sphingomyelin (SM) and triacylglycerol (TAG). Compared with traditional risk factors, new model combining lipids and traditional factors had significantly improved performance in predicting adverse cardiovascular events in CTO patients after PCI (area under the curve, 0.870 vs. 0.726, p < .05; Akaike information criterion, 129 versus 156; net reclassification improvement, 0.312, p < .001; integrated discrimination improvement, 0.244, p < .001). Nomogram was built based on the incorporated model and proved efficient by Kaplan-Meier method. CONCLUSIONS: Lipidomic profiling revealed lipid species which may participate in the formation of CTO and could contribute to the risk stratification in CTO patients undergoing PCI.
Subject(s)
Coronary Occlusion , Percutaneous Coronary Intervention , Chronic Disease , Coronary Angiography/adverse effects , Coronary Angiography/methods , Coronary Occlusion/surgery , Humans , Lipidomics , Percutaneous Coronary Intervention/methods , Prognosis , Registries , Risk Factors , Sphingomyelins , Treatment Outcome , TriglyceridesABSTRACT
BACKGROUND: Angiographic no-reflow is associated with poor outcomes in patients with ST-segment elevation myocardial infarction (STEMI). We sought to develop and validate a score system to predict angiographic no-reflow in primary percutaneous coronary intervention (PCI). METHODS: ST-segment elevation myocardial infarction patients undergoing primary PCI were consecutively enrolled and were randomly divided into the training and validation set. Angiographic no-reflow was defined as thrombolysis in myocardial infarction (TIMI) flow grade 0 to 2 after PCI. In the training set, independent predictors were identified by logistic regression analysis, and a score system (PredIction of Angiographic NO-reflow, the PIANO score) was constructed based on the ß-coefficient of each variable. The established model was evaluated for discrimination and calibration. RESULTS: Angiographic no-reflow occurred in 362 (17.8%) of 2036 patients. Age ≥70 years, absence of pre-infarction angina, total ischaemic time ≥4 h, left anterior descending as culprit artery, pre-PCI TIMI flow grade ≤1 and pre-PCI TIMI thrombus score ≥4 were independent predictors of angiographic no-reflow. The PIANO score ranged from 0 to 14 points, yielding a concordance index of 0.857 (95% confidence interval: 0.833 to 0.880), with good calibration. In the high-risk (≥8 points) group, the probability of angiographic no-reflow phenomenon was 38.7%, while it was only 4.8% in the low-risk (<8 points) group. The score system performed well in the validation set. CONCLUSIONS: We establish and validate a score system based on six clinical variables to predict angiographic no-reflow in STEMI patients undergoing primary PCI, which may help choose the optimal individual treatment strategy.
Subject(s)
Coronary Angiography , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction/surgery , Treatment Failure , Aged , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Retrospective StudiesABSTRACT
Current evidence indicates that coronary microcirculation is a key target for protecting against cardiac ischemia-reperfusion (I/R) injury. Mitochondrial calcium uniporter (MCU) complex activation and mitochondrial calcium ([Ca2+]m) overload are underlying mechanisms involved in cardiovascular disease. Histidine triad nucleotide-binding 2 (HINT2) has been reported to modulate [Ca2+]m via the MCU complex, and our previous work demonstrated that HINT2 improved cardiomyocyte survival and preserved heart function in mice with cardiac ischemia. This study aimed to explore the benefits of HINT2 on cardiac microcirculation in I/R injury with a focus on mitochondria, the MCU complex, and [Ca2+]m overload in endothelial cells. The present work demonstrated that HINT2 overexpression significantly reduced the no-reflow area and improved microvascular perfusion in I/R-injured mouse hearts, potentially by promoting endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Microvascular barrier function was compromised by reperfusion injury, but was repaired by HINT2 overexpression via inhibiting VE-Cadherin phosphorylation at Tyr731 and enhancing the VE-Cadherin/ß-Catenin interaction. In addition, HINT2 overexpression inhibited the inflammatory response by suppressing vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Mitochondrial fission occurred in cardiac microvascular endothelial cells (CMECs) subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury and resulted in mitochondrial dysfunction and mitochondrion-dependent apoptosis, the effects of which were largely relieved by HINT2 overexpression. Additional experiments confirmed that [Ca2+]m overload was an initiating factor for mitochondrial fission and that HINT2 suppressed [Ca2+]m overload via modulation of the MCU complex through directly interacting with MCU in CMECs. Regaining [Ca2+]m overload by spermine, an MCU agonist, abolished all the protective effects of HINT2 on OGD/R-injured CMECs and I/R-injured cardiac microcirculation. In conclusion, the present report demonstrated that HINT2 overexpression inhibited MCU complex-mitochondrial calcium overload-mitochondrial fission and apoptosis pathway, and thereby attenuated cardiac microvascular ischemia-reperfusion injury.
Subject(s)
Calcium Channels/metabolism , Calcium , Hydrolases/metabolism , Mitochondrial Proteins/metabolism , Reperfusion Injury , Animals , Calcium/metabolism , Endothelial Cells/metabolism , Mice , Mitochondria , Myocytes, Cardiac/metabolism , Reperfusion Injury/metabolismABSTRACT
BACKGROUND: Periprocedural myocardial injury (PMI) is a most common complication of percutaneous coronary intervention (PCI). Microembolization and inflammation underlying PMI could lead to coronary microvascular dysfunction (CMD) and vice versa. Reactive hyperemia index (RHI) assessed by peripheral artery tonometry (PAT) has been considered as a noninvasive method to assess endothelial function and CMD, which could be useful to predict PMI. METHODS: 268 patients suspected with stable coronary artery disease (CAD) and scheduled for elective coronary angiography were enrolled. RHI was measured by using the Endo-PAT2000™ device before angiography. The association among RHI, PMI, and cardiovascular events was further assessed. RESULTS: In this cohort, 189 patients (70.5%) were diagnosed with CAD and 119 patients (44.4%) underwent drug-eluting stent (DES) implantation. Compared with patients without CAD, CAD patients had lower RHI (1.88 ± 0.55 vs. 2.02 ± 0.58, P < 0.05). Patients with PMI had a lower RHI before angiography (1.75 ± 0.37 vs. 1.95 ± 0.50, P < 0.05). Receiver operating characteristic curve analysis of RHI revealed an area under the curve (AUC) of 0.61, with a sensitivity of 62.7% and specificity of 50.0% to predict PMI. Moreover, we found that CAD patients with RHI ≤ 1.81 had a higher incidence of composite cardiac events after stenting (adjusted hazard ratio (HR) 3.31, 95% confidence interval (CI) 1.07-10.22, P < 0.05). CONCLUSIONS: RHI assessment through PAT could be a promising method to predict PMI before the procedure. RHI is associated with increased risk of long-term adverse cardiac events after DES implantation.
Subject(s)
Drug-Eluting Stents , Percutaneous Coronary Intervention , Arteries , Humans , Male , Manometry , Percutaneous Coronary Intervention/adverse effects , Risk FactorsABSTRACT
Mitochondrial dysfunction plays a pivotal role in doxorubicin (DOX)-induced cardiomyopathy. Cytochrome c oxidase subunit 5A (COX5A) is a nuclear-encoded subunit of the terminal oxidase involved in mitochondrial electron transport. Although COX5A appears to play a key role in modulating the physiological activity of COX and involve in energy metabolism, the involvement of COX5A in DOX-induced cardiotoxicity remains unclear. In this study, we showed that COX5A was significantly downregulated by DOX treatment of H9c2 cells. Overexpression of COX5A in H9c2 cells effectively attenuated DOX-induced apoptosis. Meanwhile, DOX-induced decrease in mitochondrial membrane potential could be reserved by COX5A overexpression. Furthermore, COX5A overexpression relieved the DOX-induced suppression of mitochondrial respiration, due an increase in basal respiration, maximal respiration, ATP production, and spare respiratory capacity. These findings indicate that up-regulation of COX5A may inhibit the apoptosis and alleviate the mitochondrial dysfunction of DOX-treated H9c2 cells. Thus, COX5A may have potential for clinical use as a therapeutic target in DOX-induced cardiotoxicity.
Subject(s)
Antibiotics, Antineoplastic/adverse effects , Cardiotoxicity/prevention & control , Doxorubicin/adverse effects , Electron Transport Complex IV/genetics , Electron Transport Complex IV/metabolism , Apoptosis/drug effects , DNA Nucleotidylexotransferase/metabolism , Electron Transport , Gene Expression Regulation/drug effects , Humans , Membrane Potential, Mitochondrial , Mitochondria/metabolism , Mitochondria, Heart/metabolism , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Oxidative Phosphorylation , Signal TransductionABSTRACT
The glucagon-like peptide-1 analog liraglutide has been proved to exert cardioprotective role via activating prosurvival pathways and suppressing inflammation. The activation of NLRP3 inflammasome plays an important role in ischemic injury. The effect of liraglutide on NLRP3 inflammasome-dependent pyroptosis remains unclear. In this study, we established a double stimulation model with TNF-α and hypoxia to mimic ischemic environment and to induce NLRP3 inflammasome activation in H9c2 cardiomyoblasts. Pretreatment with 100â¯nM liraglutide could efficiently inhibit TNF-α and hypoxia-induced inflammasome activation, as evidenced by the decreased expression of NLRP3, caspase-1 p20 and Gasdermin D N-terminal fragment. Meanwhile, the pyroptosis was also demonstrated to be suppressed, indicated by the increased cell viability and decreased lactate dehydrogenase release in the cells. Mechanistically, liraglutide reversed the level of SIRT1 and the selective SIRT1 inhibitor EX 527 significantly abolished the anti-pyroptosis role of liraglutide. Furthermore, liraglutide diminished the levels of ROS generation and NOX4 expression, which could also be blocked by EX 527. Our results uncovered the anti-pyroptosis role of liraglutide in TNF-α and hypoxia-stimulated H9c2 cells, which was associated with SIRT1/NOX4/ROS pathway.
Subject(s)
Inflammasomes/metabolism , Liraglutide/pharmacology , NADPH Oxidase 4/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pyroptosis/drug effects , Reactive Oxygen Species/metabolism , Signal Transduction , Sirtuin 1/metabolism , Animals , Carbazoles/pharmacology , Cell Hypoxia/drug effects , Cell Line , Down-Regulation/drug effects , Rats , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The internal thoracic artery (ITA) that differs from coronary artery (CA), rarely develops atherosclerosis. Understanding the mechanism underlying such a difference will help to pave a new way to the prevention and treatment of the disease. We hypothesize herein that the difference in susceptibility to atherosclerosis between CA and ITA is attributable to the heterogeneity of perivascular adipose tissues (PVATs) surrounding these two kinds of arteries, i.e. PVAT-CA and PVAT-ITA. We isolated PVAT from eight patients of coronary heart disease (CHD) and four non-CHD patients. Gene expression patterns were analyzed by using Agilent whole gene expression profile chips. By comparison between PVAT-CA and PVAT-ITA, we identified 2053 differentially expressed genes, of which 1042 were up-regulated and 1011 were down-regulated, respectively, in CHD group. KEGG pathway and gene ontology (GO) analysis revealed that those differentially expressed genes related to inflammation, lipid metabolism and myocardial processes were particularly noted in the CHD group, but not in non-CHD. Several selected genes, including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), Toll-like receptor 2 (TLR2), Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), serum amyloid A2 (SAA2), and Leptin were validated by real-time PCR analysis. The results showed that the expression levels of IL-1ß, IL-6, and Leptin were significantly higher in PVAT-CA than in PVAT-ITA (P = 0.016, 0.021, and 0.018) in CHD patients. Levels of TLR2, TIRAP, and SAA2 expression were also higher in PVAT-CA, however no significant difference was observed (P = 0.054, 0.092, and 0.058). In conclusion, our findings demonstrate differential gene expression patterns between PVAT-CA and PVAT-ITA, revealing a high heterogeneity in PVAT. Particularly, those genes related to inflammation, lipid metabolism and myocardial processes are differentially expressed in PVAT-CA and PVAT-ITA in CHD patients, suggesting an important role of PVAT in the development of coronary atherosclerosis.
Subject(s)
Adipose Tissue/metabolism , Coronary Vessels/metabolism , Gene Expression Profiling , Mammary Arteries/metabolism , Aged , Coronary Artery Disease/etiology , Female , Humans , Leptin/blood , Male , Middle Aged , Toll-Like Receptor 2/analysisABSTRACT
Cardiac sodium channel plays a key role in the fast depolarization and maintenance of impulse conduction in cardiomyocytes. Mutations of SCN5A gene can lead to many types of arrhythmias. A 14-year-old boy with familial paternal history of sudden unexpected nocturnal death was admitted to hospital with recurrent syncope. A cardiac channelopathy was suspected and a pathogenic ion channel was searched for mutation identification. The proband manifested sinus node dysfunction, ventricular tachycardia, cardiac conduction disturbance involving atrioventricular node and His bundle. The proband and his mother received whole exome sequencing. A heterozygous in-frame deletion N1380del on exon 23 of SCN5A gene locating in a highly conserved pore residue in domain III (S5-S6) was revealed in the proband. The mutation was assessed in other family members by Sanger sequencing. The proband's living uncle and two sisters were asymptomatic mutation carriers with different degrees of cardiac conduction disturbance. Functional analysis was conducted using whole-cell patch clamping in HEK293T cells transfected with wild-type or mutant channels. The HEK293T cells transfected with plasmid pcDNA3.1-N1380del-SCN5A had no detectable sodium current. Overall, N1380del mutation of SCN5A gene leads to loss of function of sodium channel. N1380del is a pathogenetic mutation which can cause cardiac conduction defect and ventricular tachycardia.
Subject(s)
Cardiac Conduction System Disease/genetics , Mutation , NAV1.5 Voltage-Gated Sodium Channel/genetics , Tachycardia, Ventricular/genetics , Adolescent , Cardiac Conduction System Disease/pathology , Cardiac Conduction System Disease/therapy , Exons , Humans , Male , Phenotype , Prognosis , Tachycardia, Ventricular/pathology , Tachycardia, Ventricular/therapyABSTRACT
BACKGROUND: This study aims to investigate prognostic implications of coronary slow flow (CSF) and angiography-derived index of microcirculatory resistance (caIMR) in patients with angina and normal coronary arteries. METHODS: A total of 582 patients were enrolled with angiographically normal coronary arteries. caIMR was calculated using a commercial software. Patients were followed up for a median of 45 months. The primary endpoint was defined as major adverse cardiovascular events (MACEs) comprising death, myocardial infarction and readmission for angina or heart failure. RESULTS: CSF was diagnosed when TIMI grade 2 flow presented in at least one coronary artery. Multivariate analysis indicated TIMI-flow-based determination of CSF was not significantly associated with MACEs [hazard ratio (HR): 2.14; 95% confidence interval (CI): 0.87-5.31; p = 0.099), while caIMR >42 (HR: 2.53; 95% CI: 1.02-6.32; p = 0.047) were independent predictors of MACEs. Incorporation of caIMR improved the area under the curve from 0.587 to 0.642. CONCLUSIONS: caIMR was an independent prognostic factor of long-term cardiovascular events in patients with CSF. Evaluation of caIMR improved the risk stratification of patients with angiographically-normal coronary arteries.
Subject(s)
Coronary Artery Disease , Coronary Vessels , Humans , Prognosis , Coronary Vessels/diagnostic imaging , Coronary Angiography , Retrospective Studies , Microcirculation , Angina Pectoris/diagnosisABSTRACT
Background: Although vessels have the potential to recover following successful recanalization of chronic total occlusion (CTO), evidence is limited about the clinical significance of slow flow (SF) phenomenon after recanalization. The aim of this study was to evaluate the determinants, development and prognostic impact of SF after percutaneous coronary intervention (PCI) for CTO. Methods: This was a retrospective cohort study, 500 patients were consecutively enrolled undergoing CTO PCI and consecutive follow-up angiography in Zhongshan Hospital, Fudan University, between 2015 and 2020. Coronary flow was assessed by corrected Thrombolysis in Myocardial Infarction (TIMI) frame count (CTFC). The association between SF and outcomes of CTO PCI was evaluated by analyzing the clinical, angiographic, and procedural characteristics. Results: SF was observed in 29 (5.8%) patients immediately after CTO PCI. Prior myocardial infraction, right coronary artery (RCA) revascularization and lack of bilateral collaterals were independent predictors of SF. SF was associated with increased risks of periprocedural myocardial infarction (PMI) [adjusted odds ratio (adOR): 4.12; 95% confidence interval (CI): 1.68-10.07; P=0.002] and target lesion restenosis (adOR: 2.50; 95% CI: 1.10-5.72; P=0.030). In patients with baseline left ventricular ejection fraction (LVEF) ≤60%, systolic improvement was compromised in the SF group (LVEF: 55.4%±9.6% in follow up vs. 52.1%±9.4% before CTO PCI, P=0.147) compared with that of the normal group (LVEF: 55.7%±9.3% vs. 51.6%±8.5%, P<0.001). Conclusions: SF has a significant influence on the prognosis of patients undergoing CTO PCI. Achieving normal coronary flow is essential in CTO revascularization.
ABSTRACT
BACKGROUND: In our previous study, the PIANO score was constructed to predict the occurrence of no-reflow phenomenon in patients undergoing primary percutaneous coronary intervention (PCI). In the current analysis, we sought to evaluate the prognostic value and clinical usefulness of the PIANO score in this population. METHODS: Patients with acute myocardial infarction (AMI) undergoing primary PCI were consecutively enrolled and followed up in this register. The endpoint of interest was all-cause mortality at 2 years after the procedure. The clinical benefits of thrombus aspiration (TA) during primary PCI in certain subgroups were also evaluated as exploratory analyses. RESULTS: A total of 2100 patients were identified, and 54.3% had high (≥8) PIANO score. After 2-year follow-up, patients with high PIANO score had higher risk of all-cause mortality after adjustment for propensity score (6.7% vs. 3.1%, adjusted hazard ratio = 2.11 [1.21-3.68], p = 0.008), especially in the first month (adjusted hazard ratio = 2.33 [1.17-4.65], p = 0.017). Restricted cubic spline analysis indicated the linear association between the PIANO score and 2-year all-cause mortality (nonlinear p = 0.556). Further analysis demonstrated that TA did not reduce all-cause mortality in the overall patients, as well as in those with visible thrombus, high thrombus burden, or occlusive lesions. However, the PIANO score defined "high-risk" (PIANO score ≥ 8) patients could benefit from it. CONCLUSIONS: The PIANO score had potential prognostic value in patients with AMI undergoing primary PCI. It might also be helpful for identifying patients who would benefit from TA. These observations require further confirmation in future studies.
Subject(s)
Coronary Thrombosis , Myocardial Infarction , Percutaneous Coronary Intervention , Humans , Percutaneous Coronary Intervention/methods , Prognosis , Treatment Outcome , Myocardial Infarction/diagnosis , Myocardial Infarction/surgery , Coronary Thrombosis/etiologyABSTRACT
Background: Periprocedural myocardial injury (PMI) is a common complication of percutaneous coronary intervention (PCI) associated with poor prognosis. Inflammation has been demonstrated to exert a crucial role in PMI. However, how the inflammation is initiated or sustained in PMI remains elusive. Methods: RNA-seq in peripheral blood mononuclear cells (PBMCs) from 3 Non-PMI and 6 PMI patients was performed with subsequent bioinformatics analysis. RNA-seq results were verified in a patient cohort. We also established the coronary microembolization (CME) mice model to mimic PMI. The activity of caspase-1 in PBMCs was detected by flow cytometry. The levels of interleukin (IL)-1ß, IL-18 and cardiac troponin in plasma were measured by enzyme-linked immunosorbent assay. Results: We identified a total of 901 differentially expressed genes (DEGs) between Non-PMI and PMI patients. These DEGs participated in several inflammation-related processes. NOD-like receptor signaling pathway was significantly enriched in pathway analysis. All the key genes composed in the NLRP3 inflammasome, including NLRP3, PYCARD, CASP1 and IL1B, were upregulated in PMI patients. The activation of NLRP3 inflammasome was then verified by increased activity of caspase-1 in PBMCs, and elevated levels of IL-1ß and IL-18 in plasma in PMI patients. Spearman analysis confirmed tight correlations between caspase-1 activity, IL-1ß, IL-18 levels and troponin T level. In addition, caspase-1 activity, IL-1ß and IL-18 levels were also enhanced in CME mice. Conclusions: We discovered that NLRP3 inflammasome was involved in PMI, thus providing evidence supporting the therapeutic value of NLRP3 inflammasome-targeted strategies in PMI.
ABSTRACT
Aims: Altered lipid, energy metabolism and sleep disorders had been linked with coronary heart disease (CHD), however, the metabolic signatures and sleep rhythm in non-obstructive coronary atherosclerosis-CHD remain unclear. This pilot study aims to investigate the lipidome and central carbon metabolites profiles and associated sleep characteristics among CHD patients without traditional risk factors. Methods: From January to July 2021, 15 CHD patients and 15 healthy controls were randomly selected from the cardiology unit of Zhongshan Hospital, Shanghai. A total of 464 lipids and 45 central carbon metabolites (CCM) were quantified in blood plasma. Metabolic signatures were selected through orthogonal projections to latent structures discriminant analysis (OPLS-DA) and principal component analysis (PCA) was conducted to link the profiles of identified metabolites with CHD risk, sleep patterns, cardiometabolic traits and cardiac electrophysiologic parameters. Results: Using OPLS-DA, we identified 40 metabolites (variable influence on projection >1) that were altered in CHD patients, with 38 lipids, including 25 triacylglycerols (TAGs), 8 diacylglycerols (DAGs), being elevated and two CCM metabolites (i.e., succinic acid and glycolic acid) being reduced. Using PCA, four principal components (PCs) were identified and associated with increased risk of CHD. Specifically, one standard unit increasement in the PC that was characterized by high levels of DAG (18:1) and low succinic acid and the PC that was characterized by high levels of two sphingomyelins [SM (26:0) and SM (24:0)] was associated with 21% [odds ratio (OR) = 1.21, 95% CI: 1.02,1.43] and 14% (OR = 1.14,1.02,1.29) increased risk of CHD, respectively. Further regression analyses confirmed that the identified metabolites and the four PCs were positively associated with TG and ALT. Interestingly, glycolic acid was negatively associated with sleep quality and PSQI. Participants with night sleep mode tended to have a high level of the identified lipids, especially FFA (20:4). Conclusion: In the present pilot study, our findings provide clues on alterations of lipid and energy metabolism in CHD patients without traditional risk factors, with multiple triacylglycerols and diacylglycerols metabolites seemingly elevated and certain nonlipids metabolites (e.g., succinic acid and glycolic acid) decreased in cases. Considering the limit sample size, further studies are warranted to confirm our results.
ABSTRACT
AIM: To explore the beneficial effects of L-carnitine on cardiac microvascular dysfunction in diabetic cardiomyopathy from the perspectives of mitophagy and mitochondrial integrity. METHODS: Male db/db and db/m mice were randomly assigned to groups and were treated with L-carnitine or a solvent for 24 weeks. Endothelium-specific PARL overexpression was attained via adeno-associated virus serotype 9 (AAV9) transfection. Adenovirus (ADV) vectors overexpressing wild-type CPT1a, mutant CPT1a, or PARL were transfected into endothelial cells exposed to high glucose and free fatty acid (HG/FFA) injury. Cardiac microvascular function, mitophagy, and mitochondrial function were analyzed by immunofluorescence and transmission electron microscopy. Protein expression and interactions were assessed by western blotting and immunoprecipitation. RESULTS: L-carnitine treatment enhanced microvascular perfusion, reinforced endothelial barrier function, repressed the endothelial inflammatory response, and maintained the microvascular structure in db/db mice. Further results demonstrated that PINK1-Parkin-dependent mitophagy was suppressed in endothelial cells suffering from diabetic injury, and these effects were largely alleviated by L-carnitine through the inhibition of PARL detachment from PHB2. Moreover, CPT1a modulated the PHB2-PARL interaction by directly binding to PHB2. The increase in CPT1a activity induced by L-carnitine or amino acid mutation (M593S) enhanced the PHB2-PARL interaction, thereby improving mitophagy and mitochondrial function. In contrast, PARL overexpression inhibited mitophagy and abolished all the beneficial effects of L-carnitine on mitochondrial integrity and cardiac microvascular function. CONCLUSION: L-carnitine treatment enhanced PINK1-Parkin-dependent mitophagy by maintaining the PHB2-PARL interaction via CPT1a, thereby reversing mitochondrial dysfunction and cardiac microvascular injury in diabetic cardiomyopathy.