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BACKGROUND: The National Chest Pain Center Program (NCPCP) is a nationwide, quality enhancement program aimed at raising the standard of care for patients experiencing acute chest pain in China. The benefits of chest pain center (CPC) accreditation on acute coronary syndrome have been demonstrated. However, there is no evidence to indicate whether CPC accreditation improves outcomes for patients with acute aortic dissection (AAD). METHODS: We conducted a retrospective observational study of patients with AAD from 1671 hospitals in China, using data from the NCPCP spanning the period from January 1, 2016 to December 31, 2022. The patients were divided into 2 groups: pre-accreditation and post-accreditation admissions. The outcomes examined included in-hospital mortality, misdiagnosis, and Stanford type A AAD surgery. Multivariate logistic regression was employed to explore the relationship between CPC accreditation and in-hospital outcomes. Furthermore, we stratified the hospitals based on their geographical location (Eastern/Central/Western regions) or administrative status (provincial/non-provincial capital areas) to assess the impact of CPC accreditation on AAD patients across various regions. RESULTS: The analysis encompassed a total of 40,848 patients diagnosed with AAD. The post-accreditation group exhibited significantly lower rates of in-hospital mortality and misdiagnosis (12.1% vs. 16.3%, P < 0.001 and 2.9% vs. 5.4%, P < 0.001, respectively) as well as a notably higher rate of Stanford type A AAD surgery (61.1% vs. 42.1%, P < 0.001) compared with the pre-accreditation group. After adjusting for potential covariates, CPC accreditation was associated with substantially reduced risks of in-hospital mortality (adjusted OR 0.644, 95% CI 0.599-0.693) and misdiagnosis (adjusted OR 0.554, 95% CI 0.493-0.624), along with an increase in the proportion of patients undergoing Stanford type A AAD surgery (adjusted OR 1.973, 95% CI 1.797-2.165). Following CPC accreditation, there were significant reductions in in-hospital mortality across various regions, particularly in Western regions (from 21.5 to 14.1%). Moreover, CPC accreditation demonstrated a more pronounced impact on in-hospital mortality in non-provincial cities compared to provincial cities (adjusted OR 0.607 vs. 0.713). CONCLUSION: CPC accreditation is correlated with improved management and in-hospital outcomes for patients with AAD.
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Acreditação , Dissecção Aórtica , Dor no Peito , Mortalidade Hospitalar , Humanos , China/epidemiologia , Acreditação/estatística & dados numéricos , Acreditação/normas , Dissecção Aórtica/terapia , Dissecção Aórtica/mortalidade , Dissecção Aórtica/cirurgia , Dissecção Aórtica/diagnóstico , Feminino , Estudos Retrospectivos , Masculino , Pessoa de Meia-Idade , Dor no Peito/terapia , Dor no Peito/diagnóstico , Idoso , Adulto , Modelos LogísticosRESUMO
Identifying the atlas of immune cells from coronary sinus circulation (CSC) of patients with persistent atrial fibrillation (PerAF) may provide new insights into the role of immune cells in the progression of AF. Single-cell sequencing revealed substantial alterations in immune cells from CSCs of patients with PerAF, especially a markedly elevated abundance of T cells, after which we identified a T cell subset: FGFBP2(+)TRDC(-)CD4(-) T cells (Ftc-T cells), which can promote the proliferation of cardiac fibroblasts (CFs),and the proportion of Ftc-T had a positive linear with AF recurrence post catheter ablation (CA). Moreover, IFI27 was found to be highly enriched in Ftc-T cells and promoted CFs proliferation and collagen expression. Altogether, our findings represent a unique resource providing in-depth insights into the heterogeneity of the immune cell from CSC of patients with PerAF and highlight the potential role of Ftc-T cells and IFI27 for AF progression.
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Atherosclerosis is a chronic inflammatory metabolic disease with a complex pathogenesis. However, the exact details of its pathogenesis are still unclear, which limits effective clinical treatment of atherosclerosis. Recently, multiple studies have demonstrated that the gut microbiota plays a pivotal role in the onset and progression of atherosclerosis. This review discusses possible treatments for atherosclerosis using the gut microbiome as an intervention target and summarizes the role of the gut microbiome and its metabolites in the development of atherosclerosis. New strategies for the treatment of atherosclerosis are needed. This review provides clues for further research on the mechanisms of the relationship between the gut microbiota and atherosclerosis.
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BACKGROUND: Lipoprotein(a) (Lp[a]) is associated with an increased risk of myocardial infarction (MI). However, the mechanism underlying this association has yet to be fully elucidated. OBJECTIVES: This multicenter study aimed to investigate whether association between Lp(a) and MI risk is reinforced by the presence of low-attenuation plaque (LAP) identified by coronary computed tomography angiography (CCTA). METHODS: In a derivation cohort, a total of 5,607 patients with stable chest pain suspected of coronary artery disease who underwent CCTA and Lp(a) measurement were prospectively enrolled. In validation cohort, 1,122 patients were retrospectively collected during the same period. High Lp(a) was defined as Lp(a) ≥50 mg/dL. The primary endpoint was a composite of time to fatal or nonfatal MI. Associations were estimated using multivariable Cox proportional hazard models. RESULTS: During a median follow-up of 8.2 years (Q1-Q3: 7.2-9.3 years), the elevated Lp(a) levels were associated with MI risk (adjusted HR [aHR]: 1.91; 95% CI: 1.46-2.49; P < 0.001). There was a significant interaction between Lp(a) and LAP (Pinteraction <0.001) in relation to MI risk. When stratified by the presence or absence of LAP, Lp(a) was associated with MI in patients with LAP (aHR: 3.03; 95% CI: 1.92-4.76; P < 0.001). Mediation analysis revealed that LAP mediated 73.3% (P < 0.001) for the relationship between Lp(a) and MI. The principal findings remained unchanged in the validation cohort. CONCLUSIONS: Elevated Lp(a) augmented the risk of MI during 8 years of follow-up, especially in patients with LAP identified by CCTA. The presence of LAP could reinforce the relationship between Lp(a) and future MI occurrence.
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Angiografia por Tomografia Computadorizada , Lipoproteína(a) , Infarto do Miocárdio , Placa Aterosclerótica , Humanos , Masculino , Feminino , Lipoproteína(a)/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/epidemiologia , Pessoa de Meia-Idade , Placa Aterosclerótica/sangue , Placa Aterosclerótica/diagnóstico por imagem , Idoso , Angiografia Coronária , Estudos Retrospectivos , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Estudos Prospectivos , Seguimentos , Biomarcadores/sangueRESUMO
BACKGROUND: Our recently developed Coronary Artery Tree description and Lesion EvaluaTion (CatLet) angiographic scoring system is unique in its description of the variability in the coronary anatomy, the degree of stenosis of a diseased coronary artery, and its subtended myocardial territory, and can be utilized to predict clinical outcomes for patients with acute myocardial infarction (AMI) presenting ≤12 h after symptom onset. The current study aimed to assess whether the Clinical CatLet score (CCS), as compared with CatLet score (CS), better predicted clinical outcomes for AMI patients presenting >12 h after symptom onset. METHODS: CS was calculated in 1018 consecutive AMI patients enrolled in a retrospective registry. CCS was calculated by multiplying CS by the ACEF I score (age, creatinine, and left ventricular ejection fraction). Primary endpoint was major adverse cardiac events (MACEs) at 4-year-follow-up, a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization. RESULTS: Over a 4-year follow-up period, both scores were independent predictors of clinical outcomes after adjustment for a broad spectrum of risk factors. Areas-under-the-curve (AUCs) for CS and CCS were 0.72(0.68-0.75) and 0.75(0.71-0.78) for MACEs; 0.68(0.63-0.73) and 0.78(0.74-0.83) for all-cause death; 0.73(0.68-0.79) and 0.83(0.79-0.88) for cardiac death; and 0.69(0.64-0.73) and 0.75(0.7-0.79) for myocardial infarction; and 0.66(0.61-0.7) and 0.63(0.58-0.68) for revascularization, respectively. CCS performed better than CS in terms of the above-mentioned outcome predictions, as confirmed by the net reclassification and integrated discrimination indices. CONCLUSIONS: CCS was better than CS to be able to risk-stratify long-term outcomes in AMI patients presenting >12 h after symptom onset. These findings have indicated that both anatomic and clinical variables should be considered in decision-making on management of patients with AMI presenting later.
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Angiografia Coronária , Infarto do Miocárdio , Humanos , Masculino , Feminino , Infarto do Miocárdio/diagnóstico , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Fatores de Tempo , Prognóstico , Índice de Gravidade de Doença , Sistema de Registros/estatística & dados numéricos , Medição de Risco/métodos , Fatores de Risco , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/patologia , SeguimentosRESUMO
Background: The presence of mental health conditions is pervasive in patients who experienced acute myocardial infarction (AMI), significantly disrupting their recovery. Providing timely and easily accessible psychological interventions using virtual reality-based cognitive-behavioural therapy (VR-CBT) could potentially improve both acute and long-term symptoms affecting their mental health. Aims: We aim to examine the effectiveness of VR-CBT on anxiety symptoms in patients with AMI who were admitted to the intensive care unit (ICU) during the acute stage of their illness. Methods: In this single-blind randomised clinical trial, participants with anxiety symptoms who were admitted to the ICU due to AMI were continuously recruited from December 2022 to February 2023. Patients who were Han Chinese aged 18-75 years were randomly assigned (1:1) via block randomisation to either the VR-CBT group to receive VR-CBT in addition to standard mental health support, or the control group to receive standard mental health support only. VR-CBT consisted of four modules and was delivered at the bedside over a 1-week period. Assessments were done at baseline, immediately after treatment and at 3-month follow-up. The intention-to-treat analysis began in June 2023. The primary outcome measure was the changes in anxiety symptoms as assessed by the Hamilton Anxiety Rating Scale (HAM-A). Results: Among 148 randomised participants, 70 were assigned to the VR-CBT group and 78 to the control group. The 1-week VR-CBT intervention plus standard mental health support significantly reduced the anxiety symptoms compared with standard mental health support alone in terms of HAM-A scores at both post intervention (Cohen's d=-1.27 (95% confidence interval (CI): -1.64 to -0.90, p<0.001) and 3-month follow-up (Cohen's d=-0.37 (95% CI: -0.72 to -0.01, p=0.024). Of the 70 participants who received VR-CBT, 62 (88.6%) completed the entire intervention. Cybersickness was the main reported adverse event (n=5). Conclusions: Our results indicate that VR-CBT can significantly reduce post-AMI anxiety at the acute stage of the illness; the improvement was maintained at the 3-month follow-up. Trial registration number: The trial was registered at www.chictr.org.cn with the identifier: ChiCTR2200066435.
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Percutaneous coronary interventions have progressed through the era of plain balloon dilation, bare-metal stent insertion to drug-eluting stent treatment, which has significantly reduced the acute occlusion and restenosis rates of target vessels and improved patient prognosis, making drug-eluting stents the mainstream interventional treatment for coronary artery disease. In recent years, drug-coated balloons (DCBs) have become a new treatment strategy for coronary artery disease, and the drugs used in the coating and the coating technology have progressed in the past years. Without permanent implant, a DCB delivers antiproliferative drugs rapidly and uniformly into the vessel wall via the excipient during a single balloon dilation. Many evidence suggests that DCB angioplasty is an effective measure for dealing with in-stent restenosis and de novo lesions in small coronary vessels. As more clinical studies are published, new evidence is emerging for the use of DCB angioplasty in a wide range of coronary diseases, and the indications are expanding internationally. Based on the latest research from China and elsewhere, the Expert Writing Committee of the Chinese Expert Consensus on Clinical Applications of Drug-Coated Balloon has updated the previous DCB consensus after evidence-based discussions and meetings in terms of adequate preparation of in-stent restenosis lesions, expansion of the indications for coronary de novo lesions, and precise guidance of DCB treatment by intravascular imaging and functional evaluation.
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BACKGROUND AND AIMS: Survivors of acute coronary syndromes face an elevated risk of recurrent atherosclerosis-related vascular events despite advanced medical treatments. The underlying causes remain unclear. This study aims to investigate whether myocardial infarction (MI)-induced trained immunity in monocytes could sustain proatherogenic traits and expedite atherosclerosis. METHODS: Apolipoprotein-E deficient (ApoE-/-) mice and adoptive bone marrow transfer chimeric mice underwent MI or myocardial ischaemia-reperfusion (IR). A subsequent 12-week high-fat diet (HFD) regimen was implemented to elucidate the mechanism behind monocyte trained immunity. In addition, classical monocytes were analysed by flow cytometry in the blood of enrolled patients. RESULTS: In MI and IR mice, blood monocytes and bone marrow-derived macrophages exhibited elevated spleen tyrosine kinase (SYK), lysine methyltransferase 5A (KMT5A), and CCHC-type zinc finger nucleic acid-binding protein (CNBP) expression upon exposure to a HFD or oxidized LDL (oxLDL) stimulation. MI-induced trained immunity was transmissible by transplantation of bone marrow to accelerate atherosclerosis in naive recipients. KMT5A specifically recruited monomethylation of Lys20 of histone H4 (H4K20me) to the gene body of SYK and synergistically transactivated SYK with CNBP. In vivo small interfering RNA (siRNA) inhibition of KMT5A or CNBP potentially slowed post-MI atherosclerosis. Sympathetic denervation with 6-hydroxydopamine reduced atherosclerosis and inflammation after MI. Classical monocytes from ST-elevation MI (STEMI) patients with advanced coronary lesions expressed higher SYK and KMT5A gene levels. CONCLUSIONS: The findings underscore the crucial role of monocyte trained immunity in accelerated atherosclerosis after MI, implying that SYK in blood classical monocytes may serve as a predictive factor for the progression of atherosclerosis in STEMI patients.
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Aterosclerose , Infarto do Miocárdio , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Animais , Camundongos , Monócitos , Imunidade TreinadaRESUMO
BACKGROUND: Patients with chronic kidney disease (CKD) undergoing coronary angiography (CAG) are at high risk of contrast-associated acute kidney injury (CA-AKI) and mortality. Therefore, there is a clinical need to explore safe, convenient, and effective strategies for preventing CA-AKI. OBJECTIVES: This study sought to assess whether simplified rapid hydration is noninferior to standard hydration for CA-AKI prevention in patients with CKD. METHODS: This multicenter, open-label, randomized controlled study was conducted across 21 teaching hospitals and included 1,002 patients with CKD. Patients were randomized to either simplified hydration (SH) (SH group, with normal saline from 1 hour before to 4 hours after CAG at a rate of 3 mL/kg/h) or standard hydration (control group, with normal saline 12 hours before and 12 hours after CAG at a rate of 1 mL/kg/h). The primary endpoint of CA-AKI was a ≥25% or 0.5-mg/dL rise in serum creatinine from baseline within 48 to 72 hours. RESULTS: CA-AKI occurred in 29 of 466 (6.2%) patients in the SH group and in 38 of 455 (8.4%) patients in the control group (relative risk: 0.8; 95% CI: 0.5-1.2; P = 0.216). In addition, the risk of acute heart failure and 1-year major adverse cardiovascular events did not differ significantly between the groups. However, the median hydration duration was significantly shorter in the SH group than in the control group (6 vs 25 hours; P < 0.001). CONCLUSIONS: In CKD patients undergoing CAG, SH is noninferior to standard hydration in preventing CA-AKI with a shorter hydration duration.
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Injúria Renal Aguda , Insuficiência Renal Crônica , Humanos , Angiografia Coronária/efeitos adversos , Solução Salina , Resultado do Tratamento , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/prevenção & controle , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnósticoRESUMO
BACKGROUND: Pericoronary adipose tissue (PCAT) density is a biomarker of vessel inflammation, which is supposed to be increased in patients with type 2 diabetes mellitus (T2DM). However, whether the coronary inflammation revealed by this novel index could be alleviated after evolocumab treatment in T2DM remains unknown. METHODS: From January 2020 to December 2022, consecutive T2DM patients with low-density lipoprotein cholesterol ≥ 70 mg/dL on maximally tolerated statin and taking evolocumab were prospectively included. In addition, patients with T2DM who were taking statin alone were recruited as control group. The eligible patients underwent baseline and follow-up coronary CT angiography with an interval of 48-week. To render patients with evolocumab as comparable to those controls, a propensity-score matching design was used to select the matched pairs with a 1:1 ratio. Obstructive lesion was defined as the extent of coronary artery stenosis ≥ 50%; the numbers inside the brackets were interquartile ranges. RESULTS: A total of 170 T2DM patients with stable chest pain were included [(mean age 64 ± 10.6 [range 40-85] years; 131 men). Among those patients, 85 were in evolocumab group and 85 were in control group. During follow-up, low-density lipoprotein cholesterol (LDL-C) level (2.02 [1.26, 2.78] vs. 3.34 [2.53, 4.14], p < 0.001), and lipoprotein(a) (12.1 [5.6, 21.8] vs. 18.9 [13.2, 27.2], p = 0.002) were reduced after evolocumab treatment. The prevalence of obstructive lesions and high-risk plaque features were significantly decreased (p < 0.05 for all). Furthermore, the calcified plaque volume were significantly increased (188.3 [115.7, 361.0] vs. 129.3 [59.5, 238.3], p = 0.015), while the noncalcified plaque volume and necrotic volume were diminished (107.5 [40.6, 180.6] vs. 125.0 [65.3, 269.7], p = 0.038; 0 [0, 4.7] vs. 0 [0, 13.4], p < 0.001, respectively). In addition, PCAT density of right coronary artery was significantly attenuated in evolocumab group (- 85.0 [- 89.0, - 82.0] vs. - 79.0 [- 83.5, - 74.0], p < 0.001). The change in the calcified plaque volume inversely correlated with achieved LDL-C level (r = - 0.31, p < 0.001) and lipoprotein(a) level (r = - 0.33, p < 0.001). Both the changes of noncalcified plaque volume and necrotic volume were positively correlated with achieved LDL-C level and Lp(a) (p < 0.001 for all). However, the change of PCATRCA density only positively correlated with achieved lipoprotein(a) level (r = 0.51, p < 0.001). Causal mediation analysis revealed Lp(a) level mediated 69.8% (p < 0.001) for the relationship between evolocumab and changes of PCATRCA. CONCLUSIONS: In patients with T2DM, evolocumab is an effective therapy to decrease noncalcified plaque volume necrotic volume, and increase calcified plaque volume. Furthermore, evolocumab could attenuate PCAT density, at least in part, via the reduction of lipoprotein(a).
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Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Inibidores de Hidroximetilglutaril-CoA Redutases , Placa Aterosclerótica , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Tecido Adiposo , LDL-Colesterol , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Seguimentos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inflamação , Lipoproteína(a) , Placa Aterosclerótica/patologia , FemininoRESUMO
Nuclear pore complex in the nuclear envelope plays an important role in controlling the transportation of RNAs, proteins and other macromolecules between the nucleus and cytoplasm. The relationship between abnormal expression of nucleoporins and cardiovascular diseases is unclear. In this study we investigated how myocardial infarction affected the expression and function of nucleoporins in cardiomyocytes. We separately knocked down 27 nucleoporins in rat primary myocardial cells. Among 27 nucleoporins, knockdown of Nup93, Nup210 and Nup214 markedly increased the expression of ANP and BNP, two molecular markers of cardiomyocyte function. We showed that Nup93 was significantly downregulated in hypoxic cardiomyocytes. Knockdown of Nup93 aggravated hypoxia-induced injury and cell death of cardiomyocytes, whereas overexpression of Nup93 led to the opposite effects. RNA-seq and bioinformatics analysis revealed that knockdown of Nup93 did not affect the overall transportation of mRNAs from the nucleus to the cytoplasm, but regulated the transcription of a large number of mRNAs in cardiomyocytes, which are mainly involved in oxidative phosphorylation and ribosome subunits. Most of the down-regulated genes by Nup93 knockdown overlapped with the genes whose promoters could be directly bound by Nup93. Among these genes, we demonstrated that Nup93 knockdown significantly down-regulated the expression of YAP1. Overexpression of YAP1 partially rescued the function of Nup93 knockdown and attenuated the effects of hypoxia on cell injury and cardiomyocyte death. We conclude that down-regulation of Nup93, at least partially, contributes to hypoxia-induced injury and cardiomyocyte death through abnormal interaction with the genome to dynamically regulate the transcription of YAP1 and other genes. These results reveal a new mechanism of Nup93 and might provide new therapeutic targets for the treatment of ischemia-induced heart failure.
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Miócitos Cardíacos , Complexo de Proteínas Formadoras de Poros Nucleares , Animais , Ratos , Apoptose , Regulação para Baixo , Hipóxia/metabolismo , Hipóxia/patologia , Miócitos Cardíacos/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Transcrição GênicaRESUMO
Myocardial infarction is lethal to patients because of insufficient blood perfusion to vital organs. Several attempts have been made to improve its prognosis, among which nanomaterial research offers an opportunity to address this problem at the molecular level and has the potential to improve disease prevention, diagnosis, and treatment significantly. Up to now, nanomaterial-based technology has played a crucial role in broad novel diagnostic and therapeutic strategies for cardiac repair. This review summarizes various nanomaterial applications in myocardial infarction from multiple aspects, including high precision detection, pro-angiogenesis, regulating immune homeostasis, and miRNA and stem cell delivery vehicles. We also propose promising research hotspots that have not been reported much yet, such as conjugating pro-angiogenetic elements with nanoparticles to construct drug carriers, developing nanodrugs targeting other immune cells except for macrophages in the infarcted myocardium or the remote region. Though most of those strategies are preclinical and lack clinical trials, there is tremendous potential for their further applications in the future.
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Infarto do Miocárdio , Nanopartículas , Portadores de Fármacos , Humanos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/terapia , Miocárdio , Células-Tronco/fisiologiaRESUMO
Macrophages play a vital role in cardiac repair following myocardial infarction (MI). An enriched environment (EE) is involved in the regulation of macrophage-related activities and disease progression; however, whether EE affects the phenotype and function of macrophages to improve postinfarction cardiac repair remains unknown. In this study, we found that EE improved cardiac function, decreased mortality, and ameliorated adverse ventricular remodeling in mice after MI, with these outcomes closely related to the increased survival of Ly6Clow macrophages and their CCR2-MHCIIlow subsets. EE increased the expression of brain-derived neurotrophic factor (BDNF) in the hypothalamus, leading to higher circulating levels of BDNF, which, in turn, regulated the cardiac macrophages. BDNF bound to tropomyosin receptor kinase B to activate downstream ERK1/2 and AKT pathways, promoting macrophage survival. These findings demonstrate that EE optimizes postinfarction cardiac repair and highlights the significance of EE as a previously unidentified strategy for impeding adverse ventricular remodeling.
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Infarto do Miocárdio , Remodelação Ventricular , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Coração , Macrófagos/metabolismo , Camundongos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/terapia , Miocárdio/metabolismoRESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important and major player in the pathophysiology of hypercholesterolemia and atherosclerosis. Recently, PCSK9 has been implicated in the pathogenesis of inflammatory diseases. Whether PCSK9 is involved in idiopathic pulmonary arterial hypertension (IPAH) remains unclear. This study aimed to investigate the relationship between PCSK9 and IPAH. Serum PCSK9, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 ß (IL-1ß), and monocyte chemotactic protein-1 (MCP-1) were measured by enzyme linked immunosorbent assay. Transthoracic echocardiography was performed among 40 IPAH patients and 20 control subjects. Hemodynamic data were collected via right heart catheterization in patients with IPAH. Serum PCSK9, TNF-α, IL-6, IL-1ß, and MCP-1 levels were significantly higher in IPAH patients than in control subjects (p < 0.001). Among enrolled IPAH patients, PCSK9 levels were higher in WHO-FC III/IV patients compared with those in WHO-FC I/II (p < 0.05), and were positively correlated with TNF-α, IL-6, MCP-1, N-Terminal pro-brain natriuretic peptide, pulmonary arterial systolic pressure (r = 0.653, p < 0.001), pulmonary arterial diastolic pressure (r = 0.466, p = 0.002), mean pulmonary arterial pressure (mPAP, r = 0.730, <0.001), pulmonary vascular resistance (r = 0.488, p = 0.001), and right ventricle diameter (r = 0.563, p < 0.001). In multiple regression analysis, mPAP was strongly associated with serum PCSK9 (ß = 0.694, p < 0.001), independent of other variables. Receiver operating characteristic curve analysis showed the optimal cutoff value of serum PCSK9 concentration for predicting IPAH was 90.67 ng/ml, with a sensitivity of 90.0% and a specificity of 85.0%. In conclusion, IPAH patients had elevated serum PCSK9 levels which correlated the presence and severity of pulmonary hypertension. PCSK9 may be a novel potential therapeutic target.
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BACKGROUND: H type hypertension is defined as homocysteine (Hcy) ≥ 10 µmol/L in combination with primary hypertension. Studies demonstrated that the existence of hyperhomocysteine (HHcy) in hypertensive exacerbates the poor outcome of cardiocerebral incidents. This study was to investigate the current epidemic situation of H type hypertension and determine the risk factors in order to find intervention targets for H type hypertensives. METHODS: We conducted a cross-sectional study using cluster sampling design in Shanghai, China from July 2019 and April 2020. 23,652 patients with primary hypertension were enrolled in this study. Their medical information was recorded, and the level of Hcy concentrations and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms were detected. RESULTS: In total, 22,731 of 23,652 patients were recorded. The mean age was 68.9 ± 8.6 y and 43% were men. 80.0% of the enrolled patients had H type hypertension. The frequency of allele T was 40.9%, and the proportions of the CC, CT, and TT genotypes were 36.1%, 46.0%, and 17.9%, respectively. Compared with the TT genotype, the plasma Hcy concentration levels were lower in patients with the CC/CT genotype (18.96 ± 13.48 µmol/L vs. 13.62 ± 5.20/14.28 ± 5.36, F = 75.04, p < 0.01). The risk for H type hypertension was higher in elderly people. Men had ~ 5.55-fold odds of H type hypertension compared with women. Patients with CT genotype and TT genotype had ~ 1.36- and ~ 2.76-fold odds of H type hypertension compared with those with CC genotype, respectively. Smoking and diabetes were not significantly associated with H type hypertension. CONCLUSIONS: The prevalence of H type hypertension in patients with primary hypertension was 80.0%, which was higher than the 75% found in prior report in China. Age, gender, and MTHFR C677T polymorphisms rather than smoking and diabetes were independently associated with H type hypertension.
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Genótipo , Homocisteína/sangue , Hipertensão/sangue , Hipertensão/epidemiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Hiper-Homocisteinemia/complicações , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Prevalência , Fatores de RiscoRESUMO
Ischemic preconditioning induced by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischemic insult. In this study we investigated whether a short-term nonischemic stimulation of hypertrophy renders the heart resistant to subsequent ischemic injury. Male mice were subjected to transient transverse aortic constriction (TAC) for 3 days followed aortic debanding on D4 (T3D4), as well as ligation of the left coronary artery to induce myocardial infarction (MI). The TAC preconditioning mice showed markedly improved contractile function and significantly reduced myocardial fibrotic area and apoptosis following MI. We revealed that TAC preconditioning significantly reduced MI-induced oxidative stress, evidenced by increased NADPH/NADP ratio and GSH/GSSG ratio, as well as decreased mitochondrial ROS production. Furthermore, TAC preconditioning significantly increased the expression and activity of SIRT3 protein following MI. Cardiac-specific overexpression of SIRT3 gene through in vivo AAV-SIRT3 transfection partially mimicked the protective effects of TAC preconditioning, whereas genetic ablation of SIRT3 in mice blocked the protective effects of TAC preconditioning. Moreover, expression of an IDH2 mutant mimicking deacetylation (IDH2 K413R) in cardiomyocytes promoted myocardial IDH2 activation, quenched mitochondrial reactive oxygen species (ROS), and alleviated post-MI injury, whereas expression of an acetylation mimic (IDH2 K413Q) in cardiomyocytes inactivated IDH2, exacerbated mitochondrial ROS overload, and aggravated post-MI injury. In conclusion, this study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Therapeutic strategies targeting IDH2 are promising treatment approaches for cardiac ischemic injury.
Assuntos
Precondicionamento Isquêmico Miocárdico , Isocitrato Desidrogenase/metabolismo , Infarto do Miocárdio/prevenção & controle , Acetilação , Animais , Apoptose/fisiologia , Técnicas de Inativação de Genes , Isocitrato Desidrogenase/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Mutação , Infarto do Miocárdio/metabolismo , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/genética , Sirtuína 3/metabolismoRESUMO
BACKGROUND: Ischaemic preconditioning elicited by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischaemic insult. Here, we test the hypothesis that short-term non-ischaemic stimulation of hypertrophy renders the heart resistant to subsequent ischaemic injury. METHODS AND RESULTS: Transient transverse aortic constriction (TAC) was performed for 3 days in mice and then withdrawn for 4 days by aortic debanding, followed by subsequent exposure to myocardial ischaemia-reperfusion (I/R) injury. Following I/R injury, myocardial infarct size and apoptosis were significantly decreased, and cardiac dysfunction was markedly improved in the TAC preconditioning group compared with the control group. Mechanistically, TAC preconditioning markedly suppressed I/R-induced autophagy and preserved autophagic flux by deacetylating SOD2 via a SIRT3-dependent mechanism. Moreover, treatment with an adenovirus encoding SIRT3 partially mimicked the effects of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. Furthermore, in vivo lentiviral-mediated knockdown of Beclin 1 in the myocardium ameliorated the I/R-induced impairment of autophagic flux and was associated with a reduction in cell death, whereas treatment with a lentivirus encoding Beclin 1 abolished the cardioprotective effect of TAC preconditioning. CONCLUSIONS: The present study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Specifically, TAC preconditioning reduced myocardial autophagic cell death in a SIRT3/SOD2 pathway-dependent manner.
Assuntos
Autofagia , Precondicionamento Isquêmico , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismo , Animais , Apoptose , Proteína Beclina-1/antagonistas & inibidores , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Sirtuína 3/deficiência , Sirtuína 3/genéticaRESUMO
Brief episodes of ischaemia and reperfusion render the heart resistant to subsequent prolonged ischaemic insult, termed ischaemic preconditioning. Here, we hypothesized that transient non-ischaemic stress by hypertrophic stimulation would induce endogenous cardioprotective signalling and enhance cardiac resistance to subsequent ischaemic damage. Transient transverse aortic constriction (TAC) or Ang-â ¡ treatment was performed for 3-7 days in male mice and then withdrawn for several days by either aortic debanding or discontinuing Ang-â ¡ treatment, followed by subsequent exposure to regional myocardial ischaemia by in situ coronary artery ligation. Following ischaemia/reperfusion (I/R) injury, myocardial infarct size and apoptosis were markedly reduced and contractile function was significantly improved in the TAC preconditioning group compared with that in the control group. Similar results were observed in mice receiving Ang-â ¡ infusion. Mechanistically, TAC preconditioning enhanced ALDH2 activity, promoted AMPK activation and improved mitochondrial energy metabolism by increasing myocardial OXPHOS complex expression, elevating the mitochondrial ATP content and improving viable myocardium glucose uptake. Moreover, TAC preconditioning significantly mitigated I/R-induced myocardial iNOS/gp91phox activation, inhibited endoplasmic reticulum stress and ameliorated mitochondrial impairment. Using a pharmacological approach to inhibit AMPK signalling in the presence or absence of preconditioning, we demonstrated AMPK-dependent protective mechanisms of TAC preconditioning against I/R injury. Furthermore, treatment with adenovirus-encoded ALDH2 partially emulated the actions of hypertrophic preconditioning, as evidenced by improved mitochondrial metabolism, inhibited oxidative stress-induced mitochondrial damage and attenuated cell death through an AMPK-dependent mechanism, whereas genetic ablation of ALDH2 abrogated the aforementioned actions of TAC preconditioning. The present study demonstrates that preconditioning with hypertrophic stress protects the heart from I/R injury via mechanisms that improve mitochondrial metabolism, reduce oxidative/nitrative stress and inhibit apoptosis. ALDH2 is obligatorily required for the development of cardiac hypertrophic preconditioning and acts as the mediator of this process.