Background: Matrix metalloproteinase-9 (MMP-9), a key determinant of extracellular matrix degradation, might cause cerebral damage after stroke and be involved in the development of depressive symptoms. This study aimed to evaluate the association of serum MMP-9 levels and post-stroke depression (PSD). Methods and Results: Serum MMP-9 levels were determined in 558 acute ischemic stroke patients from 7 hospitals comprising the China Antihypertensive Trial in Acute Ischemic Stroke. We assessed depression status using the 24-item Hamilton Depression Rating Scale and defined PSD as a cutoff score of 8. Logistic regression was performed to estimate the risk of PSD associated with serum MMP-9. Discrimination and reclassification for PSD by MMP-9 were analyzed. A total of 222 (39.8%) stroke patients were categorized as PSD within 3 months. Serum MMP-9 concentrations were higher among PSD patients than those without PSD (658.8 vs. 485.7 ng/mL; P<0.001). The multiple-adjusted odds ratio (95% confidence interval) for the highest MMP-9 quartile compared with the lowest quartile was 4.36 (2.49-7.65) for PSD, and 1 standard deviation higher log-MMP-9 was associated with 68% (37-106%) increased odds of PSD. Adding MMP-9 to the conventional risk factors model substantially improved discrimination and reclassification for PSD (all P<0.05). Conclusions: Elevated serum MMP-9 levels in the acute phase of ischemic stroke were associated with increased risk of PSD, suggesting an important prognostic role of MMP-9 for PSD.
Background: Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective non-interventional study of stroke prevention in patients with newly diagnosed non-valvular AF (NAVF) that is being conducted in 35 countries. Methods and Results: A total of 52,081 patients with a new diagnosis of NVAF were enrolled prospectively in GARFIELD-AF. Of these, 4859 (9.3%) were recruited in Japan (2010-2016). In cohort 1 (2010-2011), few patients were on non-vitamin K antagonist oral anticoagulants (NOAC) globally. From cohort 2 onwards (2011-2016), however, there was a rapid increase in NOAC use around the globe, especially in Japan. By the last year of enrolment (2015-2016), 67.9% of patients in Japan and 43.1% of patients globally were on NOAC +/- antiplatelet therapy (AP). In Japan and globally, 17.0% and 12.2% of patients, respectively, did not receive stroke prevention treatment. Few patients in Japan (5.7%) received AP only. Compared with the other countries, the unadjusted rates of all-cause mortality and major bleeding were low, while rates of stroke/systemic embolism were similar after 1 year of follow-up. Conclusions: GARFIELD-AF continues to provide important information on the homogeneity and heterogeneity of baseline characteristics and treatment patterns in patients with newly diagnosed NVAF. This diversity reflects the differences in outcomes in Japan compared with the rest of the world.
Background: Common atrioventricular valve (CAVV) repair in patients with a single ventricle remains a great challenge and a refractory issue for pediatric cardiac surgeons. Methods and Results: From January 2007 to April 2018, 37 consecutive patients with a single ventricle who underwent CAVV repair were included in the study group. Patients were divided into 2 groups based on the repair technique: patients in Group A were treated using the bivalvation technique, and patients in Group B underwent conventional repair techniques; baseline data were similar between groups. The inhospital and follow-up mortality were 5.4% (2/37) and 11.4% (4/35), respectively. After a follow-up of 65.5 +/- 29.3 months, the estimated 1-, 5-, and 10-year overall survival rates were 94.6%, 83.4%, and 77.0%, respectively. The rates of freedom from CAVV failure were 94.3%, 72.7%, and 62.9% after 1, 5, and 10 years, respectively. In the multivariate analysis, the independent factors for CAVV repair failure were repair technique (P=0.004) and heterotaxy syndrome (P=0.003). A total of 30 patients (81.1%) completed total cavopulmonary connection (TCPC); 3 patients required re-intervention; 24 of 31 patients (77.4%) were in New York Heart Association classes II and I at the latest follow-up. Conclusions: Outcomes of CAVV repair in patients palliated by single-ventricular surgery are acceptable. The bivalvation technique is a simple and effective technique.
Background: Recent studies have suggested that pregnancy-associated plasma protein-A (PAPP-A) is involved in the pathogenesis of atherosclerosis. This study aim is to investigate the role and mechanisms of PAPP-A in reverse cholesterol transport (RCT) and inflammation during the development of atherosclerosis. Methods and Results: PAPP-A was silenced in apolipoprotein E (apoE(-/-)) mice with administration of PAPP-A shRNA. Oil Red O staining of the whole aorta root revealed that PAPP-A knockdown reduced lipid accumulation in aortas. Oil Red O, hematoxylin and eosin (HE) and Masson staining of aortic sinus further showed that PAPP-A knockdown alleviated the formation of atherosclerotic lesions. It was found that PAPP-A knockdown reduced the insulin-like growth factor 1 (IGF-1) levels and repressed the PI3K/Akt pathway in both aorta and peritoneal macrophages. The expression levels of LXR alpha, ABCA1, ABCG1, and SR-B1 were increased in the aorta and peritoneal macrophages from apoE(-/-) mice administered with PAPP-A shRNA. Furthermore, PAPP-A knockdown promoted RCT from macrophages to plasma, the liver, and feces in apoE(-/-) mice. In addition, PAPP-A knockdown elevated the expression and secretion of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), tumor necrosis factor-alpha, and interleukin-1 beta through the nuclear factor kappa-B (NF-kappa B) pathway. Conclusions: The present study results suggest that PAPP-A promotes the development of atherosclerosis in apoE(-/-) mice through reducing RCT capacity and activating an inflammatory response.
Background: Cardiac involvement occurs in more than half of the patients with light-chain amyloidosis (AL), but the characteristics, treatment and prognosis of cardiac AL (CAL) are not fully described. Methods and Results: A total of 227 patients with CAL diagnosis between January 2009 and March 2017 at Peking Union Medical College Hospital were included. Patients with Mayo stages I, II and III AL accounted for 0.9%, 49.8% and 49.3%, respectively. Autologous stem cell transplantation, bortezomib combinations, non-bortezomib regimens and palliative treatment were given as first line therapy in 3.1%, 44.1%, 30.8% and 22.0% of patients, respectively. Overall hematological response and cardiac response were achieved in 60.6% and 37.2% of evaluable patients, respectively. The median overall survival (OS) was 17 months in all patients, and 10 months in those with Mayo stage III. In patients with Mayo stage III disease who survived for >1 month, the bortezomib group survived significantly longer than the non-bortezomib group (median OS, not reached vs. 12 months, P=0.019). Three independent prognostic factors for survival were identified: N-terminal fragment of B-type natriuretic peptide (NT-proBNP) >= 5,000 pg/mL, bone marrow plasma cells >= 10%, and systolic blood pressure <100 mmHg. Conclusions: CAL patients had poor prognosis, but those treated with bortezomib combinations had a better outcome than the non-bortezomib group.
Background: We aimed to investigate the comparative cardiovascular benefits of high-dose statin, ezetimibe-statin, and PCSK9 inhibitor-statin treatments in secondary prevention patients. Methods and Results: We selected 12 randomized controlled trials (n=131,978 patients) using PubMed and Embase (inception-June 1, 2018). Subgroup differences were explored by meta-regression and Cochran Q test. The relative effects of high-dose statin, ezetimibe-statin, and PCSK9 inhibitor-statin on major cardiovascular events (MACE), and revascularization were varied and decreased gradually, of which high-dose statin resulted in lower risk of MACE and revascularization than PCSK9 inhibitor-statin per 1 mmol/L reduction of low-density lipoprotein cholesterol (LDL-C): risk ratio (RR) for MACE, 0.86 (95% confidence interval (CI), 0.81-0.90) for high-dose statin, 0.90 (95% CI, 0.83-0.96) for ezetimibe-statin, and 0.94 (95% CI, 0.92-0.96) for PCSK9 inhibitor-statin; RR for revascularization, 0.84 (95% CI, 0.77-0.90) for high-dose statin, 0.91 (95% CI, 0.81-1.00) for ezetimibe-statin, and 0.94 (95% CI, 0.90-0.97) for PCSK9 inhibitor-statin. Similar relative effects of intensive lipid-lowering treatment were also observed in analyses of myocardial infarction and stroke, although no significant difference between groups was identified. Conclusions: In secondary prevention patients, the relative benefits of high-dose statin, ezetimibe-statin, and PCSK9 inhibitor-statin treatments were varied and decreased gradually, of which high-dose statin was significantly superior to PCSK9 inhibitor-statin for improving MACE and revascularization per 1 mmol/L reduction of LDL-C.
Background: Carotid angioplasty and stenting (CAS) is emerging as an alternative treatment for carotid stenosis, but neointimal hyperplasia (NIH) remains a drawback of this treatment strategy. This study aimed to evaluate the effect of variations of carotid bifurcation geometry on local hemodynamics and NIH. Methods and Results: Hemodynamic and geometric effects on NIH were compared between 2 groups, by performing computational fluid dynamics (CFD) simulations both on synthetic models and patient-specific models. In the idealized models, multiple regression analysis revealed a significant negative relationship between internal carotid artery (ICA) angle and the local hemodynamics. In the patient-derived models, which were reconstructed from digital subtraction angiography (DSA) of 25 patients with bilateral CAS, a low time-average wall shear stress (TAWSS) and a high oscillatory shear index (OSI) were often found at the location of NIH. Larger difference values of the OSI percentage area (10.56 +/- 20.798% vs. -5.87 +/- 18.259%, P=0.048) and ECA/CCA diameter ratio (5.64 +/- 12.751% vs. -3.59 +/- 8.697%, P=0.047) were detected in the NIH-asymmetric group than in the NIH-symmetric group. Conclusions: Changes in carotid bifurcation geometry can make apparent differences in hemodynamic distribution and lead to bilateral NIH asymmetry. It may therefore be reasonable to consider certain geometric variations as potential local risk factors for NIH.
Background: The larger the left atrium anteroposterior dimension (LAD) and left atrium volume (LAV), the stronger the association with recurrent atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA). Patients with a smaller left atrium (LA) size, however, also have increased AF recurrence. Methods and Results: In 521 patients, routine 48-h Holter electrocardiogram and echocardiography were obtained at each outpatient visit every 3 months for 12 months. On multivariate analysis, AF type, LAD, and LAV calculated using the ellipsoid model/body surface area (LAVe/BSA) were independent predictors of AF recurrence. Patients were divided into 7 groups at 0.4-cm increments of LAD: <= 3 cm, LAD <= 3 cm, 3.0<LAD <= 3.4 cm, 3.4<LAD <= 3.8 cm, 3.8<LAD <= 4.2 cm, 4.2<LAD <= 4.6 cm, 4.6<LAD <= 5.0 cm; and LAD>5.0 cm. Compared with the 3.4-3.8-cm group, the adjusted HR were 3.88 (95% CI: 2.02-7.46, P<0.001), 1.03 (95% CI: 0.50-2.12, P=0.939), 0.96 (95% CI: 0.52-1.77, P=0.901), 1.36 (95% CI: 0.72-2.57, P=0.347), 3.04 (95% CI: 1.67-5.53, P<0.001), and 4.07 (95% CI: 1.93-8.60, P<0.001), respectively. Similarly, we divided LAVe/BSA into 8 groups and also observed a U-shaped curve for AF recurrence. Conclusions: Both larger and smaller LAD and LAVe/BSA were associated with a higher risk of AF recurrence 1 year after RFCA. The association of LA size and AF recurrence after RFCA is represented by a U-shaped curve.
Atherosclerotic cardiovascular disease (ACVD) is an inflammatory phenomenon that leads to structural abnormality in the vascular lumen due to the formation of atheroma by the deposition of lipid particles and inflammatory cytokines. There is a close interaction between innate immune cells (neutrophils, monocyte, macrophages, dendritic cells) and adaptive immune cells (T and B lymphocytes) in the initiation and progression of atherosclerosis. According to novel insights into the role of adaptive immunity in atherosclerosis, the activation of CD4(+) T cells in response to oxidized low-density lipoprotein-antigen initiates the formation and facilitates the propagation of atheroma, whereas CD8(+) T cells cause the rupture of a developed atheroma by their cytotoxic nature. Peripheral CD4(+) and CD8(+) T-cell counts were altered in patients with other cardiovascular risk factors. Furthermore, on evaluation of the feasibility of immune cells as a diagnostic tool, the blood CD4(+) (helper), CD8(+) (cytotoxic), and CD4(+)CD25(+)Foxp3(+) (regulatory) T cells and the ratio of CD4 to CD8 cells hold promise as biomarkers of coronary artery disease and their subtypes. T cells also could be a therapeutic target for cardiovascular diseases. The goal of this review was therefore to summarize the available information regarding immune disorders in ACVD with a special focus on the clinical implications of circulating T-cell subsets as biomarkers.
Background: Withaferin A (WFA), an anticancer constituent of the plant Withania somnifera, inhibits tumor growth in association with apoptosis induction. However, the potential role of WFA in the cardiovascular system is little-studied and controversial. Methods and Results: Two different doses of WFA were tested to determine their cardioprotective effects in myocardial ischemia/reperfusion (MI/R) injury through evaluation of cardiofunction in wild-type and AMP-activated protein kinase domain negative (AMPK-DN) gentransgenic mice. Surprisingly, cardioprotective effects (improved cardiac function and reduced infarct size) were observed with low-dose WFA (1 mg/kg) delivery but not high-dose (5 mg/kg). Mechanistically, low-dose WFA attenuated myocardial apoptosis. It decreased MI/R-induced activation of caspase 9, the indicator of the intrinsic mitochondrial pathway, but not caspase 8. It also upregulated the level of AMP-activated protein kinase (AMPK) phosphorylation and increased the MI/R inhibited ratio of Bcl2/Bax. In AMPK-deficient mice, WFA did not ameliorate MI/R-induced cardiac dysfunction, attenuate infarct size, or restore the Bcl2/Bax (B-cell lymphoma2/Mcl-2-like protein 4) ratio. Conclusions: These results demonstrated for the first time that low-dose WFA is cardioprotective via upregulation of the antiapoptotic mitochondrial pathway in an AMPK-dependent manner.