Journal of the American Heart Association最新文献

Background: Pulmonary arterial hypertension (PAH) is an incurable disease initiated by endothelial dysfunction, secondary to vascular inflammation and occlusive pulmonary arterial vascular remodeling, resulting in elevated pulmonary arterial pressure and right heart failure. Previous research has reported that dysfunction of type 2 bone morphogenetic protein receptor (BMPR2) signaling pathway in endothelium is inclined to prompt inflammation in PAH models, but the underlying mechanism of BMPR2 deficiency-mediated inflammation needs further investigation. This study was designed to investigate whether BMPR2 deficiency contributes to pulmonary arterial hypertension via the NLRP3 (NOD-like receptor family protein 3)/GSDME (gasdermin E)-mediated pyroptosis pathway.

Methods and results: NLRP3 knockout or short hairpin RNA interference of GSDME was performed in PAH animal models to investigate its effect on PAH progression. In addition, the effects of BMPR2 deficiency and restoration of BMPR2 by BMP9 (bone morphogenetic protein 9) or FK506 on pyroptosis were explored both in animal and cell models. Knockout of NLRP3 or short hairpin RNA interference of GSDME in animal models can alleviate the development of pyroptosis, accompanied with improved endothelial integrity, vascular remodeling, and right ventricular systolic pressure. Blocking BMPR2 is sufficient to induce NLRP3 upregulation and release of inflammatory factor IL-1β (interleukin-1β) in pulmonary arterial endothelial cells. Moreover, BMPR2 deficiency can induce GSDME-mediated pyroptosis through NLRP3 activation in 2 animal models, whereas activation of BMPR2 signaling by FK506 or BMP9 can reverse these phenotypes.

Conclusions: These findings provide evidence that loss of BMPR2 signaling promotes endothelial cell pyroptosis by enhancing NLRP3/GSDME signaling in PAH. Our findings may provide new insights to explore the inflammatory mechanism of PAH treatment.

Background: Acute psychological stress may induce physiological changes predisposing individuals to adverse health outcomes through hemodynamic and vascular effects. We studied the association between the aggregated stress-induced changes in hemodynamic and vascular function tests with adverse cardiovascular outcomes in patients with coronary artery disease, after adjusting for sociodemographic and clinical factors.

Methods and results: Individuals with stable coronary artery disease from 2 prospective cohort studies were studied. Hemodynamic reactivity, changes in endothelial function, and vasoconstriction during mental stress were evaluated using changes in rate-pressure product, brachial artery flow-mediated vasodilation, and peripheral arterial tonometry, respectively. A cardiovascular reactivity risk score was calculated by allotting 0 to 3 points for each quartile of increasing abnormality for each of the 3 reactivity responses and summing the quartile points from the MIPS (Mental Stress Ischemia Prognosis Study) to yield a cardiovascular reactivity risk score ranging from 0 to 9. The outcome was a composite of cardiovascular death, nonfatal myocardial infarction, and heart failure hospitalizations during follow-up. A total of 629 participants were included. After adjustment for demographic and traditional risk factors, a blunted hemodynamic response, a greater decrease in flow-mediated vasodilation, and a greater degree of peripheral vasoconstriction to mental stress were all independently associated with a higher risk of adverse outcomes in both cohorts. By adding the cardiovascular reactivity risk score, the C-statistic increased significantly by 10% (P<0.001).

Conclusions: Among individuals with stable coronary artery disease, a risk score derived from cardiovascular reactivity to mental stress was predictive of adverse cardiovascular outcomes beyond traditional cardiovascular risk factors.

Background: The triglyceride-glucose (TyG) index has been proposed as a reliable marker of insulin resistance. However, its value in patients with carotid plaque stability remains unclear. This study investigated the association between the TyG index and unstable carotid plaque.

Methods: A total of 12 068 participants were enrolled. Carotid ultrasound was used to determine the stability of carotid plaque. Logistic regression was used to analyze the relationship between the TyG index and unstable carotid plaque. The relationship between the TyG index and unstable carotid plaque was evaluated according to sex, age, and glucose metabolism states. Further, the dose-response relationship between the TyG index and unstable carotid plaque was also determined by restrictive cubic splines.

Results: Of the 12 068 participants, 11 601 had stable carotid plaque and 467 had unstable carotid plaque. In several different adjustment models, the TyG index is significantly related to the risk of unstable carotid plaque. The association between the TyG index and an unstable carotid plaque was similar between men and women, despite the fact that the odds ratio (OR) tended to be higher in men (OR, 2.80 [95% CI, 2.04-3.83]) than women (OR, 2.07 [95% CI, 1.51-2.82]), and higher in older patients (aged >60 years; (OR, 3.59 [95% CI, 2.74-4.70]) than middle-aged patients (aged ≤60 years) (OR, 2.00 [95% CI, 1.36-2.95]). The TyG index of patients with different glycemic status was significantly correlated with the risk of unstable carotid plaque, among which the OR value of diabetes (OR, 2.51 [95% CI, 1.87-3.36]) was the highest. The restrictive cubic spline analysis indicated a nonlinear relationship between the TyG index and unstable carotid plaque, with TyG index >8.63 identified as an independent risk factor for unstable carotid plaque.

Conclusions: The TyG index has a significant association with unstable carotid plaque. The association between the TyG index and unstable carotid plaque is similar between men and women, and the association in older patients is higher than that in middle-aged patients. In different glycemic status, the association between the TyG index and unstable carotid plaque is highest in patients with diabetes.

Background: The level of monocyte to high-density lipoprotein ratio (MHR) is associated with cardiovascular diseases. Carotid plaque (CP) is an independent risk factor for cardiovascular diseases. However, evidence for association of MHR with risk of CP is scarce.

Methods and results: This study involved 5260 participants aged >18 years old from the Dalian health management cohort in 2014 to 2022. The subjects were stratified into 4 groups based on the quartile of the MHR at baseline. Multivariable-adjusted Cox regression models were used to calculate the MHR-associated risk of incident CP. The mean age of the population was 46.14 years and 58.8% (n=3093) of the participants were male. Seven hundred fifty-nine (14.4%) of participants developed new-onset CP. During the follow-up of 9725 person-years, the MHR at quartile 4 group experienced a significantly higher incidence of CP than the MHR at quartile 1 group (56.9 versus 101.5 per 1000 person-years; log-rank P <0.001). Compared with the MHR at quartile 1 group, the MHR at quartile 4 group had the highest CP risk (hazard ratio. 1.389 [95% CI, 1.059-1.823]) and 10-year cardiovascular risk (China-PAR Project score: odds ratio, 1.975 [95% CI, 1441-2.708 in men]; odds ratio, 6.015 [95% CI, 1.949-18.564 in women) (P <0.001). Meanwhile, similar results were observed in multiple sensitivity analyses.

Conclusions: Elevated MHR was associated with the risk of CP. The assessment and management of MHR is helpful for the early detection of patients with CP and the primary prevention of cardiovascular diseases.

Background: Organs and tissues need to be vascularized during development. Similarly, vascularization is required to engineer thick tissues. How vessels are formed during organogenesis is not fully understood, and vascularization of engineered tissues remains a significant challenge.

Methods and results: Here, we show that the extracellular matrix protein nephronectin is required for vascularization during zebrafish development as well as adult fin regeneration and is sufficient to promote mammalian vessel formation and maturation. Nephronectin a morphants and mutants exhibit diminished axial vein sprouting and posterior intersegmental vessel growth. Notably, the angiogenesis-associated integrins itgav and itgb3.1 are coexpressed with nephronectin a in the region of the caudal vein plexus and posterior somites; nephronectin binds to integrin alpha-V/integrin beta-3.1 (ITGAV/ITGB3.1), and itgav morphants phenocopy nephronectin a mutants. In addition, nephronectin a mutants showed decreased vessel maturation compared with wild-type siblings during caudal fin regeneration in adult zebrafish. Moreover, nephronectin promotes mammalian endothelial cell migration and tube formation in 2D and 3-dimensional in vitro tissue culture. Further, nephronectin enhances vascular endothelial growth factor-induced periaortic vascular capillary interconnectivity, vessel diameter, and vessel stability.

Conclusions: Collectively, our results identify nephronectin as a proangiogenic factor during embryonic development, which can be used to improve the vascularization of engineered tissues.

Background: Apolipoprotein C3 (apo C3) is primarily secreted by the liver and is involved in promoting sterile inflammation and organ damage under pathological conditions. Previous studies have shown that apo C3 is abundant in the plasma exosomes of patients with aortic dissection (AD), but its specific role in AD remains unclear.

Methods and results: In vivo, adeno-associated virus was used to knock down hepatic apo C3 expression in an AD mouse model to assess the impact of liver-derived apo C3 on the development of AD. In vitro, recombinant apo C3 protein was added to the culture medium of J774A.1 macrophages to evaluate its effect on macrophage polarization and to identify the underlying mechanisms. Additionally, the effect of apo C3 on the function of aortic endothelial and smooth muscle cells was explored. Apo C3 in the aortas of AD mice was found to originate from abnormal hepatic secretion, which enters the bloodstream and subsequently deposits in the aorta. Adeno-associated virus-mediated hepatic apo C3 knockdown significantly reduced AD incidence (P=0.0036), macrophage infiltration (P=0.0004), and collagen deposition in the aorta (P=0.0016). Similarly, inhibiting the apo C3 receptor Toll-like receptor 2 significantly lowered AD incidence (P=0.0352). In vitro, recombinant apo C3 protein promoted M1 polarization and matrix metalloproteinase secretion in macrophages by activating the Toll-like receptor 2/NLR family pyrin domain containing 3 pathway. Additionally, apo C3 increased adhesion molecule expression in endothelial cells and induced inflammation, chemotaxis, and apoptosis in vascular smooth muscle cells.

Conclusions: Our findings highlight the role of abnormally secreted hepatic apo C3 in promoting aortic inflammation.

Background: Systemic inflammation, aging, and type 2 diabetes (T2D) lead to varying degrees of cardiovascular dysfunction and impaired aerobic exercise capacity. This study evaluates the impact of inflammation and sex differences on coronary and peripheral vascular function and exercise capacity in older individuals with and without T2D.

Methods: Older individuals (aged≥65 years) underwent biochemical and tissue inflammatory phenotyping, cardiopulmonary exercise testing, cardiovascular magnetic resonance imaging, and vascular reactivity testing. Correlation and regression analyses determined the effects of systemic inflammation, older age, and sex on cardiovascular health, stratified by T2D status.

Results: For the 133 recruited individuals (44% women; median age, 71±7 years, 41% with T2D), the presence of T2D most significantly increased the white blood cell count (P=0.004; P.adj.=0.140) among markers of systemic inflammation. White blood cell count was comparable in men and women. Hyperemic myocardial blood flow and flow-mediated and flow-independent nitroglycerin-induced brachial artery dilation were significantly impaired in men but not women with T2D. Peak oxygen consumption during exercise was lower with T2D (P=0.021), and overall reduced in women compared with men (P=0.002). Across all participants, both peak oxygen consumption during exercise and hyperemic myocardial blood flow were significantly impaired with increased white blood cell count. Women showed more adverse myocardial remodeling assessed by extracellular volume than men (P=0.008), independently of T2D status.

Conclusions: The pathophysiological manifestations of T2D on vascular function and aerobic exercise capacity are distinct in older men and women, and this may reflect underlying differences in vascular and myocardial aging in the presence of T2D.

Background: Anterior circulation stroke (ACS) differs from posterior circulation stroke (PCS) in several aspects. We hypothesize that the risk of early neurologic deterioration (END) and its responses to clopidogrel plus aspirin versus aspirin alone may be different between stroke territories.

Methods and results: This was a prespecified post hoc analysis of ATAMIS (Antiplatelet Therapy in Acute Mild to Moderate Ischemic Stroke) trial and included patients with definite infarct location who were classified into ACS and PCS according to stroke territory. Primary outcome was occurrence of END at 7 days, defined as ≥2-point increase in National Institutes of Health Stroke Scale score compared with baseline. We compared the treatment effects of clopidogrel plus aspirin versus aspirin alone in each stroke territory. From 3000 patients, 2431 eligible patients (1780 with ACS [910 assigned into clopidogrel plus aspirin and 870 assigned into aspirin alone] and 651 with PCS [371 assigned into clopidogrel plus aspirin and 280 assigned into aspirin alone]) were included. Median age was 66 years and 35.1% were women. The occurrence of END was higher in ACS than PCS (6.8% versus 3.8%, P=0.007). clopidogrel plus aspirin was associated with lower risk of END in ACS (risk difference [95% CI]: -2.4% [-4.1% to -0.8%], P=0.004), but not in PCS (risk difference [95% CI]: -0.6% [-2.7% to 1.5%], P=0.57). No significant interaction was found (P=0.69).

Conclusions: Our study demonstrated END was higher in acute mild-to-moderate ischemic stroke with anterior circulation, who derived more benefit from clopidogrel plus aspirin than aspirin alone.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02869009.