Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

Cardiovascular disease remains the leading cause of mortality worldwide, driven by risk factors that range from traditional (eg, hypertension, hyperlipidemia) to less recognized socioenvironmental contributors. These broader exposures include adverse socioeconomic status, air and noise pollution, attributes of the built environment, and ambient temperatures, among others, which exert complex mechanistic influences that often involve neural-autonomic-immune pathways that promote traditional cardiovascular disease risk factors and atherosclerosis. Advanced noninvasive imaging modalities, including positron emission tomography, computed tomography, magnetic resonance imaging, and ultrasound, allow for assessment of subclinical vascular changes, such as arterial inflammation and plaque burden, as well as assessments of changes in other organs, including the brain and inflammatory tissues, that associate with these exposures and have the potential to clarify the mechanisms of exposure-related pathology. This review synthesizes current evidence from multimodality imaging studies linking socioeconomic status, air pollution, noise, and other environmental exposures to imaging markers of cardiovascular disease. These findings suggest opportunities to deeply characterize underlying mechanisms, refine risk assessment, prioritize targeted interventions, and inform policies aimed at mitigating adverse exposures. Through this framework, we aim to catalyze a broader approach to preventing cardiovascular disease that recognizes the profound interplay among the social, environmental, and biological determinants of health.

The global rise in obesity underscores the urgent need for effective long-term weight-management strategies. Weight loss (WL) is extremely beneficial in combating obesity complications, justifying the great success of recent WL medications. However, most individuals trying to lose weight will fail to maintain a lower body weight. Weight regain following WL increases the risk of cardiovascular disease and mortality. Adipose tissue inflammation is a critical mediator of metabolic dysfunction in obesity, contributing to cardiovascular complications. In obesity, chronic low-grade inflammation, marked by immune infiltration and dysregulated adipocyte function, contributes to systemic insulin resistance and metabolic comorbidities. However, the adipose tissue response to WL and subsequent weight regain is distinct from that in non-weight-fluctuating obesity and far less studied. This review synthesizes current literature to elucidate the dynamic shifts in adipose tissue across the continuum of obesity, WL, and weight regain.

Biological sex influences the life course development of blood pressure, systemic arterial hypertension, and hypertension-associated complications through neural, hormonal, renal, and epigenetic mechanisms. Sex hormones influence blood pressure regulation through interaction with several main regulatory systems, including the autonomic nervous system, the renin-angiotensin-aldosterone system, endothelin, and renal mechanisms. The modulation of vascular function by sex hormones varies over the lifespan. A more progressive decline in vascular endothelial function and an increase in vascular remodeling and arterial stiffness with aging are found in female individuals. Epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding microRNAs, may be implicated in systemic arterial hypertension development and complications. Overall, current knowledge highlights the importance of including biological sex as a critical factor in understanding systemic arterial hypertension pathophysiology and advancing cardiovascular prevention.

Background: In genetic studies with the Hybrid Mouse Diversity Panel, we previously identified a chromosome 9 locus for atherosclerosis. We now identify NNMT (nicotinamide N-methyltransferase), an enzyme that degrades nicotinamide, as the causal gene in the locus and show that the underlying mechanism involves salvage of nicotinamide to nicotinamide adenine dinucleotide (NAD).

Methods: Gain/loss of function studies in macrophages were performed to examine the role of NAD levels in macrophage proliferation and apoptosis in atherosclerosis.

Results: Global inhibition of NNMT using an antisense oligonucleotide reduced atherosclerosis lesion area 5- to 10-fold in both male and female mice on a hyperlipidemic background. Selective inhibition of NNMT in liver and adipose, the major tissues expressing high levels of the enzyme, using siRNA (small interfering RNA), had little or no effect on atherosclerosis. Therefore, we hypothesized that levels of NAD in macrophages might contribute. This was confirmed by showing that transplantation with bone marrow from Nnmt knockout mice resulted in reduced lesional macrophage proliferation, increased macrophage apoptosis, and reduced atherosclerosis. Consistent with this conclusion, reduced expression of macrophage CD38, an enzyme that degrades NAD, reduced both macrophage proliferation and atherosclerosis. Moreover, cultured macrophages from heterozygous Nnmt knockout mice exhibited reduced proliferation, increased apoptosis, and an increased NAD/NADH (nicotinamide adenine dinucleotide, reduced) ratio.

Conclusions: These findings reveal a role for nicotinamide salvage and NAD turnover in macrophage proliferation and survival in the context of atherosclerosis.

Background: Residual cardiovascular risk remains, despite achieving low-density lipoprotein cholesterol targets with high-intensity statins. Traditional risk scores are suboptimal. This study evaluated the prognostic utility of a 9-plex apolipoprotein panel in recent patients with acute coronary syndrome on statins and its role in predicting treatment benefit by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, enabling precision medicine.

Methods: Baseline serum samples from 11 843 participants in the ODYSSEY OUTCOMES trial (https://www.clinicaltrials.gov; Unique identifier: NCT01663402) were analyzed using mass spectrometry to measure Apo(a), ApoA-I, ApoA-II, ApoA-IV, ApoB, ApoC-I, ApoC-II, ApoC-III, and ApoE. Using logistic regression, probabilities of major adverse cardiovascular events (MACE) and all-cause death over a median follow-up of 2.9 years were estimated based on baseline apolipoproteins and lipid concentrations. Clinical performance was assessed by comparing the area under the curve (AUC) of 3 models: the apolipoprotein panel, the lipid panel (total cholesterol, high-density lipoprotein cholesterol, and triglycerides), and a combination. In addition, prediction models estimating the treatment benefit of alirocumab by the apolipoprotein panel were developed.

Results: The prognostic performance of the apolipoprotein panel for MACE showed an AUC (95% CI) of 0.648 (0.626-0.670), compared with 0.579 (0.557-0.602) for the lipid panel. For all-cause death, the apolipoprotein panel had an AUC of 0.699 (0.664-0.733), while the lipid panel had an AUC of 0.599 (0.564-0.635). Adding the apolipoprotein panel significantly improved the performance of the conventional lipid panel (P<0.0001): AUC, 0.659 (0.637-0.681) for MACE and 0.724 (0.691-0.756) for all-cause death. Higher risk for MACE based on the baseline apolipoprotein panel was found to predict greater treatment benefit with alirocumab.

Conclusions: A multiplex apolipoprotein panel led to better prediction of MACE and all-cause death, beyond lipids, in patients with postacute coronary syndrome on optimized statin therapy. The panel also predicts the treatment benefit of alirocumab. Further validation of this approach is now needed, and if confirmed and improved, it could lead to better disease prediction and management in the future.

Background: Carotid plaque vulnerability, driven by metabolic dysfunction and obesity, is a critical determinant of ischemic stroke risk. However, the heterogeneity of obesity phenotypes-defined by metabolic health-remains underexplored in cardiovascular risk stratification. Therefore, this study employs high-resolution magnetic resonance vessel wall imaging to assess differences in high-risk carotid plaque features among obesity subtypes stratified by metabolic dysfunction and body mass index.

Methods: This multicenter, cross-sectional study of 1037 Chinese adults with symptomatic carotid atherosclerosis utilized magnetic resonance vessel wall imaging to assess differences in high-risk carotid plaque features-intraplaque hemorrhage (IPH), lipid-rich necrotic core, and fibrous cap rupture-across 4 obesity phenotype subgroups: metabolically healthy normal weight (MHNW), metabolically abnormal normal weight, metabolically healthy obese (MHO), and metabolically abnormal obese (MAO).

Results: Of 1037 eligible patients, the proportion of patients in MHNW, metabolically abnormal normal weight, MHO, and MAO groups was 51.6% (n=535), 6.9% (n=72), 16.7% (n=173), and 24.8% (n=257), respectively. Both prevalences of high-risk carotid plaque (22.5% versus 16.6% in MHNW; P=0.002) and IPH (17.1% versus 10.1% in MHNW; P<0.001) in the MAO group were higher than those in the MHNW and MHO groups (all P<0.05). The MHO group exhibited plaque stability similar to MHNW, whereas metabolically abnormal normal weight had greater maximum wall thickness (P=0.004) than MHO and higher IPH prevalence than MHNW (P=0.054). Several carotid plaque morphological variables significantly differed among the 4 groups (all P<0.05). In further adjusted logistic regression models, MAO was independently associated with IPH (P=0.015), alongside male sex, advanced age, and antihypertensive agent use.

Conclusions: This study redefines the role of obesity in atherosclerosis by prioritizing metabolic health over body mass index, demonstrating that MAO is independently associated with IPH and exhibits elevated high-risk carotid plaque/IPH prevalence versus MHNW/MHO. The robustness of IPH as a metabolic instability indicator warrants particular attention.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02017756.