Plaque rupture is influenced by both plaque components and the dynamic behavior of the arterial wall. This study aimed to characterize dynamic changes in carotid lumen and wall using magnetic resonance black blood cine imaging and to determine their value in discriminating plaque vulnerability. Patients with symptomatic carotid atherosclerotic stenosis scheduled for carotid endarterectomy were retrospectively recruited and underwent black blood cine imaging. Histological slices were used to identify intraplaque hemorrhage, lipid-rich necrotic core, calcification, loose matrix, and fibrous cap rupture, and were matched with magnetic resonance images. Dynamic changes in lumen area, wall area, normalized wall index (NWI), and maximum wall thickness were calculated, while static measurements were derived by averaging these parameters over cardiac phases. These measurements were compared using independent t or Mann-Whitney U tests, depending on data normality. Logistic regression and receiver operating characteristic analyses were conducted to discriminate fibrous cap rupture and to distinguish symptomatic status. Eighty magnetic resonance cine slices from 29 patients (mean age, 64.9±7.6 years; 22 males) were matched with histology. Slices with intraplaque hemorrhage (P=0.019) or lipid-rich necrotic core (P=0.016) exhibited lower NWI changes. Maximum wall thickness changes were higher in loose matrix slices (P=0.032) but reduced in calcification slices (P=0.036). Maximum wall thickness changes were protective against fibrous cap rupture (odds ratio, 0.871; P=0.008; area under the receiver operating characteristic curve, 0.765). Symptomatic arteries showed lower maximum wall thickness, wall area, and NWI changes, but higher lumen area changes (P<0.05). Static lumen area and NWI were significantly altered in slices with intraplaque hemorrhage, lipid-rich necrotic core, or loose matrix (P<0.05), but static measurements showed no significant association with fibrous cap rupture. In discriminating symptomatic from asymptomatic arteries, combining NWI and lumen area changes achieved an area under the receiver operating characteristic curve of 0.946, whereas static NWI reached an area under the receiver operating characteristic curve of 0.971. Dynamic changes assessed by magnetic resonance black blood cine imaging are associated with plaque components, fibrous cap rupture, and symptomatic status, suggesting their potential as quantitative markers of plaque vulnerability.

This review focuses on describing the potential pathogenic roles of endothelial Ca2+ and K+ signaling in the development and progression of pulmonary hypertension through its putative regulation of cellular senescence and inflammasome activation. Ca2+ influx through mechanosensitive and receptor-operated cation channels and Ca2+ release from the endoplasmic reticulum are involved in upregulating the cell cycle inhibitors p53, p21, and p16 (which result in cellular senescence) by activating the AKT/mTORC1 pathway in lung vascular endothelial cells. A rise in cytosolic Ca2+ concentration, resulting from Ca2+ influx and release in lung vascular endothelial cells, is also necessary to activate both canonical (NLRP3 [NOD-like receptor family pyrin domain-containing 3]) and noncanonical inflammasomes, thereby promoting vascular and perivascular inflammation. Furthermore, K+ efflux through multiple types of K+-permeable channels and pores (eg, K+ ionophores, toxin-formed pores/channels, nonselective cation channels, and Ca2+-activated K+ channels) is sufficient for canonical (NLRP3) inflammasome activation. The senescent endothelial cells release senescence-associated secretory phenotype factors that subsequently cause endothelial-to-mesenchymal transition in adjacent endothelial cells and promote cell proliferation/migration in adjacent smooth muscle cells and (myo)fibroblasts, leading to vascular remodeling and occlusive intimal lesions, and pulmonary hypertension.

The ZC3HC1 (zinc finger C3HC-type containing 1) gene has been linked to various cardiovascular traits, including coronary artery disease, blood pressure, and carotid intima-media thickness with opposing effects. This study aimed to investigate the role of ZC3HC1 in smooth muscle cell (SMC) biology and its contribution to neointima formation. SMC phenotypes (proliferation and migration) were analyzed according to rs11556924 genotype, small interfering RNA-mediated knockdown of human ZC3HC1, or complete knockout of murine Zc3hc1. Transcriptomic profiling and contractile marker expression were used to define SMC states. The impact of complete gene loss on injury-induced neointima formation was examined in vivo using Zc3hc1-/- mice. Subcellular localization of murine NIPA (nuclear interaction partner of anaplastic lymphoma kinase; encoded by Zc3hc1) during the cell cycle was analyzed by immunofluorescence microscopy. The coronary artery disease-protective rs11556924-T allele was associated with reduced ZC3HC1 expression and enhanced SMC migration. ZC3HC1 knockdown in human SMCs replicated this phenotype, increasing migration and proliferation, and leading to CCNB1 (cyclin B1) accumulation with reduced expression of contractile markers. Following arterial injury, Zc3hc1-/- mice exhibited exaggerated neointima formation and enhanced SMC migration. In contrast to small interfering RNA experiments, complete Zc3hc1 loss resulted in reduced SMC proliferation and lower CCNB1 levels. Transient knockdown of Zc3hc1 in wild-type mouse SMCs increased proliferation, recapitulating findings in human cells. Immunofluorescence revealed colocalization of NIPA and CCNB1 at the cleavage furrow, suggesting a role in mitotic exit. ZC3HC1 acts as a dosage-sensitive modulator of SMC phenotype. Partial reduction promotes a synthetic, proliferative state and neointima formation, while complete loss induces a quiescent phenotype. These findings provide mechanistic insight into the paradoxical clinical associations of the rs11556924-T allele and identify ZC3HC1 as a potential target for modulating SMC phenotypes in vascular disease.

Proton pump inhibitors (PPIs) may potentially reduce clopidogrel's antiplatelet effect and increase cardiovascular risk. The degree of CYP (cytochrome P450) 2C19 inhibition varies among PPIs. Few studies have evaluated individual PPIs by CYP2C19 inhibition strength across countries. This study aimed to compare the incidence of cardiovascular events between strong CYP2C19-inhibiting potency and weak CYP2C19-inhibiting potency (weak or non-CYP2C19-inhibiting PPIs) in patients receiving clopidogrel. We conducted an international observational cohort study using 14 databases from the United States, South Korea, and Taiwan. We included patients aged ≥18 years who received clopidogrel with PPIs from 1985 to 2023. PPIs were classified into strong CYP2C19-inhibiting PPIs and weak or non-CYP2C19-inhibiting PPIs based on CYP2C19 inhibition. We compared the hazard ratios and 95% CIs for major adverse cardiovascular events, including myocardial infarction, stroke, and cardiovascular mortality, using the Cox proportional hazards model after 1:1 propensity score matching. Secondary outcomes included cardiovascular mortality, myocardial infarction, stroke, and all-cause mortality. A random-effects model calculated pooled hazard ratios and 95% CIs. Only databases meeting all diagnostic criteria were included in the meta-analysis. Large-scale propensity score matching identified 166 005 patient pairs. During the 365-day follow-up, the risk of major adverse cardiovascular events did not differ significantly between patients receiving clopidogrel plus strong CYP2C19-inhibiting PPIs and those receiving clopidogrel plus weak or non-CYP2C19-inhibiting PPIs (17.63 per 1000 person-years versus 16.82 per 1000 person-years; calibrated hazard ratio, 1.00 [95% CI, 0.79-1.26]). No significant difference was observed in the risk of secondary outcomes (calibrated hazard ratio, cardiovascular mortality 1.10 [95% CI, 0.87-1.39], myocardial infarction 0.98 [95% CI, 0.81-1.19], stroke 1.05 [95% CI, 0.87-1.27], and all-cause mortality 1.18 [95% CI, 0.93-1.50]). Concomitant use of clopidogrel and strong CYP2C19-inhibiting PPIs was not associated with a higher cardiovascular risk compared with concomitant use of clopidogrel and weak or non-CYP2C19-inhibiting PPIs. This large-scale study does not support the clinical significance of potential interactions between PPIs and clopidogrel.

Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Disruption of vascular smooth muscle cell (VSMC) homeostasis plays a vital role in triggering TAD. ELA (ELABELA) is a novel endogenous ligand for APJ (angiotensin receptor AT1-related receptor protein). However, the effects of ELA on TAD formation and development remain elusive. Four-week-old C57BL/6J male mice were treated with β-aminopropionitrile monofumarate or β-aminopropionitrile monofumarate combined with Ang II (angiotensin II) to induce TAD models, and the aortic rupture occurred mainly in the descending thoracic region. ELA or saline was infused via osmotic minipumps into mice for 4 weeks. Transcriptomic studies and VSMC-derived conditioned medium were used to investigate the downstream molecular mechanisms of ELA. ELA infusion mitigated TAD development and prevented aortic media degradation in mice, which was reversed by APJ antagonist ML221. Exogenous ELA prevented the disruption of VSMC homeostasis under PDGF (platelet-derived growth factor) stimulation in VSMCs. Based on transcriptomic studies, we showed that ELA significantly inhibits NLRP3 (NLR family pyrin domain-containing 3)/IL (interleukin)-1β pathway activation and modulates NET (neutrophil extracellular trap) formation in vivo and in vitro. In human neutrophils, ELA significantly inhibited NETs' formation, which is prevented by reactive oxidative species supplementation. Using VSMC-derived conditioned medium, we showed that NLRP3/IL-1β-related NETs' formation connects cellular signaling from VSMCs to neutrophils, leading to disruption of VSMC homeostasis. Notably, ELA was downregulated in both plasma and aortic tissues of human TAD, and lower plasma ELA levels were associated with an increased risk of TAD. We provide evidence that ELA prevents TAD progression and aortic medial degeneration, primarily by maintaining VSMC homeostasis, which may be linked to the inhibition of NETosis in neutrophils and NLRP3/IL-1β-related cellular signaling between VSMCs and neutrophils. ELA shows promise as a target for pharmacological therapy and diagnostic TAD management.

Sleep-disordered breathing (SDB) is a group of disorders defined by intermittent closure or narrowing of the upper airway, caused either by mechanical obstruction or dysregulation of the respiratory centers in the brainstem. The effects of SDB on cardiovascular and metabolic health and disease have been an area of growing interest. Many studies have shown mechanistic links between physiological changes seen in SDB and important cardiometabolic outcomes. In particular, SDB induces alterations in autonomic function, swings in intrathoracic pressure, systemic inflammation, sleep fragmentation, and oxidative stress, with diverse effectors including alterations in cellular gene expression, for example, through microRNA and hypoxia-inducible factor 1, changes in the gut microbiome, and many others. Ultimately, these mechanistic pathways have implications on vascular and myocardial dysfunction, hypertension, insulin sensitivity, lipid metabolism, and weight gain. Several treatment modalities exist for SDB, and are chosen based on the specific disease process and patient preference/tolerance. These therapies result in an improvement in symptoms related to SDB severity and varying levels of cardiometabolic disease risk mitigation. In this review, we will present some important mechanisms of SDB that increase the risk for cardiometabolic disease, and we will discuss therapies and their intended targets.

Immunothrombosis entails a tight interplay between thrombotic and inflammatory pathways and plays a pathological role in ischemic stroke and venous thrombosis. The mTOR (mechanistic target of rapamycin) is a canonical serine/threonine kinase and is involved in platelet signaling and thrombus stabilization in vitro. Activation of platelet mTOR is upregulated in aging and inflammatory disorders. However, its role in vivo is poorly understood. We used mice specifically lacking mTOR in platelets and assessed platelet activation and platelet-leukocyte interactions in response to platelet agonists. In addition, we examined the role of platelet mTOR in models of hemostasis, thrombosis, inflammatory bleeding, and sterile immunothrombosis, including ischemic stroke and venous thrombosis. Platelets lacking mTOR had a small activation defect and had lower procoagulant potential. In the absence of mTOR, activated platelets interacted less with monocytes and neutrophils. In addition, platelet mTOR regulated platelet-mediated neutrophil activation. Platelet cytoplasmic calcium flux was similar in the presence and absence of mTOR, whereas clot retraction was reduced in the absence of platelet mTOR, suggesting a role for mTOR in selectively regulating Rac1 (Ras-related C3 botulinum toxin substrate 1)-dependent pathways involved in sustained platelet function. In vivo, the absence of platelet mTOR did not impact hemostasis, inflammatory bleeding in the lung and skin, or FeCl3-induced arterial thrombosis. In contrast, platelet-specific mTOR knockout mice were protected from ischemic stroke brain injury and stasis-induced venous thrombosis due to reduced thrombosis and inflammation. Platelet mTOR is a critical mediator of sterile immunothrombosis, although it is dispensable for hemostasis in mice. The immunothrombotic-specific effects of mTOR make it an attractive therapeutic target with a good safety profile.

Vascular and valvular calcification significantly contributes to cardiovascular morbidity, particularly in patients with diabetes, atherosclerosis, advanced age, and chronic kidney disease. Currently, there are no effective treatments to prevent or reverse calcification, emphasizing the urgent need for robust preclinical models to help identify therapeutic targets and strategies. Preclinical models for vascular and valvular calcification should accurately reflect human disease pathology and progression, ideally including the influence of key underlying conditions and diseases (age, diabetes, renal disease, and hyperlipidemia), as well as sexual dimorphism, each of which may require a different model. Standardized and reproducible end points are essential, with preference for assessments that align with clinically utilized modalities (eg, computed tomography and echocardiography). Murine models of cardiovascular calcification described herein have contributed substantially to our understanding of cardiovascular calcification though the translation toward clinically impactful therapies has, thus far, been limited. Improving clinical translation demands the use of models that replicate human comorbidities, disease progression, and outcomes. Further development of improved models, particularly those that demonstrate clinically important features such as plaque rupture, will facilitate effective translation of therapeutic strategies to clinical practice.

Atherosclerosis is a leading cause of cardiovascular diseases, and microRNA-26b (miR-26b) has emerged as a significant regulator in its development. This study investigates the role of nonhematopoietic miR-26b in atherosclerosis. To study the specific role of nonhematopoietic cell miR-26b in atherosclerosis development, we used a reverse bone marrow transplantation model combined with 12-week Western-type diet feeding. Nonhematopoietic-specific miR-26b deficiency exacerbated atherosclerosis, characterized by larger plaques with increased collagen and necrotic core content. Enhanced VCAM-1 (vascular cell adhesion molecule 1) expression correlated with elevated leukocyte adhesion in ex vivo perfusion studies. Restoration of miR-26b levels in human coronary artery endothelial cells reduced inflammatory responses and leukocyte adhesion. Our findings highlight that nonhematopoietic miR-26b plays a protective role in atherosclerosis by modulating endothelial cell function, suggesting potential therapeutic applications for miR-26b mimics in cardiovascular disease management.