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Background: Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease.

Methods: AVD progression and its consequences for cardiac function were examined in a murine wire injury-induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by LC-MS. Calcification of valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by LC-MS.

Results: Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression.

Conclusions: Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.

Background: Arteriovenous malformations (AVMs) are characteristic of hereditary hemorrhagic telangiectasia. Loss-of-function mutations in the activin receptor-like kinase 1 (Alk1) are linked to hemorrhagic telangiectasia type 2.

Methods: Endothelial-specific deletion of Alk1, endothelial lineage tracing, transcriptomics of single-cell analysis, and electron microscopy were performed to examine the vascular phenotype and characteristics of ALK1-deficient endothelial cells (ECs) after EC-specific Alk1 deletion. Ischemia assays were used to examine the cell capacity for vascular malformation. Connectivity Map with transcriptomic analysis was applied to identify chemical compounds. Specific methods for arteriovenous malformations, such as micro-computed tomography, with other molecular and cell biological tools were also performed.

Results: We performed endothelial-specific deletion of Alk1 in mice and found severe arteriovenous malformations and vascular leakage. The transcriptomics of single-cell analysis revealed a new distinctive cell cluster formed after Alk1 deletion where the cells coexpressed arterial and lymphatic endothelial markers. The analysis projected that these cells potentially originated from arterial ECs after Alk1 deletion. This new population was referred to as arterial-lymphatic-like ECs according to its cellular markers, and its appearance was validated in the pulmonary small arteries after Alk1 deletion. Transplantation of these cells caused vascular malformations. Endothelial lineage tracing confirmed that these new arterial-lymphatic-like ECs were derived from ALK1 depleted ECs, potentially arterial ECs. We discovered that SOX17 (SRY-box transcription factor 17) induction was responsible for the derivation of these arterial-lymphatic-like ECs. We showed that direct binding of MDM2 (mouse double minute 2) was required for Sox17 to execute this activity. Inhibition of MDM2 reduced the arteriovenous malformations in the mouse model.

Conclusions: Together, our studies revealed the mechanistic underpinnings of ALK1 signaling in regulating the endothelial phenotype and provided possibilities for new therapeutic strategies in hemorrhagic telangiectasia type 2.

Background: Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood.

Methods: We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide).

Results: At baseline, cognitive function was normal (MMSE score 28-30) in 1809 of 2895 patients (62.5%), borderline (score 24-27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemia attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first HF hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06-1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21-2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death.

Conclusions: In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.

To achieve cardiovascular health (CVH) equity in the United States, an understanding of the social and structural factors that contribute to differences and disparities in health is necessary. The Asian American population is the fastest-growing racial group in the United States but remains persistently underrepresented in health research. There is heterogeneity in how individual Asian American ethnic groups experience CVH and cardiovascular disease outcomes, with certain ethnic groups experiencing a higher burden of adverse social conditions, disproportionately high burden of suboptimal CVH, or excess adverse cardiovascular disease outcomes. In this scientific statement, upstream structural and social determinants that influence CVH in the Asian American population are highlighted, with particular emphasis on the role of social determinants of health across disaggregated Asian American ethnic groups. Key social determinants that operate in Asian American communities include socioeconomic position, immigration and nativity, social and physical environments, food and nutrition access, and health system-level factors. The role of underlying structural factors such as health, social, and economic policies and structural racism is also discussed in the context of CVH in Asian Americans. To improve individual-, community-, and population-level CVH and to reduce CVH disparities in Asian American ethnic subgroups, multilevel interventions that address adverse structural and social determinants are critical to achieve CVH equity for the Asian American population. Critical research gaps for the Asian American population are given, along with recommendations for strategic approaches to investigate social determinants of health and intervene to reduce health disparities in these communities.

Background: This trial aimed to assess the efficacy, acceptability, and safety of a first-trimester screen-and-prevent strategy for preterm preeclampsia in Asia.

Methods: Between August 1, 2019, and February 28, 2022, this multicenter stepped wedge cluster randomized trial included maternity/diagnostic units from 10 regions in Asia. The trial started with a period where all recruiting centers provided routine antenatal care without study-related intervention. At regular 6-week intervals, one cluster was randomized to transit from nonintervention phase to intervention phase. In the intervention phase, women underwent first-trimester screening for preterm preeclampsia using a Bayes theorem-based triple-test. High-risk women, with adjusted risk for preterm preeclampsia ≥1 in 100, received low-dose aspirin from <16 weeks until 36 weeks.

Results: Overall, 88.04% (42 897 of 48 725) of women agreed to undergo first-trimester screening for preterm preeclampsia. Among those identified as high-risk in the intervention phase, 82.39% (2919 of 3543) received aspirin prophylaxis. There was no significant difference in the incidence of preterm preeclampsia between the intervention and non-intervention phases (adjusted odds ratio [aOR], 1.59 [95% CI, 0.91-2.77]). However, among high-risk women in the intervention phase, aspirin prophylaxis was significantly associated with a 41% reduction in the incidence of preterm preeclampsia (aOR, 0.59 [95% CI, 0.37-0.92]). In addition, it correlated with 54%, 55%, and 64% reduction in the incidence of preeclampsia with delivery at <34 weeks (aOR, 0.46 [95% CI, 0.23-0.93]), spontaneous preterm birth <34 weeks (aOR, 0.45 [95% CI, 0.22-0.92]), and perinatal death (aOR, 0.34 [95% CI, 0.12-0.91]), respectively. There was no significant between-group difference in the incidence of aspirin-related severe adverse events.

Conclusions: The implementation of the screen-and-prevent strategy for preterm preeclampsia is not associated with a significant reduction in the incidence of preterm preeclampsia. However, low-dose aspirin effectively reduces the incidence of preterm preeclampsia by 41% among high-risk women. The screen-and-prevent strategy for preterm preeclampsia is highly accepted by a diverse group of women from various ethnic backgrounds beyond the original population where the strategy was developed. These findings underpin the importance of the widespread implementation of the screen-and-prevent strategy for preterm preeclampsia on a global scale.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03941886.