Zhiling Luo

BACKGROUND: Cerebral ischemia following subarachnoid hemorrhage (SAH) has traditionally been considered transient because functional alterations of the cerebral microcirculation are thought to be self-limiting. However, we identified a previously unrecognized vasculopathy, perivascular fibrosis of the cerebral microcirculation (PFCM), characterized by excessive type I collagen deposition after SAH. This study investigated the mechanisms underlying PFCM and its subsequent effects on cerebral hemodynamics. METHODS: In vivo SAH was modeled in mice by autologous blood injection, whereas oxygenated hemoglobin (OxyHb) exposure was used to mimic SAH in vitro . Pericyte-deficient mice ( Pdgfrβ ^+/- ) and pericyte-specific vestigial-like family member 3 (VGLL3) conditional knockout mice ( Vgll3 ^ΔPC ) were generated. Pericyte contractility was measured by nanoindentation and traction force microscopy. Molecular mechanisms were examined using Western blotting, immunofluorescence, CUT&Tag, RNA-seq, transmission electron microscopy, and molecular docking. PFCM, impaired dilation of the cerebral microcirculation, and cerebral autoregulation were assessed by two-photon imaging, transcranial Doppler with continuous blood pressure monitoring, super-resolution ultrasound imaging, and photoacoustic imaging. RESULTS: After SAH, mice developed long-term cerebral autoregulation dysfunction marked by impaired dilation of the cerebral microcirculation, with the abnormality being most evident within the relatively lower blood pressure range. The marked reduction in PFCM in Pdgfrβ ^+/- mice indicated that pericytes were the principal cellular contributors. Mechanistically, OxyHb-induced cytoskeletal remodeling in vitro increased pericyte contractility and promoted nuclear translocation of SAH-upregulated VGLL3. This was followed by increased genomic occupancy, Col1a1 transcriptional activation, and type I collagen deposition. Pericyte-specific VGLL3 knockout abolished PFCM and, consequently, significantly alleviated long-term cerebral autoregulation dysfunction. CONCLUSIONS: Our findings identify PFCM mediated by pericytic VGLL3 as a novel vasculopathy leading to long-term cerebral autoregulation dysfunction after SAH. Clinical Perspective: What Is New?: PFCM is a previously unrecognized vasculopathy that is mediated by pericytic VGLL3 after SAH in mice. PFCM is associated with persistent cerebral autoregulation dysfunction and impaired dilation of the cerebral microcirculation, challenging the traditional concept that cerebral ischemia after SAH is only transient and self-limiting. Pericyte-specific VGLL3 knockout abolished PFCM and, consequently, significantly attenuated long-term cerebral autoregulation dysfunction after SAH. What Are the Clinical Implications?: Suppressing pericyte hypercontractility reduced early cerebral ischemia and was accompanied by less PFCM and reduced persistent cerebral autoregulation dysfunction after SAH. Pericytic VGLL3 lies within the hypercontractility-PFCM pathway and may therefore represent a specific therapeutic target for hemodynamic impairment after SAH. The findings suggest that cerebral ischemia after SAH may be aggravated by hypovolemia or hypotension. This observation supports careful cardiovascular management and further evaluation of integrated heart-brain treatment strategies Abstract Figure:

(1) Aim: The incidence of high-altitude pulmonary hypertension (HAPH) has risen in recent years and is expected to continue increasing; however, its diagnosis remains challenging. In this study, we employed proteomics and metabolomics to identify the proteins and metabolic biomarkers that contribute to the development of HAPH. (2) Methods: We applied integrated proteomics and metabolomics to match blood samples from 40 HAPH patients and 40 healthy controls in Yunnan’s high-altitude regions to characterize molecular profiles, identify biomarkers, and develop a predictive model. (3) Results: Proteomic analysis identified four proteins (A2IPH7, K1C14, PSME2, SERPINE2) commonly dysregulated in HAPH patients from two high-altitude regions. SERPINE2 was notably downregulated and showed a negative correlation with clinical severity, which was further validated in HAPH rat lung tissues and supported by UK Biobank data for idiopathic PAH. Concurrent metabolomics uncovered 11 shared metabolites, largely acyl fatty acids, enriched in pathways such as unsaturated fatty acid synthesis. Integration of these multi-omics data enabled the development of a robust predictive model. (4) Conclusion: Our study identified key protein and metabolic biomarkers involved in HAPH development, which were validated in animal models. Based on these findings, a predictive model was developed, highlighting SERPINE2 and 11 metabolites as promising targets for the prediction and prevention of HAPH.

Background: Coronary microvascular dysfunction (CMD) persists after percutaneous coronary intervention (PCI) in individuals with coronary artery disease (CAD). This study assessed CMD using combined dipyridamole‐exercise stress echocardiography (DExE) and myocardial strain/work to evaluate the impact on left ventricular (LV) function. Methods: This prospective study enrolled CAD individuals who underwent left anterior descending artery PCI and DExE assessment at 3 months post‐PCI to evaluate myocardial strain/work parameters at rest and stress. The primary endpoint was adverse clinical events, and the secondary endpoint was Seattle Angina Questionnaire (SAQ) health status at 1‐year. Results: The cohort comprised 84 individuals (54 ± 10 years, 17.9% female). Participants were stratified into two groups by coronary flow velocity reserve (CFVR): CFVR ≥ 2.5 group ( n = 63) and CFVR < 2.5 group ( n = 21). Compared with the CFVR ≥ 2.5 group, the CFVR < 2.5 group showed impaired LV functional reserve, with lower global longitudinal strain (GLS), global work index (GWI), and global work efficiency (GWE) at peak exercise and recovery, lower peak exercise global constructive work (GCW), higher recovery global wasted work (GWW), and smaller absolute changes ΔE—R (difference before vs. after exercise stress) in GLS, GWI, and GCW (all p < 0.05). In multivariable analysis, peak exercise GCW, recovery GWW, and ΔGCW (E − R) were independent predictors of CMD. At 1 year, no adverse clinical events occurred, and the CFVR ≥ 2.5 group had higher SAQ physical limitation (92.86 ± 11.38 vs. 82.14 ± 17.93), quality of life (95.63 ± 10.57 vs. 83.33 ± 19.90), and summary score (94.05 ± 8.51 vs. 85.71 ± 15.71) than the CFVR < 2.5 group (all p < 0.05). Conclusions: Combined DExE with myocardial strain/work analysis effectively evaluates LV function in CMD. Decreased CFVR post‐PCI is associated with impaired LV function and worse 1‐year quality of life outcomes, underscoring the need for close cardiac function monitoring in post‐PCI CMD individuals. Trial Registration: URL: https://www.chictr.org.cn/ ; Unique identifier: ChiCTR2500103229.

Piezo1 plays a key role in the immune response during sepsis. To date, our understanding of the role of Piezo1 in inflammatory diseases has mostly been limited to influencing vasomotor function and regulating inflammatory infiltration. Whether and how Piezo1 in macrophages is involved in developing septic cardiac dysfunction has never been explored. Here, we have successfully established a mouse model with myeloid cell-specific knockdown of Piezo1. The intraperitoneal injection of lipopolysaccharide (LPS) resulted in a significant increase in cardiac macrophage infiltration, as well as an increase in the expression of inflammatory factors and the inflammatory response. However, myeloid cell-specific knockdown of Piezo1 impaired this response, leading to an increase in macrophage polarization towards the M2 type and the decreased inflammatory response. As a result, myocardial injury caused by sepsis was attenuated. We have also demonstrated that the PI3K/AKT pathway is significantly activated after Piezo1 knockdown, resulting in reduced myocardial dysfunction. Our data indicate that myeloid cell-specific knockdown of Piezo1 can influence macrophage polarization and thus exert cardioprotective effects in a murine model of sepsis, providing potential ideas and targets for the treatment of infectious cardiac dysfunction.

Background The burden of valvular heart disease (VHD) is rising rapidly globally, accompanied by substantial geographical disparities. Although altitude may influence cardiovascular system, no community-based studies have yet explored altitudinal differences in VHD epidemiology. Objective This study aims to investigate the prevalence, spectrum and aetiology of VHD in different altitude areas. Methods We conducted two sequential community-based echocardiography screening programmes in Yunnan Province of China and included 5059 eligible participants aged 35 years and older. The multivariable Poisson regression models with robust variance were performed to assess the association of different altitude groups with VHD and its subtypes. Results The prevalence of overall VHD, clinically significant VHD and clinically significant regurgitant VHD was 36.7%, 2.5% and 2.4%, respectively. After stratification by altitude, the prevalence of any VHD among participants in the Conclusions Adults living at high altitudes have a higher prevalence risk of VHD; significant altitudinal differences exist in the characteristics and aetiology of VHD. The findings could provide insights into primary prevention and early screening for VHD in low- and middle-income countries where a majority of the population lives at high altitudes.

Background Ventricular septal defect (VSD) is the most common congenital heart disease. Although a small number of genes associated with VSD have been found, the genetic factors of VSD remain unclear. In this study, we evaluated the association of 10 candidate single nucleotide polymorphisms (SNPs) with isolated VSD in a population from Southwest China. Methods Based on the results of 34 congenital heart disease whole-exome sequencing and 1000 Genomes databases, 10 candidate SNPs were selected. A total of 618 samples were collected from the population of Southwest China, including 285 VSD samples and 333 normal samples. Ten SNPs in the case group and the control group were identified by SNaPshot genotyping. The chi-square (chi(2)) test was used to evaluate the relationship between VSD and each candidate SNP. The SNPs that had significant P value in the initial stage were further analysed using linkage disequilibrium, and haplotypes were assessed in 34 congenital heart disease whole-exome sequencing samples using Haploview software. The bins of SNPs that were in very strong linkage disequilibrium were further used to predict haplotypes by Arlequin software. ViennaRNA v2.5.1 predicted the haplotype mRNA secondary structure. We evaluated the correlation between mRNA secondary structure changes and ventricular septal defects. Results The chi(2) results showed that the allele frequency of FLT4 rs383985 (P = 0.040) was different between the control group and the case group (P < 0.05). FLT4 rs3736061 (r(2) = 1), rs3736062 (r(2) = 0.84), rs3736063 (r(2) = 0.84) and FLT4 rs383985 were in high linkage disequilibrium (r(2) > 0.8). Among them, rs3736061 and rs3736062 SNPs in the FLT4 gene led to synonymous variations of amino acids, but predicting the secondary structure of mRNA might change the secondary structure of mRNA and reduce the free energy. Conclusions These findings suggest a possible molecular pathogenesis associated with isolated VSD, which warrants investigation in future studies.