Development and validation of a nomogram for arterial stiffness.

Even though as a gold standard for noninvasive measurement of arterial stiffness, carotid-femoral pulse wave velocity (cfPWV) is not widely used in primary healthcare institutions due to time-consuming and unavailable equipment. The aim of this study was to develop a convenient and low-cost nomogram model for arterial stiffness screening. A cross-sectional study was undertaken in the department of general practice, the First Affiliated Hospital of Fujian Medical University. Arterial stiffness was defined as cfPWV ≥ 10 m/s. A total of 2717 participants were recruited to construct the nomogram using the least absolute shrinkage and selection operator and logistic regressions. Receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis, clinical impact curve were used to evaluate the performance of the model. The model was validated internally and externally (399 participants) by bootstrap method. Arterial stiffness was identified in 913 participants (33.60%). Age, sex, waist to hip ratio, systolic blood pressure, duration of diabetes, heart rate were selected to construct the nomogram model. Good discrimination and accuracy were exhibited with area under curve of 0.820 (95% CI 0.803-0.837) in ROC curve and mean absolute error = 0.005 in calibration curve. A positive net benefit was shown in decision curve analysis and clinical impact curve. A satisfactory agreement was displayed in internal validation and external validation. The low cost and user-friendly nomogram is suitable for arterial stiffness screening in primary healthcare institutions.

The zinc transporter ZIP12 regulates monocrotaline-induced proliferation and migration of pulmonary arterial smooth muscle cells via the AKT/ERK signaling pathways.

BACKGROUND: The zinc transporter ZIP12 is a membrane-spanning protein that transports zinc ions into the cytoplasm from the extracellular space. Recent studies demonstrated that upregulation of ZIP12 is involved in elevation of cytosolic free zinc and excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) induced by hypoxia. However, the expression of ZIP12 and its role in pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT) in rats have not been evaluated previously. The aim of this study was to investigate the effect of ZIP12 on the proliferation and migration of PASMCs and its underlying mechanisms in MCT-induced PAH. METHODS: A PAH rat model was generated by intraperitoneal injection of 20 mg/kg MCT twice at one-week intervals. PASMCs were isolated from the pulmonary arteries of rats with MCT-induced PAH or control rats. The expression of ZIP12 and related molecules was detected in the lung tissues and cells. A ZIP12 knockdown lentivirus and an overexpressing lentivirus were constructed and transfected into PASMCs derived from PAH and control rats, respectively. EdU assays, wound healing assays and Western blotting were carried out to explore the function of ZIP12 in PASMCs. RESULTS: Increased ZIP12 expression was observed in PASMCs derived from MCT-induced PAH rats. The proliferation and migration of PASMCs from PAH rats were significantly increased compared with those from control rats. These results were corroborated by Western blot analysis of PCNA and cyclin D1. All these effects were significantly reversed by silencing ZIP12. Comparatively, ZIP12 overexpression resulted in the opposite effects as shown in PASMCs from control rats. Furthermore, selective inhibition of AKT phosphorylation by LY294002 abolished the effect of ZIP12 overexpression on enhancing cell proliferation and migration and partially suppressed the increase in ERK1/2 phosphorylation induced by ZIP12 overexpression. However, inhibition of ERK activity by U0126 resulted in partial reversal of this effect and did not influence an increase in AKT phosphorylation induced by ZIP12 overexpression. CONCLUSIONS: ZIP12 is involved in MCT-induced pulmonary vascular remodeling and enhances the proliferation and migration of PASMCs. The mechanism of these effects was partially mediated by enhancing the AKT/ERK signaling pathways.

Development of a nomogram for screening the risk of left ventricular hypertrophy in Chinese hypertensive patients.

Left ventricular hypertrophy (LVH) is an important risk factor for cardiovascular morbidity and mortality in hypertensives. Therefore, early identification of at-risk patients is necessary. The objective of this study was to estimate the risk of LVH among Chinese hypertensives by designing a nomogram. 832 hypertensives were divided into two groups based on the presence of LVH. The least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression were successively applied for optimal variable selection and nomogram construction. Discrimination power, calibration, and clinical usefulness were evaluated using the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis. Internal validation was performed using the bootstrap method. The nomogram included five predictors, namely gender, duration of hypertension, age, body mass index (BMI), and systolic blood pressure. The area under the ROC curve (AUC) was 0.724 (95% CI: 0.687-0.761), indicating moderate discrimination. The calibration curve showed an excellent agreement between the predicted LVH and the actual LVH probability. The risk threshold between 5% and 72% according to the decision curve analysis, and the nomogram is clinically beneficial. Internal validation by bootstrapping with 1000 samples showed a good C-index of 0.715, which suggested that the predictive abilities for the training set and testing set were in consistency. Our study proposed a nomogram that can be utilized to assess the LVH risk rapidly for Chinese hypertensives. This tool could be useful in identifying patients at high risk for LVH. Further studies are required to ascertain the stability and applicability of this nomogram.

Relationship between lactate dehydrogenase and albuminuria in Chinese hypertensive patients.

Lactate dehydrogenase (LDH) has been reported to be positively correlated with albuminuria assessed by urinary albumin-to-creatinine ratio (UACR) in patients with sickle cell disease; both LDH and albuminuria are positively associated with the severity of hypertension (HTN). Here, a cross-sectional study was performed to investigate the association between LDH and albuminuria in Chinese hypertensives. A total of 1169 Chinese individuals (aged 58.0 ± 11.5 years, 60.4% male), who were admitted to our hospital, were included in this study. Based on the level of LDH, all hypertensives (n = 802) were divided into three groups: HTN1 (lowest tertile of LDH, n = 264), HTN2 (mediate tertile of LDH, n = 268), and HTN3 (highest tertile of LDH, n = 270). Hypertensives with hyperhomocysteinemia were defined as hypertensives with homocysteine ≥15µmol/L. Meanwhile, 367 normotensives served as controls. Compared with normotensives, the levels of LDH and UACR were significantly higher in hypertensives (p < .05). There was an increasing trend of albuminuria (UACR ≥30 mg/g) from control, HTN1, HTN2 to HTN3 group (4% vs. 12.1% vs. 14.9% vs. 19.6%, χ2  = 38.886, p < .001). Stepwise multiple regression analysis showed an independent association between LDH and UACR in patients with HTN (ß = 0.085, p < .05), but not in normotensives. After further stratification in hypertensive patients, this correlation remained in the male (ß = 0.161, p < .001), elderly (age ≥65 years, ß = 0.174, p < .001) and especially hypertensives with hyperhomocysteinemia (ß = 0.402, p < .001). LDH combined with white blood cell (WBC) counts was observed to have better discrimination for albuminuria than creatinine united with cystatin C in hypertensives according to receiver operation characteristic curves (area under curve: 0.637 vs. 0.535, z = 2.563, p = .0104). In conclusion, the level of LDH was associated with albuminuria in Chinese patients with HTN, particularly in hypertensives with hyperhomocysteinemia. LDH combined with WBC provided better prediction of albuminuria than routine renal function assessment in hypertensives. Further studies are needed to confirm LDH as an early marker for the risk of kidney involvement among hypertensives.

Relationship between high-normal albuminuria and arterial stiffness in Chinese population.

High-normal albuminuria is related to the morbidity and mortality of cardiovascular disease. Arterial stiffness has been regarded as a predictor of cardiovascular disease. However, the relationship between high-normal albuminuria and arterial stiffness is uncertain in Chinese population. A total of 1343 Chinese participants (aged 58.9 ± 12.1 years, 63.53% male) were included in this study. High-normal albuminuria was defined as urinary albumin-to-creatinine ratio (UACR) above the median within normal albuminuria. Based on the level of UACR, all participants were divided into low-normal albuminuria group (UACR < 6.36 mg/g, n = 580), high-normal albuminuria group (6.36 mg/g ≤ UACR < 30 mg/g, n = 581), microalbuminuria (30 mg/g ≤ UACR < 300 mg/g, n = 162), and macroalbuminuria (UACR ≥ 300 mg/g, n = 20). Arterial stiffness was assessed by measuring carotid-femoral pulse wave velocity (cfPWV). With the increment of UACR, the level of cfPWV was increased gradually (P < .001). Stepwise multiple regression analysis showed that systolic blood pressure, age, serum creatinine, heart rate, logarithmic (LG)-transformed UACR, and fasting plasma glucose were independently associated with cfPWV in all subjects (P < .001). LG-UACR was found to be related to cfPWV in high-normal albuminuria and macroalbuminuria subjects. After further stratification in the high-normal albuminuria subjects, their relation remained in male, elderly over 65 years old, or normotensives. In summary, UACR is associated with arterial stiffness in subjects with proteinuria excretion in high normal level. High-normal albuminuria might be an early indicator of arterial stiffness, especially in male, elderly, or normotensives in Chinese population. Furthermore, age and blood pressure are still observed to be the most important risk factor of arterial stiffness.

Transcriptomic analysis identifies Toll-like and Nod-like pathways and necroptosis in pulmonary arterial hypertension.

Inflammation and immunity play a causal role in the pathogenesis of pulmonary vascular remodelling and pulmonary arterial hypertension (PAH). However, the pathways and mechanisms by which inflammation and immunity contribute to pulmonary vascular remodelling remain unknown. RNA sequencing was used to analyse the transcriptome in control and rats injected with monocrotaline (MCT) for various weeks. Using the transcriptional profiling of MCT-induced PAH coupled with bioinformatics analysis, we clustered the differentially expressed genes (DEGs) and chose the increased expression patterns associated with inflammatory and immune response. We found the enrichment of Toll-like receptor (TLR) and Nod-like receptor (NLR) pathways and identified NF-κB-mediated inflammatory and immune profiling in MCT-induced PAH. Pathway-based data integration and visualization showed the dysregulated TLR and NLR pathways, including increased expression of TLR2 and NLRP3, and their downstream molecules. Further analysis revealed that the activation of TLR and NLR pathways was associated with up-regulation of damage-associated molecular patterns (DAMPs) and RIPK3-mediated necroptosis was involved in the generation of DAMPs in MCT-induced PAH. Collectively, we identify RIPK3-mediated necroptosis and its triggered TLR and NLR pathways in the progression of pulmonary vascular remodelling, thus providing novel insights into the mechanisms underlying inflammation and immunity in the pathogenesis of PAH.

RNA sequencing analysis of monocrotaline-induced PAH reveals dysregulated chemokine and neuroactive ligand receptor pathways.

Pulmonary arterial hypertension (PAH) is a serious disease characterized by elevated pulmonary artery pressure, inflammatory cell infiltration and pulmonary vascular remodeling. However, little is known about the pathogenic mechanisms underlying the disease onset and progression. RNA sequencing (RNA-seq) was used to identify the transcriptional profiling in control and rats injected with monocrotaline (MCT) for 1, 2, 3 and 4 weeks. A total of 23200 transcripts and 280, 1342, 908 and 3155 differentially expressed genes (DEGs) were identified at the end of week 1, 2, 3 and 4, of which Svop was the common top 10 DEGs over the course of PAH progression. Functional enrichment analysis of DEGs showed inflammatory/immune response occurred in the early stage of PAH development. KEGG pathway enrichment analysis of DEGs showed that cytokine-cytokine receptor interaction and neuroactive ligand-receptor interaction were in the initiation and progression of PAH. Further analysis revealed impaired expression of cholinergic receptors, adrenergic receptors including alpha1, beta1 and beta2 receptor, and dysregulated expression of γ-aminobutyric acid receptors. In summary, the dysregulated inflammation/immunity and neuroactive ligand receptor signaling pathways may be involved in the onset and progression of PAH.

Low-Grade Albuminuria Is Associated with Left Ventricular Hypertrophy and Diastolic Dysfunction in Patients with Hypertension.

INTRODUCTION: Microalbuminuria is a risk factor for cardiovascular morbidity and mortality in hypertensive patients. However, the relationship between low-grade albuminuria, a higher level of albuminuria below microalbuminuria threshold, and hypertension-related organ damage is unclear. Left ventricular (LV) hypertrophy (LVH) is well recognized to be a subclinical organ damage of hypertension, and LV diastolic dysfunction is also reported to be an early functional cardiac change of hypertension that predicts heart failure. The present study aimed to investigate the association of low-grade albuminuria with LVH and LV diastolic dysfunction in hypertensive patients. METHODS: This cross-sectional observational clinical study was retrospectively performed in 870 hypertensive patients admitted to our hospital. Urinary albumin to creatinine ratio (UACR) was calculated to assess the levels of albuminuria: macroalbuminuria (≥300 mg/g), microalbuminuria (≥30 mg/g, but <300 mg/g), and normal albuminuria (<30 mg/g). Low-grade albuminuria was defined as sex-specific highest tertile within normal albuminuria (8.1-29.6 mg/g in males and 11.8-28.9 mg/g in females). LVH and LV diastolic dysfunction were identified as recommended by American Society of Echocardiography. RESULTS: Of the 870 patients, 765 (87.9%) had normal albuminuria, 77 (8.9%) had microalbuminuria, and 28 (3.2%) had macroalbuminuria. Percentage of LVH and LV diastolic dysfunction was increased with ascending UACR. UACR was independently associated with LVH and LV diastolic dysfunction, even in patients with normal albuminuria. Multivariable logistic regression showed that the patients with the highest tertile within normal albuminuria had nearly 80% increase in LVH and nearly 60% increase in LV diastolic dysfunction (adjusted OR for LVH 1.788, 95% CI 1.181-2.708, p = 0.006; adjusted OR for LV diastolic dysfunction 1.567, 95% CI 1.036-2.397, p = 0.034). After further stratification analyses in patients with normal albuminuria, it was shown that this independent association persisted in female patients, those who were younger than 70 years old, and those with duration of hypertension <15 years. CONCLUSION: Low-grade albuminuria was associated with LVH and LV diastolic dysfunction in hypertensive patients, especially in patients younger than 70 years old, and those with duration of hypertension <15 years.