The percentage of circulating fibrocytes is associated with increased morbidity of pulmonary hypertension in patients on hemodialysis.

INTRODUCTION: Pulmonary hypertension (PH) is highly prevalent in patients receiving dialysis. The precise mechanisms underlying PH in hemodialysis (HD) patients have not been adequately addressed. Emerging experimental evidence indicates that circulating fibrocytes may contribute significantly to this process. METHODS: We measured the proportion of circulating fibrocytes using flow cytometry analysis and prospectively analyzed patients during HD from February 1, 2017, to February 1, 2022. Then we investigated correlations between circulating fibrocytes, inflammation cytokines, PH, and their affective factors that predict the prognosis of HD patients. RESULTS: The cohort included 192 patients. During a follow-up of 5 years, we registered 66 all-cause deaths, and 11 patients received kidney transplantation. The incidence of PH among HD patients was 30.9%. We found that the circulating fibrocyte level significantly correlated with pulmonary arterial systolic pressure (r = 0.412, p < 0.05). In the multiple logistic regression analysis, the percentage of circulating fibrocytes was an independent predictor of PH (odds ratio [OR]: 2.080, 95% confidence interval [CI]: 1.539-2.812, p < 0.001). Controlling for confounding covariates in the multivariate Cox regression models, the presence of PH conferred an increased risk of all-cause mortality in HD patients [hazard ratio (HR): 2.183, 95% CI:1.257-3.788, p = 0.006]. CONCLUSION: The prevalence of PH was high in HD patients and was associated with higher all-cause mortality. Higher circulating fibrocyte level was an independent predictor of the presence of PH; these fibrocytes may serve as early detection markers and novel therapeutic targets.

Effects of triglyceride glucose (TyG) and TyG-body mass index on sex-based differences in the early-onset heart failure of ST-elevation myocardial infarction.

BACKGROUND AND AIM: Heart failure (HF) is an important complication of ST-elevation myocardial infarction (STEMI), including early- and late-onset HF. This study aimed to investigate the association between insulin resistance (IR)-related parameters triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) index and early-onset HF in STEMI between sexes. METHODS AND RESULTS: This cross-sectional study included patients with STEMI who underwent primary percutaneous coronary intervention (PCI) between January 2016 and September 2022. Patients were divided into tertiles according to TyG/TyG-BMI index levels in males and females. The presence of early-onset HF was compared between tertiles in both sexes. Moreover, patients were stratified according to the tertiles of TyG/Tyg-BMI index. Differences in early-onset HF of STEMI were compared between males and females in each tertile group. 1118 patients were included in this study, 20.3% of whom were females. The incidence rate of early-onset HF was significantly higher in females than in males (29% vs. 14.8%). TyG-BMI index was negatively correlated with early-onset HF. In both females and males, there was no difference in the occurrence of early-onset HF between the highest and lowest TyG/TyG-BMI index groups. Sex disparity was observed in females who had a significantly higher prevalence of early-onset HF than males in each TyG/TyG-BMI index tertile group; however, after adjustment, the differences disappeared. CONCLUSIONS: For patients with STEMI who undergo primary PCI, the incidence of early-onset HF is higher in females than in males. The TyG/TyG-BMI index do not contribute to the difference in early-onset HF between sexes.

Sacubitril/Valsartan Ameliorates Crizotinib-Induced Cardiotoxicity in Mice.

Background: Lung cancer is one of the major cause of death globally. Crizotinib is a first-line drug used in treating non-small-cell lung cancer (NSCLC). However, the pathophysiological mechanisms underlying its cardiotoxicity are unknown. This study investigated the mechanisms of crizotinib-induced cardiotoxicity and explored whether this toxicity can be prevented by the angiotensin receptor/neprilysin inhibitor sacubitril/valsartan. Methods: Male C57BL/6 mice were randomly divided into three groups: control, crizotinib (40 mg ⋅ kg - 1 ⋅ d - 1 for four weeks), and crizotinib + sacubitril/valsartan (40 mg ⋅ kg - 1 ⋅ d - 1 /60 mg ⋅ kg - 1 ⋅ d - 1 for four weeks). Expression of genes in myocardial tissue were detected by transcriptomic sequencing, with verification of the differentially expressed genes (DEGs) using Real time-polymerase chain reaction (RT-PCR). Blood pressure (BP) and cardiac function of animals were measured using non-invasive monitoring and echocardiography approaches. Ventricular refractory period (RP), as well as the induction rate and score of ventricular arrhythmias (VAs) were detected by in vivo electrophysiology. Epicardial conductance was measured by mapping. Expression of Myh7 in myocardium was detected by western blot and RT-PCR. Results: DEGs detected using transcriptomic sequencing included 10 up-regulated and 20 down-regulated genes. The first 5 DEGs identified were Myh7, Ngp, Lcn2, Ciart and Ptgds. Kyoto Encyclopedia of Genes and Genomes (KEGG) result indicated that Myh7 is involved in myocarditis, cardiomyopathy, and cardiac muscle contraction. Crizotinib treatment increased blood pressure, prolonged QTc interval, shortened ventricular RP, increased the incidence and score of right VAs, and increased Myh7 expression. Most of these responses were limited by sacubitril/valsartan. Conclusions: Crizotinib induced a range of cardiotoxic side effects in a mouse model and increased Myh7 expression represents a biomarker for this response. These cardiovascular toxic responses can be largely prevented by sacubitril/valsartan.

Fragmented QRS complex on a 12-lead electrocardiogram predicts cardiovascular and all-cause mortality in dialysis patients.

BACKGROUND: Cardiovascular disease (CVD) is the most common cause of mortality in end-stage renal disease (ESRD) patients. Fragmented QRS complex (fQRS) has been reported as a helpful marker in evaluating various cardiovascular pathologies. We aimed to investigate the value of the fQRS complex clinical decision of ESRD patients receiving dialysis. METHODS: This prospective observational study included 411 patients receiving hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) between 2016-01-01 and 2020-12-31. The primary outcomes were all-cause and cardiovascular (CV) mortality. RESULTS: HD patients have elevated values of fQRS complex compared to CAPD patients (39.1% vs. 28.2%, P = 0.027). Significantly, fQRS complex in the anterior/lateral leads is associated with all-cause and CV mortality stronger than fQRS in the inferior leads (P = 0.008). In a multivariate Cox regression analysis, HD patients with fQRS complex had a higher incidence of all-cause mortality (hazard ratio [HR] = 1.860; 95% confidence interval [CI]: [1.032, 3.349]; p = 0.041) and CV mortality (HR = 2.989; 95% CI [1.357, 6.584]; p = 0.007). For CAPD patients, fQRS complex was also associated with increased risk of all-cause mortality (HR = 1.593; 95% CI [1.023, 2.580]; p = 0.049) and increased risk of CV mortality (HR = 2.392; 95% CI [1.348, 4.173]; p = 0.013). CONCLUSIONS: The presence of the fQRS complex was an independent predictor of all-cause and CV mortality in HD and CAPD patients. We suggested a potential role of the fQRS complex in CV risk strata for dialysis patients and the choice of dialysis modality.

CD137 Signaling Mediates Pulmonary Artery Endothelial Cell Proliferation Under Hypoxia By Regulating Mitochondrial Dynamics.

Altered mitochondrial dynamics affect pulmonary artery endothelial cells (PAECs) proliferation, contributing to the development of pulmonary hypertension. CD137 signaling promotes mitochondrial fission. We hypothesize CD137 signaling is involved in the excessive proliferation of PAECs. The levels of CD137 protein were increased in the lung tissue of hypoxic mice and hypoxic-stimulated PAECs. Activation of CD137 signal in hypoxic-PAECs upregulated the levels of hypoxia-inducible factor-2α (HIF-2α), glucose transporters type 4, the lactate transporter monocarboxylate transporter 4, key glycolysis rate-limiting enzymes and promoted mitochondrial division; moreover, increased glucose uptake, lactic acid and ATP production and proliferative cells were observed in these PAECs. Whereas, knockdown HIF-2α reversed CD137 signal-mediated effects in PAECs mentioned above. Compared with wild-type mice, the proliferation of PAECs and the percentage of vascular lateral wall thickness decreased in CD137 knockout mice. Together, CD137 signal participated in pulmonary vascular remodeling through the regulation of mitochondrial dynamics dependent on HIF-2α in PAECs.

FUNDC1/USP15/Drp1 ameliorated TNF-α-induced pulmonary artery endothelial cell proliferation by regulating mitochondrial dynamics.

Mitochondrial dysfunction in pulmonary artery endothelial cells (PAECs) is related to the pathogenesis of pulmonary hypertension (PH). The mitochondrial receptor protein FUN14 domain containing 1 (FUNDC1) was found to be involved in pulmonary artery smooth muscle cell proliferation in PH. However, its role in PAECs remains unclear. We investigated FUNDC1 expression in the pulmonary artery endothelium in both monocrotaline-induced animal models and TNF-α-stimulated cell models. Additionally, the effect of FUNDC1 on PAECs proliferation and its possible mechanism were also investigated. We observed decreased FUNDC1 protein levels in animals and in vitro in PAECs. FUNDC1 deficiency in PAECs upregulated the expression of the deubiquitination enzyme ubiquitin-specific peptidase 15 (USP15), enhanced dynamin-related protein1 (Drp1)-mediated mitochondrial division, and increased mitochondrial ROS levels via the deubiquitination of Drp1. Additionally, FUNDC1 deficiency increased aerobic glycolysis, the production of ATP and lactic acid, and glucose uptake. FUNDC1 overexpression inhibited PAECs proliferation. Moreover, FUNDC1 overexpression in combination with a mitochondrial division or aerobic glycolysis inhibitor enhanced its inhibitory effect on cell proliferation. Our study findings suggest that FUNDC1 deficiency induced by inflammation can promote PAECs proliferation by regulating mitochondrial dynamics and cell energy metabolism via the USP15/Drp1 pathway.