The adipose-neural axis is involved in epicardial adipose tissue-related cardiac arrhythmias.

Dysfunction of the sympathetic nervous system and increased epicardial adipose tissue (EAT) have been independently associated with the occurrence of cardiac arrhythmia. However, their exact roles in triggering arrhythmia remain elusive. Here, using an in vitro coculture system with sympathetic neurons, cardiomyocytes, and adipocytes, we show that adipocyte-derived leptin activates sympathetic neurons and increases the release of neuropeptide Y (NPY), which in turn triggers arrhythmia in cardiomyocytes by interacting with the Y1 receptor (Y1R) and subsequently enhancing the activity of the Na+/Ca2+ exchanger (NCX) and calcium/calmodulin-dependent protein kinase II (CaMKII). The arrhythmic phenotype can be partially blocked by a leptin neutralizing antibody or an inhibitor of Y1R, NCX, or CaMKII. Moreover, increased EAT thickness and leptin/NPY blood levels are detected in atrial fibrillation patients compared with the control group. Our study provides robust evidence that the adipose-neural axis contributes to arrhythmogenesis and represents a potential target for treating arrhythmia.

Ligustrazine Nanoparticle Hitchhiking on Neutrophils for Enhanced Therapy of Cerebral Ischemia-Reperfusion Injury.

Ischemic stroke is a refractory disease that endangers human health and safety owing to cerebral ischemia. Brain ischemia induces a series of inflammatory reactions. Neutrophils migrate from the circulatory system to the site of cerebral ischemia and accumulate in large numbers at the site of inflammation across the blood-brain barrier. Therefore, hitchhiking on neutrophils to deliver drugs to ischemic brain sites could be an optimal strategy. Since the surface of neutrophils has a formyl peptide receptor (FPR), this work modifies a nanoplatform surface by the peptide cinnamyl-F-(D)L-F-(D)L-F (CFLFLF), which can specifically bind to the FPR receptor. After intravenous injection, the fabricated nanoparticles effectively adhered to the surface of neutrophils in peripheral blood mediated by FPR, thereby hitchhiking with neutrophils to achieve higher accumulation at the inflammatory site of cerebral ischemia. In addition, the nanoparticle shell is composed of a polymer with reactive oxygen species (ROS)-responsive bond breaking and is encased in ligustrazine, a natural product with neuroprotective properties. In conclusion, the strategy of hitching the delivered drugs to neutrophils in this study could improve drug enrichment in the brain, thereby providing a general delivery platform for ischemic stroke or other inflammation-related diseases.

Characteristics, treatments and survival of pulmonary arterial hypertension associated with congenital heart disease in China: Insights from a national multicenter prospective registry.

BACKGROUND: The purpose of this registry was to provide insights into the characteristics, treatments and survival of patients with PAH-CHD in China. METHODS: Patients diagnosed with PAH-CHD were enrolled in this national multicenter prospective registry. Baseline and follow-up data on clinical characteristics, PAH-targeted treatments and survival were collected. RESULTS: A total of 1060 PAH-CHD patients (mean age 31 years; 67.9% females) were included, with Eisenmenger syndrome (51.5%) being the most common form and atrial septal defects (37.3%) comprising the most frequent underlying defect. Approximately 33.0% of the patients were in World Health Organization functional class III to IV. The overall mean pulmonary arterial pressure and pulmonary vascular resistance were 67.1 (20.1) mm Hg and 1112.4 (705.9) dyn/s/cm5, respectively. PAH-targeted therapy was utilized in 826 patients (77.9%), and 203 patients (19.1%) received combination therapy. The estimated 1-, 3-, 5-, and 10-year survival rates of the overall cohort were 96.9%, 92.9%, 87.6% and 73.0%, respectively. Patients received combination therapy had significantly better survival than those with monotherapy (p = 0.016). NT-proBNP >1400 pg/ml, SvO2 ≤ 65% and Borg dyspnea index ≥ 3 and PAH-targeted therapy were independent predictors of mortality. Hemoglobin > 160g/L was a unique predictor for mortality in Eisenmenger syndrome. CONCLUSIONS: Chinese PAH-CHD patients predominantly exhibit Eisenmenger syndrome and have significantly impaired exercise tolerance and right ventricular function at diagnosis, which are closely associated with long-term survival. PAH-targeted therapy including combination therapy showed a favorable effect on survival in PAH-CHD. The long-term survival of Chinese CHD-PAH patients remains to be improved.

A Nomogram for Predicting 3-Year Mortality in Patients with Pulmonary Hypertension due to Left Heart Failure: A Retrospective Analysis of a Prospective Registry Study.

INTRODUCTION: Pulmonary hypertension due to left heart failure (PH-LHF) is a disease with high prevalence and 3-year mortality rates. Consequently, timely identification of patients with high mortality risk is critical. This study aimed to build a nomogram for predicting 3-year mortality and screening high-risk PH-LHF patients. METHODS: This nomogram was developed on a training cohort of 175 patients with PH-LHF diagnosed by right heart catheterization. Multivariate Cox regression was used to identify independent predictors and develop this nomogram. The median total points obtained from the nomogram were used as a cutoff point, and patients were classified into low- and high-risk groups. The concordance index (C-index) and calibration curve were utilized to ascertain the predictive accuracy and discriminative ability of the nomogram. External validation was performed using a validation cohort of 77 PH-LHF patients from other centers. RESULTS: Multivariate Cox regression showed that the New York Heart Association Functional classification (NYHA FC), uric acid level, and mean pulmonary arterial pressure were all independent predictors and incorporated into the nomogram. The nomogram showed good discrimination (C-index of 0.756; 95% CI: 0.688-0.854) and good calibration. The Kaplan-Meier survival analysis showed that patients in the high-risk group had worse survival (p < 0.001). In the external validation, the nomogram showed both good discrimination (C-index of 0.738; 95% CI: 0.591-0.846) and calibration. CONCLUSION: The nomogram had a good performance in predicting 3-year mortality and can effectively identify high-risk patients. The nomogram may help to reduce the mortality of PH-LHF.

A smart nanoplatform for enhanced photo-ferrotherapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Emerging therapies, such as ferroptosis mediated cancer therapy and phototherapy, offer new opportunities for HCC treatment. The combination of multiple treatments is often more effective than monotherapy, but many of the current treatments are prone to serious side effects, resulting in a serious decline in patients' quality of life. Therefore, the combination therapy of tumor in situ controllable activation will improve the efficacy and reduce side effects for precise treatment of tumor. Herein, we synthesized a GSH-activatable nanomedicine to synergize photothermal therapy (PTT) and ferrotherapy. We utilized a near-infrared dye SQ890 as both an iron-chelating and a photothermal converter agent, which was encapsulated with a GSH-sensitive polymer (PLGA-SS-mPEG), to attain the biocompatible SQ890@Fe nanoparticles (NPs). In the tumor microenvironment (TME), SQ890@Fe NPs showed a GSH-activated photothermal effect that could increase the Fenton reaction rate. Meanwhile, the depletion of GSH could further increase ferroptosis effect. In turn, the increasing radical generated by ferrotherapy could impair the formation of heat shock proteins (HSPs) which could amplify PTT effects by limiting the self-protection mechanism. Overall, the intelligent nanomedicine SQ890@Fe NPs combines ferrotherapy and PTT to enhance the efficacy and safety of cancer treatment through the mutual promotion of the two treatment mechanisms, providing a new dimension for tumor combination therapy.

Prevalence, risk factors, and survival associated with pulmonary hypertension and heart failure among patients with underlying coronary artery disease: a national prospective, multicenter registry study in China.

BACKGROUND: Coronary artery disease (CAD) is the commonest cause of heart failure (HF), whereas pulmonary hypertension (PH) has not been established or reported in this patient population. Therefore, we assessed the prevalence, risk factors, and survival in CAD-associated HF (CAD-HF) complicated with PH. METHODS: Symptomatic CAD-HF patients were continuously enrolled in this prospective, multicenter registry study. Echocardiography, coronary arteriography, left and right heart catheterization (RHC), and other baseline clinical data were recorded. Patients were followed up and their survival was recorded. RESULTS: One hundred and eighty-two CAD-HF patients were enrolled, including 142 with HF with a preserved ejection fraction (heart failure with preserved ejection fraction [HFpEF]; left ventricular ejection fraction [LVEF] ≥50%) and 40 with a reduced ejection fraction (heart failure with reduced ejection fraction [HFrEF]; LVEF < 50%). PH was diagnosed with RHC in 77.5% of patients. Patients with PH showed worse hemodynamic parameters and higher mortality. HFrEF-PH patients had worse survival than HFpEF-PH patients. CAD-HF patients with an enlarged left ventricular end-diastolic diameter and reduced hemoglobin were at higher risk of PH. Nitrate treatment reduced the risk of PH. Elevated creatinine and mean pulmonary arterial pressure (mPAP), diastolic pressure gradient (DPG) ≥7 mmHg, and previous myocardial infarction (MI) entailed a higher risk of mortality in CAD-HF patients with PH. CONCLUSIONS: PH is common in CAD-HF and worsens the hemodynamics and survival in these patients. Left ventricle enlargement and anemia increase the risk of PH in CAD-HF. Patients may benefit from nitrate medications. Renal impairment, elevated mPAP, DPG ≥7 mmHg, and previous MI are strong predictors of mortality in CAD-HF-PH patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02164526.

The prevalence and survival of pulmonary hypertension due to left heart failure: A retrospective analysis of a multicenter prospective cohort study.

Background: Pulmonary hypertension due to left heart failure (PH-LHF) is currently the most common form of pulmonary hypertension (PH) encountered in clinical practice. Despite significant advances that have improved our understanding of PH-LHF over the past two decades, the mortality is still high in recent decades. This study aimed to describe the prevalence and survival of patients with PH-LHF, and explored the potential risk factors which may predict the prognosis of PH-LHF. Methods: A retrospective analysis of a prospective cohort study of left heart failure (LHF) patients who underwent right heart catheterization (RHC) between January 2013 and November 2016 was performed. The endpoint was all-cause mortality. Follow-ups were performed every 6 months ± 2 weeks. Results: A total of 480 patients with LHF were enrolled, with 215 (44.8%) having PH-LHF. The proportion of PH-LHF was significantly lower in coronary artery disease (CAD) group than without CAD (41.3 vs. 57.8%, p = 0.003). However, multivariable logistic regression analysis revealed that CAD was not associated with PH-LHF (Adjusted OR: 1.055, 95% CI: 0.576 - 1.935, p = 0.862). 75 of 215 (34.9%) patients with PH-LHF died during a median follow-up period of 84.6 months. The 1-, 3-, 5-, and 8-year survival rates of all PH-LHF patients were 94.3, 76.9, 65.8, and 60.2%, respectively. New York Heart Association Functional Class (NYHA FC), hemoglobin, and systolic pulmonary artery pressure (sPAP) were associated with mortality of PH-LHF in multivariate Cox analysis. Conclusion: PH is commonly identified in patients with LHF, with a prevalence of approximately 45%. The mortality is still high in patients with PH-LHF. NYHA FC, hemoglobin, and sPAP are independent risk predictors of mortality for PH-LHF. These findings may be useful for risk stratification in future clinical trial enrollment.

Impact of borderline pulmonary hypertension due to left heart failure on mortality in a multicenter registry study: A 3-year survivorship analysis.

Background: Patients with left heart failure (LHF) are often associated with the development of pulmonary hypertension (PH) which leads to an increased risk of death. Recently, the diagnostic standard for PH has changed from mean pulmonary arterial pressure (mPAP) ≥25 mmHg to >20 mmHg. Nonetheless, the effect of borderline PH (mPAP: 21-24 mmHg) on the prognosis of LHF patients is unclear. This study aimed to investigate the relationship between borderline PH and 3-year clinical outcomes in LHF patients. Methods: A retrospective analysis of a prospective cohort study was done for LHF patients who underwent right heart catheterization (RHC) between January 2013 and November 2016. The primary outcome was all-cause mortality; the secondary outcome was rehospitalization. Results: Among 344 patients, 62.5% were identified with a proportion of PH (mPAP ≥ 25), 10.8% with borderline PH (21-24), and 26.7% with non-PH (≤20), respectively. Multivariable Cox analysis revealed that borderline PH patients had a higher adjusted mortality risk (HR = 3.822; 95% CI: 1.043-13.999; p = 0.043) than non-PH patients. When mPAP was treated as a continuous variable, the hazard ratio for death increased progressively with increasing mPAP starting at 20 mmHg (HR = 1.006; 95% CI: 1.001-1.012). There was no statistically significant difference in adjusted rehospitalization between borderline PH and non-PH patients (HR = 1.599; 95% CI: 0.833-3.067; p = 0.158). Conclusions: Borderline PH is independently related to increased 3-year mortality in LHF patients. Future research is needed to evaluate whether more close monitoring, and managing with an intensifier improves clinical outcomes in borderline PH caused by LHF. Clinical trials registration: www.clinicaltrials.gov NCT02164526.

Characteristics, goal-oriented treatments and survival of pulmonary arterial hypertension in China: Insights from a national multicentre prospective registry.

BACKGROUND AND OBJECTIVE: Nationally representative reports on the characteristics and long-term survival of pulmonary arterial hypertension (PAH) from developing countries are scarce. The applicability of the current main risk stratifications and the longitudinal changes in goal-oriented treatments have yet to be elucidated in real-world settings. Therefore, we aimed to provide insights into the characteristics, goal-oriented treatments and survival of PAH in China and to explore the applicability of the main risk stratifications in our independent cohort. METHODS: PAH patients were consecutively enrolled from a national prospective multicentre registry. Data on baseline, follow-up re-evaluation and therapeutic changes were collected. RESULTS: A total of 2031 patients were enrolled, with congenital heart disease (CHD)-PAH (45.2%) being the most common aetiology. The mean age was 35 ± 12 years, and 76.2% were females. At baseline, approximately 20% of the patients with intermediate or high risk received combination treatment. At follow-up, approximately half of the re-evaluated patients did not achieve low-risk profiles, and even among patients who received combination therapy at baseline, 4% of them still worsened. The rate of combination therapy increased significantly from 6.7% before 2015 to 35.5% thereafter. The main risk assessment tools demonstrated good performance for predicting survival both at baseline and at follow-up. CONCLUSION: Chinese PAH patients show both similar and distinct features compared to other countries. Current main risk stratifications can significantly discriminate patients at different risk levels. There were still many patients not achieving low-risk profiles at follow-up, indicating more aggressive treatment should be implemented to optimize the goal-oriented treatment strategy.

Risk prediction in pulmonary hypertension due to chronic heart failure: incremental prognostic value of pulmonary hemodynamics.

BACKGROUND: There is no generally accepted comprehensive risk prediction model cooperating risk factors associated with heart failure and pulmonary hemodynamics for patients with pulmonary hypertension due to left heart disease (PH-LHD). We aimed to explore outcome correlates and evaluate incremental prognostic value of pulmonary hemodynamics for risk prediction in PH-LHD. METHODS: Consecutive patients with chronic heart failure undergoing right heart catheterization were prospectively enrolled. The primary endpoint was all-cause mortality. Individual variable selection was performed by machine learning methods. Cox proportional hazards models were conducted to identify the association between variables and mortality. Incremental value of hemodynamics was evaluated based on the Seattle heart failure model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) scores. RESULTS: A total of 276 PH-LHD patients were enrolled, with a median follow-up time of 34.7 months. By L1-penalized regression model and random forest approach, diastolic pressure gradient (DPG) and mixed venous oxygen saturation (SvO2) were the hemodynamic predictors most strongly associated with mortality (coefficient: 0.0255 and -0.0176, respectively), with consistent significance after adjusted for SHFM [DPG: HR 1.067, 95% CI 1.024-1.113, P = 0.022; SvO2: HR 0.969, 95% CI 0.953-0.985, P = 0.002] or MAGGIC (DPG: HR 1.069, 95% CI 1.026-1.114, P = 0.011; SvO2: HR 0.970, 95% CI 0.954-0.986, P = 0.004) scores. The inclusion of DPG and SvO2 improved risk prediction compared with using SHFM [net classification improvement (NRI): 0.468 (0.161-0.752); integrated discriminatory index (IDI): 0.092 (0.035-0.171); likelihood ratio test: P < 0.001] or MAGGIC [NRI: 0.298 (0.106-0.615); IDI: 0.084 (0.033-0.151); likelihood ratio: P < 0.001] scores alone. CONCLUSION: In PH-LHD, pulmonary hemodynamics can provide incremental prognostic value for risk prediction. CLINICAL TRIAL REGISTRATION: NCT02164526 at https://clinicaltrials.gov .

Quercetin Inhibits Pulmonary Arterial Endothelial Cell Transdifferentiation Possibly by Akt and Erk1/2 Pathways.

This study aimed to investigate the effects and mechanisms of quercetin on pulmonary arterial endothelial cell (PAEC) transdifferentiation into smooth muscle-like cells. TGF-ß1-induced PAEC transdifferentiation models were applied to evaluate the pharmacological actions of quercetin. PAEC proliferation was detected with CCK8 method and BurdU immunocytochemistry. Meanwhile, the identification and transdifferentiation of PAECs were determined by FVIII immunofluorescence staining and α-SMA protein expression. The related mechanism was elucidated based on the levels of Akt and Erk1/2 signal pathways. As a result, quercetin effectively inhibited the TGF-ß1-induced proliferation and transdifferentiation of the PAECs and activation of Akt/Erk1/2 cascade in the cells. In conclusion, quercetin is demonstrated to be effective for pulmonary arterial hypertension (PAH) probably by inhibiting endothelial transdifferentiation possibly via modulating Akt and Erk1/2 expressions.