Skeletal Muscle SIRT3 Deficiency Contributes to Pulmonary Vascular Remodeling in Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling. METHODS: Using skeletal muscle-specific Sirt3 knockout mice (Sirt3skm-/-) and mass spectrometry-based comparative secretome analysis, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF. RESULTS: Sirt3skm-/- mice exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Comparative analysis of secretome by mass spectrometry revealed elevated secretion levels of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3skm-/- mice and animal models of PH-HFpEF. CNPY2 levels were also higher in pulmonary artery smooth muscle cells of subjects with obesity compared with nonobese subjects. Moreover, treatment with recombinant LOXL2 protein promoted pulmonary artery endothelial cell migration/proliferation and pulmonary artery smooth muscle cell proliferation through regulation of CNPY2-p53 signaling. Last, skeletal muscle-specific Loxl2 deletion decreased pulmonary artery endothelial cell and pulmonary artery smooth muscle cell expression of CNPY2 and improved pulmonary pressures in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: This study demonstrates a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. This study suggests a new endocrine signaling axis that links skeletal muscle health and SIRT3 deficiency to remote CNPY2 regulation in the pulmonary vasculature through myokine LOXL2. Our data also identify skeletal muscle SIRT3, myokine LOXL2, and CNPY2 as potential targets for the treatment of PH-HFpEF.

Unraveling the role of the FHL family in cardiac diseases: Mechanisms, implications, and future directions.

Heart diseases are a major cause of morbidity and mortality worldwide. Understanding the molecular mechanisms underlying these diseases is essential for the development of effective diagnostic and therapeutic strategies. The FHL family consists of five members: FHL1, FHL2, FHL3, FHL4, and FHL5/Act. These members exhibit different expression patterns in various tissues including the heart. FHL family proteins are implicated in cardiac remodeling, regulation of metabolic enzymes, and cardiac biomechanical stress perception. A large number of studies have explored the link between FHL family proteins and cardiac disease, skeletal muscle disease, and ovarian metabolism, but a comprehensive and in-depth understanding of the specific molecular mechanisms targeting FHL on cardiac disease is lacking. The aim of this review is to explore the structure and function of FHL family members, to comprehensively elucidate the mechanisms by which they regulate the heart, and to explore in depth the changes in FHL family members observed in different cardiac disorders, as well as the effects of mutations in FHL proteins on heart health.

[Analysis of Risk Factors of Chronic Pulmonary Heart Disease in Patients With Pneumoconiosis]. / å°˜è‚ºç— æ‚£è€ å‘ç”Ÿæ ¢æ€§è‚ºå¿ƒç— çš„å±é™©å› ç´ åˆ†æž.

Objective: To explore the risk factors for developing chronic pulmonary heart disease in patients with pneumoconiosis. Methods: The medical records of pneumoconiosis patients admitted to an occupational disease hospital in Sichuan Province between January 2012 and November 2021 were collected. Kaplan-Meier (K-M) method, or product-limit method, was used to plot the incidence curves of pulmonary heart disease in the pneumoconiosis patients. Cox proportional hazard regression model was used to analyze the influencing factors associated with chronic pulmonary heart disease in patients with pneumoconiosis. Results: A total of 885 pneumoconiosis patients were included in this study. The follow-up time was 12 to 115 months and the median follow-up time was 43 months. A total of 138 patients developed chronic pulmonary heart disease and the incidence density of pulmonary heart disease was 38.50/1000 person-years. Multivariate Cox proportional hazard regression analysis showed that the influencing factors of pneumoconiosis inpatients developing chronic pulmonary heart disease included the following, being 50 and older (hazard ratio [HR]=1.85, 95% confidence interval [CI]: 1.25-2.74), stage Ⅲ pneumoconiosis (HR=2.43, 95% CI: 1.48-4.01), resting heart rate≥100 beats/min (HR=2.62, 95% CI: 1.63-4.21), the complication of chronic obstructive pulmonary disease (COPD) (HR=4.52, 95% CI: 2.12-9.63), underweight (HR=2.40, 95% CI: 1.48-3.87), overweight and obesity (HR=0.54, 95% CI: 0.34-0.86), and triacylglycerol (TG) (HR=0.69, 95% CI: 0.49-0.99). Conclusion: Old age, stage Ⅲ pneumoconiosis, high resting heart rate, low BMI, and the complication of COPD are risk factors for chronic pulmonary heart disease in pneumoconiosis patients, while overweight and obesity and TG are protective factors. Early identification of the risk factors and the adoption of the corresponding prevention measures are the key to preventing chronic pulmonary heart disease in patients with pneumoconiosis.

[Network Meta-analysis of traditional Chinese medicine injections in treatment of chronic pulmonary heart disease].

Based on the network Meta-analysis, the efficacy and safety of different traditional Chinese medicine(TCM) injections in the treatment of chronic pulmonary heart disease(CPHD) were systematically evaluated. CNKI, Wanfang, VIP, SinoMed, Web of Science, PubMed, EMbase, and Cochrane Library were searched to collect randomized controlled trial(RCT) of TCM injection in the treatment of CPHD from inception to October 1, 2023. The quality of the included studies was evaluated by the bias risk assessment tool recommended by the Cochrane systematic evaluation manual version 5.3. Stata 17.0 and RevMan 5.4 software were used for statistical analysis of the data. Finally, 103 RCTs were included, involving 9 332 patients and 13 kinds of TCM injections. Network Meta-analysis yielded the following results.(1)In terms of improving the total clinical effective rate, the top three intervention measures in SUCRA ranking are Shuxuetong Injection + conventional western medicine>Ligustrazine Injection + conventional western medicine>Xinmailong Injection + conventional western medicine.(2)In terms of reducing pulmonary artery pressure, the top three intervention measures in SUCRA ranking are Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine>Ligustrazine Injection + conventional western medicine>Shenmai Injection + conventional western medicine.(3)In terms of improving left ventricular ejection fraction(LVEF), the top three intervention measures in SUCRA ranking are Xinmailong Injection + conventional western medicine>Danhong Injection + conventional western medicine>Ginkgo Damo Injection + conventional western medicine.(4) In terms of reducing brain natriuretic peptide(BNP), the top three intervention measures in SUCRA ranking are Xinmailong Injection + conventional wes-tern medicine>Ginkgo Damo Injection + conventional western medicine>Danhong Injection + conventional western medicine.(5) In terms of increasing arterial oxygen partial pressure(PaO_2) and reducing arterial carbon dioxide partial pressure(PaCO_2), the top three intervention measures in SUCRA ranking are Shenxiong Glucose Injection + conventional western medicine>Shenmai Injection + conventional western medicine>Shenfu Injection + conventional western medicine.(6) In terms of improving arterial oxygen saturation(SaO_2), the top three intervention measures in SUCRA ranking are Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine>Xinmailong Injection + conventional western medicine>Shenmai Injection + conventional western medicine.(7) In terms of increasing the percentage of forced expiratory volume in the first second(FEV_1%), the top three intervention measures in SUCRA ranking are Shenfu Injection + conventional western medicine>Tanshinone Sodium Ⅱ_A Sulfonate Injection + conventional western medicine>Shenmai Injection + conventional western medicine.(8) In terms of increasing the proportion of forced expiratory volume to forced vital capacity in the first second(FEV_1/FVC), the top three intervention measures in SUCRA ranking are Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine>Shuxuetong Injection + conventional western medicine>Danhong Injection + conventional western medicine.(9) In terms of safety, neither the experimental group nor the control group experienced any serious adverse drug reactions during the treatment period. In summary, combining TCM injection with conventional western medicine treatment can improve the comprehensive efficacy of treating CPHD, reduce pulmonary artery pressure, and improve cardiopulmonary function and arterial blood gas levels. However, due to the limitations of the quality and quantity of research methodology included, the above conclusions need to be further validated by more well-designed and high-quality RCT.

[Network Meta-analysis of Chinese patent medicines in treatment of chronic pulmonary heart disease].

Network Meta-analysis was performed to compare the efficacy and safety of Chinese patent medicines in treating chronic pulmonary heart disease. CNKI, VIP, Wanfang, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library were searched for randomized controlled trial(RCT) of treating chronic pulmonary heart disease with Chinese patent medicines with the time interval from inception to December 2023. The Cochrane risk-of-bias tool was used for quality assessment of the included articles. RevMan 5.4 and Stata 17.0 were employed to establish the risk of bias map and perform the network Meta-analysis, respectively. Ultimately, a total of 95 RCTs involving 8 787 cases and 11 different Chinese patent medicines were included. Network Meta-analysis yielded the following results based on the surface under the cumulative ranking curve(SUCRA).(1)In terms of cardiac function improves clinical total effective rate, SUCRA the top three were Wenxin Granules + conventional western medicine, Tongxinluo Capsules + conventional western medicine, and Qishen Yiqi Dropping Pills + conventional western medicine.(2)For improving forced expiratory volume in the first se-cond(FEV1), SUCRA the top three were Danting Feixin Granules + conventional western medicine, Tongxinluo Capsules + conventional western medicine, and Bufei Huoxue Capsules + conventional western medicine.(3)Regarding increasing the FEV1/forced vital capacity(FVC%) value, SUCRA the top three were Qili Qiangxin Capsules + conventional western medicine, Shexiang Baoxin Pills + conventional western medicine, and Qishen Yiqi Dropping Pills + conventional western medicine.(4)In terms of increasing the partial pressure of oxygen(PaO_2), SUCRA the top three were Qili Qiangxin Capsules + conventional western medicine, Qishen Yiqi Dropping Pills + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(5)In terms of reducing the partial pressure of carbon dioxide(PaCO_2), SUCRA the top three were Tongxinluo Capsules + conventional western medicine, Qishen Yiqi Dropping Pills + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(6)In terms of increasing left ventricular ejection fraction(LVEF), SUCRA the top three were Bufei Huoxue Capsules + conventional western medicine, Qishen Yiqi Dropping Pills + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(7)In terms of decreasing brain natriu-retic peptide(BNP), SUCRA the top three were Compound Danshen Dropping Pills + conventional western medicine, Qili Qiangxin Capsules + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(8)In terms of improving the hematocrit level, SUCRA the top three were Qishen Yiqi Dropping Pills + conventional western medicine, Compound Danshen Dropping Pills + conventional western medicine, and Tongxinluo Capsules + conventional western medicine. In terms of safety, 26 RCTs reported adverse reactions, which primarily involved the circulatory and digestive systems. The combination of Chinese patent medicines with conventional western medicine has demonstrated enhanced therapeutic effects on chronic pulmonary heart disease. However, due to the varying quality and sample sizes of included studies and the absence of direct comparisons between Chinese patent medicines, the conclusions should be further validated by multicenter studies with larger sample sizes and higher methodological rigor.

Diagnostic, prognostic and clinical value of left ventricular radial strain to identify paradoxical septal motion in ventilated patients with the acute respiratory distress syndrome: an observational prospective multicenter study.

BACKGROUND: Acute cor pulmonale (ACP) is prognostic in patients with acute respiratory distress syndrome (ARDS). Identification of paradoxical septal motion (PSM) using two-dimensional echocardiography is highly subjective. We sought to describe feature-engineered metrics derived from LV radial strain changes related to PSM in ARDS patients with ACP of various severity and to illustrate potential diagnostic and prognostic yield. METHODS: This prospective bicentric study included patients under protective ventilation for ARDS related to COVID-19 who were assessed using transesophageal echocardiography (TEE). Transgastric short-axis view at mid-papillary level was used to visually grade septal motion, using two-dimensional imaging, solely and combined with LV radial strain: normal (grade 0), transient end-systolic septal flattening (grade 1), prolonged end-systolic septal flattening or reversed septal curvature (grade 2). Inter-observer variability was calculated. Feature engineering was performed to calculate the time-to-peak and area under the strain curve in 6 LV segments. In the subset of patients with serial TEE examinations, a multivariate Cox model analysis accounting for new-onset of PSM as a time-dependent variable was used to identify parameters associated with ICU mortality. RESULTS: Overall, 310 TEE examinations performed in 182 patients were analyzed (age: 67 [60-72] years; men: 66%; SAPSII: 35 [29-40]). Two-dimensional assessment identified a grade 1 and grade 2 PSM in 100 (32%) and 48 (15%) examinations, respectively. Inter-rater reliability was weak using two-dimensional imaging alone (kappa = 0.49; 95% CI 0.40-0.58; p < 0.001) and increased with associated LV radial strain (kappa = 0.84, 95% CI 0.79-0.90, p < 0.001). The time-to-peak of mid-septal and mid-lateral segments occurred significantly later in systole and increased with the grade of PSM. Similarly, the area under the strain curve of these segments increased significantly with the grade of PSM, compared with mid-anterior or mid-inferior segments. Severe acute cor pulmonale with a grade 2 PSM was significantly associated with mortality. Requalification in an upper PSM grade using LV radial strain allowed to better identify patients at risk of death (HR: 6.27 [95% CI 2.28-17.2] vs. 2.80 [95% CI 1.11-7.09]). CONCLUSIONS: In objectively depicting PSM and quantitatively assessing its severity, TEE LV radial strain appears as a valuable adjunct to conventional two-dimensional imaging.

Biallelic variants of ATP13A3 cause dose-dependent childhood-onset pulmonary arterial hypertension characterised by extreme morbidity and mortality.

BACKGROUND: The molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in the ATP13A3 gene were recently identified as a new cause of adult-onset PAH. However, the contribution of ATP13A3 risk alleles to child-onset PAH remains largely unexplored. METHODS AND RESULTS: We report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelic ATP13A3 variants. Disease onset ranged from birth to 2.5 years and was characterised by high mortality. Using genome sequencing of parent-offspring trios, we identified a homozygous missense variant in one case, which was subsequently confirmed to cosegregate with disease in an affected sibling. Independently, compound heterozygous variants in ATP13A3 were identified in two affected siblings and in an unrelated third family. The variants included three loss of function variants (two frameshift, one nonsense) and two highly conserved missense substitutions located in the catalytic phosphorylation domain. The children were largely refractory to treatment and four died in early childhood. All parents were heterozygous for the variants and asymptomatic. CONCLUSION: Our findings support biallelic predicted deleterious ATP13A3 variants in autosomal recessive, childhood-onset PAH, indicating likely semidominant dose-dependent inheritance for this gene.

[Construction and validation of a risk prediction model for pneumoconiosis patients complicated with chronic pulmonary heart disease based on Tei index].

Objective: To conduct a statistical analysis on the condition of patients with pneumoconiosis complicated with chronic pulmonary heart disease based on the Tei index, and to establish a relevant prediction model. Methods: In March 2022, a retrospective analysis of 226 patients diagnosed with pneumoconiosis in the Department of Occupational Disease of Yantai Yantaishan Hospital from January 2016 to January 2022 was conducted. The patients with pneumoconiosis complicated by pulmonary heart disease were included in the pulmonary heart disease group and others were included in the non-pulmonary heart disease group. logistic regression analysis was used to screen out the relevant factors and establish a risk prediction model. Hosmer-Lemeshow test was applied to determine the goodness of fit of the model, and the receiver operating characteristic (ROC) area under the curve (AUC) was used to evaluate the predictive effect of the model. Results: Among the 226 patients with pneumoconiosis, 58 patients had chronic pulmonary heart disease, accounting for 25.7% of the surveyed population. The logistic analysis showed that the course of disease, pneumoconiosis stage and Tei index were influencing factors of pneumoconiosis complicated with pulmonary heart disease (P<0.05). A risk prediction model for pneumoconiosis patients complicated with pulmonary heart disease was developed: Z=6.253X(1)+1.265X(2)+1.423X(3)+9.264, in which X(1) was the stage of pneumoconiosis, X(2) was the course of disease, and X(3) was the Tei index. Hosmer-Lemeshow test was used to evaluate the goodness of fit of the risk prediction model for pneumoconiosis patients complicated with pulmonary heart disease, the results indicated that the prediction model was in good agreement with the actual situation (χ(2)=11.59, P=0.254). The diagnostic ability of the model was evaluated by the ROC curve, and the results showed that its AUC was 0.897, the sensitivity was 0.947, and the specificity was 0.784. Conclusion: The course of disease, pneumoconiosis stage and Tei index are the influencing factors of pneumoconiosis complicated with pulmonary heart disease. The model constructed based on these factors has a good prediction effect, which can provide a basis for the early detection and intervention of pneumoconiosis complicated with pulmonary heart disease.

[Analysis of serum CA125 and related influencing factors in silicosis patients with pulmonary heart disease].

Objective: To analyze the serum carbohydrate antigen 125 (CA125) level and its influencing factors in male silicosis patients with pulmonary heart disease. Methods: In October 2021, data of 38 male patients with simple silicosis (silicosis group), 28 cases of silicosis with pulmonary heart disease (pulmonary heart disease group), and 27 healthy controls (control group) in the same age group were collected in inpatient and outpatient of Nanjing Occupational Disease Prevention and Control Hospital from January 2017 to December 2020. The serum CA125 levels of the three groups were compared, and the correlation between disease-related indexes and serum CA125 in silicosis patients with pulmonary heart disease was analyzed, as well as the influencing factors of pulmonary heart disease and serum CA125 levels in silicosis patients. Results: The serum CA125 level[ (19.95±7.52) IU/ml] in pulmonary heart disease group was higher than that in silicosis group[ (12.98±6.35) IU/ml] and control group[ (9.17±5.32) IU/ml] (P<0.05). There was no significant difference in serum CA125 level between the silicosis group and the control group (P>0.05). Serum CA125 levels were positively correlated with blood uric acid and fasting blood glucose in silicosis patients with pulmonary heart disease (r=0.39, 0.46, P<0.05). Serum CA125 level was a risk factor for silicosis patients with pulmonary heart disease (OR=1.13, 95%CI: 1.02-1.24, P<0.05). Dust exposure time, lactate dehydrogenase and smoking history were positively correlated with serum CA125 level in silicosis patients (P<0.05) . Conclusion: The serum CA125 level of male silicosis patients with pulmonary heart disease is significantly increased, and the level of CA125 is correlated with the level of fasting blood glucose and blood uric acid.

Echocardiographic Ventricular Septal Motion Abnormalities Are Associated With Pre-Capillary Pulmonary Hypertension in Patients With Preserved Left Ventricular Function.

BACKGROUND: Ventricular septal motion abnormalities (VSMA) are common echocardiographic finding in patients with pulmonary hypertension (PHTN). This study sought to evaluate the relationship between echocardiographic findings and the classification of PHTN. METHODS: This study retrospectively studied 146 consecutive patients referred for right heart catheterisation for clinically suspected PHTN. VSMA were defined as any echocardiographic description of leftward abnormal septal motion or position. RESULTS: VSMA were present in 42 patients (29%). Patients with VSMA were younger and more likely to have prior pulmonary embolism. They also had less obstructive sleep apnoea, hypertension and dyslipidaemia. By echocardiography, patients with VSMA had lower left ventricular mass, left atrial size and lateral wall E/e' ratio. At cardiac catheterisation, PHTN was confirmed in all (100%) patients with VSMA (compared with 75% in patients without VSMA); 98% with VSMA had elevated pulmonary vascular resistance (compared with 55% without VSMA; p<0.005 for all). VSMA were found to have 91% sensitivity and 51% specificity for the diagnosis of pre-capillary PHTN. On multivariate analysis, VSMA were found to be strong independent predictors for the diagnosis of pre-capillary PHTN (HR, 9.15; 95% CI, 3.0-28.2; p<0.001). Left atrial enlargement was also a strong negative predictor for pre-capillary PHTN (HR, 0.14; 95% CI, 0.05-0.36; p<0.001). CONCLUSION: Ventricular septal motion abnormalities were strongly associated with pre-capillary PHTN in patients with suspected PHTN. The findings suggest that patients with VSMA should be further evaluated by right heart catheterisation.

[Systematic review and sequential analysis of Tanshinone â ¡_A Sodium Sulfonate Injection combined with enalapril in treatment of acute exacerbation of pulmonary heart disease].

To systematically evaluate the clinical efficacy and safety of Tanshinone Ⅱ_A Sodium Sulfonate Injection combined with enalapril in the treatment of patients with acute exacerbation of pulmonary heart disease. The randomized controlled trial(RCT) on Tanshinone Ⅱ_A Sodium Sulfonate Injection combined with enalapril for acute exacerbation of pulmonary heart disease was screened from EMbase, PubMed, Web of Science, Cochrane Library, VIP, CNKI, and Wanfang from inception to March 20, 2022. Meta-analysis of each index was performed in RevMan 5.3 and TSA 0.9. Finally, 41 RCTs involving 3 865 patients were included. Meta-analysis showed that the observation group had higher total response rate(RR=1.21, 95%CI[1.18, 1.24], P<0.000 01), lower plasma viscosity(MD=-0.25, 95%CI[-0.34,-0.16], P<0.000 01), lower whole blood viscosity(MD=-0.99, 95%CI[-1.14,-0.85], P<0.000 01), and lower hematokrit(MD=-9.03, 95%CI[-10.57,-7.50], P<0.000 01) than the control group. The incidence of adverse effects showed no significant difference between groups(RR=1.42, 95%CI[0.82, 2.45], P=0.21). Sequential analysis showed that Tanshinone Ⅱ_A Sodium Sulfonate Injection combined with enalapril exerted definite efficacy in the treatment of acute exacerbation of pulmonary heart disease, and the possibility of false positives was excluded. Based on the existing evidence, Tanshinone Ⅱ_A Sodium Sulfonate Injection combined with enalapril can improve the total response rate and reduce plasma viscosity, whole blood viscosity, and hematocrit, demonstrating good safety in patients with acute exacerbation of pulmonary heart disease. In the future, more RCT with large sample size, rigorous design, and in accordance with international norms are needed to further validate the results.

Comparison of the investigational device exemption and post-approval trials of the Melody transcatheter pulmonary valve.

OBJECTIVE: We compared 5-year outcomes of transcatheter pulmonary valve (TPV) replacement with the Melody TPV in the post-approval study (PAS) and the investigational device exemption (IDE) trial. BACKGROUND: As a condition of approval of the Melody TPV after the IDE trial, the Food and Drug Administration required that a PAS be conducted to evaluate outcomes of TPV replacement in a "real-world" environment. The 5-year outcomes of the PAS have not been published, and the IDE and PAS trials have not been compared. METHODS: The cohorts comprised all patients catheterized and implanted at 5 IDE sites and 10 PAS sites. Differences in trial protocols were detailed. Time-related outcomes and valve-related adverse events were compared between the two trials with Kaplan-Meier curves and log-rank testing. RESULTS: 167 patients (median age, 19 years) were catheterized and 150 underwent TPV replacement in the IDE trial; 121 were catheterized (median age, 17 years) and 100 implanted in the PAS. Freedom from hemodynamic dysfunction (p = .61) or any reintervention (p = .74) over time did not differ between trials. Freedom from stent fracture (p = .003) and transcatheter reintervention (p = .010) were longer in PAS, whereas freedom from explant (p = .020) and TPV endocarditis (p = .007) were shorter. Clinically important adverse events (AEs) were reported in 14% of PAS and 7.2% of IDE patients (p = .056); the incidence of any particular event was low in both. CONCLUSIONS: Hemodynamic and time-related outcomes in the PAS and IDE trials were generally similar, confirming the effectiveness of the Melody TPV with real-world providers. There were few significant complications and limited power to identify important differences in AEs. The lack of major differences in outcomes between the two studies questions the usefulness of mandated costly post-approval studies as part of the regulatory process for Class III medical devices.

Identification and Functional Characterization of Hypoxia-Induced Endoplasmic Reticulum Stress Regulating lncRNA (HypERlnc) in Pericytes.

RATIONALE: Pericytes are essential for vessel maturation and endothelial barrier function. Long noncoding RNAs regulate many cellular functions, but their role in pericyte biology remains unexplored. OBJECTIVE: Here, we investigate the effect of hypoxia-induced endoplasmic reticulum stress regulating long noncoding RNAs (HypERlnc, also known as ENSG00000262454) on pericyte function in vitro and its regulation in human heart failure and idiopathic pulmonary arterial hypertension. METHODS AND RESULTS: RNA sequencing in human primary pericytes identified hypoxia-regulated long noncoding RNAs, including HypERlnc. Silencing of HypERlnc decreased cell viability and proliferation and resulted in pericyte dedifferentiation, which went along with increased endothelial permeability in cocultures consisting of human primary pericyte and human coronary microvascular endothelial cells. Consistently, Cas9-based transcriptional activation of HypERlnc was associated with increased expression of pericyte marker genes. Moreover, HypERlnc knockdown reduced endothelial-pericyte recruitment in Matrigel assays (P<0.05). Mechanistically, transcription factor reporter arrays demonstrated that endoplasmic reticulum stress-related transcription factors were prominently activated by HypERlnc knockdown, which was confirmed via immunoblotting for the endoplasmic reticulum stress markers IRE1α (P<0.001), ATF6 (P<0.01), and soluble BiP (P<0.001). Kyoto encyclopedia of genes and gene ontology pathway analyses of RNA sequencing experiments after HypERlnc knockdown indicate a role in cardiovascular disease states. Indeed, HypERlnc expression was significantly reduced in human cardiac tissue from patients with heart failure (P<0.05; n=19) compared with controls. In addition, HypERlnc expression significantly correlated with pericyte markers in human lungs derived from patients diagnosed with idiopathic pulmonary arterial hypertension and from donor lungs (n=14). CONCLUSIONS: Here, we show that HypERlnc regulates human pericyte function and the endoplasmic reticulum stress response. In addition, RNA sequencing analyses in conjunction with reduced expression of HypERlnc in heart failure and correlation with pericyte markers in idiopathic pulmonary arterial hypertension indicate a role of HypERlnc in human cardiopulmonary disease.

Clinical usefulness of right ventricular 3D area strain in the assessment of treatment effects of balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension: comparison with 2D feature-tracking MRI.

OBJECTIVES: To evaluate the usefulness of right ventricular (RV) area strain analysis via cardiac MRI (CMRI) as a tool for assessing the treatment effects of balloon pulmonary angioplasty (BPA) in inoperable chronic thromboembolic pulmonary hypertension (CTEPH), RV area strain was compared to two-dimensional (2D) strain with feature-tracking MRI (FTMRI) before and after BPA. METHODS: We retrospectively analyzed 21 CTEPH patients who underwent BPA. End-systolic global area strain (GAS), longitudinal strain (LS), circumferential strain (CS), and radial strain (RS) were measured before and after BPA. Changes in GAS and RV ejection fraction (RVEF) values after BPA were defined as ΔGAS and ΔRVEF. Receiver operating characteristic (ROC) analyses were performed to determine the optimal cutoff of the strain at after BPA for detection of improved patients with decreased mean pulmonary artery pressure (mPAP) less than 30 mmHg and increased RVEF more than 50%. RESULTS: ROC analysis revealed the optimal cutoffs of strains (GAS, LS, CS, and RS) for identifying improved patients with mPAP < 30 mmHg (cutoff (%) = - 41.2, - 13.8, - 16.7, and 14.4: area under the curve, 0.75, 0.56, 0.65, and 0.75) and patients with RVEF > 50% (cutoff (%) = - 37.2, - 29.5, - 2.9, and 14.4: area under the curve, 0.81, 0.60, 0.56, and 0.56). CONCLUSIONS: Area strain analysis via CMRI may be a more useful tool for assessing the treatment effects of BPA in patients with CTEPH than 2D strains with FTMRI. KEY POINTS: • Area strain values can detect improvement of right ventricular (RV) pressure and function after balloon pulmonary angioplasty (BPA) equally or more accurately than two-dimensional strains. • Area strain analysis is a useful analytical method that reflects improvements in complex RV myocardial deformation by BPA. • Area strain analysis is a robust method with reproducibility equivalent to that of 2D strain analysis.

Associations between short-term exposure to gaseous pollutants and pulmonary heart disease-related mortality among elderly people in Chengdu, China.

BACKGROUND: Pulmonary heart disease (PHD) has become a global burden, especially in low- and middle-income countries. However, very few studies have assessed the influence of air pollution on PHD. This is the first study to explore the association between gaseous pollutants and PHD-related mortality in the central Sichuan Basin of southwestern China. METHODS: Data on PHD-related mortality among elderly people (aged 60 and older) from 2013 to 2017 were collected from the Population Death Information Registration and Management System (PDIRMS). Data on air pollutants were collected from all 24 Municipal Environmental Monitoring Sites in Chengdu, and data on daily temperature, relative humidity, and atmospheric pressure were collected from the Chengdu Municipal Meteorological Bureau. An epidemiological design of time-stratified case-crossover was conducted to assess the association between short-term exposure to ambient gaseous pollutants and PHD-related mortality among elderly people. RESULTS: About 54,920 PHD-related deaths among people aged 60 and older were reported. After controlling for daily temperature, relative humidity, and atmospheric pressure, an IQR concentration increase in levels of sulfur dioxide (SO2) (13 µg/m3), nitrogen dioxide (NO2) (17 µg/m3), and ozone (O3) (74 µg/m3) was associated with 7.8, 6.2, and 5.5% increases in PHD-related mortality in people aged 60 and older, respectively. People over age 70 might have even higher susceptibility to PHD-related mortality associated with SO2, NO2, and O3. Females and individuals with alternative marital statuses (widowed, divorced, or never married) had twice and more than twice the PHD-related mortality risk associated with SO2 and NO2 than males and married individuals, respectively. CONCLUSIONS: Increased concentrations of ambient SO2, NO2, and O3 were significantly and positively associated with PHD-related mortality in Chengdu, China. Sociodemographic factors - including gender, age, and marital status - may modify the acute health effects of gaseous pollutants.

[Clinical significance of the N-terminal pro-B-type natriuretic peptide levels in pneumoconiosis patients with chronic pulmonary heart disease].

Objective: To determine the diagnosis value and therapy significance of peripheral blood N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in pneumoconiosis patients with chronic pulmonary heart disease (CPHD) . Methods: A total of 22 pneumoconiosis complicated with CPHD (A group) , 20 pneumoconiosis complicated with coronary heart disease (B group) and 25 pneumoconiosis without heart disease (C group) were selected. The level of blood NT-proBNP was examined and analyzed in the three groups. We observed the difference blood level of NT-proBNP concentration between before and after of therapy in pneumoconiosis patients with CPHD. The optimal cutoff value of blood NT-proBNP was determined according to the principle of maximum Youden's index associated with clinical analysis. Results: Blood NT-proBNP concentrations were 543.19±78.92, 1017.38±731.06, 109.56±57.46 pg/ml in three groups, respectively. Compared with C group, there was a significant increase in the blood levels of NT-proBNP in both A and B groups (P<0.05, P<0.01) , especially for B group. Compared with NT-proBNP 543.19±78.92 pg/ml before therapy, the153.34±58.40 pg/ml was significantly declined after therapy in B group (P<0.05) . The optional threshold for peripheral blood NT-proBNP level as a diagnostic indicator for pneumoconiosis complicated with CPHD was 450 pg/ml. The specificity and sensitivity of NT-proBNP were 95.46% and 54.17%, respectively. Conclusion: Blood NT-proBNP level may be useful as a tool for monitoring the effect of pneumoconiosis patients with CPHD treatment with higher sensitivity in. Blood NT-proBNP cut-off >450 pg/ml should be applied in clinical practice as a valuable diagnostic prediction for pneumoconiosis patients with CPHD.

Association of Borderline Pulmonary Hypertension With Mortality and Hospitalization in a Large Patient Cohort: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.

BACKGROUND: Pulmonary hypertension (PH) is associated with increased morbidity across the cardiopulmonary disease spectrum. Based primarily on expert consensus opinion, PH is defined by a mean pulmonary artery pressure (mPAP) ≥25 mm Hg. Although mPAP levels below this threshold are common among populations at risk for PH, the relevance of mPAP <25 mm Hg to clinical outcome is unknown. METHODS AND RESULTS: We analyzed retrospectively all US veterans undergoing right heart catheterization (2007-2012) in the Veterans Affairs healthcare system (n=21,727; 908-day median follow-up). Cox proportional hazards models were used to evaluate the association between mPAP and outcomes of all-cause mortality and hospitalization, adjusted for clinical covariates. When treating mPAP as a continuous variable, the mortality hazard increased beginning at 19 mm Hg (hazard ratio [HR]=1.183; 95% confidence interval [CI], 1.004-1.393) relative to 10 mm Hg. Therefore, patients were stratified into 3 groups: (1) referent (≤18 mm Hg; n=4,207); (2) borderline PH (19-24 mm Hg; n=5,030); and (3) PH (≥25 mm Hg; n=12,490). The adjusted mortality hazard was increased for borderline PH (HR=1.23; 95% CI, 1.12-1.36; P<0.0001) and PH (HR=2.16; 95% CI, 1.96-2.38; P<0.0001) compared with the referent group. The adjusted hazard for hospitalization was also increased in borderline PH (HR=1.07; 95% CI, 1.01-1.12; P=0.0149) and PH (HR=1.15; 95% CI, 1.09-1.22; P<0.0001). The borderline PH cohort remained at increased risk for mortality after excluding the following high-risk subgroups: (1) patients with pulmonary artery wedge pressure >15 mm Hg; (2) pulmonary vascular resistance ≥3.0 Wood units; or (3) inpatient status at the time of right heart catheterization. CONCLUSIONS: These data illustrate a continuum of risk according to mPAP level and that borderline PH is associated with increased mortality and hospitalization. Future investigations are needed to test the generalizability of our findings to other populations and study the effect of treatment on outcome in borderline PH.

Prolyl-4 Hydroxylase 2 (PHD2) Deficiency in Endothelial Cells and Hematopoietic Cells Induces Obliterative Vascular Remodeling and Severe Pulmonary Arterial Hypertension in Mice and Humans Through Hypoxia-Inducible Factor-2α.

BACKGROUND: Vascular occlusion and complex plexiform lesions are hallmarks of the pathology of severe pulmonary arterial hypertension (PAH) in patients. However, the mechanisms of obliterative vascular remodeling remain elusive; hence, current therapies have not targeted the fundamental disease-modifying mechanisms and result in only modest improvement in morbidity and mortality. METHODS AND RESULTS: Mice with Tie2Cre-mediated disruption of Egln1 (encoding prolyl-4 hydroxylase 2 [PHD2]; Egln1(Tie2)) in endothelial cells and hematopoietic cells exhibited spontaneous severe PAH with extensive pulmonary vascular remodeling, including vascular occlusion and plexiform-like lesions, resembling the hallmarks of the pathology of clinical PAH. As seen in patients with idiopathic PAH, Egln1(Tie2) mice exhibited unprecedented right ventricular hypertrophy and failure and progressive mortality. Consistently, PHD2 expression was diminished in lung endothelial cells of obliterated pulmonary vessels in patients with idiopathic PAH. Genetic deletions of both Egln1 and Hif1a or Egln1 and Hif2a identified hypoxia-inducible factor-2α as the critical mediator of the severe PAH seen in Egln1(Tie2) mice. We also observed altered expression of many pulmonary hypertension-causing genes in Egln1(Tie2) lungs, which was normalized in Egln1(Tie2)/Hif2a(Tie2) lungs. PHD2-deficient endothelial cells promoted smooth muscle cell proliferation in part through hypoxia-inducible factor-2α-activated CXCL12 expression. Genetic deletion of Cxcl12 attenuated PAH in Egln1(Tie2) mice. CONCLUSIONS: These studies defined an unexpected role of PHD2 deficiency in the mechanisms of severe PAH and identified the first genetically modified mouse model with obliterative vascular remodeling and pathophysiology recapitulating clinical PAH. Thus, targeting PHD2/hypoxia-inducible factor-2α signaling is a promising strategy to reverse vascular remodeling for treatment of severe PAH.