Impact of Epicardial Adipose Tissue on Right Cardiac Function and Prognosis in Pulmonary Arterial Hypertension.

BACKGROUND: Although epicardial adipose tissue (EAT) is linked to effects on survival in left-sided heart failure, the association between EAT and right-sided heart failure caused by pulmonary arterial hypertension (PAH) remains unknown. RESEARCH QUESTION: What are the potential impacts of EAT volume (EATV) on right ventricular function, biomarkers of myocardial injury, and long-term prognosis in patients with PAH?. STUDY DESIGN AND METHODS: A total of 135 age- and BMI-matched patients with PAH and 49 control subjects were included in this study. EATV was quantified by using cardiac magnetic resonance and was related to clinical correlates, N-terminal pro-brain natriuretic peptide, and cardiac function. Levels of EATV associated with the risk of clinical worsening were evaluated on a continuous scale (restricted cubic splines) and by previously defined centile categories with Cox proportional hazards regression models and Kaplan-Meier survival estimates. RESULTS: Compared with the control subjects, patients with PAH had a lower EATV (ln [EATV], 3.2 ± 0.8 mL vs 3.5 ± 0.7 mL; P = .034). The association of EATV with right ventricular end-diastolic volume (Pnonlinear = .001), right ventricular end-diastolic volume index (P < .001), right ventricular cardiac output (P = .003), N-terminal pro-brain natriuretic peptide (P = .030), and the risk of clinical worsening (P = .014) was U shaped. Compared with individuals with middle-level EATV, multivariable-adjusted hazard ratio for clinical worsening was 6.0 (95% CI, 1.3-27.8) for the individuals with low-level EATV and 6.8 (95% CI, 1.5-30.2) for high-level EATV in patients with PAH. INTERPRETATION: Patients with PAH had a decreased EATV compared with control subjects. EATV exhibited a U-shaped association with right ventricular function and biomarkers of myocardial injury in patients with PAH. Low and high levels of EATV might reduce long-term event-free survival in patients with PAH. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry; No. ChiCTR2100049804; www.chictr.org.cn.

Analysis of relationship between P wave dispersion and diagnosis of pulmonary arterial hypertension and risk stratification.

BACKGROUND: The aim of this study was to measure the P-wave dispersion(PWD) in the ECG of patients with pulmonary arterial hypertension(PAH). METHODS: A total of 103 PAH patients were collected, including 55 patients related with congenital heart disease(CHD) and 44 patients with idiopathic pulmonary arterial hypertension(IPAH). In addition, 30 CHD patients without PAH (nPAH-CHD group) and 30 healthy controls (HCG group) were collected as control. Patients in the PAH group were categorized into the low-risk group (30 cases), moderate-risk group (53 cases) and high-risk group (20 cases), followed by comparison of PWD difference between groups. The ROC curve was used to evaluate the diagnostic efficacy of PWD on PAH-CHD and IPAH. RESULTS: The levels of PWD and maximum P wave duration(Pmax) in PAH-CHD and IPAH group were significantly higher than those in nPAH-CHD and HCG group (P < 0.05). PWD level was positively correlated with right ventricular end-diastolic diameter(RVD), right atrial end-systolic diameter(RAS), mean pulmonary arterial pressure(mPAP), pulmonary vascular resistance(PVR)(r = 0.407, 0.470, 0.477, 0.423, P < 0.001), and was negatively correlated with systolic displacement of tricuspid valve annulus(TAPSE) level (r = -0.551, P < 0.001). After risk quantification in 103 PAH patients, we found that PWD was significantly different among the low-risk, moderate-risk and high-risk groups (43.89 ± 9.91 vs. 51.29 ± 6.61, 62.15 ± 10.44, P < 0.001). CHD-PAH and IPAH were identified by PWD with a cut off value of 41.5 ms (P < 0.001), and a cut off value of 41.45 ms (P < 0.001), respectively. CONCLUSIONS: PWD might be an effective ECG indicator for PAH, which might be used as a relatively economical indicator for PAH patients to assist in early diagnosis, disease severity assessment and prognosis evaluation.

Evaluating the role of serum uric acid in the risk stratification and therapeutic response of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD).

Background: Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular disease that negatively impacts quality of life, exercise capacity, and mortality. This study sought to investigate the relationship between serum uric acid (UA) level and the disease severity and treatment response of patients with PAH and congenital heart disease (PAH-CHD). Methods: This study included 225 CHD patients and 40 healthy subjects. Serum UA was measured in all patients, and UA levels and haemodynamic parameters were re-evaluated in 20 patients who had received PAH-specific drug treatment for at least 7 ± 1 month. Results: Serum UA levels were significantly higher in PAH-CHD patients than in CHD patients with a normal pulmonary artery pressure and normal subjects (347.7 ± 105.7 µmol/L vs. 278.3 ± 84.6 µmol/L; 347.7 ± 105.7 µmol/L vs. 255.7 ± 44.5 µmol/L, p < 0.05). UA levels in the intermediate and high risk groups were significantly higher than those in the low-risk group (365.6 ± 107.8 µmol/L vs. 311.2 ± 82.8 µmol/L; 451.6 ± 117.6 µmol/L vs. 311.2 ± 82.8 µmol/L, p < 0.05). Serum UA levels positively correlated with mean pulmonary arterial pressure, WHO functional class, pulmonary vascular resistance, and NT-proBNP (r = 0.343, 0.357, 0.406, 0.398; p < 0.001), and negatively with mixed venous oxygen saturation (SvO2) and arterial oxygen saturation (SaO2) (r = -0.293, -0.329; p < 0.001). UA significantly decreased from 352.7 ± 97.5 to 294.4 ± 56.8 µmol/L (p = 0.001) after PAH-specific drug treatment for at least 6 months, along with significant decreases in mean pulmonary arterial pressure and pulmonary vascular resistance and increases in cardiac index and mixed SvO2. Conclusion: Serum UA can be used as a practical and economic biomarker for risk stratification and the evaluation of PAH-specific drug treatment effects for patients with PAH-CHD.

Differential expression spectrum and targeted gene prediction of tRNA-derived small RNAs in idiopathic pulmonary arterial hypertension.

Background: Idiopathic pulmonary arterial hypertension (PAH) is a potentially fatal pulmonary vascular disease with an extremely poor natural course. The limitations of current treatment and the unclear etiology and pathogenesis of idiopathic PAH require new targets and avenues of exploration involved in the pathogenesis of PAH. tRNA-derived small RNAs (tsRNAs), a new type of small non-coding RNAs, have a significant part in the progress of diverse diseases. However, the potential functions behind tsRNAs in idiopathic PAH remain unknown. Methods: Small RNA microarray was implemented on three pairs of plasma of idiopathic PAH patients and healthy controls to investigate and compare tsRNAs expression profiles. Validation samples were used for real-time polymerase chain reaction (Real-time PCR) to verify several dysregulated tsRNAs. Bioinformatic analysis was adopted to determine potential target genes and mechanisms of the validated tsRNAs in PAH. Results: Microarray detected 816 statistically significantly dysregulated tsRNAs, of which 243 tsRNAs were upregulated and 573 were downregulated in PAH. Eight validated tsRNAs in the results of Real-time PCR were concordant with the small RNA microarray: four upregulated (tRF3a-AspGTC-9, 5'tiRNA-31-GluCTC-16, i-tRF-31:54-Val-CAC-1 and tRF3b-TyrGTA-4) and four downregulated (5'tiRNA-33-LysTTT-4, i-tRF-8:32-Val-AAC-2, i-tRF-2:30-His-GTG-1, and i-tRF-15:31-Lys-CTT-1). The Gene Ontology analysis has shown that the verified tsRNAs are related to cellular macromolecule metabolic process, regulation of cellular process, and regulation of cellular metabolic process. It is disclosed that potential target genes of verified tsRNAs are widely involved in PAH pathways by Kyoto Encyclopedia of Genes and Genomes. Conclusion: This study investigated tsRNA profiles in idiopathic PAH and found that the dysregulated tsRNAs may become a novel type of biomarkers and possible targets for PAH.

Effect of multidisciplinary team (MDT) centred on pregnant women with pulmonary hypertension on treatment and outcomes of pregnancy.

BACKGROUND: The importance of multidisciplinary team (MDT) centred on pregnant women with pulmonary hypertension (PH) has been highlighted. However, rare studies have explored its effects on pregnancy outcomes. This study seeks to investigate whether and how the MDT has an effect on the treatment and outcomes of PH pregnant women. METHODS: A pre- and post-intervention study was conducted based on an interrupted time series design to compare the treatment and outcomes of patients with PH before (pre-MDT) and after (post-MDT) implementation of the MDT. PH was defined as pulmonary artery systolic pressure (sPAP) ≥ 35 mmHg measured by echocardiography or right heart catheterization and sPAP at 35-60 mmHg and over 60 mmHg was defined as mild and severe PH, respectively. All results were analyzed by T-tests, Chi square tests or Fisher exact test and two-sided p value < 0.05 was set to be statistically significant. RESULTS: 149 pregnancies were found in 143 women with PH. Overall, 46 pregnancies were elective abortions, remaining 49 and 54 pregnancies completing delivery in the pre-MDT group and post-MDT group, respectively. Five (10.2%) mother and seven (8.6%) neonatal died in the former, while no maternal deaths but 1.9% neonatal death occurred in the latter. In subgroup analysis, maternal and fetal/neonatal complications were higher in patients with severe PH and World Health Organization functional class (WHO FC) III/IV and all maternal deaths occurred in class III/IV women. In pre-MDT and post-MDT groups, there were 8 and 22 pregnant women receiving the pulmonary-specific therapy and completing delivery, respectively. The percentage of heart failure and urgent cesarean of pre-MDT group was higher than the post-MDT group (30.6% vs. 12.9%, p = 0.02; 40.8% vs. 14.8%, p = 0.01, respectively). CONCLUSION: Implementing the MDT decreased the rate of urgent caesarean section and heart failure in patients with PH and no maternal deaths occurred in the post-MDT group. Pregnant women with severe PH and WHO FC III/IV might have a poor prognosis, whereas the use of pulmonary-specific therapy might improve outcomes of pregnancy.

Apolipoprotein A5 ameliorates MCT induced pulmonary hypertension by inhibiting ER stress in a GRP78 dependent mechanism.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic, progressive lung vascular disease accompanied by elevated pulmonary vascular pressure and resistance, and it is characterized by increased pulmonary artery smooth muscle cell (PASMC) proliferation. Apolipoprotein A5 (ApoA5) improves monocrotaline (MCT)-induced PAH and right heart failure; however, the underlying mechanism remains unknown. Here we speculate that ApoA5 has a protective effect in pulmonary vessels and aim to evaluate the mechanism. METHODS: ApoA5 is overexpressed in an MCT-induced PAH animal model and platelet-derived growth factor (PDGF)-BB-induced proliferating PASMCs. Lung vasculature remodeling was measured by immunostaining, and PASMC proliferation was determined by cell counting kit-8 and 5-ethynyl-2'-deoxyuridine5-ethynyl-2'-deoxyuridine incorporation assays. Coimmunoprecipitation-mass spectrometry was used to investigate the probable mechanism. Next, its role and mechanism were further verified by knockdown studies. RESULTS: ApoA5 level was decreased in MCT-induced PAH lung as well as PASMCs. Overexpression of ApoA5 could help to inhibit the remodeling of pulmonary artery smooth muscle. ApoA5 could inhibit PDGF-BB-induced PASMC proliferation and endoplasmic reticulum stress by increasing the expression of glucose-regulated protein 78 (GRP78). After knocking down GRP78, the protecting effects of ApoA5 have been blocked. CONCLUSION: ApoA5 ameliorates MCT-induced PAH by inhibiting endoplasmic reticulum stress in a GRP78 dependent mechanism.

Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation.

Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated. Methods: The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated. Results: Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation. Conclusion: Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation.

Recent Advances of Artificial Intelligence in Cardiovascular Disease.

Cardiovascular disease (CVD) is one of the most serious health disorders with increasing prevalence and high morbidity and mortality. Although diagnosis and treatment of CVD have achieved huge breakthrough in recent years, it still needs additional enhancements, which result in the demand for new techniques. Artificial intelligence (AI) is an emerging science field that has been widely used to guide diseases diagnosis, evaluation and treatment. AI techniques are promising in CVD to explore novel pathogenic genes phenotype, guide optimal individualized therapeutic strategy, improve the management and quality of discharged patients, predict disease prognosis, and as adjuvant therapy tool. Thus, we summarize the latest application of AI techniques in clinical diagnosis, evaluation and treatment of CVD, aiming to provide novel beneficial evidence of AI and promote its application in CVD.

3-Bromopyruvate ameliorates pulmonary arterial hypertension by improving mitochondrial metabolism.

AIMS: Abnormal mitochondrial metabolism is an essential factor for excessive proliferation of pulmonary artery smooth muscle cells (PASMCs), which drives the pathological process of pulmonary arterial hypertension (PAH). 3-Bromopyruvate (3-BrPA) is an effective glycolytic inhibitor that improves mitochondrial metabolism, thereby repressing anomalous cell proliferation. MAIN METHODS: An experimental PAH model was established by injection of monocrotaline (MCT) in male Sprague Dawley rats, following which rats were assigned to three groups: control, MCT, and 3-BrPA groups. Three days post injection of MCT, rats were treated with 3-BrPA or vehicle for 4 weeks. At the end of the study, hemodynamic data were measured to confirm PAH condition. Indicators of pulmonary arterial and right ventricular (RV) remodeling as well as the proliferative ability of PASMCs were assayed. Additionally, mitochondrial morphology and function, and antiglycolytic and antiproliferative pathways and genes were analyzed. KEY FINDINGS: Treatment with 3-BrPA effectively improved pulmonary vascular remodeling and right ventricular function, inhibited PASMC proliferation, and preserved mitochondrial morphology and function. Besides, 3-BrPA treatment inhibited the PI3K/AKT/mTOR pathway and regulated the expression of antiproliferative genes in PASMCs. However, bloody ascites, bloating, and cirrhosis of organs were observed in some 3-BrPA treated rats. SIGNIFICANCE: 3-BrPA acts as an important glycolytic inhibitor to improve energy metabolism and reverse the course of PAH. However, 3-BrPA is associated with side effects in MCT-induced rats, indicating that it should be caution in drug delivery dosage, and further studies are needed to evaluate this toxicological mechanism.

Novel Mechanisms of Exercise-Induced Cardioprotective Factors in Myocardial Infarction.

Exercise training has been reported to ameliorate heart dysfunction in both humans and animals after myocardial infarction (MI). Exercise-induced cardioprotective factors have been implicated in mediating cardiac repair under pathological conditions. These protective factors secreted by or enriched in the heart could exert cardioprotective functions in an autocrine or paracrine manner. Extracellular vesicles, especially exosomes, contain key molecules and play an essential role in cell-to-cell communication via delivery of various factors, which may be a novel target to study the mechanism of exercise-induced benefits, besides traditional signaling pathways. This review is designed to demonstrate the function and underlying protective mechanism of exercise-induced cardioprotective factors in MI, with an aim to offer more potential therapeutic targets for MI.

Long non-coding RNA RNF7 promotes the cardiac fibrosis in rat model via miR-543/THBS1 axis and TGFß1 activation.

Cardiac fibrosis (CF) is regulated by multiple factors, including transforming growth factor ß1 (TGFß1) and non-coding RNAs. Thrombospondin 1 (TSP1) is a physiologic regulator of TGFß activation. Here, we performed microarray analyses on mRNAs and lncRNAs differentially-expressed in the CF and normal rat hearts. KEGG signaling annotation and GO enrichment analyses were performed to validate the roles of extracellular matrix (ECM) and TSP1-enhanced TGFß activation in CF. The co-expression network between differentially-expressed lncRNAs and ECM-related factors was constructed to identify candidate lncRNAs and miRNAs. We found that lncRNA Homo sapiens ring finger protein 7 (lnc RNF7) was significantly correlated with TSP1 and ECM. Lnc RNF7 silence could attenuate isoproterenol (ISP)-induced CF in rat heart in vivo and in rat cardiac fibroblasts in vitro. Moreover, angiotensin II (Ang II) -induced CF in rat cardiac fibroblasts could also be attenuated by Lnc RNF7 silence. Furthermore, miR-543 could simultaneously target lnc RNF7 and 3' UTR of TSP1. Lnc RNF7 silence suppressed, while miR-543 inhibition promoted TSP1 protein and TGFß activation, as well as ECM markers expression. The effects of lnc RNF7 silence was significantly reversed by miR-543 inhibition. In conclusion, CF progression might be regulated by lnc RNF7/miR-543 axis via TSP1-mediated TGFß activation.

A novel mechanism of Smads/miR-675/TGFßR1 axis modulating the proliferation and remodeling of mouse cardiac fibroblasts.

Cardiac fibroblasts (CFs) can over-proliferate during the progression of cardiac fibrosis, accompanied by a net accumulation of extracellular matrix proteins. Based on the profibrotic actions of transforming growth factor beta 1 (TGFß1), investigating the mechanisms of TGFß1 function in CFs may provide new directions to treatment for cardiac fibrosis. microRNAs (miRNAs) could control CFs proliferation or remodeling via binding to 3'-untranslated region of messenger RNA (mRNA) to negatively regulate gene expression. In the present study, we downloaded several microarray analyses results from GEO attempting to identify miRNAs and possible downstream targets that may be involved in TGF-ß1 function in CFs and to detect the cellular and molecular functions of the identified miRNA-mRNA axis. Here, we identified miR-675 as a downregulated miRNA by TGFß1 by bioinformatics analyses and experimental verification. Upon TGFß1 stimulation, the protein levels of Α-SMAΑ-SMA, collagen I, and POSTN, and the secreted collagen in the cell culture supernatant significantly increased, whereas the miR-675 expression decreased. Smads mediate TGFß1-induced suppression on miR-675 via binding miR-675 promoter region. miR-675 overexpression could inhibit, whereas miR-675 inhibition could enhance TGFß1-induced mouse CFs (MCF) remodeling and proliferation. TGFß receptor 1 (TGFßR1), a critical receptor in TGFß1/Smad signaling, is a direct downstream target of miR-675. TGFßR1 overexpression significantly reverses the effect of miR-675 overexpression on MCF remodeling and proliferation. In summary, miR-675 targets TGFßR1 to attenuate TGFß1-induced MCF remodeling and proliferation. We demonstrate a novel mechanism of the Smads/miR-675/TGFßR1 axis modulating TGFß1-induced MCF remodeling and proliferation.