刘冰洋
中国医学科学院阜外医院 肺血管病中心
BACKGROUND:Gut microbiota assumes an essential role in the development and progression of pulmonary arterial hypertension (PAH). Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite, is correlated with the prognosis of patients with PAH. However, the correlation between changes in TMAO (ΔTMAO) and the prognosis of PAH remains elusive.OBJECTIVES:To investigate the association between ΔTMAO and prognosis of PAH, and explore whether dynamic assessment of TMAO level was superior to measurement at a single time point in predicting prognosis.DESIGN:Single-center cohort study.METHODS:Consecutive patients diagnosed with PAH and had at least two TMAO measurements taken from May 2019 to June 2020 were eligible. The outcome events of this study were defined as adverse clinical events.RESULTS:A total of 117 patients with PAH who had two TMAO measurements and follow-up were included in this study. Patients with ΔTMAO ⩾1.082 μmol/L had over four times increased risk of adverse clinical events than their counterparts after adjusting for confounders [hazard ratio (HR) 4.050, 95% confidence interval (CI): 1.468-11.174; p = 0.007]. Patients with constant high TMAO levels at both time points had the highest risk of adverse clinical events compared with patients with constant low TMAO levels (HR 3.717, 95% CI: 1.627-8.492; p = 0.002). ΔTMAO was also associated with changes in parameters reflecting PAH severity (p < 0.05).CONCLUSION:Changes in TMAO were independently correlated with prognosis in patients with PAH, irrespective of baseline level of TMAO. ΔTMAO also correlated with alteration in disease severity. Repeated assessment of TMAO level contributes to better identification of patients with increased risk of adverse clinical events.
Therapeutic advances in respiratory disease 2024
BACKGROUND:An increased acetylcholine (ACh) level in the right ventricle tissue of pulmonary hypertension (PH) was revealed, which indicated the important role of ACh in disease pathogenesis. However, the relationship between plasma ACh levels and disease conditions and patients' prognosis has not been investigated. We aimed to explore the association between plasma ACh levels and the prognosis of patients with PH. We also discussed the feasibility of plasma ACh as a biomarker, which may contribute to the management of PH patients in the future.METHODS:Patients with confirmed PH in Fuwai Hospital from April 2019 to August 2020 were enrolled. The primary clinical outcome in this study was defined as a composite outcome, including death/lung transplantation, heart failure, and worsening of symptoms. Fasting plasma was collected to detect the ACh levels. The association between ACh levels and patients' prognosis was explored.RESULTS:Finally, four hundred and eight patients with PH were enrolled and followed for a mean period of 2.5 years. Patients in the high ACh group had worse World Health Organization Functional Class (WHO-FC), lower 6-minute walk distance (6 MWD), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP). Notably, echocardiographic and hemodynamic parameters in the high metabolite group also suggested a worse disease condition compared with the low ACh group. After adjusting for confounders, compared with low ACh patients, those with high metabolite levels still have worse prognoses characterized as elevated risk of mortality, heart failure, and symptoms worsening.CONCLUSION:High circulating ACh levels were associated with severe PH conditions and poor prognosis, which might serve as a potential biomarker in PH.
BMC pulmonary medicine 2024
Background:Evaluation of the tricuspid valve (TV) is crucial for clinical decision making and post-treatment follow-up in pulmonary hypertension (PH) patients. However, little is known about 4-dimensional (4D) TV geometric remodeling in patients with PH. The aim of this study was to examine the 4D geometry of the TV in PH and its correlation with PH severity.Methods:A total of 74 PH patients with mean pulmonary arterial pressure >25 mmHg and 15 age- and gender-matched healthy individuals were consecutively included from September 2017 to December 2018 in National Center for Cardiovascular Diseases, Fuwai Hospital. All participants underwent 2-dimensional (2D) and 4D transthoracic echocardiography and PH patients underwent right heart catheterization (RHC) within 48 hours of echocardiography. TV geometry was analyzed using a dedicated 4D echocardiography from the right ventricular-focused apical view.Results:Compared with controls, PH patients had significantly larger 4D tricuspid annular (TA) and TV tenting sizes except in the 2-chamber diameter. In high-quality image cases, maximal tenting height (MTH), coaptation point height, tenting volume and 4-chamber diameter had good or moderate correlation with PH severity graded according to RHC mean pulmonary artery pressure (r=0.705, r=0.644, r=0.602, r=0.472, respectively; P<0.001 for all). In multivariable linear regression analysis, PH severity was independently associated with coaptation point height (F=18.070, P<0.001 with an R2=0.647) and MTH (F=25.576, P<0.001 with an R2=0.378). Among all 4D TV parameters, MTH had the highest area under the receiver operating characteristic (ROC) curve (AUC) in high-quality image cases [AUC =0.857, 95% confidence interval (CI): 0.743-0.972; P<0.001], comparable to echocardiographic systolic pulmonary arterial pressure (AUC =0.847, 95% CI: 0.733-0.961; P<0.001).Conclusions:In PH, TV geometric remodeling occurs mainly in TA septal-lateral dimension and TV tenting height. Worsening PH is an independent determinant of TV coaptation point height and MTH, not TA size. MTH shows a great diagnostic potential to detect severe PH.
Quantitative imaging in medicine and surgery 2024
Mounting evidence has confirmed that essential hypertension (EH) is closely related to low-grade inflammation, but there is still a lack of in-depth understanding of the state of immune cells in the circulating blood of patients with EH. We analyzed whether hypertensive peripheral blood immune cell balance was destroyed. The peripheral blood mononuclear cells (PBMCs) of all subjects were analyzed using time-of-flight cytometry (CyTOF) based on 42 kinds of metal-binding antibodies. CD45+ cells were categorized into 32 kinds of subsets. Compared with the health control (HC) group, the percentage of total dendritic cells, two kinds of myeloid dendritic cell subsets, one intermediate/nonclassical monocyte subset and one CD4+ central memory T cell subset in the EH group, was significantly higher; the percentage of low-density neutrophils, four kinds of classical monocyte subsets, one CD14lowCD16- monocyte subset, one naive CD4+ and one naive CD8+ T cell subsets, one CD4+ effector and one CD4+ central memory T cell subsets, one CD8+ effector memory T cell subset, and one terminally differentiated γδ T cell subset, decreased significantly in EH. What is more, the expression of many important antigens was enhanced in CD45+ immune cells, granulocytes, and B cells in patients with EH. In conclusion, the altered number and antigen expression of immune cells reflect the imbalanced immune state of the peripheral blood in patients with EH.
Cardiovascular therapeutics 2023
BACKGROUNDS:Mounting evidences have highlighted the association between metabolites and cardiovascular diseases. Our previous works have demonstrated that circulating metabolite, trimethylamine oxide, was associated with prognosis of patients with pulmonary hypertension (PH). Choline is a precursor of trimethylamine oxide and its role in PH remains unknown. Here, we aimed to validate the hypothesis that circulating choline levels were associated with prognoses in patients with PH.METHODS:Inpatients diagnosed with PH-defined as mean pulmonary arterial pressure ≥ 25 mmHg by right heart catheterisation-from Fuwai Hospital were enrolled after excluding relative comorbidities. Fasting blood samples were obtained to assess choline levels and other clinical variables. The primary endpoints were defined as death, escalation of targeted medication, rehospitalization due to heart failure, PH deterioration. The follow-up duration was defined as the time from the choline examination to the occurrence of outcomes or the end of the study. The associations between circulating choline levels and disease severity and prognoses were explored.RESULTS:Totally, 272 inpatients with PH were enrolled in this study. Patients were divided into high and low choline groups according to the 50th quartile of circulating choline levels, defined as 12.6 µM. After confounders adjustment, the high circulating choline levels were still associated with poor World Health Organization functional class, elevated N-terminal pro-B-type natriuretic peptide, and decreased cardiac output index indicating the severe disease condition. Moreover, elevated choline levels were associated with poor prognoses in PH patients even after adjusting for confounders (hazard ratio = 1.934; 95% CI, 1.034-3.619; P = 0.039). Subgroup analyses showed that choline levels predicted the prognosis of patients with pulmonary arterial hypertension but not chronic thromboembolic pulmonary hypertension.CONCLUSIONS:Choline levels were associated with disease severity and poor prognoses of patients with PH, especially in pulmonary arterial hypertension suggesting its potential biomarker role.
BMC pulmonary medicine 2023
BACKGROUND:Trimethylamine N-oxide (TMAO), the gut microbiota-dependent metabolite, is a potential biomarker in several cardiovascular diseases. However, no study has investigated its value in pulmonary hypertension (PH). Therefore, this study aimed to explore the association between plasma TMAO levels and prognosis in patients with PH.METHODS:Inpatients with idiopathic/heritable pulmonary arterial hypertension (IPAH/HPAH), PAH associated with congenital heart disease (CHD-PAH), and chronic thromboembolic pulmonary hypertension (CTEPH) at Fuwai Hospital were enrolled after excluding those with relative comorbidities. The endpoint was defined as a composite outcome including death, rehospitalisation due to heart failure, and at least 15% decreased 6-min walk distance from the baseline. Fasting blood samples were collected to measure plasma levels of TMAO and other clinical indicators. The associations between TMAO levels with disease severity and patients' prognosis were investigated.RESULTS:In total, 163 patients with PH were included, with a mean follow-up duration of 1.3 years. After adjusting for confounding factors, elevated TMAO levels were still associated with severe disease conditions. TMAO levels dynamically decreased in stable and improved patients after treatment [ΔTMAO = - 0.2 (- 1.6, 0.7) μmol/L, P = 0.006]. Moreover, high plasma TMAO levels predicted a poor prognosis in the PH cohort (P < 0.001), and the association remained significant after adjusting the confounders, including treatment, risk stratification, and PH subtypes.CONCLUSION:Elevated plasma TMAO levels were associated with severe disease conditions and poor prognosis in patients with PH, indicating its potential biomarker role in PH.
Respiratory research 2022
BACKGROUND:Arrhythmia is not uncommon among pulmonary hypertension (PH) population, and may be associated with disease severity.HYPOTHESIS:To investigate different spectrums and prevalence of arrhythmias in different clinical PH groups in Chinese population.METHODS:Patients diagnosed with PH between April 15, 2019, and August 2, 2021, were enrolled prospectively. The prevalence of different types of arrhythmias in PH patients were calculated. Logistic regression analyses were conducted to determine independent predictors for arrhythmia.RESULTS:One thousand patients were enrolled. The prevalence of any arrhythmia, sinus node dysfunction, sinus tachycardia, atrial fibrillation, atrial flutter, other types of atrial tachycardia, atrioventricular block, and ventricular tachycardia is 44.4%, 12.2%, 15.2%, 8.1%, 4.1%, 10.2%, 7.1%, and 2.5%. Logistic regression analyses revealed that older age and larger right ventricle (odds ratio: 1.111 and 1.095, p < .05) were independently related with higher probability of supraventricular arrhythmia; Complicating with coronary artery disease, larger right ventricle, and increased left ventricular end-diastolic diameter (odds ratio: 19.540, 1.106, and 1.085, p < .05) were independently correlated with sinus node dysfunction/atrioventricular block in patients with pulmonary arterial hypertension.CONCLUSIONS:Nearly half of PH patients experienced at least one type of arrhythmia. The most common seen arrhythmias were supraventricular arrhythmia, sinus tachycardia, and sinus node dysfunction. Older age and larger right ventricle were independently related with higher probability of supraventricular arrhythmia; Complicating with coronary artery disease, larger right ventricle and increased left ventricular end-diastolic diameter were independently correlated with higher probability of sinus node dysfunction/atrioventricular block in patients with pulmonary arterial hypertension.
Clinical cardiology 2022
Aims:We aimed to examine the hypothesis that circulating trimethylamine-N-oxide (TMAO) levels serve as a biomarker in pulmonary arterial hypertension (PAH), and to determine whether 3,3-dimethyl-1-butanol (DMB), a TMAO inhibitor, exerted a protective effect in monocrotaline (MCT)-induced PAH rats.Methods and results:In-patients with PAH were prospectively recruited from the Fuwai Hospital. Fasting blood samples were obtained to assess the TMAO levels and other laboratory values during the initial and second hospitalization. In a MCT-induced PAH rat, a normal diet and water supplemented with or without 1% DMB were administered for 4 weeks. The TMAO levels, haemodynamic examinations, changes in organ-tissue, and molecular levels were evaluated. In total, 124 patients with PAH were enrolled in this study. High TMAO levels were correlated with increased disease severity and poor prognosis even after adjusting for confounders. The TMAO levels in the rats decreased in the MCT + DMB group, accompanied by improved haemodynamic parameters, decreased right ventricular hypertrophy, and amelioration of pulmonary vascular remodelling. The decrease in abnormal apoptosis, excessive cell proliferation, transforming growth factor-β expression, and restoration of endothelial nitric oxide synthase after DMB treatment further explained the amelioration of PAH.Conclusion:Increased TMAO levels were associated with poor prognosis in patients with PAH, and DMB played a protective effect in MCT-induced PAH rat.
European heart journal open 2022
Background Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (PAP) ≥25 mm Hg measured by right heart catheterization. However, the upper limit of a normal mean PAP is 20 mm Hg. There is a gap between the upper limit of normal and the threshold for diagnosing PH. Therefore, we aimed to investigate whether individuals with a mildly elevated PAP, defined as 20 mm Hg < mean PAP <25 mm Hg, are at an increased risk of progression to PH or mortality than those with a normal PAP. Methods and Results We reviewed studies evaluating the risk of progression to PH and/or mortality in individuals with a mildly elevated PAP versus those with a normal PAP. The mean PAP value of each participant was confirmed by right heart catheterization. We reviewed 1213 studies and 8 fulfilled our inclusion criteria. Our results indicated that individuals with a mildly elevated PAP were 1.81 to 2.45 times more likely to progress to PH than individuals with a normal PAP. There was a statistically significant difference in mortality between the mildly elevated PAP and normal PAP groups (hazard ratio, 2.48; 95% CI, 1.69-3.64). We also pooled survival probabilities in each arm to obtain a summary survival curve for each group, and the pooled survival rates in the mildly elevated PAP group were numerically lower than those in the normal PAP group. Conclusions Our study revealed that individuals with a mildly elevated PAP were at an increased risk of progression to PH and mortality than those with a normal PAP.
Journal of the American Heart Association 2021
Background: Four-dimensional automatic right ventricular quantification technology (4D auto-RVQ) is a new method that can simultaneously measure right ventricular (RV) structure and strain. The role of 4D auto-RVQ in determining RV function and hemodynamics is not clear. The role of 4D auto-RVQ in determining RV function and hemodynamics is not clear. We assessed the 4D auto-RVQ to measure right heart structure, function, and hemodynamics in patients with pulmonary hypertension (PHTN) correlated with right heart catheterization (RHC). Methods: We enrolled a prospective cohort of 103 patients with PHTN and 25 healthy controls between September 2017 and December 2018. All patients with PHTN underwent echocardiography and RHC. Patients were included if they underwent two-dimensional (2D) and 4D auto-RVQ echocardiographic sequences on the same day as RHC. We analyzed RV functional indices using 2D and 4D auto-RVQ analyses. We divided patients with PHTN into three groups according to echocardiographic image quality as follows: high (n = 24), average (n = 48), and poor (n = 4). Hemodynamic parameters were measured using RHC, including mean right atrial pressure, mean pulmonary arterial pressure, RV cardiac index (RV-CI), and pulmonary vascular resistance. Results: There were significant differences in most 2D and 4D auto-RVQ parameters between patients with PHTN and healthy controls. Interobserver variability showed significant agreement with 4D auto-RVQ for most measurements except for 4D end-diastolic volume. Indices measured by auto 4D-RVQ in the high-quality image group had a good correlation with RHC but not in the average- and poor-quality image group. Mid-RV diameter showed the best predictive power for the right RV-CI [area under the curve (AUC) 0.935; 95% confidence interval (CI), 0.714-0.997; p < 0.001]. RV end-systolic volume >121.50 mL had a 71.43% sensitivity and a 100% specificity to predict right RV-CI (AUC, 0.890; 95% CI, 0.654-0.986; p < 0.001). Conclusions: 4D auto-RVQ may be used to estimate RV function and some hemodynamic changes compared with RHC in PHTN patients with high image quality. Furthermore, a large sample of the study is needed to evaluate RV function by 4D auto-RVQ in PHTN patients with average image quality.
Frontiers in cardiovascular medicine 2021
