Association of non-insulin-based insulin resistance indices with disease severity and adverse outcome in idiopathic pulmonary arterial hypertension: a multi-center cohort study.

BACKGROUND: Insulin resistance (IR) plays an important role in the pathophysiology of cardiovascular disease. Recent studies have shown that diabetes mellitus and impaired lipid metabolism are associated with the severity and prognosis of idiopathic pulmonary arterial hypertension (IPAH). However, the relationship between IR and pulmonary hypertension is poorly understood. This study explored the association between four IR indices and IPAH using data from a multicenter cohort. METHODS: A total of 602 consecutive participants with IPAH were included in this study between January 2015 and December 2022. The metabolic score for IR (METS-IR), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose (TyG) index, and triglyceride-glucose-body mass index (TyG-BMI) were used to quantify IR levels in patients with IPAH. The correlation between non-insulin-based IR indices and long-term adverse outcomes was determined using multivariate Cox regression models and restricted cubic splines. RESULTS: During a mean of 3.6 years' follow-up, 214 participants experienced all-cause death or worsening condition. Compared with in low to intermediate-low risk patients, the TG/HDL-C ratio (2.9 ± 1.7 vs. 3.3 ± 2.1, P = 0.003) and METS-IR (34.5 ± 6.7 vs. 36.4 ± 7.5, P < 0.001) were significantly increased in high to intermediate-high risk patients. IR indices correlated with well-validated variables that reflected the severity of IPAH, such as the cardiac index and stroke volume index. Multivariate Cox regression analyses indicated that the TyG-BMI index (hazard ratio [HR] 1.179, 95% confidence interval [CI] 1.020, 1.363 per 1.0-standard deviation [SD] increment, P = 0.026) and METS-IR (HR 1.169, 95% CI 1.016, 1.345 per 1.0-SD increment, P = 0.030) independently predicted adverse outcomes. Addition of the TG/HDL-C ratio and METS-IR significantly improved the reclassification and discrimination ability beyond the European Society of Cardiology (ESC) risk score. CONCLUSIONS: IR is associated with the severity and long-term prognosis of IPAH. TyG-BMI and METS-IR can independently predict clinical worsening events, while METS-IR also provide incremental predictive performance beyond the ESC risk stratification.

Usefulness of risk assessment tools in predicting hemodynamic outcome after balloon pulmonary angioplasty: a comparative analysis.

OBJECTIVES: Several parameters of widely used risk assessment tools for pulmonary arterial hypertension (PAH) have been linked to hemodynamic outcomes of balloon pulmonary angioplasty (BPA). Therefore, we aimed to determine whether these risk assessment tools could be used to predict hemodynamic outcomes following BPA. METHODS: In this retrospective study, we included 139 patients with chronic thromboembolic pulmonary hypertension who had undergone BPA at Center for Pulmonary Vascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China). We compared the accuracies of seven well-validated risk assessment tools for predicting hemodynamic outcomes following BPA. A favorable hemodynamic outcome was defined as a mean pulmonary arterial pressure < 30 mmHg at follow-up. RESULTS: The baseline risk profiles varied significantly among the risk assessment tools. The US Registry to Evaluate Early and Long-Term PAH Disease Management risk scales and the French risk assessment tools rated most patients as high-risk, while the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) series and laboratory examination-based risk scales categorized most patients as having intermediate-risk profile. COMPERA 2.0 (4-strata) exhibited the highest predictive power among all risk stratifications. Noninvasive risk stratification (COMPERA 2.0 [3-strata]) showed a comparable predictive ability to that of invasive risk stratification (COMPERA 1.0) (area under the curve 0.649 vs. 0.648). Moreover, incorporating diffusing capacity of the lungs for carbon monoxide and tricuspid regurgitation velocity into COMPERA 2.0 (4-strata) further enhanced its predictive power (net reclassification index 0.153, 95% confidence interval 0.009-0.298, p = 0.038). Additionally, this refined COMPERA version had a high calibration accuracy (slope 0.96). CONCLUSION: Although the risk strata distribution varied among different risk assessment tools, the proportion of patients achieving favorable hemodynamics decreased with the escalation of risk stratification in most models. The well-validated risk assessment tools for PAH could also predict hemodynamic outcomes following BPA, and the refined COMPERA 2.0 model exhibited the highest predictive ability among these. Applying risk assessment tools before BPA can facilitate early identification of patients in need of closer monitoring and more intensive interventions, contributing to a better prognosis after BPA.

Blood urea nitrogen to serum albumin ratio as a new indicator of disease severity and prognosis in idiopathic pulmonary artery hypertension.

BACKGROUND: Emerging evidence has shown that the blood urea nitrogen to serum albumin ratio (BAR) is associated with the severity and prognosis of heart failure. However, its role in idiopathic pulmonary arterial hypertension (IPAH) remains unclear. This study investigated the associations between BAR and functional status, echocardiographic findings, hemodynamics, and long-term outcomes among patients with IPAH. METHODS: This study included consecutive patients who underwent right heart catheterization (RHC) and were diagnosed with IPAH between January 2013 and January 2018 at Fuwai Hospital. The primary outcome was the worsening of clinical symptoms. Spearman correlation coefficients were used to evaluate the association between the BAR and established markers of IPAH severity. Receiver operating characteristic (ROC) curve analysis was used to determine BAR's optimal cut-off and predictive performance. Kaplan-Meier analysis and Cox proportional hazard models assessed the relationship between BAR and clinical worsening. RESULTS: A total of 340 patients with IPAH were included in this study. BAR correlated with well-validated variables that reflected the severity of IPAH, such as World Health Organization functional class, 6-min walk distance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, mixed venous oxygen saturation, and cardiac index. Kaplan-Meier curves indicated that patients with BAR＞3.80 had a significantly higher clinical worsening rate (log-rank test, P < 0.001) than those with BAR≤3.80. Multivariate Cox analysis showed that BAR could independently predict clinical worsening [hazard ratio(HR):2.642, 95 % confidence interval (CI):1.659-4.208, P < 0.001]. In addition, BAR provided additional predictive value for the European Society of Cardiology (ESC)/European Respiratory Society (ERS) risk assessment score. CONCLUSIONS: BAR reflects disease severity and is independently associated with the prognosis of patients with IPAH.

Optimal short-term outcomes in balloon pulmonary angioplasty: the minimum frequency of three sessions annually.

BACKGROUND: Balloon pulmonary angioplasty (BPA) is typically performed in a sequential manner. OBJECTIVES: This study aimed to determine the lowest frequency of BPA for patients who could not reach treatment goals in a short period. DESIGN: Retrospective cohort. METHODS: We retrospectively enrolled 186 BPA-treated patients diagnosed with chronic thromboembolic pulmonary hypertension. According to the accumulative number of performed BPA sessions or treated pulmonary vessels or the ratio of the number of treated pulmonary vessels/the number of baseline lesions (T/P) prior to the initial occurrence of clinical outcome or censored date, we divided patients into different groups. The principal outcome was clinical worsening. RESULTS: After stratifying patients by the number of performed BPA sessions, most baseline parameters were comparable among groups. During follow-up, 31 (16.7%) of 186 patients experienced clinical worsening. The 6-month cumulative clinical worsening-free survival rates of ⩾2 performed sessions group were significantly higher than that of 1 performed session group. The 12-month cumulative rates of clinical worsening-free survival exhibited a declining pattern in the subsequent sequence: ⩾3, 2, and 1 performed BPA sessions, and this trend persisted when follow-up time exceeded 12 months. The 6-, 12-, and 24-month cumulative clinical worsening-free survival rates were comparable between patients with 3 and ⩾4 performed BPA sessions. Similar results were also observed when stratifying patients by the accumulative number of treated pulmonary vessels (⩽8, 9-16, ⩾17) and T/P (⩽0.789, 0.790-1.263, ⩾1.264). CONCLUSION: To achieve optimal short-term outcomes, patients might need to undergo ⩾2 BPA sessions or have ⩾9 pulmonary vessels treated or have T/P ⩾0.790 within 6 months, and undergo ⩾3 BPA sessions or have ⩾17 pulmonary vessels treated or have T/P ⩾1.264 within 12 months.

The least number of BPA session to reach a favorable outcomeWhy was the study done? Balloon pulmonary angioplasty (BPA) has been recommended for patients with chronic thromboembolic pulmonary hypertension, which can significantly improve patients' hemodynamics. However, BPA is typically performed in a stepwise manner, and the duration from the initial session to the final session could extend over a year. If patients could not quickly undergo adequate number of BPA sessions and reach hemodynamic target due to various reasons, what is the best frequency of BPA for them? What did the researchers do? We retrospectively enrolled 186 BPA-treated patients diagnosed with chronic thromboembolic pulmonary hypertension. According to the accumulative number of BPA sessions, we divided patients into different groups to identify the best frequency of BPA to improve prognosis. What did the researchers find? Patients who received at least two BPA sessions within six months had significantly better prognosis than those with one BPA session. Patients who received at least three BPA sessions within a year had significantly better prognosis than those with two BPA sessions. What do the findings mean? To achieve optimal short-term outcome, patients might need to undergo at least two BPA sessions within six months, and undergo at least three BPA sessions within a year.

The significance of dynamic monitoring plasma TMAO level in pulmonary arterial hypertension - a cohort study.

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.

Role of the Systemic Inflammatory Response Index in Predicting Disease Severity and Prognosis in Idiopathic Pulmonary Arterial Hypertension.

Introduction: Mounting evidence indicates a possible connection between the systemic inflammatory response index (SIRI) and the prognosis of heart failure, but its role in idiopathic pulmonary arterial hypertension (IPAH) is not well understood. This study aimed to investigate the relationship between SIRI and variables such as functional ability, echocardiography results, hemodynamic measurements, and long-term outcomes in patients with IPAH. Methods: The study included 426 consecutive IPAH patients who underwent right heart catheterization at Fuwai Hospital from January 2013 to December 2020. SIRI was calculated using composite inflammation indicators from routine blood tests. The main outcome measure was clinical deterioration. Spearman correlation coefficients were used to assess associations between SIRI and indicators of IPAH severity. Receiver operating characteristic (ROC) curve analysis was conducted to determine the optimal SIRI threshold and predictive ability. Kaplan-Meier analysis and Cox proportional hazard models were used to examine the relationship between SIRI and clinical deterioration. Results: SIRI showed positive associations with indicators such as N-terminal pro-brain natriuretic peptide, right ventricular end-diastolic diameter, pericardial effusion, mean pulmonary arterial pressure, and pulmonary vascular resistance. Conversely, SIRI had inverse relationships with 6-minute walking distance and left ventricular end-diastolic diameter. Kaplan-Meier curves revealed a significantly higher rate of clinical deterioration in individuals with SIRI > 0.741 compared to those with SIRI ≤ 0.741 (P < 0.001). Adjusted Cox analysis showed SIRI remained an independent predictor of clinical worsening (hazard ratio 1.366, 95% confidence interval 1.073-1.738, P = 0.011). ROC analysis demonstrated SIRI provided additional predictive value beyond the risk assessment score of the European Society of Cardiology/European Respiratory Society. Discussion: In summary, SIRI could predict the severity and prognosis of IPAH independently. It was associated with various indicators of IPAH severity and was a significant predictor of clinical deterioration. SIRI also offered additional predictive value beyond existing risk assessment scores.

Circulating acetylcholine serves as a potential biomarker role in pulmonary hypertension.

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.

Angiographic classification of total occlusion and its implication on balloon pulmonary angioplasty.

AIMS: Despite refinements in balloon pulmonary angioplasty (BPA), total occlusion remains a challenge in chronic thromboembolic pulmonary hypertension (CTEPH). Owing to their low success and high complication rates, most interventional cardiologists are reluctant to address total occlusion, and there is a paucity of literature on BPA performance in total occlusion. We aimed to classify total occlusion according to morphology and present an illustrative approach for devising a tailored treatment strategy for each distinct type of total occlusion. METHODS AND RESULTS: All patients diagnosed with CTEPH who underwent BPA between May 2018 and May 2022 at Fuwai Hospital in Beijing, China, were included retrospectively. A total of 204 patients with CTEPH who underwent BPA were included in this study. Among these, 38 occluded lesions were addressed in 33 patients. Based on the morphology, we categorized the lesions into three groups: pointed-head, round-head, and orifice occlusions. Pointed-head occlusion could be successfully addressed using soft-tip wire, round-head occlusion warranted hard-tip wire and stronger backup, and orifice occlusion warranted the strongest backup force. The success rates for each group were as follows: pointed-head (95.45%), round-head (46.15%), and orifice occlusion (33.33%), with orifice occlusion having the highest complication rate (50%). The classification of occlusion was associated with BPA success (round-head occlusion vs. pointed-head occlusion, OR 24.500, 95% CI 2.498-240.318, P = 0.006; orifice occlusion vs. pointed-head occlusion, OR 42.000, 95% CI 3.034-581.434, P = 0.005). CONCLUSIONS: Occlusion morphology has a significant impact on BPA success and complication rates. A treatment strategy tailored to each specific occlusive lesion, as outlined in the present study, has the potential to serve as a valuable guide for clinical practitioners.

Pulmonary artery dilatation in different causes of pulmonary hypertension.

Pulmonary artery (PA) dilatation is commonly observed in patients with pulmonary hypertension (PH). However, the clinical aspects of PA dilatation in various etiology of PH remain unknown. In this study, we investigated the clinical and imaging characteristics of 1018 patients with different subtypes of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The independent determinants for all-cause death were identified using univariate and multivariate Cox proportional hazard models. PA dilatation was identified in 88.8% of the patients, and 27.2% had a PA diameter/ascending aorta diameter ratio greater than 1.5. PA diameter was shown to be significantly correlated with hemodynamic parameters and symptom duration in idiopathic PAH patients. PA diameter only correlated with pulmonary circulation volume in patients with PAH associated with congenital heart disease. PA diameter correlated with symptom duration and right ventricular end-diastolic dimension in CTEPH patients. PA diameter correlated with right ventricular end-diastolic dimension in patients with PAH associated with connective tissue disease. Only 6-min walk distance, but not PA dilatation, predicts all-cause death independently. In conclusion, PA dilatation is a common finding in PH patients. The clinical feature of PA dilatation varies greatly between PH types. PA dilatation is not associated with all-cause death.

Etiological classification and manifestation of pulmonary artery dissection: A literature review and case analysis.

Background: Pulmonary artery dissection (PAD) is an uncommon condition associated with high mortality rates. To date, a comprehensive examination of various underlying causes of PAD remains unexplored. Methods: We used the search words "pulmonary artery dissection," "pulmonary artery dilatation," and "pulmonary artery rupture" in the public database, and examined the medical records of PAD patients treated in our hospital. Data on demographics, aetiology, PAD locations, histopathology, treatments, and outcomes, were collected. Results: A total of 145 patients with PAD (135 cases from the literature and 10 cases from our hospital) were analysed. PAD aetiology was categorized into four groups: congenital heart diseases (CHD) associated with pulmonary arterial hypertension (PAH), non-CHD associated with pulmonary hypertension (PH), aortic dissection-related, and miscellaneous causes. The most frequent cause, accounting for 32.4 % of PAD cases, was congenital heart disease, followed by idiopathic PAH (13 %) and chronic obstructive pulmonary disease (6 %). Patients with CHD were typically younger at the time of PAD diagnosis (median age: 35 years old) when compared with those suffering from aortic dissection, PH-associated conditions, or other causes (median age: 45, 55, and 56 years old, respectively). Imaging of the pulmonary artery proved effective in diagnosing PAD. The outcomes were generally poor. 44.7 % (21/47) of patients with CHD associated with PAH and 47.7 % (21/44) of non-CHD PH-associated diseases died during follow-up. Multidisciplinary team consultations are crucial when making decisions on management of PAD. Characteristic PAD histopathology features included thickened intima and hypertrophied media with atheromatous degeneration, disrupted elastic fibres, and lymphocytic infiltration. Conclusions: PAD aetiology can be divided into four main categories, with CHD associated with PAH being the leading cause. Despite the similar histopathology features, clinical manifestations and outcomes vary according to the aetiology.

Development and validation of a nomogram for predicting hemodynamic response to balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension.

BACKGROUND: Balloon pulmonary angioplasty (BPA) can effectively alleviate pulmonary hypertension in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Identifying predictors of unfavorable hemodynamic response to BPA is essential to guide clinical practice. Therefore, our objective was to construct and validate a nomogram to facilitate clinicians predicting hemodynamic response to BPA. METHODS: Patients with CTEPH and underwent BPA from May 2018 to April 2022 were retrospectively collected. Favorable hemodynamic response to BPA was defined as a mean pulmonary arterial pressure ≤30 mmHg and/or a reduction in pulmonary vascular resistance ≥30 % at follow-up. RESULTS: A total of 155 patients were included. At baseline, patients with favorable hemodynamic response had significantly lower proportion of occlusive lesions (11.11 % vs. 26.32 %, P = 0.017), higher diffusing capacity of the lungs for carbon monoxide (63.77 % ± 14.10 % vs. 59.11 % ± 11.78 %, P = 0.039), and better cardiac morphology than counterparts. LASSO regression and random forest were used to construct prediction models respectively. The LASSO regression model demonstrated better predictive ability and accuracy than the random forest model, as evidenced by higher area under curve (0.745 vs. 0.740) and lower Brier score (0.192 vs. 0.195). A nomogram was constructed based on the LASSO regression model, consisting of right ventricular end-diastolic diameter/left ventricular end-diastolic diameter, number of treated pulmonary vessels and proportion of occlusion lesions. High predictive ability of the LASSO model was preserved in validation (C index 0.744). CONCLUSIONS: The current study constructed a nomogram with high accuracy in predicting BPA hemodynamic outcome, which could facilitate decision-making in clinical practice.

Circulating choline levels are associated with prognoses in patients with pulmonary hypertension: a cohort study.

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.

Angiographic classification of pulmonary vascular lesion in Takayasu arteritis: A cohort study.

BACKGROUND: Percutaneous transluminal pulmonary angioplasty (PTPA) can significantly improve the haemodynamics and prognosis of patients with Takayasu arteritis and pulmonary artery involvement. However, the choice of PTPA is mainly based on clinical experience. We aim to classify pulmonary artery lesions in Takayasu arteritis according to pulmonary angiogram and evaluate the PTPA success rate and technical difficulty of different types of lesions. METHODS: We enrolled consecutive patients diagnosed with Takayasu arteritis and pulmonary artery involvement. Patients who underwent pulmonary angiography were included. RESULTS: A total of 365 pulmonary vascular lesions were observed in 63 patients based on pulmonary angiography. According to morphology, distal blood flow of the lesions and PTPA treatment success rate, we classified the pulmonary arterial lesions into 4 groups: type A, stenosis; type B, dilation; type C, subtotal occlusion; type D, total occlusion. Total occlusion was further subclassified as D1, cone-shape occlusion; D2, pocket-like occlusion; and D3, ostium occlusion. The success rate of PTPA was higher in stenosis and subtotal occlusion, whereas ostium occlusion had the lowest success rate. The 2-year survival rate was 97.3% in patients who underwent PTPA. CONCLUSIONS: The morphology of pulmonary lesions in Takayasu arteritis had a significant impact on the PTPA success rate. The failure rate and technical difficulty of PTPA increased in the following order: stenosis, dilation, subtotal occlusion, and total occlusion. Our classification scheme could guide the performance of PTPA for pulmonary artery lesions in Takayasu arteritis.

Higher circulating Trimethylamine N-oxide levels are associated with worse severity and prognosis in pulmonary hypertension: a cohort study.

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.

Patient-specific and gene-corrected induced pluripotent stem cell-derived endothelial cells elucidate single-cell phenotype of pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterized by the preferential remodeling of the pulmonary venules. Hereditary PVOD is caused by biallelic variants of the EIF2AK4 gene. Three PVOD patients who carried the compound heterozygous variants of EIF2AK4 and two healthy controls were recruited and induced pluripotent stem cells (iPSCs) were generated from human peripheral blood mononuclear cells (PBMCs). The EIF2AK4 c.2965C>T variant (PVOD#1), c.3460A>T variant (PVOD#2), and c.4832_4833insAAAG variant (PVOD#3) were corrected by CRISPR-Cas9 in PVOD-iPSCs to generate isogenic controls and gene-corrected-iPSCs (GC-iPSCs). PVOD-iPSC-endothelial cells (ECs) exhibited a decrease in GCN2 protein and mRNA expression when compared with control and GC-ECs. PVOD-ECs exhibited an abnormal EC phenotype featured by excessive proliferation and angiogenesis. The abnormal phenotype of PVOD-ECs was normalized by protein kinase B inhibitors AZD5363 and MK2206. These findings help elucidate the underlying molecular mechanism of PVOD in humans and to identify promising therapeutic drugs for treating the disease.

Predictors of early response to balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension.

BACKGROUND: To achieve favorable hemodynamics, the number of balloon pulmonary angioplasty (BPA) sessions varied significantly among patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Increased BPA sessions burdened patients financially and psychologically. We aim to identify baseline characteristics that could predict early BPA response. METHODS: Consecutive patients who were diagnosed with inoperable CTEPH and received BPA between May 2018 and October 2021 at Fuwai Hospital were retrospectively collected. Patients were categorized into 'Early BPA responders' or 'Non-early BPA responders' according to the hemodynamic outcome within the first three BPA sessions. RESULTS: In total, 101 patients were included into analysis. At baseline, non-early BPA responders had lower female proportion, longer disease duration, and poorer laboratory test results compared with early responders, whereas hemodynamics were comparable. After the first three BPA sessions, hemodynamic improvement was more significant in early responders. Incidence of complication was comparable between the two groups. Multivariable logistic analysis identified that female sex (odds ratio [OR]: 7.155, 95% confidence interval [CI]: 1.323-38.692, p = 0.022), disease duration (OR: 0.851, 95% CI: 0.727-0.995, p = 0.043), baseline total bilirubin (OR: 0.934, 95% CI: 0.875-0.996, p = 0.038), and baseline NT-proBNP (OR: 0.473, 95% CI: 0.255-0.879, p = 0.018) were independently associated with early BPA response. Combination of these four parameters could predict 90% early BPA response. CONCLUSIONS: Patients with shorter disease duration, female sex, lower baseline NT-proBNP, and lower baseline total bilirubin are more likely to achieve early hemodynamic response to BPA. Moreover, early hemodynamic response was not accompanied with increased incidence of procedure-related complications.

The original and two new derivative versions of the COMPERA 2.0 risk assessment model: useful tools for guiding balloon pulmonary angioplasty.

BACKGROUND: The COMPERA 2.0 4-stratum (4-S) risk score has been demonstrated superior over the 3-stratum (3-S) one in patients with pulmonary arterial hypertension and medically managed patients with chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to determine the prognostic value of the original 4-S and 3-S COMPERA 2.0 risk score and two new derivative versions in CTEPH patients who underwent balloon pulmonary angioplasty (BPA). METHODS: We retrospectively enrolled 175 BPA-treated patients with CTEPH. We assessed the risk stratification before and after each BPA session of CTEPH patients by the original 4-S and 3-S COMPERA 2.0 risk score (by rounding decimal to the nearest integer) and two new proposed derivative versions: the modified version (by rounding decimal to the next integer) and a hybrid version that fuses the original and modified versions. The primary endpoint was clinical worsening events. The secondary outcomes were achieving low-risk profile and mean pulmonary arterial pressure (mPAP) < 30 mmHg at follow-up. We used the Kaplan-Meier curve analysis to assess the survival differences between stratified patients. The comparative model's performance was evaluated in terms of discrimination by Harrell's C-index. RESULTS: All versions of COMPERA 2.0 4-S model outperformed the 3-S one in discriminating the differences in echocardiographic and hemodynamic parameters and clinical worsening-free survival rates. The original and hybrid 4-S model could independently predict the primary and secondary endpoints, and the hybrid version seemed to perform better. The first BPA session could significantly improve risk profiles, and these changes were associated with the likelihood of experiencing clinical worsening events, achieving a low-risk profile and mPAP < 30 mmHg at follow-up. The number of BPA sessions required to achieve low risk/mPAP < 30 mmHg increased as the baseline risk score escalated. CONCLUSIONS: The COMPERA 2.0 4-S model outperformed the 3-S one in BPA-treated patients with CTEPH. The 4-S model, especially its hybrid version, could be used to predict clinical outcome before the initiation of BPA and monitor treatment response.

High-circulating gut microbiota-dependent metabolite trimethylamine N-oxide is associated with poor prognosis in pulmonary arterial hypertension.

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-ß 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.

High Betaine and Dynamic Increase of Betaine Levels Are Both Associated With Poor Prognosis of Patients With Pulmonary Hypertension.

Background and Objective: The association between plasma betaine levels and cardiovascular diseases (CVDs) has been revealed except for pulmonary hypertension (PH). In this study, we aimed to explore the role of betaine in patients with PH. Methods: Inpatients with PH at Fuwai Hospital were enrolled after excluding relative comorbidities. Each patient received at least one follow-up through a clinical visit, and the fasting blood was obtained both at the first and second hospitalization for betaine detection. The primary endpoint was defined as composite outcome events and the mean duration was 14.3 (6.9, 21.3) months. The associations of betaine and changes of betaine (Δbetaine) with disease severity and prognosis were explored. Results: Finally, a total of 216 patients with PH were included and the medians for betaine plasma levels in the total patients group, low betaine, and high betaine groups were 49.8 (39.0, 68.3) µM, 39.0 (33.5, 44.7) µM, and 68.1 (57.8, 88.7) µM, respectively. High betaine was associated with poor World Health Organization Functional Class (WHO-FC), increased N-terminal pro-brain natriuretic peptide (NT-proBNP), low tricuspid annular plane systolic excursion (TAPSE), and cardiac output index even after adjusting for confounders. Patients with high betaine were over twice the risk to receive the poor prognosis than those with a low level [hazard ratio (HR) = 2.080, (95% CI: 1.033-4.188)]. Moreover, the decrease of betaine level after further treatment was positively correlated to ΔNT-proBNP indicating Δbetaine might be an effector of disease severity, and dynamic increase of betaine was also associated with poor prognosis in PH. Conclusion: Betaine was associated with disease severity and might be an effector in PH. Patients with increased levels or with dynamic rise of betaine heralded a poor prognosis.

A case report of a long-term survivor after inadvertent ligation of the left pulmonary artery during intended ductal ligation.

Background: Patent ductus arteriosus (PDA) can close on its own during childhood. Patent ductus arteriosus with left pulmonary artery (LPA) occlusion is rare. Here, we describe possible aetiologies of this condition and treatment strategies based on recent guidelines. Case summary: A 35-year-old man experienced shortness of breath for 20 years. Physical examination revealed pitting oedema, digital clubbing, and bi-phasic murmur along the left sternal border at the 2nd and 3rd intercostal space. Congenital heart disease was suspected. Echocardiography revealed a severely dilated pulmonary trunk and PDA; however, the LPA was not visible. The patient has undergone PDA ligation surgery >30 years ago, which may have caused accidental LPA ligation; however, extreme elevation of pulmonary pressure led to increased difficulties in performing LPA reconstruction and PDA division. Therefore, pulmonary arterial hypertension (PAH) initial combination therapy with parenteral prostanoids was prescribed. The patient's condition improved gradually. Discussion: Inadvertent ligation of the LPA instead of PDA is a rare and usually fatal complication during ductal ligation. Patients who survive this catastrophic complication usually develop the progressive pulmonary vascular disease with increased pulmonary pressure and impaired lung parenchyma resulting in right heart and respiratory failure. Early and regular follow-up with cardiac imaging studies is important to diagnose this complication. Reconstruction of the ligated LPA and PDA late in the disease course is difficult due to the development of pulmonary arterial hypertension. Initial PAH combination therapy may be valuable for relieving the patients' symptoms at that stage. Heart and lung transplantation can also be considered in suitable patients.