Risk Of Pulmonary Hypertension Research Articles

Abstract 4132249: Preoperative identification of respiratory viral genomes in the trachea but not in the nasopharynx is a risk factor for postoperative pulmonary hypertension in patients with congenital cardiac communications

Introduction: Pulmonary vascular remodeling is a key determinant of outcomes in patients undergoing surgery for congenital cardiac communications (CCCs). Respiratory epithelial cells infected by viruses express cytokines and growth factors with potential impact on airway and vascular remodeling. Hypothesis: Preoperative exposure to respiratory viruses renders CCC patients susceptible to postoperative pulmonary hypertension. Aims: To investigate if asymptomatic patients carrying respiratory viral genomes (RVGs) in the airways are at risk for pulmonary hypertension following cardiac surgery. To analyze the role of postoperative inflammatory reaction. Methods: The study comprised patients with unrestrictive CCCs undergoing surgery under cardiopulmonary bypass (CPB). In the absence of any signs of recent infection, RVGs were searched for in nasopharyngeal aspirates 2-3 days before surgery, and in tracheal aspirates collected in the operating room (RT-PCR, panel for 19 viruses). Serum levels of 36 inflammatory proteins were measured by chemiluminescence preoperatively and 4 hours post CPB. Pulmonary/systemic mean arterial pressure ratio (PAP/SAP) computed during the first 12 hours postoperatively (invasive assessment) was defined as the study outcome. A cutoff level was set at 0.40. Results: Sixty patients were enrolled (age 11 [7-16] months, median with interquartile range). Preoperative PAP/SAP was 0.78 (0.63-0.88). RVGs were present in nasopharyngeal and tracheal aspirates in 64% and 38% of patients, respectively. The presence of RVGs in tracheal aspirates was associated with an upward shift of postoperative PAP/SAP curve (p=0.006). The same was not observed for positive tests in nasopharyngeal aspirates (p=0.343). Of all factors analyzed as possible predictors of postoperative PAP/SAP >0.40, only preoperative peripheral oxygen saturation and the presence of RVGs in the trachea were selected at multivariate analysis (respective OR with 95% CI, 0.40 [0.23-0.72] and 4.42 [1.17-16.78]. Heightened post-CPB levels of interleukin-1 receptor antagonist and chemokines MIF and MCP-1 were found to increase the risk of having a PAP/SAP >0.40 in RVG carriers (respective OR with 95% CI, 2.04 [1.09-3.81], 2.34 [1.15-4.74] and 2.18 [1.07-4.43]. Conclusion: The observed relation of postoperative hemodynamics to respiratory viruses and post-CPB inflammatory reaction may have pathophysiological and therapeutic implications in pulmonary hypertension associated with congenital heart disease.

Increased risk of persistent pulmonary hypertension of the newborn in twin anaemia polycythaemia sequence donors.

Introduction This study aimed to describe the prevalence and risk factors for respiratory complications in monochorionic twins with twin anaemia polycythaemia sequence (TAPS). Methods All neonates diagnosed with postnatal TAPS at our centre between 2002 and 2023 were included in this retrospective study. The primary outcome was the prevalence of respiratory complications, including respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD) and persistent pulmonary hypertension of the newborn (PPHN). Secondary outcomes included need of respiratory support during admission and a risk-factor analysis for adverse respiratory outcome. Results In our study of 100 postnatally diagnosed TAPS pregnancies, 32% (62/199) experienced RDS and 13% (25/199) had BPD, with no difference between donors and recipients. PPHN occurred in 7% of cases, more frequently in donors (11%, 11/100) than in recipients (3%, 3/100) (OR = 1.3, 95%CI 0.2-2.6). Lower gestational age at birth and severe fetal anaemia were found to be significant independent risk factors associated with PPHN in TAPS twins (OR = 0.3, 95%CI 0.1-0.5), respectively (OR = 1.9, 95%CI 0.8-3.1). Conclusion TAPS donor twins have a four-fold increased risk of PPHN due to anaemia compared to recipient twins. Given the life-threatening nature of PPHN, TAPS twins should be born in hospitals equipped to treat it.

Derivation and internal validation of prediction models for pulmonary hypertension risk assessment in a cohort inhabiting Tibet, China.

Individuals residing in plateau regions are susceptible to pulmonary hypertension (PH) and there is an urgent need for a prediction nomogram to assess the risk of PH in this population. A total of 6603 subjects were randomly divided into a derivation set and a validation set at a ratio of 7:3. Optimal predictive features were identified through the least absolute shrinkage and selection operator regression technique, and nomograms were constructed using multivariate logistic regression. The performance of these nomograms was evaluated and validated using the area under the curve (AUC), calibration curves, the Hosmer-Lemeshow test, and decision curve analysis. Comparisons between nomograms were conducted using the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices. NomogramI was established based on independent risk factors, including gender, Tibetan ethnicity, age, incomplete right bundle branch block (IRBBB), atrial fibrillation (AF), sinus tachycardia (ST), and T wave changes (TC). The AUCs for NomogramI were 0.716 in the derivation set and 0.718 in the validation set. NomogramII was established based on independent risk factors, including Tibetan ethnicity, age, right axis deviation, high voltage in the right ventricle, IRBBB, AF, pulmonary P waves, ST, and TC. The AUCs for NomogramII were 0.844 in the derivation set and 0.801 in the validation set. Both nomograms demonstrated satisfactory clinical consistency. The IDI and NRI indices confirmed that NomogramII outperformed NomogramI. Therefore, the online dynamic NomogramII was established to predict the risks of PH in the plateau population.

Derivation and internal validation of prediction models for pulmonary hypertension risk assessment in a cohort inhabiting Tibet, China

Individuals residing in plateau regions are susceptible to pulmonary hypertension (PH) and there is an urgent need for a prediction nomogram to assess the risk of PH in this population. A total of 6603 subjects were randomly divided into a derivation set and a validation set at a ratio of 7:3. Optimal predictive features were identified through the least absolute shrinkage and selection operator regression technique, and nomograms were constructed using multivariate logistic regression. The performance of these nomograms was evaluated and validated using the area under the curve (AUC), calibration curves, the Hosmer–Lemeshow test, and decision curve analysis. Comparisons between nomograms were conducted using the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) indices. NomogramI was established based on independent risk factors, including gender, Tibetan ethnicity, age, incomplete right bundle branch block (IRBBB), atrial fibrillation (AF), sinus tachycardia (ST), and T wave changes (TC). The AUCs for NomogramI were 0.716 in the derivation set and 0.718 in the validation set. NomogramII was established based on independent risk factors, including Tibetan ethnicity, age, right axis deviation, high voltage in the right ventricle, IRBBB, AF, pulmonary P waves, ST, and TC. The AUCs for NomogramII were 0.844 in the derivation set and 0.801 in the validation set. Both nomograms demonstrated satisfactory clinical consistency. The IDI and NRI indices confirmed that NomogramII outperformed NomogramI. Therefore, the online dynamic NomogramII was established to predict the risks of PH in the plateau population.

Angiopoietin-2 and D-dimer add prognostic information to clinical risk in pulmonary arterial hypertension

Thrombosis and endothelial injury are pathologic hallmarks of pulmonary arterial hypertension (PAH). We aimed to evaluate whether markers of endothelial dysfunction and coagulation in the blood would provide insight into disease activity, treatment response, and outcomes in PAH. MethodsWe prospectively collected baseline and 3-month follow-up blood samples from treatment-naïve PAH patients (n=22) and those who had a clinical indication to intensify therapy (n=19). In addition, we recruited 12 healthy people and clinically stable PAH patients (n=45) as controls who had two blood samples collected twice within 14 days. We generated platelet-free plasma and measured D-dimer, angiopoietin-2, thrombin time, soluble P-selectin, von Willebrand factor, and vascular endothelial growth factor. We assessed treatment response with Reveal Lite 2 scores (all patients had NT-pro-BNP, 6-minute-walk, and functional class assessment at both visits) and followed clinical outcomes for 3 years. ResultsAngiopoietin-2 levels were elevated and fell with response to effective therapy (drop in Reveal Lite 2 score). At follow-up, persistently elevated angiopoietin-2 levels predicted clinical events and even identified low-risk participants who subsequently had events. D-dimer levels were also elevated in PAH patients but didn’t change in response to therapy. Several other abnormalities in endothelial and platelet activation were identified (including elevated soluble P-selectin, elevated von Willebrand factor, and elevated vascular endothelial growth factor) but these did not change with treatment or predict outcome. ConclusionsAngiopoietin-2 and D-dimer are elevated in PAH patients and may add prognostic information to routine clinical assessment.

Novel CMR-assessed right ventricular-pulmonary artery coupling index independently associates with exercise capacity and clinical risk in pulmonary arterial hypertension

Abstract Background We defined a novel noninvasive right ventricle (RV)–pulmonary artery (PA) coupling index as the ratio of cardiovascular magnetic resonance (CMR)-assessed RV direct flow (RVDF) and PA pulse wave velocity (PWV), and investigated its associations with exercise capacity and clinical risk in pulmonary arterial hypertension (PAH). Method 43 PAH patients (mean age 46±12 years, M:F 7:36) and 60 healthy volunteers (mean age 46±13 years, M:F 11:48) underwent CMR and cardiopulmonary exercise test (CPET) within one week. From cine CMR, RV ejection fraction (EF) and RV end-diastolic volume (RVEDV) were calculated using volumetric analysis; and tricuspid annular plane systolic excursion (TAPSE), feature tracking. PAPWV was the ratio of early systolic DPA flow and DPA area measured from instantaneous phase and magnitude through plane 2D flow CMR images across the pulmonary trunk, respectively. RVDF was the 4D flow CMR-assessed blood volume entering and exiting the RV in one cardiac cycle, indexed to RVEDV. RV-PA coupling was RVDF/PAPWV. Based on CPET-assessed peak oxygen consumption (PVO2), all 103 participants were stratified into two groups: PVO2>15 ml/kg/min; and PVO2≤15 ml/kg/min. Based on the REVEAL (Registry to Evaluate Early and Long-term PAH Disease Management) 2.0 score, the 43 PAH patients were stratified into low risk (score ≤6) and intermediate to high risk (score >6) groups. Results RVDF/PAPWV was significantly lower in PAH vs. controls (7.9 vs. 20.4 %/(m/s), P<0.001); and in PAH patients with intermediate to high risk vs. low risk (4.6 vs. 9.4 %/(m/s), P=0.001). On multivariable analyses, RVDF/PAPWV was an independent predictor of PVO2≤15 ml/kg/min (=0.302, P=0.001) among all participants, and of REVEAL 2.0 score >6 (=0.621, P=0.009) among PAH patients. Compared to RVEF and TAPSE, RVDF/PAPWV had numerically higher discrimination (p values non-significant based on Delong test) for PVO2≤15 ml/kg/min (AUC=0.914 vs. 0.872, 0.843); and among PAH patients, REVEAL 2.0 score >6 (AUC=0.851 vs. 0.723 and 0.728) (Figure). Conclusion CMR-derived noninvasive RVDF/PAPWV independently associates with exercise capacity and PAH clinical risk, supporting its utility as an imaging marker of disease progression and therapeutic response.

Echocardiographic insights redefining risk in pulmonary arterial hypertension: a focus on right atrial volume index for enhanced stratification

Abstract Introduction In Pulmonary arterial hypertension (PAH), the right atrium plays a critical role, and its size, determined by echocardiography, is crucial for risk stratification. Despite this, current guidelines still prioritize right atrial area (RAA) over the right atrial volume index (RAVI). This approach is contrary to the recommendations of international echocardiography societies since 2016, which advocate for the use of RAVI for a more accurate assessment. Purpose Identify the RAVI value corresponding to the RAA, in PAH risk stratification used in the 2022 ESC guidelines. Methods We conducted a retrospective analysis of all consecutive patients of a single-center, since 2002. Patient's echocardiograms were revised for simultaneous assessment of RAA and right atrial volume index (RAVI). Over an average follow-up of 6.7 years (SD 5.9), we recorded a cohort of 82 patients diagnosed with PAH. From this group, we excluded 27 patients with congenital etiologies, 14 due to the insufficient quality of echocardiographic data, and one patient identified as an extreme statistical outlier. A Pearson's correlation analysis was used to access the correlation between RAA and RAVI for PAH diagnosis. Results A total of 40 patients were included with a mean age at diagnosis of 48.85 years (SD 17.82), predominantly female (77.5 %). The most prevalent etiologies were idiopathic (32.5%) and connective tissue disease-associated PAH (27.5%). Clinical presentations included right heart failure signs in 30% of patients, rapid symptom progression in 12.5%, syncope history in 15% and 77.5% in WHO-FC III-IV. Average 6-MWD and NT-proBNP levels were 392,1 m (SD 120,2) and 1636,18 ng/L (SD 2576,14), respectively. Average hemodynamics parameters were right atrial pressure 7,39 mmHg (SD 4,940); cardiac index 2,28 L/min/m2 (SD 2,06); stroke volume index 3,38 mL/m2 (SD 3,92) and mixed venous oxygen saturation 65,68% (SD 10,86). Average echocardiographic parameters were RAA 20,14 cm2 (SD 4,80); TAPSE/sPAP 0,34 mm/mmHg (SD 0,18) and RAVI 37,78 mL/m2 (SD 13,67), with 10% of pericardial effusion. Statistical analysis revealed a strong and significant correlation between RAA and RAVI (r=0.82, 95% CI: 0.69-0.90, p<0.001). The derived linear relationship is expressed as "y=2.8*X -18". Therefore, an RAA value of 18 cm² translates to a RAVI of 32 mL/m², while an RAA of 26 cm² corresponds to a RAVI of 55 mL/m². Conclusion Our study supports a revision in HAP risk assessment guidelines, suggesting a shift to a more comprehensive approach using right atrial volume index (RAVI) measurements. We propose categorizing risk as low for RAVI < 32 mL/m², intermediate for RAVI between 32 and 55 mL/m², and high for RAVI > 55 mL/m². This recommendation aligns with the standards of international societies and is grounded in best clinical practices, considering that indexing measurements of the right atrium to body size potentially offers greater accuracy than absolute values.

Comparison of pulmonary arterial risk assessment tools to predict mortality or morbidity in treatment naive and previously diagnosed patients

Abstract Background Pulmonary arterial hypertension (PAH) risk stratification (1-year prediction of risk) is crucial and should be the most accurate to ensure appropriate aggressiveness of the treatment choices. According to the European guidelines, several risk tools can be used both at baseline and/or follow-up assessment. Yet, a comparison of risk tools performances only in treatment-naïve or only previously diagnosed patients is still missing. Aims To compare the available risk assessment tools performances to predict 1-year mortality but also 1-year clinical worsening in treatment-naïve and previously diagnosed PAH patients. Methods Eight PAH trials (AMBITION, ARIES1, ARIES2, FREEDOM, GRIPHON, PATTENT, PHIRST and SERAPHIN) provided by the FDA were harmonized and treatment-naïve patients were separated from previously diagnosed patients. Outcomes were 1-year mortality and 1-year clinical worsening (i.e., morbidity) either from baseline assessment or at follow-up. Kaplan-Meier and log-rank tests were performed for each of the following risk tools: European 4-strata, REVEAL2.0, REVEAL Lite, noninvasive FRENCH. In each subgroup, their C-indices were calculated and compared using a total of 100 bootstrap samples from the original data, providing a robust method for comparing across the different tools. Results Among the 4,122 patients included, 1,701 (41%) were treatment-naïve and 2,411 (59%) were previously diagnosed patients. Compared to treatment naïve patients, previously diagnosed patients were younger (p<0.001), with lower level of natriuretic peptide (p=0.013), higher 6MWD (p<0.001) and higher mPAP (p<0.001). At 1-year, the mortality rate was the same in the 2 subgroups (5.6% 5.1%, p=0.05) but clinical worsening occurred more often among previously diagnosed patients (19% vs 8.4%, p<0.001). Each of the risk tools were able to predict both 1-year mortality or morbidity in each subgroup, especially among previously diagnosed or at follow-up, with fair to good C-index (Figure 1). Forrest plots of 95%CI for the C-index differences among the 100 bootstrap samples showed that REVEAL 2.0 was the best performer, followed by REVEAL Lite (Figure 2). Conclusions In this large dataset, we showed that all PAH risk tools were able to predict not only 1-year mortality but also 1-year morbidity, both in treatment naïve and previously diagnosed patients. REVEAL 2.0 depicted the higher C-index.Figure 1.C-index for PAH risk toolsFigure 2.Forrest plots of 95%CI

Efficacy and tolerability of triple sequential combination therapies with selexipag in patients with pulmonary arterial hypertension: insights from a single-centre study

Abstract Background and aims In this single-centre study we aimed to evaluate the efficacy and tolerability of prostacyclin receptor agonist selexipag in patients with pulmonary arterial hypertension (PAH). Methods The study included 110 out of the 1071 patients enrolled in the Evaluation of Pulmonary Hypertension Risk factors Associated with Survival study (EUPHRATES) and treated with selexipag added on background dual PAH therapies. The ESC/ERS 2022, SPAHR, French Registry, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Results Age (mean+SD) was 43.4+16.5 years and 84.5 % of patients were female. The PAH was idiopatic, and was associated with congenital heart disease (CHD), connective tissue disease (CTD) and drug in 47.2 %, 46.4 %, 5.5 % and 1 %, respectively. Background dual therapies, functional class (FC) was II, III and IV in 20 %, 65 %, and 15 % of patients. Six-minute walk distance (6MWD) was 314 + 134 m and serum N-terminal-pro-brain natriuretic peptide (NT-proBNP) level was 882+1732 ng/l. Tricuspid annular planary excursion (TAPSE) and tissue velocity (St), right atrial area and pulmonary arterial diameter were 2.02+0.48 cm,12.4+2.8 cm/sec,21.4+7.2 cm2 and 3.54+0.77 cm, respectively. Invasively evaluated pulmonary arterial mean pressure was 60.2±19.9 mm Hg, and pulmonary vascular resistance was 12.3±10.8 Wood units. COMPERA 2.0 1st, 2nd, 3rd and 4th risk strata were noted in 15.5 %, 31.8 %, 2.7 % and 10 %, and French Registry strata 0,1,2 and 3 were documented in 70 %, 14.5 %, 11 %, and 4.5 %, respectively. The SPAHR and REVEAL Lite 2 scores were 1.9+0.5 and 5.9+2.6, respectively. Background combinations were as follows; macitentan+tadalafil in 46.6 %, macitentan+sildenafil in13.6 %, macitentan+ riociguat in 6.8 %, bosentan +tadalafil in 8.7 %, bosentan+sildenafil in 16.5 %, bosentan+riociguat in 1 %, ambrisentan +tadalafil in 1.9 %, and ambrisentan+sildenafil in 2.9 % of patients. Maximally tolerable selexipag doses (ug)were 1600 bid in 21%, 1400 bid in 5 %, 1200 bid in 11%, 1000 bid in 17%, 800 bid in 12%, 600 bid in 9%, 400 bid in 14%, and 200 bid in 11%.Median follow-up period was 527( 278-831) days, and discontiuation rates of selexipag was 13.6 %. Headache, jaw-pain, diarrhoea, nausea, vomiting and flushing were main side effects. The changes in FC, 6MWD, Nt-pro-BNP and echocardiographic measures were not significant. French Registry score (p<0.001) and COMPERA 2.0 score (p<0.001) showed improvements, but SPAHR and REVEAL lite 2 did not. However, other PAH cohort compared with IPAH showed more pronounced improvements in REVEAL lite 2 and SPAHR scores. Clinical worsening and mortality rates were 23.6 % and 10.9 %, respectively. Survival for 1, 3 and 5 years were 95.8 %, 95.8 and 83.7 % in IPAH, and 92.6 %, 84.1 % and 78.8 % in other PAH patients. Conclusion Our results seem to be consistent with efficacy and tolerability of selexipag-included combinations in patients with PAH.

Changing patterns in clinical, echocardiographic and haemodynamic characteristics, and management strategies that may be translated to improved survival in pulmonary hypertension

Abstract Background and aims In this retrospective analysis of a single-center series on pulmonary hypertension (PH), we aimed to evaluate clinical, echocardiographic, and hemodynamic characteristics, management strategies, morbidity, and mortality in PH subgroups across three consecutive periods. Methods The study included 1071 patients enrolled in the Evaluation of Pulmonary Hypertension Risk factors Associated with Survival study (EUPHRATES). In reference to enrollment time, patients were assessed in three periods ; before 2016, the era of primarily monotherapy or sequential combinations; between 2016 and 2019, post-approval and reimbursement of macitentan in our country, marking a shift towards more proactive sequential combinations; and after 2019, signifying the initiation of earlier sequential combinations with selexipag in pulmonary arterial hypertension (PAH). The ESC/ERS 2022 risk scoring, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Annual incidence curves for mortality and CEP were evaluated, but 2020 analysis was adjusted to account for the possible adverse effects of the COVID-19. Results During the 1st, 2nd and 3rd periods, 481, 352, and 238 patients with PH were diagnosed, respectively. Incident cases comprised 91% of them. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), group II, III, IV and V PH were documented in 24 %, 28 %, 4.6 %, 4.3 %, 11%, 27 % and 0.7 % of patients, respectively. Age and female dominance remained unchanged. Incidences of Group 1 PH and CHD-PAH decreased while IPAH, drug-associated PAH, and Group II and IV PH increased across three periods (p-values varying from <0.001 to 0.03). Although baseline functional class became worse (p=0.013), six-minute walk distance, N-terminal pro brain natriuretic peptide and risk scores showed no change (p=NS). Baseline echo and hemodynamic measures became better, and triple combinations increased after 2019 (p<0.001 for all). For overall PH, rates of all-cause mortality and CEPs at 1st, 2nd and 3rd periods were 52 % and 59 %, 30 % and 35 %, and 11 % and 13 %, respectively (p< 0.001, for all). Mortality rates for 1st, 2nd and 3rd periods were 36 %, 38 % and 26 % in IPAH, 60 %, 28 % and 13 % in CHD-PAH, 55 %, 22% and 22% in CTD-PAH, 38 %, 38% and 24 % in group IV PH, respectively (p< 0.001, for all). Mortality curves showed sudden increases in 2020, but excluding 2020, a steady improvement in the annual mortality was evident. Conclusions Our findings suggest a trend towards better clinical, echocardiographic, and hemodynamic presentations and improved survival in the PAH subgroups, and Group IV PH across the three periods that might be attributed to more proactive management strategies favouring earlier initiation of combinations.

High-Sensitivity Cardiac Troponin [hs-cTn] as a Valuable Biomarker for Pulmonary Hypertension Risk Stratification: A Contemporary Review of the Literature.

Background: Pulmonary hypertension (PH) can lead to cardiac failure, thereby significantly affecting life expectancy and quality of life. Due to inadequate disease surveillance and risk assessment, clinical challenges persist despite advances in diagnosis and treatment. We aimed to review the potential of high-sensitivity cardiac troponin (hs-cTn) as a biomarker for predicting outcomes in PH patients. Methods: A thorough examination of the PubMed and Google Scholar databases was conducted through March 2023. Studies involving adult PH patients and hsTn as a prognostic indicator of outcomes such as mortality, hospitalization, and disease progression were included, after screening their titles and abstracts. Two independent evaluators extracted data, with the quality assessed using the JBI critical appraisal tool. Results: This review uncovered eight studies that examined the prognostic value of hs-cTn in PH patients. Higher hs-cTn levels were associated with increased mortality and hospitalization rates, according to the studies. The severity of PH, cardiac dysfunction, right ventricular function, and systolic dysfunction were associated with hs-cTn. Multiple studies have demonstrated that hsTn has the potential to identify high-risk PH patients who could benefit from targeted therapies and increased clinical monitoring. Conclusions: This review suggests that hsTn may be a biomarker for PH risk stratification and prognosis. Across PH subtypes, elevated hsTn levels predict poor outcomes. However, large-scale prospective studies are needed to confirm hs-cTn's function in diagnosing pulmonary hypertension and determine its potential value in treatment.

Longitudinal echocardiographic parameters for evaluation of pulmonary hypertension in preterm infants with very low birth weight.

Echocardiography is essential for the evaluation of pulmonary hypertension. We determined the feasible quantitative parameter for screening and monitoring pulmonary hypertension in preterm infants. This secondary analysis of a prospective cohort single-centre study was conducted between August 2019 and September 2020. Serial echocardiography was performed 7 and 28 days after birth and at 36 weeks postmenstrual age. The data of infants who developed pulmonary hypertension at 36 weeks postmenstrual age were compared with those without pulmonary hypertension. We also modelled the parameters' trend and performed an interaction test using multi-level Gaussian regression. Out of 30 infants enrolled in the study, 79 echocardiograms were analysed. Left ventricular eccentric index was obtainable in all infants, while tricuspid jet velocity was measurable in 44.1%. Left ventricular eccentric index correlated well with tricuspid regurgitation jet velocity (r = 0.77, P < 0.001). Six infants were diagnosed with newly developed or persistent pulmonary hypertension at 36 weeks postmenstrual age. Serial left ventricular eccentric index showed a significantly different increasing trend in the pulmonary hypertension group (change per day: +0.004; P = 0.090) from the decreasing trend among a non-pulmonary hypertension group (change per day: -0.001; P = 0.041) (P for interaction = 0.007). Right ventricular systolic function and right ventricular isovolumic systolic velocity revealed a reducing trend in the pulmonary hypertension group, which was different from the improving trend in non-pulmonary hypertension infants. Infants with low current weight, low postmenstrual age, and requiring high-flow oxygen therapy at day 28 of life trended to increase the risk of late pulmonary hypertension. Left ventricular eccentric index and right ventricular isovolumic systolic velocity were feasible for assessing pulmonary hypertension and should be incorporated into pulmonary hypertension evaluation. Serial left ventricular eccentric index and right ventricular isovolumic systolic velocity may help predict late pulmonary hypertension and early detection of right ventricular dysfunction.

Cancer as an Independent Mortality Risk in Chronic Thromboembolic Pulmonary Hypertension

BackgroundThe management of chronic thromboembolic pulmonary hypertension (CTEPH) has advanced significantly in recent years, thereby improving patient prognosis. However, the impact of cancer on the outcomes of patients with CTEPH under current treatment remains unclear. This study aimed to investigate the prevalence of cancer in patients with CTEPH and determine how comorbid cancer affects their prognosis and clinical course. MethodsData from an ongoing Japanese prospective cohort study were analyzed. Prevalence and primary cancer sites were evaluated. The association of a history of cancer with a composite endpoint, including all-cause death, lung transplantation, and worsening of CTEPH, as well as venous thromboembolism and bleeding events, was assessed. ResultsOf the 1,270 patients in the cohort, 134 (10.6%) had a history of cancer, with the most common primary sites being the breast in women and the prostate in men. The incidence of composite outcome and all-cause death was higher in those with a history of cancer (p<0.001, log-rank test). In the Cox proportional hazard model, age- and sex-adjusted hazard ratios for the composite outcome and all-cause death were 2.69 (95% confidence interval, 1.48–4.89, p=0.001) and 4.25 (95% confidence interval, 1.98–9.10, p<0.001), respectively, for patients with a history of cancer. No significant differences in venous thromboembolism and bleeding events were observed between patients with and those without a history of cancer. ConclusionsA history of cancer, with a prevalence of 10.6%, is an independent risk factor for mortality in patients with CTEPH undergoing the currently recommended treatment.

G6pdN126D Variant Increases the Risk of Developing VEGFR (Vascular Endothelial Growth Factor Receptor) Blocker-Induced Pulmonary Vascular Disease.

G6PD (glucose-6-phosphate-dehydrogenase) is a key enzyme in the glycolytic pathway and has been implicated in the pathogenesis of cancer and pulmonary hypertension-associated vascular remodeling. Here, we investigated the role of an X-linked G6pd mutation (N126D polymorphism), which is known to increase the risk of cardiovascular disease in individuals from sub-Saharan Africa and many others with African ancestry, in the pathogenesis of pulmonary hypertension induced by a vascular endothelial cell growth factor receptor blocker used for treating cancer. CRISPR-Cas9 genome editing was used to generate the G6pd variant (N126D; G6pdN126D) in rats. A single dose of the vascular endothelial cell growth factor receptor blocker sugen-5416 (SU; 20 mg/kg in DMSO), which is currently in a Phase 2/3 clinical trial for cancer treatment, was subcutaneously injected into G6pdN126D rats and their wild-type littermates. After 8 weeks of normoxic conditions, right ventricular pressure and hypertrophy, pulmonary artery remodeling, the metabolic profile, and cytokine expression were assessed. Right ventricular pressure and pulmonary arterial wall thickness were increased in G6PDN126D+SU/normoxic rats. Simultaneously, levels of oxidized glutathione, inositol triphosphate, and intracellular Ca2+ were increased in the lungs of G6PDN126D+SU/normoxic rats, whereas nitric oxide was decreased. Also increased in G6PDN126D+SU/normoxic rats were pulmonary levels of plasminogen activator inhibitor-1, thrombin-antithrombin complex, and expression of proinflammatory cytokines CCL3 (chemokine [C-C motif] ligand), CCL5, and CCL7. Our results suggest G6PDN126D increases inositol triphosphate-Ca2+ signaling, inflammation, thrombosis, and hypertrophic pulmonary artery remodeling in SU-treated rats. This suggests an increased risk of vascular endothelial cell growth factor receptor blocker-induced pulmonary hypertension in those carrying this G6PD variant.

Biomarker screening for pulmonary hypertension in VLBW infants at risk for bronchopulmonary dysplasia.

Very low birth weight (VLBW) infants demonstrate altered alveolar and pulmonary vascular development and carry an increased risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Risk stratification for BPD-associated PH (BPD-PH) in at-risk infants may help tailor management, improve outcomes, and optimize resource utilization. VLBW infants were screened for PH with blood gas measurements, serum NT-proBNP and bicarbonate (HCO3) levels, and echocardiograms if they remained on respiratory support at 34 weeks corrected gestational age. We then tested 11 models using different cutoffs for NT-proBNP and HCO3 to predict infants at low risk of BPD-PH. We identified PH in 34 of 192 (17.6%) VLBW infants. The median NT-proBNP in VLBWs with PH was 2769 pg/mL versus 917 pg/mL in those without PH (p < 0.0001). A model with NT-proBNP < 950 pg/mL and HCO3 < 32 mmol/L had a sensitivity of 100%, specificity of 34.2%, and negative predictive value of 100%. Using this model, 54 of 192 (28%) of the patients in this study would have been categorized as low risk for PH and could have avoided a screening echocardiogram. NT-proBNP and HCO3 together may serve as sensitive and cost-effective screening tools for BPD-PH in VLBW infants. NT-proBNP and HCO3 concentrations obtained together may help identify very low birth weight infants at risk for bronchopulmonary dysplasia who should undergo screening for pulmonary hypertension with echocardiography. This large dataset demonstrates that NT-proBNP and HCO3 levels together are more sensitive than NT-proBNP alone in identifying VLBW infants to undergo echocardiography. The combination of NT-proBNP and HCO3 levels may identify VLBW infants at low risk for pulmonary hypertension and thus those who may be able to avoid screening echocardiography.

Non-invasive prediction of pulmonary vascular disease-related exercise intolerance and survival in non-group 1 pulmonary hypertension.

The clinical utility of pulmonary hypertension (PH) risk scores in non-group 1 PH with pulmonary vascular disease (PVD) remains unresolved. We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH-related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c-statistic to predict death was compared separately in (i) pre-capillary PH groups 3/4/5, and (ii) combined post- and pre-capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular-pulmonary artery (RV-PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c-statistic for predicting death (0.699, 95% confidence interval [CI] 0.660-0.737, p < 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656-0.734, p < 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c-statistic difference -0.072, 95% CI -0.123 to -0.020, p = 0.006, and -0.043, 95% CI -0.067 to -0.018, p = 0.0007, respectively). RV function and RV-PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p > 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non-invasively identified non-group 1 PH with more advanced PVD with worse exercise capacity, RV-PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p < 0.05 for all). Non-invasive REVEAL risk predicts mortality in non-group 1 PH without incremental prognostic value from detailed RV function or RV-PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non-invasively identifies greater pulmonary vascular dysfunction and right heart-related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non-group 1 PH.

Pulmonary vascular diseases at high altitude - is it safe to live in the mountains?

This review addresses the concern of the health effects associated with high-altitude living and chronic hypoxia with a focus on pulmonary hypertension. With an increasing global population residing at high altitudes, understanding these effects is crucial for public health interventions and clinical management. Recent literature on the long-term effects of high-altitude residence and chronic hypoxia is comprehensively summarized. Key themes include the mechanisms of hypoxic pulmonary vasoconstriction, the development of pulmonary hypertension, and challenges in distinguishing altitude-related pulmonary hypertension and classical pulmonary vascular diseases, as found at a low altitude. The findings emphasize the need for research in high-altitude communities to unravel the risks of pulmonary hypertension and pulmonary vascular diseases. Clinically, early and tailored management for symptomatic individuals residing at high altitudes are crucial, as well as access to advanced therapies as proposed by guidelines for pulmonary vascular disease. Moreover, identifying gaps in knowledge underscores the necessity for continued research to improve understanding and clinical outcomes in high-altitude pulmonary vascular diseases.

Cardiac Disease in Egyptian Thalassemia Major and Sickle Cell Disease Adolescents in relation to Vitamin D Status Using Echocardiogram &amp; Ultrafast Magnetic Resonance Imaging

Abstract Background Cardiovascular complications are well recognized in patients with β-thalassemia major (β-TM) and sickle cell disease (SCD). Vitamin D deficiency is prevalent in patients with transfusion-dependent thalassemia and there is an association between vitamin D deficiency and both left ventricular function and iron overload in thalassemia. However, the relationship between vitamin D and cardiac iron is not well studied in Egypt and the role of vitamin D in cardiac disease in SCD and β-TM needs to be assessed. Aim To assess vitamin D status in children and adolescents with SCD and β-TM in relation to cardiac complications using echocardiography and cardiac magnetic resonance (CMR) T2*. Methods Forty-one patients with SCD and 35 patients with β-TM without symptomatic cardiac disease were studied stressing on history of splenectomy and transfusion history. Markers of hemolysis, serum ferritin and vitamin D levels were measured. Liver iron concentration (LIC) was assessed by magnetic resonance imaging (MRI). Screening for cardiovascular abnormalities was performed by the non-invasive Doppler echocardiography and CMR was used to assess myocardial iron overload. Results Echocardiography showed that cardiac functions were significantly impaired in β-TM patients compared with SCD while the frequency of pulmonary hypertension risk (elevated TRV ≥2.5 m/sec) was consistent between both β-TM and SCD groups. Cardiac T2* (which reflects cardiac iron overload) was significantly lower while myocardial iron concentration (MIC) was significantly higher in β -TM patients compared with SCD group. Vitamin D levels were decreased in both SCD and β-TM patients than control levels; however, SCD patients had significantly lower vitamin D levels. Low vitamin D levels were significantly associated withincreased risk of pulmonary hypertension in the SCD group while In β-TM group, vitamin D levels were significantly lower in patients with cardiac disease and those with serum ferritin levels ≥ 2500 µg/L. A significant evidence of diastolic dysfunction was found in SCD and β-TM patients who had low serum vitamin D level &amp;lt; 20 ng/mL. Vitamin D levels were negatively correlated to serum ferritin and LIC while positively correlated to cardiac T2*. Conclusion Low vitamin D levels were associated with cardiopulmonary dysfunction in adolescents with SCD and β-TM. Vitamin D deficiency in those patients was linked to cardiac iron overload leading to iron induced cardiomyopathy. Proper chelation therapy is mandatory to improve cardiac disease, iron overload and consequently, vitamin D status in β-TM patients.

An analysis of exogenous harmful substance exposure as risk factors for COPD and hypertension co-morbidity using PSM.

Some occupational and environmental exposures could increase the risk of chronic obstructive pulmonary disease (COPD) and hypertension in various work and living environments. However, the effect of exposure to multiple exogenous harmful substances on COPD and hypertension co-morbidities remains unclear. Participants were selected from eight hospitals in five provinces in China using a multistage cluster sampling procedure. Participants' demographic, exposure, and disease information were collected through questionnaires, spirometry, and blood pressure examinations. Demographic data were used as matching factors, and 1:1 matching between the exposed and non-exposed groups was performed by employing propensity score matching (PSM) to minimize the influence on the results. A one-way chi-squared analysis and multifactorial logistic regression were used to analyze the association between the exposure to exogenous harmful substances (metals and their compound dust, inorganic mineral dust, organic chemicals, and livestock by-products) and the co-morbidity of COPD and hypertension. There were 6,610 eligible participants in the final analysis, of whom 2,045 (30.9%) were exposed to exogenous harmful substances. The prevalence of co-morbidities of COPD and hypertension (6.0%) in the exposure group was higher than their prevalence in the total population (4.6%). After PSM, exogenous harmful substance exposure was found to be a risk factor for the co-morbidity of COPD and hypertension [odds ratio (OR) = 1.347, 95% confidence interval (CI): 1.011-1.794], which was not statistically significant before PSM (OR = 1.094, 95% CI: 0.852-1.405). Meanwhile, the results of different outcomes showed that the association between hypertension and exogenous harmful substance exposure was not statistically significant (OR = 0.965, 95% CI: 0.846-1.101). Smoking (OR = 4.702, 95% CI: 3.321-6.656), history of a respiratory disease during childhood (OR = 2.830, 95% CI: 1.600-5.006), and history of respiratory symptoms (OR = 1.897, 95% CI: 1.331-2.704) were also identified as risk factors for the co-morbidity of COPD and hypertension. The distribution of exogenous harmful substance exposure varies in the population, and the prevalence of co-morbidities is generally higher in susceptible populations. Exposure to exogenous harmful substances was found to be a key risk factor after adjusting for demographic confounders.

Meconium Aspiration Syndrome, Hypoxic-Ischemic Encephalopathy and Therapeutic Hypothermia-A Recipe for Severe Pulmonary Hypertension?

Hypoxic-ischemic encephalopathy (HIE) is the leading cause of mortality among term newborns globally. Infants born through meconium-stained amniotic fluid are at risk of developing meconium aspiration syndrome (MAS) and HIE. Simultaneous occurrence of MAS and HIE is a perilous combination for newborns due to the risk of persistent pulmonary hypertension of the newborn (PPHN). Moreover, therapeutic hypothermia (TH), which is the current standard of care for the management of HIE, may increase pulmonary vascular resistance (PVR) and worsen PPHN. Infants with MAS and HIE require close cardiorespiratory and hemodynamic monitoring for PPHN. Therapeutic strategies, including oxygen supplementation, ventilation, use of surfactant, inhaled nitric oxide and other pulmonary vasodilators, and systemic vasopressors, play a critical role in the management of PPHN in MAS, HIE, and TH. While TH reduces death or disability in infants with HIE, infants with MAS and HIE undergoing TH need close hemodynamic monitoring for PPHN.