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.

Serum PM20D1 levels in patients with idiopathic pulmonary arterial hypertension and its clinical significance.

OBJECTIVE: This study aimed to investigate the serum levels of Peptidase M20 domain containing 1 (PM20D1) in idiopathic pulmonary arterial hypertension (IPAH) patients and examine its association with lipid metabolism, echocardiography, and hemodynamic parameters. METHODS: This prospective observational research enrolled 103 IPAH patients from January 2018 to January 2022. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum PM20D1 levels in all patients before treatment within 24 h of admission. Demographic data, echocardiography, hemodynamic parameters and serum biomarkers were also collected. RESULTS: The IPAH patients in the deceased group had significantly elevated age, right atrial (RA), mean pulmonary arterial pressure (mPAP), mean right atrial pressure (mRAP), pulmonary capillary wedge pressure (PCWP), pulmonary vascular resistance (PVR) and significantly decreased 6 min walking distance (6MWD) and tricuspid annulus peak systolic velocity (TASPV). IPAH patients showed significant decreases in serum PM20D1, low-density lipoprotein cholesterol (LDL-C), and albumin (ALB). Additionally, PM20D1 was negatively correlated with RA, NT-proBNP and positively correlated with PVR, ALB, 6MWD, and TAPSV. Moreover, PM20D1 has the potential as a biomarker for predicting IPAH patients' prognosis. Finally, logistic regression analysis indicated that PM20D1, ALB, NT-proBNP, PVR, TASPV, RA and 6MWD were identified as risk factors for mortality in IPAH patients. CONCLUSION: Our findings indicated that the serum levels of PM20D1 were significantly decreased in IPAH patients with poor prognosis. Moreover, PM20D1 was identified as a risk factor associated with mortality in IPAH patients.

Fractional exhaled nitric oxide in idiopathic pulmonary arterial hypertension and mixed connective tissue disease complicating pulmonary hypertension.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) has been extensively studied in various causes of pulmonary hypertension (PH), but its utility as a noninvasive marker remains highly debated. The objective of our study was to assess FeNO levels in patients with idiopathic pulmonary arterial hypertension (IPAH) and mixed connective tissue disease complicating pulmonary hypertension (MCTD-PH), and to correlate them with respiratory functional data, disease severity, and cardiopulmonary function. METHODS: We collected data from 54 patients diagnosed with IPAH and 78 patients diagnosed with MCTD-PH at the Shanghai Pulmonary Hospital Affiliated to Tongji University. Our data collection included measurements of brain natriuretic peptide (pro-BNP), cardiopulmonary exercise test (CPET), pulmonary function test (PFT), impulse oscillometry (IOS), and FeNO levels. Additionally, we assessed World Health Organization functional class (WHO-FC) of each patient. RESULTS: (1) The fractional exhaled concentration of nitric oxide was notably higher in patients with IPAH compared to those with MCTD-PH. Furthermore, within the IPAH group, FeNO levels were found to be lower in cases of severe IPAH compared to mild IPAH (P = 0.024); (2) In severe pulmonary hypertension as per the WHO-FC classification, FeNO levels in IPAH exhibited negative correlations with FEV1/FVC (Forced Expiratory Velocity at one second /Forced Vital Capacity), MEF50% (Maximum Expiratory Flow at 50%), MEF25%, and MMEF75/25% (Maximum Mid-expiratory Flow between 75% and 25%), while in severe MCTD-PH, FeNO levels were negatively correlated with R20% (Resistance at 20 Hz); (3) ROC (Receiving operator characteristic curve) analysis indicated that the optimal cutoff value of FeNO for diagnosing severe IPAH was 23ppb; (4) While FeNO levels tend to be negatively correlated with peakPETO2(peak end-tidal partial pressure for oxygen) in severe IPAH, in mild IPAH they had a positive correlation to peakO2/Heart rate (HR). An interesting find was observed in cases of severe MCTD-PH, where FeNO levels were negatively correlated with HR and respiratory exchange ratio (RER), while positively correlated with O2/HR throughout the cardiopulmonary exercise test. CONCLUSION: FeNO levels serve as a non-invasive measure of IPAH severity. Although FeNO levels may not assess the severity of MCTD-PH, their significant makes them a valuable tool when assessing severe MCTD-PH.

[Genetic diagnostics and molecular approaches in pulmonary arterial hypertension]. / Genetische Diagnostik und molekulare Ansätze bei pulmonalarterieller Hypertonie.

The recently published new European guidelines for diagnosis and treatment of pulmonary hypertension now offer the so far most extensive description of genetic testing and counselling for pulmonary arterial hypertension patients. In addition, the importance of a clinical screening of healthy mutation carriers is highlighted as well as the genetic testing of patients with a suspicion of pulmonary veno-occlusive disease. We frame the respective parts of the guidelines on genetic testing and counselling in the context of recent data and provide comments. Finally, we give an outlook on novel molecular approaches starting from Sotatercept, addressing ion channels and novel therapeutic developments.

[Genetic counselling and testing in pulmonary arterial hypertension - A consensus statement on behalf of the International Consortium for Genetic Studies in PAH - French version]. / Conseil génétique et dépistage de l'hypertension artérielle pulmonaire ­ consensus du Consortium international pour les études génétiques dans l'HTAP ­ version française.

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.

Heritable Pulmonary Arterial Hypertension Diagnosed during the Postpartum Period: A Case Report and Literature Review.

Approximately one-third of bone morphogenic protein receptor-2 (BMPR2) mutation carriers develop pulmonary arterial hypertension (PAH), which indicates that additional risk factors are needed for the manifestation of the disease. It is questionable whether pregnancy is a risk factor for PAH development in these patients. We represent a 30-year-old woman with a heterozygous BMPR2 mutation who was diagnosed with PAH during the postpartum period and reviewed the literature in this report. We also discussed the possible underlying mechanisms that might have resulted in PAH development during pregnancy in BMPR2 mutation carriers.

Impact of diabetes mellitus on disease severity and patient survival in idiopathic pulmonary arterial hypertension: data from the Polish multicentre registry (BNP-PL).

BACKGROUND: Recent studies revealed that alterations in glucose and lipid metabolism in idiopathic pulmonary arterial hypertension (IPAH) are associated with disease severity and poor survival. However, data regarding the impact of diabetes mellitus (DM) on the prognosis of patients with IPAH remain scarce. The aim of our study was to determine that impact using data from a national multicentre prospective pulmonary hypertension registry. METHODS: We analysed data of adult patients with IPAH from the Database of Pulmonary Hypertension in the Polish population (BNP­PL) between March 1, 2018 and August 31, 2020. Upon admission, clinical, echocardiographic, and haemodynamic data were collected at 21 Polish IPAH reference centres. The all-cause mortality was assessed during a 30-month follow-up period. To adjust for differences in age, body mass index (BMI), and comorbidities between patients with and without DM, a 2-group propensity score matching was performed using a 1:1 pairing algorithm. RESULTS: A total of 532 patients with IPAH were included in the study and 25.6% were diagnosed with DM. Further matched analysis was performed in 136 patients with DM and 136 without DM. DM was associated with older age, higher BMI, more advanced exertional dyspnea, increased levels of N-terminal pro-brain natriuretic peptide, larger right atrial area, increased mean right atrial pressure, mean pulmonary artery pressure, pulmonary vascular resistance, and all-cause mortality compared with no DM. CONCLUSIONS: Patients with IPAH and DM present with more advanced pulmonary vascular disease and worse survival than counterparts without DM independently of age, BMI, and cardiovascular comorbidities.

Single-Cell Transcriptome Analysis of Peripheral Neutrophils From Patients With Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND: Idiopathic pulmonary hypertension (IPAH) is a rare and devastating disease often accompanied by persistent inflammation and immune responses. We aim to provide a reference atlas of neutrophils to facilitate a better understanding of cellular phenotypes and discovery of candidate genes. METHODS: Peripheral neutrophils from naive patients with IPAH and matched controls were profiled. Whole-exon sequencing was performed to exclude known genetic mutations before establishing single-cell RNA sequencing. Marker genes were validated by flow cytometry and histology in a separate validation cohort. RESULTS: Seurat clustering analysis revealed that the landscape of neutrophils encompassed 5 clusters, including 1 progenitor, 1 transition, and 3 functional clusters. The intercorrelated genes in patients with IPAH were mainly enriched in antigen processing presentation and natural killer cell mediated cytotoxicity. We identified and validated differentially upregulated genes, including MMP9 (matrix metallopeptidase 9), ISG15 (ISG15 ubiquitin-like modifier), and CXCL8 (C-X-C motif ligand 8). The positive proportions and fluorescence quantification of these genes were significantly increased in CD16+ neutrophils in patients with IPAH. The higher proportion of positive MMP9 neutrophils increased mortality risk after adjustment for age and sex. Patients with higher proportions of positive MMP9 neutrophils had worse survival, while the fraction of ISG15- or CXCL8-positive expression neutrophils failed to predict outcome. CONCLUSIONS: Our study yields a comprehensive dataset of the landscape of neutrophils in patients with IPAH. The predictive values of a neutrophil cluster characterized by higher MMP9 expression indicate a functional role for neutrophil-specific matrix metalloproteinases in the pathogenesis of pulmonary arterial hypertension.

Identification of diagnostic biomarkers for idiopathic pulmonary hypertension with metabolic syndrome by bioinformatics and machine learning.

Idiopathic pulmonary hypertension (IPAH) is a condition that affects various tissues and organs and the metabolic and inflammatory systems. The most prevalent metabolic condition is metabolic syndrome (MS), which involves insulin resistance, dyslipidemia, and obesity. There may be a connection between IPAH and MS, based on a plethora of studies, although the underlying pathogenesis remains unclear. Through various bioinformatics analyses and machine learning algorithms, we identified 11 immune- and metabolism-related potential diagnostic genes (EVI5L, RNASE2, PARP10, TMEM131, TNFRSF1B, BSDC1, ACOT2, SAC3D1, SLA2, P4HB, and PHF1) for the diagnosis of IPAH and MS, and we herein supply a nomogram for the diagnosis of IPAH in MS patients. Additionally, we discovered IPAH's aberrant immune cells and discuss them here.

Clinical differences between children and adults with idiopathic and heritable pulmonary arterial hypertension.

BACKGROUND: Although previous studies have demonstrated that paediatric pulmonary arterial hypertension remains distinct from that in adults, there are limited studies evaluating a direct comparison between children and adults. The aim of this head-to-head comparison study was to compare the gender, haemodynamic parameters, and prognosis between paediatric and adult pulmonary arterial hypertension. METHODS AND RESULTS: We retrospectively assessed the clinical differences in 40 childhood-onset (under 20 years old) patients and 40 adult-onset patients with idiopathic and heritable pulmonary arterial hypertension who were followed up at two centres. There was no female predominance among patients with childhood-onset pulmonary arterial hypertension (child female: 42.5%, adult female: 80%). The percent of New York Heart Association functional class IV in adult-onset pulmonary arterial hypertension tended to be higher than those in childhood-onset pulmonary arterial hypertension (22.5 and 10%, respectively), although children had worse haemodynamic parameters at diagnosis (mean pulmonary artery pressure (children versus adults); median 65 mmHg versus 49 mmHg, p < 0.001). There was no significant difference in the event-free survival rate between the two groups (95% vs. 85%) during the follow-up period (median, 96 months; range, 1-120 months). CONCLUSIONS: Although paediatric pulmonary arterial hypertension patients had worse haemodynamic parameters at diagnosis than adults, children survived as long as adults with appropriate therapeutic strategies.

Idiopathic pulmonary arterial hypertension patients with a high H2FPEF-score: Insights from the Amsterdam UMC PAH-cohort.

BACKGROUND: The idiopathic pulmonary arterial hypertension (iPAH) phenotype is changing from a predominantly young female patient to an older, frequently obese patient of either sex. Many newly diagnosed iPAH-patients have risk factors for left ventricular diastolic dysfunction (LVDD), possibly affecting management and treatment. AIM: To determine whether the H2FPEF-score identifies a subgroup of iPAH-patients with blunted response to PAH-targeted treatment. STUDY DESIGN AND METHODS: We performed a retrospective analysis of 253 treatment-naïve iPAH-patients (1989-2019) with a confirmed diagnosis after right heart catheterization by a multidisciplinary team. Follow-up RHC measurements were available in 150 iPAH-patients. iPAH-patients were stratified by the H2FPEF-score; a score ≥5 identified a higher possibility of (concealed) LVDD. RESULTS: The presence of a high H2FPEF-score in incident iPAH-patients rose 30% in thirty years. Patients with a H2FPEF-score ≥5 were older, more often male and/or obese, and had more comorbidities than patients with a H2FPEF-score ≤1. A high H2FPEF-score was associated with worse survival and poor functional capacity. Right ventricular function was equally depressed among iPAH-groups. Imaging and invasive hemodynamic measurements suggested concealed LVDD in iPAH patients with a high H2FPEF-score. At follow-up, hemodynamic and functional responses were similar in iPAH-patients with a high or low H2FPEF-score. CONCLUSIONS: While a high H2FPEF-score in iPAH is associated with a worse prognosis and signs of LVDD, hemodynamic and functional responses to PAH treatment are not predicted by the H2FPEF-score.

Prevalence and clinical significance of conduction disease in patients with idiopathic pulmonary arterial hypertension.

Anatomical and physiological changes in the right heart as a direct consequence of the upstream pressure overload characteristic of idiopathic pulmonary hypertension (IPAH) are likely to lead to conduction disease in these patients. However, the prevalence and clinical implications of atrioventricular conduction disease in IPAH patients are not well-characterized. In this observational cohort study, we show that conduction disease is far more prevalent in a cohort of 175 IPAH patients than a group of matched comparators (37.1% vs 10.8%), and is associated with older age, male sex and more severe right heart dilatation. However, conduction disease is independently associated with worse functionality and higher mortality in this patient group. Prospective study is required to substantiate this, and whether intervention such as prophylactic pacing could restore prognosis.

ECG in the clinical and prognostic evaluation of patients with pulmonary arterial hypertension: an underestimated value.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease leading to right ventricular (RV) failure and manifests in decreasing exercise tolerance. Our study aimed to assess the usefulness of electrocardiographic parameters reflecting right heart hypertrophy as predictors of clinical status in PAH. METHODS: The retrospective analysis included 26 patients, mean 49 ± 17 years of age, diagnosed with PAH, and eligible to undergo cardiopulmonary exercise test (CPET). The relations between ECG values and parameters obtained in procedures such as six-minute walk test (6-MWT), echocardiography, right heart catheterization (RHC), and CPET were analyzed. RESULTS: P-wave amplitude in lead II correlated positively with CPET parameter of respiratory response: minute ventilation to carbon dioxide production slope (VE/VCO2 slope; r = 0.436, p = 0.029) and echocardiographic estimated RA pressure (RAP; r = 0.504, p = 0.02). RV Sokolow-Lyon index (RVSLI) positively correlated with echocardiographic parameters reflecting RV function, overload, and afterload-tricuspid regurgitation pressure gradient (TRPG; r = 0.788, p < 0.001), RV free wall thickness (r = 0.738, p < 0.001), and mean pulmonary arterial pressure (mPAPECHO; r = 0.62, p = 0.0016), respectively, as well as VE/VCO2 slope (r = 0.593, p = 0.001) and mPAP assessed directly in RHC (mPAPRHC; r = 0.469, p = 0.0497). R-wave in lead aVR correlated positively with TRPG (r = 0.719, p < 0.001), mPAPECHO (r = 0.446, p = 0.033), and several hemodynamic criteria of PAH diagnosis: positively with mPAPRHC (r = 0.505, p = 0.033) and pulmonary vascular resistance (r = 0.554, p = 0.026) and negatively with pulmonary capillary wedge pressure (r = -0.646, p = 0.004). QRS duration correlated positively with estimated RAP (r = 0.589, p = 0.004), vena cava inferior diameter (r = 0.506, p = 0.016), and RA area (r = 0.679, p = 0.002) and negatively with parameters of exercise capacity: peak VO2 (r = -0.486, p = 0.012), CPET maximum load (r = - 0.439, p = 0.025), and 6-MWT distance (r = -0.430, p = 0.046). ROC curves to detect intermediate/high 1-year mortality risk (based on ESC criteria) indicate RVSLI (cut-off point: 1.57 mV, AUC: 0.771) and QRS duration (cut-off points: 0.09 s, AUC: 703 and 0.1 s, AUC: 0.759) as relevant predictors. CONCLUSION: Electrocardiography appears to be an important and underappreciated tool in PAH assessment. ECG corresponds with clinical parameters reflecting PAH severity.

Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension.

BACKGROUND: A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years. METHODS: Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes' discovery. RESULTS: A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH. CONCLUSIONS: Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes.

Early implementation of renal replacement therapy after lung transplantation does not impair long-term kidney function in patients with idiopathic pulmonary arterial hypertension.

OBJECTIVES: In patients with idiopathic pulmonary arterial hypertension, cardiac function can be impaired in the early postoperative phase after lung transplantation because the chronically untrained left ventricle is prone to fail. Thus, restrictive fluid management is pivotal to unload the left heart. In our institution, continuous renal replacement therapy is implemented liberally whenever a patient cannot be balanced negatively. It remains unclear whether such strategy impairs long-term kidney function. METHODS: We retrospectively reviewed our institutional database for patients with idiopathic pulmonary arterial hypertension who underwent transplantation between 2000 and 2018. The impact of postoperative continuous renal replacement therapy on long-term outcomes was investigated using a linear mixed model and multivariable Cox regression. RESULTS: A total of 87 idiopathic pulmonary arterial hypertension lung transplant recipients were included in this analysis. In 38 patients (43%), continuous renal replacement therapy was started in the early postoperative period for a median of 16 days (10-22). In this group, urine production significantly decreased and patients began to acquire a positive fluid balance; however, homeostatic functions of the kidney were still preserved at the time of continuous renal replacement therapy initiation. All patients were successfully weaned from continuous renal replacement therapy and fully recovered their kidney function at the time of hospital discharge. No difference in kidney function was found between continuous renal replacement therapy and noncontinuous renal replacement therapy in patients within 5 years. CONCLUSIONS: Early implementation of continuous renal replacement therapy for perioperative volume management does not impair long-term kidney function in idiopathic pulmonary arterial hypertension lung transplant recipients. Our data suggest that such a strategy leads to excellent long-term outcomes.

Predictive value of chest HRCT for survival in idiopathic pulmonary arterial hypertension.

BACKGROUND: Little attention has been paid to chest high resolution computed tomography (HRCT) findings in idiopathic pulmonary arterial hypertension (IPAH) patients so far, while a couple of small studies suggested that presence of centrilobular ground-glass opacifications (GGO) on lung scans could have a significant negative prognostic value. Therefore, the aims of the present study were: to assess frequency and clinical significance of GGO in IPAH, and to verify if it carries an add-on prognostic value in reference to multidimensional risk assessment tool recommended by the 2015 European pulmonary hypertension guidelines. METHODS: Chest HRCT scans of 110 IPAH patients were retrospectively analysed. Patients were divided into three groups: with panlobular (p)GGO, centrilobular (c)GGO, and normal lung pattern. Association of different GGO patterns with demographic, functional, haemodynamic, and biochemical parameters was tested. Survival analysis was also performed. RESULTS: GGO were found in 46% of the IPAH patients: pGGO in 24% and cGGO in 22%. Independent predictors of pGGO were: positive history of haemoptysis, higher number of low-risk factors, and lower cardiac output. Independent predictors of cGGO were: positive history of haemoptysis, younger age, higher right atrial pressure, and higher mixed venous blood oxygen saturation. CGGO had a negative prognostic value for outcome in a 2-year perspective. This effect was not seen in the longer term, probably due to short survival of cGGO patients. CONCLUSIONS: Lung HRCT carries a significant independent prognostic information in IPAH, and in patients with cGGO present on the scans an early referral to lung transplantation centres should be considered.

Myocardial adaptation and exercise performance in patients with pulmonary arterial hypertension assessed with patient-specific computer simulations.

Myocardial function and exercise reserve are important determinants of outcome in pulmonary arterial hypertension (PAH) but are incompletely understood. For this study, we performed subject-specific computer simulations, based on invasive measurements and cardiac magnetic resonance imaging (CMR), to investigate whole circulation properties in PAH at rest and exercise and determinants of exercise reserve. CMR and right heart catheterization were performed in nine patients with idiopathic PAH, and CMR in 10 healthy controls. CMR during exercise was performed in seven patients with PAH. A full-circulation computer model was developed, and model parameters were optimized at the individual level. Patient-specific simulations were used to analyze the effect of right ventricular (RV) inotropic reserve on exercise performance. Simulations achieved a high consistency with observed data. RV contractile force was increased in patients with PAH (127.1 ± 28.7 kPa vs. 70.5 ± 14.5 kPa, P < 0.001), whereas left ventricular contractile force was reduced (107.5 ± 17.5 kPa vs. 133.9 ± 10.3 kPa, P = 0.002). During exercise, RV contractile force increased by 1.56 ± 0.17, P = 0.001. In silico experiments confirmed RV inotropic reserve as the important limiting factor for cardiac output. Subject-specific computer simulation of myocardial mechanics in PAH is feasible and can be used to evaluate myocardial performance. With this method, we demonstrate marked functional myocardial adaptation to PAH in the resting state, primarily composed of increased contractile force development by RV myofibers, and we show the negative impact of reduced RV inotropic reserve on cardiac output during exercise.NEW & NOTEWORTHY Computer simulations of the myocardial mechanics and hemodynamics of rest and exercise were performed in nine patients with pulmonary arterial hypertension and 10 control subjects, with the use of data from invasive catheterization and from cardiac magnetic resonance. This approach allowed a detailed analysis of myocardial adaptation to pulmonary arterial hypertension and showed how reduction in right ventricular inotropic reserve is the important limiting factor for an increase in cardiac output during exercise.

Potential of C-X-C motif chemokine ligand 1/8/10/12 as diagnostic and prognostic biomarkers in idiopathic pulmonary arterial hypertension.

OBJECTIVE: This study aimed to evaluate the clinical role of C-X-C motif chemokine ligand (CXCL) family members in idiopathic pulmonary arterial hypertension (IPAH) patients. METHODS: CXCL1, CXCL8, CXCL10 and CXCL12 expressions in the serum samples of IPAH patients (N = 39) and age-/gender-matched controls (N = 40) were detected by enzyme-linked immunosorbent assay. In IPAH patients, clinical features were collected, and survival information was documented. RESULTS: CXCL1 (P < 0.001), CXCL8 (P = 0.001), CXCL10 (P < 0.001) and CXCL12 (P < 0.001) were increased in IPAH patients compared with controls, and receiver's operating characteristic curves showed that their combination was highly correlated with IPAH risk (area under curve: 0.881, 95% confidence interval: 0.805-0.958). Meanwhile, CXCL1 was positively correlated with mean pulmonary artery pressure (mPAP) (P = 0.029) and high-sensitive C-reactive protein (HsCRP) (P = 0.015); CXCL8 was positively correlated with mPAP (P = 0.044) and HsCRP (P = 0.018) but negatively correlated with 6-minute walk test (6MWT) distance (P = 0.029); CXCL10 was positively correlated with mean right artery pressure (P = 0.002); and CXCL12 was positively correlated with World Health Organization functional class (P = 0.047), mPAP (P = 0.009), pulmonary vascular resistance (P = 0.004) and HsCRP (P = 0.003) but negatively correlated with 6MWT distance (P = 0.003) in IPAH patients. Moreover, CXCL12 was negatively correlated with overall survival (OS) (P = 0.025), whereas CXCL1, CXCL8 and CXCL10 only showed minor tendencies to be negatively correlated with OS in IPAH patients without statistical significance (all P > 0.05). CONCLUSION: CXCL1, CXCL8, CXCL10 and CXCL12 associate with increased IPAH risk, unfavourable clinical features; besides, CXCL12 correlates with worse OS in IPAH patients.

Genetic Counseling and Testing in Pulmonary Arterial Hypertension.

A subgroup of patients diagnosed with pulmonary arterial hypertension (PAH) carry transmissible pathogenic gene mutations. For many of these patients, the heritable nature of their disease can only be uncovered by genetic testing. Because identification of PAH patients who carry pathogenic gene mutations has important implications for other family members, genetic counseling and testing should be offered to patients diagnosed with idiopathic or familial PAH. This review describes the current state of genetic counseling and testing for patients diagnosed with PAH.