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.

Contrast reflux into the inferior vena cava on computer tomographic pulmonary angiography is a predictor of 24-hour and 30-day mortality in patients with acute pulmonary embolism.

BACKGROUND: Acute pulmonary embolism (PE) is a common disease with a high mortality. Computed tomographic pulmonary angiography (CTPA) represents the current gold standard for the evaluation of patients with suspected PE. PURPOSE: To search possible CTPA predictors of 24-h and 30-day mortality in PE. MATERIAL AND METHODS: Overall, 224 patients with PE (46.4% women, mean age 64.7 ± 16.7 years) were acquired. CTPA was performed on a multi-slice CT scanner. The following radiological parameters were estimated: thrombotic obstruction index; diameter of the pulmonary trunk (mm); short axis ratio of right ventricle/left ventricle; diameter of the azygos vein (mm); diameter of the superior and inferior vena cava (mm); and reflux of contrast medium into the inferior vena cava (IVC). RESULTS: Patients who died within the first 24 h after admission (n = 32, 14.3%) showed a reflux grade 3 into IVC more often than survivors (odds ratio [OR] 7.6, 95% confidence interval [CI] 3.3-17.7; P < 0.001). Other relevant CTPA parameters were diameter of IVC (OR 1.1, 95% CI 1.01-1.21; P = 0.034) and diameter of the pulmonary trunk (OR 0.91, 95% CI 0.82-1.01, P = 0.074), whereas the Mastora score showed nearly no influence (OR 1.01, 95% CI 0.99-1.02, P = 0.406). Furthermore, 61 (27.2%) patients died within the first 30 days after admission. These patients showed a reflux grade 3 into IVC more often than survivors (OR 3.4, 95% CI 1.7-7.0; P = 0.001). Other CTPA parameters, such as diameter of IVC (OR 1.04, 95% CI 0.97-1.12; P = 0.277) and diameter of the pulmonary trunk (OR 0.96, 95% CI 0.89-1.04; P = 0.291), seem to have no relevant influence, whereas Mastora score did (OR 0.99, 95% CI 0.976-0.999, P = 0.045). CONCLUSION: Subhepatic contrast reflux into IVC is a strong predictor of 24-h and 30-day mortality in patients with acute PE.

Computed Tomography Embolus Texture Analysis as a Prognostic Marker of Acute Pulmonary Embolism.

Texture analysis is a quantitative imaging analysis that provides novel biomarkers beyond conventional image reading. Our aim was to use texture analysis of pulmonary emboli derived from thoracic computed tomography for prediction of mortality and prognosis of acute pulmonary embolism (PE). Overall, 216 patients (116 female, 53.7%) were included in the analysis. Texture analysis was calculated on axial slices of the contrast enhanced pulmonary angiography of the proximal embolus. Clinical scores, serological parameters, need for intubation, intensive care unit (ICU) admission and mortality was assessed and correlated with the texture features. In the correlation analysis, there were several associations with mortality in days, the highest for the parameter S(0,5)SumVarnc (r = -0.43, P < 0.001). Another parameter, S(3,-3)AngScMom correlated with sepsis-related organ failure assessment score (SOFA)-score (r = 0.31, P < 0.001). Several texture features correlated with venous lactate and glucose levels. In discrimination analysis, there were significant differences in regard to texture features between survivors and non-survivors and between patients with and without the need for ICU admission (P = 0.02, respectively). These results highlight the potential clinical benefit of texture features in patients with acute PE as novel imaging biomarkers. Further studies are needed to validate these results.

Role of visceral fat areas defined by thoracic CT in acute pulmonary embolism.

OBJECTIVE: Visceral adipose tissue (VAT) has been established as an important parameter of body composition. It can be assessed by imaging modalities like computed tomography (CT). The purpose of the present study was to analyse the prognostic role of VAT derived from thoracic CT in patients with acute pulmonary embolism (PE). METHODS: The clinical database of our center was retrospectively screened for patients with acute PE between 2014 and 2017. Overall, 184 patients were included into the analysis. VAT was assessed on axial slices of the thoracic CT at the level of the first lumbar vertebra. Clinical scores, serological parameters, need for intubation, ICU admission and 30 days mortality were assessed. RESULTS: Using the previously reported threshold of 100 cm² for visceral obesity definition 136 (73.9%), patients were considered as visceral obese. There was a moderate correlation between VAT and BMI (r = 0.56, p < 0.0001). There was also a moderate correlation between VAT and body height (r = 0.41, p =< 0.0001). Of all investigated clinical scores relating to acute PE, only the GENEVA score correlated weakly with VAT (r = 0.15, p = 0.04). There were significant correlations between VAT and creatinine (r = 0.38, p < 0.0001) and Glomerular filtration rate (r = -0.21, p = 0.005). No associations were identified for VAT and mortality or visceral obesity and mortality. CONCLUSION: VAT was not associated with mortality in patients with acute pulmonary embolism. ADVANCES IN KNOWLEDGE: Visceral obesity is frequent in patients with acute pulmonary embolism but it is not associated with mortality.

Low skeletal muscle mass defined by thoracic CT as a prognostic marker in acute pulmonary embolism.

OBJECTIVE: Sarcopenia defined as low skeletal muscle mass (LSMM) is associated with several clinically relevant factors in people who are critically ill. The aim of the present study was to analyze the role of LSMM derived from thoracic computed tomography (CT) for prediction of mortality and prognosis of acute pulmonary embolism (PE). METHODS: The clinical database of our department was retrospectively screened for patients with acute PE between 2013 and 2017. Overall, 234 patients were included in the analysis. LSMM was assessed on axial slides at the thoracic vertebra 5 (Th5) level of contrast-enhanced pulmonary angiography thoracic CT. The skeletal muscle index (SMI) was calculated by adjusting the muscle area to height. All-cause 30-d mortality was used as a primary outcome. RESULTS: Overall, 64 participants (27.4% of the sample) died. SMI was slightly higher for survivors than non-survivors (57.7 ± 11.9 versus 55.6 ± 14.3 cm2/m2; P = 0.07). SMI was associated with 30-d mortality in univariate as well as multivariate analysis (respective hazard ratios and 95% CI: 1.06, 1.03-1.09; 1.08, 1.04-1.11). CONCLUSIONS: SMI at Th5 derived from thoracic CT has a relevant effect on 30-d mortality in people with acute PE and should be included in the clinical routine.

A New Index for the Prediction of 30-Day Mortality in Patients With Pulmonary Embolism: The Pulmonary Embolism Mortality Score (PEMS).

Our aim was to analyze possibility of combination of basic clinical and radiological signs to predict 30-day mortality after acute pulmonary embolism (PE). We included 486 patients. Age, gender, simplified pulmonary embolism index (sPESI), pH, troponin, N-terminal natriuretic peptide, minimal systolic and diastolic blood pressure, O2 saturation, syncope, need for vasopressors, thrombotic obstruction, vessel diameter, short axis ratio right ventricle/left ventricle, and contrast medium reflux into the inferior vena cava (IVC) were analyzed. A backward algorithm in a logistic regression model was used to identify relevant risk factors. Multiple logistic regression analysis identified that sPESI, pH, minimal diastolic blood pressure, IVC reflux, and need for vasopressors influenced 30-day mortality. A score for mortality prediction was constructed (the Pulmonary Embolism Mortality Score): sPESI >2 points (1 point), pH <7.35 (1 point), minimal diastolic blood pressure <45 mm Hg (1 point), IVC reflux (1 point), and need for vasopressors (2 points). Patients with >3 points showed higher 30-day mortality (sensitivity: 84.9%, specificity: 83.0%, positive predictive value: 51.8%, negative predictive value: 96.2%). The net reclassification improvement compared with the sPESI was 0.94 (95% CI = 0.73-1.15). In conclusion, a new score can predict 30-day mortality in patients with PE and is more sensitive than sPESI.

Pulmonary Vessel Obstruction Does Not Correlate with Severity of Pulmonary Embolism.

The aim of the present study was to analyze possible relationships between pulmonary vessel obstruction and clinically relevant parameters and scores in patients with pulmonary embolism (PE). Overall, 246 patients (48.8% women and 51.2% men) with a mean age of 64.0 ± 17.1 years were involved in the retrospective study. The following clinical scores were calculated in the patients: Wells score, Geneva score, and pulmonary embolism severity index (PESI) score. Levels of D-dimer (µg/mL), lactate, pH, troponin, and N-terminal natriuretic peptide (BNP, pg/mL) were acquired. Thrombotic obstruction of the pulmonary arteries was quantified according to Mastora score. The data collected were evaluated by means of descriptive statistics. Spearman's correlation coefficient was used to analyze associations between the investigated parameters. P values < 0.05 were taken to indicate statistical significance. Mastora score correlated weakly with lactate level and tended to correlate with D-dimer and BNP levels. No other clinical or serological parameters correlated significantly with clot burden. Thrombotic obstruction of pulmonary vessels did not correlate with clinical severity of PE.

Mutually reinforcing effects of genetic variants and interferon-ß 1a therapy for pulmonary arterial hypertension development in multiple sclerosis patients.

Based on a small number of cases, interferon beta (IFN-ß) has been added to the list of drugs that might induce pulmonary arterial hypertension (PAH) in the current European guidelines for the diagnosis and treatment of pulmonary hypertension. Here, we propose that multiple sclerosis patients who are genetically predisposed to PAH may be at higher risk to develop disease when treated with IFN-ß. We included two patients with multiple sclerosis who developed a manifest PAH after five amd eight years on IFN-ß 1a therapy, respectively (without confirmed right heart catheterization). In both patients, PAH markedly improved after discontinuation of IFN-ß 1a and initiation of targeted PAH therapy. For genetic analysis, we used a PAH-gene panel based on next-generation sequencing of 16 PAH and 38 candidate genes. In one of the two patients, we could identify a nonsense variant in the PAH gene ATP13A3. The second patient showed a missense variant of the CYP1B1 gene, which might be linked to PAH predisposition. The results of this study support the hypothesis that multiple sclerosis patients who receive IFN-ß 1a therapy might be at higher risk for the development of manifest PAH, if they carry a pathogenic variant or sequence variant genetically predisposing to the disease. However, further studies are necessary to systematically investigate the presence of predisposing PAH gene variants in these patients.