Correlation between short-term air pollution exposure and unprovoked lung embolism. Prospective observational (Contamina-TEP Group).

BACKGROUND: The aim was to analyze the temporal relationship between short-term air pollution exposure and acute symptomatic unprovoked pulmonary embolism (PE). PATIENTS/METHODS: We performed a prospective, multicenter study in consecutive patients diagnosed with acute symptomatic unprovoked PE from February 2012 to January 2013. We analyzed demographic and clinical data, patients' addresses, meteorological and air pollutants data (PM10, SO2, CO, NO2, ozone emission data). We considered the number of days the patient had symptoms, and the study period constituted the previous 30 days. Likewise, the mean annual data of the reference season were calculated as well as the data of the 30-day study period corresponding to the same dates in the previous 3 years in order to obtain the monthly mean of the different pollutants for each period. RESULTS: A total of 162 patients with acute symptomatic PE were recruited (43.2% unprovoked PE). The air pollutants could be determined in 50% of the patients with unprovoked PE, and a final analysis was performed in 35 patients. In the multiple comparison analysis to verify a possible correlation between the study period and the annual median, only NO2 showed a statistically significant association (p = 0.009). When comparing the study period with the previous 3 years, only NO2 maintained a statistically significant association for the 3 study periods. CONCLUSIONS: We found a relationship between short-term exposure to NO2 and the presence of unprovoked PE.

Comparison of All-Cause Mortality Following VTE Treatment Between Propensity Score-Adjusted Observational Studies and Matched Randomized Controlled Trials: Meta-Epidemiologic Study.

BACKGROUND: It is unknown whether propensity score-adjusted observational studies produce results comparable to those of randomized controlled trials (RCTs) that address similar VTE treatment issues. METHODS: The PubMed and Web of Science databases were systematically searched for propensity score-adjusted observational studies, RCTs, and meta-analyses of RCTs that estimated all-cause mortality following VTE treatment. After identifying distinct clinical treatment issues evaluated in the eligible observational studies, a standardized algorithm was used to identify and match at least one RCT or RCT meta-analysis publication for paired study design analyses. Meta-analyses were used to summarize groups of studies. Treatment efficacy statistics (relative ORs) were compared between the paired observational and RCT studies, and the summary relative ORs for all study design pairs were also calculated. RESULTS: The observational and RCT study pairs assessed seven clinical treatment issues. Overall, the observational study-RCT pairs did not exhibit significantly different mortality estimates (summary relative OR, 0.89; 95% CI, 0.32-1.46; I2 = 23%). However, two of the seven treatment issue study pairs (thrombolysis vs anticoagulation for pulmonary embolism; once- vs twice-daily enoxaparin for VTE) exhibited a significantly different treatment effect direction, and there was a substantial (nonsignificant) difference in the magnitude of the effect in another two of the study pairs (rivaroxaban vs vitamin K antagonists for VTE; home treatment vs hospitalization for DVT). CONCLUSIONS: This systematic comparison across seven VTE treatment topics suggests that propensity score-adjusted observational studies and RCTs often exhibit similar all-cause mortality, although differences in the direction or the magnitude of estimated treatment effects may occasionally occur. TRIAL REGISTRY: PROSPERO; CRD42018087819; URL: http://www.crd.york.ac.uk/PROSPERO.

Catheter-directed aspiration thrombectomy and low-dose thrombolysis for patients with acute unstable pulmonary embolism: Prospective outcomes from a PE registry.

OBJECTIVES: To evaluate the efficacy and safety of aspiration thrombectomy in combination with low-dose catheter-directed thrombolysis for acute unstable pulmonary embolism (PE). BACKGROUND: Acute unstable (PE) is a life-threatening condition requiring treatment escalation, but many patients cannot receive full-dose systemic thrombolysis due to contraindications. METHODS: Eligible patients had a PE with sustained hypotension. We used a 115-cm, 8-F continuous aspiration mechanical thrombectomy catheter to perform mechanical thrombectomy, followed by catheter-directed thrombolysis with low-dose urokinase. The primary efficacy outcome was the change in the pulmonary artery pressure after aspiration thrombectomy and catheter-directed thrombolysis. Secondary efficacy outcomes were stabilization of hemodynamics post-procedure and survival to hospital discharge. The primary safety outcome was major procedure-related complications and major bleeding events. RESULTS: We included 54 patients with acute unstable PE. After thrombectomy, mean systolic pulmonary artery pressure decreased from 60.2 mm Hg to 55.2 mm Hg (P < 0.01), and to 40.5 mm Hg after catheter thrombolysis (P < 0.0001). The in-hospital PE-related death occurred in six patients (11%; 95% confidence interval [CI], 4.2-23%) at a mean follow-up of 1.1 days, and hemodynamics stabilized in the remaining 48 patients. Minor complications after thrombectomy included arrhythmias (4 of 48 patients, 8.3%; 95% CI, 2.3-20%), and minor bleeding episodes (3 of 48 patients; 6.2%; 95% CI, 1.3-17%). Major complication occurred in one patient (2.1%; 95% CI, 0.1-11%) who developed hemorrhagic transformation of paradoxical embolic stroke following catheter-directed thrombolysis. CONCLUSIONS: Aspiration thrombectomy followed by catheter-directed thrombolysis was overall effective and safe in treating patients with acute unstable PE.

Meta-Analysis of Prevalence and Short-Term Prognosis of Hemodynamically Unstable Patients With Symptomatic Acute Pulmonary Embolism.

There remains limited information about the prevalence and outcomes of hemodynamic unstable patients with acute pulmonary embolism (PE). We performed a systematic review and meta-analysis of prospective registries that enrolled patients with acute PE to assess the prevalence and prognostic significance of hemodynamic instability for the primary outcome of short-term all-cause mortality, and the secondary outcome of short-term PE-related mortality. We also assessed the association between use of thrombolytic therapy versus no use and short-term outcomes in the subgroup of unstable patients. We used a random-effects model to pool study results; and I2 testing to assess for heterogeneity. The authors' search retrieved 4 studies that enrolled 1,574 patients with unstable PE (1,574/40,363; 3.9%; 95% confidence interval [CI], 3.7% to 4.1%). Hemodynamic instability had a significant association with short-term all-cause mortality (odds ratio [OR], 5.9; 95% CI, 2.7 to 13.0; I2 = 94%), and with PE-related death (OR, 8.2; 95% CI, 3.4 to 19.7). In unstable patients, thrombolytic therapy was associated with reduced odds of short-term all-cause mortality (OR, 0.69; 95% CI, 0.49 to 0.95), and PE-related death (OR, 0.66; 95% CI, 0.45 to 0.97). In conclusion, hemodynamic instability significantly increased the risk of death shortly after PE diagnosis. Use of thrombolytic therapy was associated with significantly reduced short-term mortality.

Accuracy and Interobserver Reliability of the Simplified Pulmonary Embolism Severity Index Versus the Hestia Criteria for Patients With Pulmonary Embolism.

OBJECTIVES: The objective was to assess and compare the accuracy and interobserver reliability of the simplified Pulmonary Embolism Severity Index (sPESI) and the Hestia criteria for predicting short-term mortality in patients with pulmonary embolism (PE). METHODS: This prospective cohort study evaluated consecutive eligible adults with PE diagnosed in the emergency department (ED) at a large, tertiary, academic medical center in the era January 1, 2015, to December 30, 2017. We assessed and compared sPESI and Hestia criteria prognostic accuracy for 30-day all-cause mortality after PE diagnosis and their interobserver reliability for classifying patients as low risk or high risk. Two clinician investigators scored both prediction tools during the ED evaluation. We used the kappa statistic to test for agreement. RESULTS: The 488-patient cohort had a mean (±SD) age of 69.0 (±17.1) years and an approximately even sex distribution. The investigators classified one-quarter of patients as low risk using the sPESI and Hestia criteria (28% vs. 27%, respectively). During the 30-day follow-up, 31 of the 488 (6.4%) patients died. Patients classified as low risk according to the sPESI and the Hestia criteria had a similar 30-day mortality (sPESI 0.7% [1/135], 95% confidence interval [CI] = 0.0%-4.0%; Hestia 2.3% [3/132], 95% CI = 0.5%-6.5%). The two observers had good agreement (κ = 0.80) for the Hestia criteria and very good agreement (κ = 0.97) for the sPESI. CONCLUSION: The sPESI and the Hestia criteria had similar risk classification determination and prognostic accuracy for 30-day mortality after PE. However, the succinct and more objective sPESI had higher interobserver reliability than the Hestia criteria.

Evaluación clínica frente a escalas estandarizadas para el pronóstico de los pacientes con tromboembolia pulmonar aguda sintomática / Clinical gestalt versus prognostic scores for prognostication of patients with acute symptomatic pulmonary embolism

Fundamento y objetivos: Determinar la utilidad de la estratificación pronóstica empírica para identificar a pacientes con tromboembolia de pulmón (TEP) aguda sintomática y bajo riesgo de complicaciones precoces. Pacientes y métodos: Este estudio incluyó a un total de 154 pacientes consecutivos diagnosticados de TEP aguda sintomática en un hospital universitario terciario. Comparamos la capacidad pronóstica de la escala clínica Pulmonary Embolism Severity Index (PESI), la escala PESI simplificada (PESIs) y la evaluación empírica de: 1) 2médicos adjuntos (uno con y otro sin experiencia en el manejo de pacientes con TEP); 2) un residente de cuarto año de Neumología; 3) un residente de tercer año de Neumología, y 4) un residente de segundo año de Neumología. El evento primario de mal pronóstico fue la mortalidad por todas las causas durante el primer mes después del diagnóstico de la TEP. Resultados: Durante los primeros 30 días después del diagnóstico de la TEP se produjo el fallecimiento de 13 pacientes (8,4%; intervalo confianza [IC] del 95%, 4,1-12,8%). Hubo una tendencia (no estadísticamente significativa) a clasificar más pacientes de bajo riesgo mediante la escala PESI o la evaluación empírica que con la escala PESIs (36,4, 31,3 y 28,6%, respectivamente). No se produjo ningún evento en el grupo de pacientes de bajo riesgo según la escala PESIs. Se detectó una mayor eficacia pronóstica de la estratificación empírica conforme mayor fue la experiencia clínica de los evaluadores (84,6 vs. 92,3%; p = 0,049). Conclusiones: La escala PESIs es la herramienta más eficaz para identificar pacientes con TEP aguda sintomática y bajo riesgo de muerte por todas las causas durante el primer mes de seguimiento. La evaluación pronóstica empírica realizada por médicos experimentados no es menos eficaz que la realizada mediante escalas estandarizadas

Background and objective: To determine the accuracy of clinical gestalt to identify patients with acute symptomatic pulmonary embolism (PE) at low-risk for short-term complications. Patients and methods: This study included a total of 154 consecutive patients diagnosed with acute symptomatic PE in a tertiary university hospital. We compared the prognostic accuracy of the Pulmonary Embolism Severity Index (PESI), the simplified PESI (sPESI), and clinical gestalt of 1) 2senior physicians (one with and one without experience in the management of patients with PE), 2) a fourth-year resident of Pneumology, 3) a third-year resident of Pneumology, and 4) a second-year resident of Pneumology. The primary outcome was all-cause mortality during the first month after the diagnosis of PE. Results: Thirty-day all-cause mortality was 8.4% (13/154; 8.4%; 95% confidence interval [CI], 4.1-12.8%). The PESI and clinical gestalt classified more patients as low-risk, compared to the sPESI (36.4%, 31.3% y 28.6%, respectively). There were no deaths in the sPESI low-risk category (negative predictive value 100%). Prognostic accuracy increased with increasing experience (84.6 vs. 92.3%; P=.049). Conclusions: The sPESI showed the best accuracy at correctly identifying low-risk patients with acute symptomatic PE. Clinical gestalt is not inferior to standardized clinical prediction rules to prognosticate patients with acute PE

Éxito en la recuperación de filtro de vena cava inferior opcional: Análisis de 246 pacientes / Success in Optional Vena Cava Filter Retrieval. An Analysis of 246 Patients

Objetivo: El objetivo de este estudio fue calcular el porcentaje de filtros de vena cava inferior (FVCI) opcionales finalmente recuperados y las variables asociadas a la imposibilidad para su recuperación en una cohorte de pacientes con enfermedad tromboembólica venosa (ETEV). Métodos: Se realizó un estudio observacional retrospectivo. La variable principal fue el porcentaje de FVCI recuperables finalmente extraídos. Se realizó regresión logística para identificar las variables asociadas al fracaso de la recuperación del FVCI. Resultados: Durante el período de estudio se implantaron 246 FVCI, 151 (61%) en pacientes con contraindicación para la anticoagulación, 69 (28%) para la prevención de tromboembolia de pulmón en pacientes de alto riesgo y 26 (11%) en pacientes con recurrencia trombótica a pesar de anticoagulación correcta. De los 236 pacientes que sobrevivieron el primer mes, se intentó la retirada del FVCI en todos ellos y fue posible en 226 pacientes (96%). La tasa más baja de retirada se produjo en el grupo de pacientes con recurrencias trombóticas mientras estaban anticoagulados, comparados con los pacientes con contraindicación para anticoagular y con los pacientes de alto riesgo (79 vs. 97 vs. 100%, respectivamente; p < 0,01). El tiempo de retraso hasta el intento de retirada fue significativamente mayor para los pacientes a los que no se les pudo retirar el FVCI (137,8 ± 65,3 días) comparados con los pacientes a los que se les pudo retirar el FVCI (46,3 ± 123,1 días; p < 0,001). Conclusiones: En este estudio de un único centro se consiguió la retirada del FVCI en el 96% de los casos. El retraso en el intento de retirada del FVCI se asoció de manera significativa al fracaso en su extracción

Objective: This study assessed vena cava filter (VCF) retrieval rates and factors associated with retrieval failure in a single center cohort. Methods: We conducted an observational retrospective cohort study. The primary endpoint was the percentage of patients whose VCF was retrieved. We performed logistic regression to identify variables associated with retrieval failure. Results: During the study period, 246 patients received a VCF and met the eligibility requirements to be included in the study; 151 (61%) patients received a VCF due to contraindication to anticoagulation, 69 (28%) patients had venous thromboembolism (VTE) and a high risk of recurrence, and 26 (11%) patients received a filter due to recurrent VTE while on anticoagulant therapy. Of 236 patients who survived the first month after diagnosis of VTE, VCF was retrieved in 96%. Retrieval rates were significantly lower for patients with recurrent VTE while on anticoagulation, compared with patients with contraindication to anticoagulation or patients with a high risk of recurrence (79% vs. 97% vs. 100%, respectively; P<0.01). Mean time to retrieval attempt was significantly associated with retrieval failure (137.8 ± 65.3 vs. 46.3 ± 123.1 days, P<0.001). Conclusions: In this single center study, VCF retrieval success was 96%. A delay in the attempt to retrieve the VCF correlated significantly with retrieval failure

Success in Optional Vena Cava Filter Retrieval. An Analysis of 246 Patients. / Éxito en la recuperación de filtro de vena cava inferior opcional: Análisis de 246 pacientes.

OBJECTIVE: This study assessed vena cava filter (VCF) retrieval rates and factors associated with retrieval failure in a single center cohort. METHODS: We conducted an observational retrospective cohort study. The primary endpoint was the percentage of patients whose VCF was retrieved. We performed logistic regression to identify variables associated with retrieval failure. RESULTS: During the study period, 246 patients received a VCF and met the eligibility requirements to be included in the study; 151 (61%) patients received a VCF due to contraindication to anticoagulation, 69 (28%) patients had venous thromboembolism (VTE) and a high risk of recurrence, and 26 (11%) patients received a filter due to recurrent VTE while on anticoagulant therapy. Of 236 patients who survived the first month after diagnosis of VTE, VCF was retrieved in 96%. Retrieval rates were significantly lower for patients with recurrent VTE while on anticoagulation, compared with patients with contraindication to anticoagulation or patients with a high risk of recurrence (79% vs. 97% vs. 100%, respectively; P<0.01). Mean time to retrieval attempt was significantly associated with retrieval failure (137.8 ± 65.3 vs. 46.3 ± 123.1 days, P<0.001). CONCLUSIONS: In this single center study, VCF retrieval success was 96%. A delay in the attempt to retrieve the VCF correlated significantly with retrieval failure.

Assessment of coexisting deep vein thrombosis for risk stratification of acute pulmonary embolism.

BACKGROUND: In patients with acute pulmonary embolism (PE), studies have shown an association between coexisting deep vein thrombosis (DVT) and short-term prognosis. It is not known whether complete compression ultrasound testing (CCUS) improves the risk stratification of their disease beyond the recommended prognostic models. METHODS: We included patients with normotensive acute symptomatic PE and prognosticated them with the European Society of Cardiology (ESC) risk model for PE. Subsequently, we determined the prognostic significance of coexisting DVT in patients with various ESC risk categories. The primary endpoint was a complicated course after the diagnosis of PE, defined as death from any cause, haemodynamic collapse, or adjudicated recurrent PE. RESULTS: According to the ESC model, 37% of patients were low-risk, 56% were intermediate-low risk, and 6.7% were intermediate-high risk. CCUS demonstrated coexisting DVT in 375 (44%) patients. Among the 313 patients with low-risk PE, coexisting DVT (46%) did not show a significant increased risk of complicated course (2.8%; 95% confidence interval [CI], 0.8%-7.0%), compared with those without DVT (0.6%; 95% CI, 0%-3.2%), (P = 0.18). Of the 478 patients with intermediate-low risk PE, a complicated course was 14% and 6.8% for those with and without DVT, respectively (P = 0.01). Of the 57 patients that had intermediate-high risk PE, a complicated course occurred in 17% and 18% for those with and without DVT, respectively (P = 1.0). CONCLUSIONS: In normotensive patients with PE, testing for coexisting DVT might improve risk stratification of patients at intermediate-low risk for short-term complications.

Clinical gestalt versus prognostic scores for prognostication of patients with acute symptomatic pulmonary embolism. / Evaluación clínica frente a escalas estandarizadas para el pronóstico de los pacientes con tromboembolia pulmonar aguda sintomática.

BACKGROUND AND OBJECTIVE: To determine the accuracy of clinical gestalt to identify patients with acute symptomatic pulmonary embolism (PE) at low-risk for short-term complications. PATIENTS AND METHODS: This study included a total of 154 consecutive patients diagnosed with acute symptomatic PE in a tertiary university hospital. We compared the prognostic accuracy of the Pulmonary Embolism Severity Index (PESI), the simplified PESI (sPESI), and clinical gestalt of 1) 2senior physicians (one with and one without experience in the management of patients with PE), 2) a fourth-year resident of Pneumology, 3) a third-year resident of Pneumology, and 4) a second-year resident of Pneumology. The primary outcome was all-cause mortality during the first month after the diagnosis of PE. RESULTS: Thirty-day all-cause mortality was 8.4% (13/154; 8.4%; 95% confidence interval [CI], 4.1-12.8%). The PESI and clinical gestalt classified more patients as low-risk, compared to the sPESI (36.4%, 31.3% y 28.6%, respectively). There were no deaths in the sPESI low-risk category (negative predictive value 100%). Prognostic accuracy increased with increasing experience (84.6 vs. 92.3%; P=.049). CONCLUSIONS: The sPESI showed the best accuracy at correctly identifying low-risk patients with acute symptomatic PE. Clinical gestalt is not inferior to standardized clinical prediction rules to prognosticate patients with acute PE.

Diclofenac for reversal of right ventricular dysfunction in acute normotensive pulmonary embolism: A pilot study.

BACKGROUND: The inflammatory response associated with acute pulmonary embolism (PE) contributes to the development of right ventricular (RV) dysfunction. Nonsteroidal anti-inflammatory drugs (NSAIDs) may facilitate the reversal of PE-associated RV dysfunction. METHODS: We randomly assigned normotensive patients who had acute PE associated with echocardiographic RV dysfunction and normal systemic blood pressure to receive intravenous (IV) diclofenac (two doses of 75mg in the first 24h after diagnosis) or IV placebo. All patients received standard anticoagulation with subcutaneous low-molecular-weight heparin (LMWH) and an oral vitamin K antagonist. RV dysfunction was defined by the presence of, at least, two of the following criteria: i) RV diastolic diameter>30mm in the parasternal window; ii) RV diameter>left ventricle diameter in the apical or subcostal space; iii) RV free wall hypokinesis; and iv) estimated pulmonary artery systolic pressure>30mmHg. Persistence of RV dysfunction at 48h and 7days after randomization were the primary and secondary efficacy outcomes, respectively. The primary safety outcome was major bleeding within 7days after randomization. RESULTS: Of the 34 patients randomly assigned to diclofenac or placebo, the intention-to-treat analysis showed persistent RV dysfunction at 48h in 59% (95% confidence interval [CI], 33-82%) of the diclofenac group and in 76% (95% CI, 50-93%) of the placebo group (difference in risk [diclofenac minus standard anticoagulation], -17 percentage points; 95% CI, -47 to 17). Similar proportions (35%) of patients in the diclofenac and placebo groups had persistent RV dysfunction at 7days. Major bleeding occurred in none of patients in the diclofenac group and in 5.9% (95% CI, 0.2-29%) of patient in the placebo group. CONCLUSIONS: Due to slow recruitment, our study is inconclusive as to a potential benefit of diclofenac over placebo to reverse RV dysfunction in normotensive patients with acute PE. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01590342.

Análisis de los genes BMPR2, TBX4 y KCNK3 y correlación genotipo-fenotipo en pacientes y familias españolas con hipertensión arterial pulmonar / Molecular analysis of BMPR2, TBX4, and KCNK3and Genotype-Phenotype correlations in spanish patients and families with idiopathic and hereditary pulmonary arterial hypertension

Introducción y objetivos: Avances recientes en genética han permitido el descubrimiento de nuevos genes relacionados con la hipertensión arterial pulmonar, como TBX4 y KCNK3. El fenotipo y el pronóstico asociado a ellos se han detallado escasamente y se desconoce su papel en la población española. El objetivo de este estudio es caracterizar genotípicamente una cohorte española de pacientes con hipertensión arterial pulmonar idiopática y hereditaria, describiendo el fenotipo y los factores pronósticos asociados a BMPR2 y a los nuevos genes (KCNK3 y TBX4). Métodos: Se seleccionó a 165 pacientes adultos con hipertensión arterial pulmonar: 143 con hipertensión arterial pulmonar idiopática y 22 con hipertensión arterial pulmonar familiar. Se compararon las características basales y la supervivencia libre de eventos entre los distintos subgrupos, se analizaron los factores predictores de mal pronóstico y se llevó a cabo el cribado familiar. Resultados: El estudio genético fue positivo en 16 pacientes con hipertensión arterial pulmonar idiopática (11,10%) y 15 con hipertensión arterial pulmonar familiar (68,18%), y se hallaron 19 mutaciones en BMPR2, 4 en TBX4 y 3 en KCNK3. Se observó mayor supervivencia libre de eventos en las formas asociadas a TBX4 (p < 0,01). El diagnóstico en clases funcionales avanzadas fue el único factor pronóstico en las formas heredables. El cribado de familiares fue positivo en el 37,5%. Conclusiones: En la población española con hipertensión arterial pulmonar puede existir un sustrato genético diferente, con menor proporción de mutaciones en BMPR2. A la vista de nuestros resultados, las formas asociadas a TBX4 podrían conllevar un fenotipo más benigno, y el diagnóstico tardío sería un factor de mal pronóstico en las formas heredables de la enfermedad (AU)

Introduction and objectives: Recent advances in genetics have led to the discovery of new genes associated with pulmonary arterial hypertension, such as TBX4 and KCNK3. The phenotype and prognosis associated with these new genes have been scarcely described and their role in the Spanish population is unknown. The aim of this study was to characterize the genetics of a Spanish cohort of patients with idiopathic and hereditary pulmonary arterial hypertension and to describe the phenotype and prognostic factors associated with BMPR2 and the new genes (KCNK3 and TBX4). Methods: A total of 165 adult patients were screened for BMPR2, KCNK3, and TBX4 mutations, 143 with idiopathic pulmonary arterial hypertension and 22 with hereditary pulmonary arterial hypertension. Baseline characteristics and survival were compared among the different subgroups and predictors of poor outcomes were analyzed. We also performed family screening. Results: The genetic study identified a possibly associated mutation in 11.10% of the idiopathic cases (n = 16) and in 68.18% of the hereditary cases (n = 15). There were 19 mutations in BMPR2, 4 in TBX4, and 3 in KCNK3. The forms associated with TBX4 showed the highest survival rate (P < .01). Advanced functional class at diagnosis was the only factor associated with poor outcomes in the hereditary forms. In the family screening, 37.5% of relatives tested positive. Conclusions: The genetics of pulmonary arterial hypertension in the Spanish population may differ from other populations, with a lower proportion of BMPR2 causative mutations. In our cohort, TBX4-related forms of pulmonary arterial hypertension showed a more benign course and late diagnosis was the only predictor of adverse outcomes in the hereditary forms of the disease (AU)

Molecular Analysis of BMPR2, TBX4, and KCNK3 and Genotype-Phenotype Correlations in Spanish Patients and Families With Idiopathic and Hereditary Pulmonary Arterial Hypertension.

INTRODUCTION AND OBJECTIVES: Recent advances in genetics have led to the discovery of new genes associated with pulmonary arterial hypertension, such as TBX4 and KCNK3. The phenotype and prognosis associated with these new genes have been scarcely described and their role in the Spanish population is unknown. The aim of this study was to characterize the genetics of a Spanish cohort of patients with idiopathic and hereditary pulmonary arterial hypertension and to describe the phenotype and prognostic factors associated with BMPR2 and the new genes (KCNK3 and TBX4). METHODS: A total of 165 adult patients were screened for BMPR2, KCNK3, and TBX4 mutations, 143 with idiopathic pulmonary arterial hypertension and 22 with hereditary pulmonary arterial hypertension. Baseline characteristics and survival were compared among the different subgroups and predictors of poor outcomes were analyzed. We also performed family screening. RESULTS: The genetic study identified a possibly associated mutation in 11.10% of the idiopathic cases (n = 16) and in 68.18% of the hereditary cases (n = 15). There were 19 mutations in BMPR2, 4 in TBX4, and 3 in KCNK3. The forms associated with TBX4 showed the highest survival rate (P < .01). Advanced functional class at diagnosis was the only factor associated with poor outcomes in the hereditary forms. In the family screening, 37.5% of relatives tested positive. CONCLUSIONS: The genetics of pulmonary arterial hypertension in the Spanish population may differ from other populations, with a lower proportion of BMPR2 causative mutations. In our cohort, TBX4-related forms of pulmonary arterial hypertension showed a more benign course and late diagnosis was the only predictor of adverse outcomes in the hereditary forms of the disease.