Hipertensión pulmonar y leiomiomas uterinos, ¿existe relación causal? Serie de casos y revisión fisiopatológica / Pulmonary Hypertension and Uterine Leiomyomas, Is there a Causal Relationship? Case Series and Pathophysiological Review

Introducción: Los leiomiomas uterinos son un tipo de neoplasia benigna de frecuente aparición en mujeres de edad reproductiva, relacionados con enfermedad tromboem- bólica venosa. Este vínculo surge del efecto producido por la compresión de fibromas que genera estasis venosa en la región pelviana. Sin embargo, este pareciera no ser el único factor que lo relaciona con el desarrollo posterior de hipertensión pulmonar, sino que su presencia es gatillo de una serie de fenómenos que influyen sobre la vasculatu - ra pulmonar y también a nivel sistémico. Método: Revisión de una serie de casos (seis) atendidos en nuestra unidad, seguido de una revisión sobre la relación entre leiomio- mas y distintas formas de hipertensión pulmonar con una revisión desde la fisiopatología. Resultado y conclusiones: Encontramos sustento bibliográfico en los múltiples caminos fisiopatológicos que relacionan los mediadores vasculares comunes, que parecieran ser el punto clave en la relación entre estas dos patologías.

Introduction: Uterine leiomyomas are a type of benign neoplasm that frequently appears in women of reproductive age, related to venous thromboembolic disease. This link arises from the effect produced by the compression of fibroids, which generates venous stasis in the pelvic region. However, this seems not to be the only factor that re- lates it to the subsequent development of pulmonary hypertension, but rather its presence is a trigger for a series of phenomena that influence the pulmonary vasculature and also at a systemic level. Method: Review of a series of cases (six) cared for in our unit, followed by a review on the relationship between leiomyomas and different forms of pulmonary hypertension with a review from the pathophysiology. Result and conclusions: We found bibliographic support in the multiple pathophysiological paths that relate the common vascular mediators, which appear to be the key point in the relationship between these two pathologies.

Hipertensión pulmonar en cardiopatías congénitas del adulto / Pulmonary hypertension in adult congenital heart disease / Hipertensão pulmonar na cardiopatia congênita do adulto

Introducción: la hipertensión pulmonar asociada a cardiopatías congénitas del adulto implica un amplio espectro de situaciones clínicas complejas de difícil manejo para el cardiólogo clínico. Revisión: se repasarán los principales aspectos fisiopatológicos relacionados con el desarrollo de hipertensión pulmonar en los diferentes grupos de cardiopatías congénitas, así como los criterios para establecer el diagnóstico. Se discutirá el tratamiento guiado por perfil de riesgo y los grupos farmacológicos disponibles en nuestro medio. Por último, se discutirán grupos especiales, como el síndrome de Eisenmenger y la embarazada con cardiopatía e hipertensión pulmonar. Conclusión: es importante tener presente de todas formas que la hipertensión pulmonar en este escenario puede tener un mal pronóstico (como en el síndrome de Eisenmenger), por lo cual se deben realizar los mayores esfuerzos para hacer un diagnóstico precoz y tratamiento oportuno de estos pacientes.

Introduction: pulmonary hypertension associated with congenital heart disease in adults involves a wide spectrum of complex clinical situations that are difficult to manage for the clinical cardiologist. Review: the main pathophysiological aspects related to the development of pulmonary hypertension in the different groups of congenital heart disease will be reviewed, as well as the criteria to establish the diagnosis. Treatment guided by risk profile and the pharmacological groups available in our setting will be discussed. Finally, special groups such as Eisenmenger syndrome and pregnant women with heart disease and pulmonary hypertension will be discussed. Conclusion: it is important to keep in mind, however, that pulmonary hypertension in this scenario could have a poor prognosis (for example in Eisenmenger syndrome), which is why every effort should be made to make an early diagnosis and timely treatment of these patients.

Introdução: a hipertensão pulmonar associada à cardiopatia congênita em adultos envolve um amplo espectro de situações clínicas complexas e de difícil manejo para o cardiologista clínico. Revisão: serão revistos os principais aspectos fisiopatológicos relacionados ao desenvolvimento da hipertensão pulmonar nos diferentes grupos de cardiopatias congênitas, bem como os critérios para estabelecer o diagnóstico. Serão discutidos o tratamento guiado pelo perfil de risco e os grupos farmacológicos disponíveis em nosso meio. Por fim, serão discutidos grupos especiais como síndrome de Eisenmenger e gestantes com cardiopatia e hipertensão pulmonar. Conclusão: de qualquer forma, é importante ter em mente que a hipertensão pulmonar nesse cenário pode ter um prognóstico ruim (como na síndrome de Eisenmenger), razão pela qual todo esforço deve ser feito para o diagnóstico precoce e tratamento oportuno desses pacientes.

Do the Different Types of Pulmonary Hypertension Cause the Same Effect on Right Heart and Serum Asymmetrical Dimethylarginine Levels in Female Patients?

ABSTRACT Objective: Right-heart function is a major determinant of clinical outcome in patients with elevated pulmonary artery pressure due to pulmonary venous hypertension (PVH) and pulmonary arterial hypertension (PAH). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. This study aimed to evaluate if different types of pulmonary hypertension (PH) would cause the same effect on right-heart functions and serum ADMA levels in female patients. Methods: This study included patients with PAH as group I, patients with PVH due to mitral stenosis (mitral valve area ≤ 1.5 cm2, without any additional valve or left-heart disease and systolic pulmonary artery pressure ≥ 50 mmHg in transthoracic echocardiography) as group II, and healthy control subjects as group III. Transthorasic echocardiographic evaluations for right-heart functions were performed according to the guidelines of the American Society of Echocardiography. Venous blood samples were collected, and the serum ADMA concentrations were obtained with the ELISA kit (DRG® International Inc., Springfield, NJ, USA). Results: Patients in groups I and II had higher ADMA levels than healthy control subjects. Right-atrium area and dimensions, right-ventricular (RV) volumes, grade of tricuspid regurgitation, systolic pulmonary arterial pressure, RV wall thickness, and RV outflow tract diameters were significantly higher in group I patients than in group II patients. Right-ventricular myocardial performance index was lower, and RV fractional area change and tricuspid valve systolic tissue Doppler velocity were higher in group II patients than in group I patients. Conclusion: This study demonstrated that both PAH and PVH caused increase in right-heart dimensions and impairment in right-heart functions.

Análisis de los resultados del programa de ecocardiografía funcional neonatal en un hospital pediátrico de tercer nivel / Analysis of the results of the neonatal functional echocardiography program in a third-level pediatric hospital

Resumen Introducción: Se ha demostrado la utilidad del estudio ecocardiográfico en las enfermedades que afectan a los neonatos en estado crítico, por lo que se debe capacitar al neonatólogo para la toma y la interpretación de variables hemodinámicas que apoyen la toma de decisiones. El objetivo de este estudio fue describir los resultados del programa de ecocardiografía funcional neonatal y comparar las variables clínicas y hemodinámicas entre sobrevivientes y no sobrevivientes. Métodos: Durante un periodo de 2 años se realizó un estudio observacional, transversal y comparativo en neonatos que fueron evaluados con ecocardiografía funcional neonatal por alteraciones hemodinámicas del conducto arterioso persistente, hipertensión pulmonar aguda y crónica, estado de choque y búsqueda de trombos y vegetaciones. Se evaluaron parámetros de funcionalidad de los ventrículos derecho e izquierdo, presión pulmonar y subrogados de sobrecarga pulmonar. Se realizó un análisis comparativo (U de Mann Whitney y Χ2). De acuerdo con los resultados, se emitieron recomendaciones para el inicio, el ajuste o el retiro de fármacos vasoactivos. Resultados: Se realizaron 269 estudios en 119 neonatos (64.7% prematuros, mortalidad del 15%) atendidos por hipertensión pulmonar aguda (38%), conducto arterioso persistente (27%), choque (19%), hipertensión pulmonar crónica (14%) o búsqueda de trombos (2%). Se recomendó cambiar el manejo en el 45% de los estudios. El grupo de no sobrevivientes presentó diferencias significativas en los parámetros de función sistólica del ventrículo derecho y aumento de su poscarga. Conclusiones: La causa principal de la evaluación con ecocardiografía funcional neonatal fue la hipertensión pulmonar. De forma global, se recomendó un ajuste farmacológico en el 45% de los casos.

Abstract Background: Echocardiography is useful in the group of comorbidities of critically ill newborns. The targeted neonatal echocardiography program trains neonatologists for acquiring and interpreting hemodynamic variables to support decision making. This study aimed to describe the results of the functional echocardiography program (fNE) and compare clinical and hemodynamic variables between survivors and non-survivors. Methods: Observational, cross-sectional, and comparative study of neonates that received a fNE evaluation for hemodynamic disturbances related to patent ductus arteriosus (PDA), acute and chronic pulmonary hypertension (aPH, cPH), state of shock and thrombus/vegetations surveillance for two years. Functional parameters of the right and left ventricle, pulmonary pressure, and surrogates of pulmonary over circulation were assessed. Comparative analysis with U Mann Whitney test and Χ2 was performed. Based on the results, recommendations to start, adjust, or withdraw vasoactive medications were issued. Results: Of 269 studies on 119 neonates (65% premature, 15% mortality), the reasons for consultation were aPH (38%), PDA (27%), shock (19%), cPH (14%), and thrombus surveillance (2%). A change in management was recommended on 45% of studies. Non-survivors presented significant differences in the right ventricular (RV) systolic performance and an increased right ventricular afterload. Conclusions: The main indication for fNE was pulmonary hypertension. A pharmacological adjustment was recommended on 45% of the cases.

Pulmonary Hypertension in General Cardiology Practice / Hipertensão Pulmonar na Prática do Cardiologista

Abstract The finding of pulmonary hypertension (PH) by echocardiography is common and of concern. However, echocardiography is just a suggestive and non-diagnostic assessment of PH. When direct involvement of pulmonary circulation is suspected, invasive hemodynamic monitoring is recommended to establish the diagnosis. This assessent provides, in addition to the diagnostic confirmation, the correct identification of the vascular territory predominantly involved (arterial pulmonary or postcapillary). Treatment with specific medication for PH (phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostacyclin analogues) has been proven effective in patients with pulmonary arterial hypertension, but its use in patients with PH due to left heart disease can even be damaging. In this review, we discuss the diagnosis criteria, how etiological investigation should be carried out, the clinical classification and, finally, the therapeutic recommendations for PH.

Resumo O achado de hipertensão pulmonar (HP) em avaliação ecocardiográfica é frequente e preocupante. No entanto, o ecocardiograma é apenas um exame sugestivo e não diagnóstico de HP. Quando se suspeita de acometimento direto da circulação pulmonar, está indicada medida hemodinâmica invasiva para estabelecer o diagnóstico. Essa avaliação permite, além da confirmação diagnóstica, a correta identificação do território vascular predominantemente acometido (arterial pulmonar ou pós-capilar). O tratamento com as medicações específicas de HP (inibidores da fosfodiestarese 5, antagonistas do receptor de endotelina, análogos da prostaciclina e estimulador da guanilil ciclase solúvel) é comprovadamente eficaz para pacientes com hipertensão arterial pulmonar, mas seu uso em pacientes com HP decorrente de doença cardíaca de câmaras esquerdas pode até mesmo ser prejudicial. Discutiremos nesta revisão o critério diagnóstico, a maneira de proceder a investigação etiológica, a classificação clínica e, finalmente, as recomendações terapêuticas na HP.

Vascular endothelial growth factor and pulmonary hypertension in children with beta thalassemia major / Fator de crescimento endotelial vascular e hipertensão pulmonar em crianças com talassemia beta maior

Abstract Objective: The purpose of this study was to illustrate the association between vascular endothelial growth factor level and pulmonary artery hypertension in children with β-thalassemia major. Method: This case-control study was conducted on 116 children with β-thalassemia major; 58 of them had pulmonary artery hypertension. They were compared to 58 healthy children who were age and sex-matched (control group). Serum levels of vascular endothelial growth factor and echocardiographic assessment were done for all children. Results: Vascular endothelial growth factor serum level was significantly higher in children with β-thalassemia major with pulmonary artery hypertension than in those without pulmonary artery hypertension, as well as in control groups (p < 0.001). Vascular endothelial growth factor serum level had a significant positive correlation with pulmonary artery pressure and serum ferritin, as well as a significant negative correlation with the duration of chelation therapy. Logistic regression analysis revealed that elevated vascular endothelial growth factor (Odd Ratio = 1.5; 95% Confidence Interval, 1.137-2.065; p = 0.005) was an independent risk factor of pulmonary artery hypertension in such children. Vascular endothelial growth factor serum level at a cutoff point of >169 pg/mL had 93.1% sensitivity and 93.1% specificity for the presence of pulmonary artery hypertension in children with β-thalassemia major. Conclusion: Elevated vascular endothelial growth factor serum level is associated with pulmonary artery hypertension in children with β-thalassemia.

Resumo: Objetivo: A finalidade deste estudo foi exemplificar a associação entre o nível de fator de crescimento endotelial vascular e a hipertensão arterial pulmonar em crianças com talassemia beta maior. Método: Este estudo caso-controle foi realizado em 116 crianças com talassemia beta maior; 58 das quais apresentaram hipertensão arterial pulmonar em comparação com 58 crianças saudáveis pareadas por idade e sexo (grupo de controle). Os níveis séricos do fator de crescimento endotelial vascular e a avaliação ecocardiográfica foram realizados em todas as crianças. Resultados: O nível sérico do fator de crescimento endotelial vascular foi significativamente maior em crianças com talassemia beta maior com hipertensão arterial pulmonar que as crianças sem hipertensão arterial pulmonar e os grupos de controle (p < 0,001). O nível sérico do fator de crescimento endotelial vascular apresentou uma correlação positiva significativa com a pressão arterial pulmonar e a ferritina sérica e correlação negativa significativa com a duração da terapia de quelação. A análise de regressão logística revelou que o fator de crescimento endotelial vascular elevado (RC = 1,5; IC de 95%: 1,137-2,065; p = 0,005) foi um fator de risco independente de hipertensão arterial pulmonar nessas crianças. O nível sérico do fator de crescimento endotelial vascular no ponto de corte > 169 (pg/mL) apresentou 93,1% de sensibilidade e 93,1% de especificidade na presença de hipertensão arterial pulmonar em crianças com talassemia beta maior. Conclusão: O nível sérico do fator de crescimento endotelial vascular elevado está associado à hipertensão arterial pulmonar em crianças com talassemia beta.

Valoración de ecuaciones derivadas del flujo pulmonar y regurgitación tricuspídea: utilidad en el test de vasoreactividad pulmonar / Valuation of equations derived from Pulmonary Flow and Tricuspid Regurgitation: usefulness in Pulmonary Vasoreactivity Testing

RESUMEN: Antecedentes: La presión media arterial pulmonar (PMAP) es una variable hemodinámica indispensable para el diagnóstico, clasificación y pronóstico de la Hipertensión Pulmonar (HP). Su cuantificación se realiza en forma invasiva por cateterismo cardíaco derecho (CCD) y no invasivamente por ecocardiografía Doppler. Masuyama propuso su medición mediante el gradiente transvalvular pulmonar diastólico derivado de la velocidad máxima inicial de la regurgitación pulmonar (∆RPi2) correspondiendo cercanamente a la medición invasiva. Objetivos: Revalidar 3 métodos ecocardiográficos que estiman la PMAP y valorar la utilidad del método de Chemla en el Test de Reactividad Vascular Pulmonar (TRVP). Métodos: Estudio prospectivo, observacional, doble ciego divido en dos etapas. A) o I) 30 pacientes se realizó ecocardiografía Doppler diagnóstica en nuestro centro. Se midieron regurgitación tricuspídea (RT) y tiempo de aceleración pulmonar (TAP) para derivar las siguientes ecuaciones: 1) 0.61xPSAP+1.95 (Chemla) 2) Gradiente presión media RT (∆PmRT) +PAD (presión-aurícula derecha) (Aduen) y 3) 79-0.45xTAP o 90-0.60xTAP, según sea el valor del TAP. B) o II) 10 pacientes enrolados para realizar el TRVP comparando la medición ecocardiográfica (Chemla) con CCD. Resultados: En la primera parte del estudio se encontró alta correlación entre las 3 ecuaciones: ChemlaAduen, R2=0.91; Chemla-Kitabatake, R2=0.87; Aduen-Kitabatake, R2=0,91. En la segunda parte comparando la PMAP-Chemla y Cateterismo derecho (CD) obtuvimos alta correlación: en tiempo 0, 30 min y recuperación:(R2=0.87, 0.99, 0.98, respectivamente). Ambas partes del estudio mostraron límites de concordancia satisfactoria con valor medio de la diferencia entre los métodos cercano a 1 en el t30 y tR del TRVP. Conclusión: los métodos dependientes de la medición de la RT son efectivos y confiables para estimar la PMAP. El método de Chemla es útil en el TRVP.

ABSTRACTS: Background: Mean Pulmonary arterial pressure (PMAP)is an indispensable hemodynamic variable for the diagnosis, classification and prognosis of Pulmonary Hypertension (PH). Its quantification is performed invasively by cardiac catheterization and non-invasively by Doppler echocardiography. Masuyama proposed its measurement by the transvalvular diastolic pulmonary gradient derived from the initial maximum velocity of pulmonary regurgitation(ΔPRi2) corresponding closely to the invasive measurement. Objectives: to compare 3 known echocardiographic methods to estimate MPAP and demonstrate the usefulness of the Chemla method in the Pulmonary Vascular Reactivity Test (PVRT). Methods: prospective, observational, double-blind study divided into two stages. A) 30 patients underwent diagnostic Doppler echocardiography. Tricuspid regurgitation (TR) and pulmonary acceleration time (PAT) were measured to derive the equations: 1) 0.61xSPAP + 1.95 (Chemla) 2) Gradient mean pressure TR (ΔPmTR) + RAP (right atrium pressure) (Aduen).3) 79-0.45xPAT o 90-0.60xPAT depending on the value of PAT. B) 10 patients enrolled to PVRT comparing the echocardiographic measurement (Chemla) with right catheterization. Results: in the first part of the study a high correlation between the 3 equations was found : ChemlaAduen, R2 = 0.91; Chemla-Kitabatake, R2=0.87; Aduen-Kitabatake, R2=0.91. In the second part comparing the MPAP-Chemla and RHC we obtained a high correlation in time 0, 30 min and recovery: (R2=0.87,0,99,0.98, respectively). Both parts of the study showed satisfactory limits concordance with mean value of the difference between the methods close to 1 in the t30 and tR of the TRVP. Conclusion: the methods dependent on the measurement of the TR are effective and reliable for estimating MPAP. The Chemla method is useful in the PVRT.

Oferta de oxigênio, remoção de dióxido de carbono, transferência de energia aos pulmões e comportamento da hipertensão pulmonar durante o suporte com oxigenação por membrana extracorpórea: um modelo matemático / Oxygen delivery, carbon dioxide removal, energy transfer to lungs and pulmonary hypertension behavior during venous-venous extracorporeal membrane oxygenation support: a mathematical modeling approach

RESUMO Objetivo: Descrever a transferência de energia do ventilador mecânico para os pulmões; o acoplamento entre a transferência de oxigênio por oxigenação por membrana extracorpórea venovenosa (ECMO-VV) e o consumo de oxigênio do paciente; a remoção de dióxido de carbono com ECMO; e o efeito potencial da oxigenação venosa sistêmica na pressão arterial pulmonar. Métodos: Modelo matemático com cenários hipotéticos e utilização de simulações matemáticas por computador. Resultados: A transição de ventilação protetora para ventilação ultraprotetora em um paciente com síndrome da angústia respiratória aguda grave e complacência respiratória estática de 20mL/cmH2O reduziu a transferência de energia do ventilador para os pulmões de 35,3 para 2,6 joules por minuto. Em um paciente hipotético, hiperdinâmico e ligeiramente anêmico com consumo de oxigênio de 200mL/minuto, é possível atingir saturação arterial de oxigênio de 80%, ao mesmo tempo em que se mantém o equilíbrio entre a transferência de oxigênio pela ECMO e o consumo de oxigênio do paciente. O dióxido de carbono é facilmente removido e a pressão parcial de dióxido de carbono normal é facilmente obtida. A oxigenação do sangue venoso, por meio do circuito da ECMO, pode direcionar o estímulo da pressão parcial de oxigênio na vasoconstrição pulmonar por hipóxia para valores normais. Conclusão: A ventilação ultraprotetora reduz amplamente a transferência de energia do ventilador para os pulmões. A hipoxemia grave no suporte com ECMO-VV pode ocorrer, a despeito do acoplamento entre a transferência de oxigênio, por meio da ECMO, e o consumo de oxigênio do paciente. A faixa normal de pressão parcial de dióxido de carbono é fácil de atingir. O suporte com ECMO-VV potencialmente alivia a vasoconstrição pulmonar hipóxica.

ABSTRACT Objective: To describe (1) the energy transfer from the ventilator to the lungs, (2) the match between venous-venous extracorporeal membrane oxygenation (ECMO) oxygen transfer and patient oxygen consumption (VO2), (3) carbon dioxide removal with ECMO, and (4) the potential effect of systemic venous oxygenation on pulmonary artery pressure. Methods: Mathematical modeling approach with hypothetical scenarios using computer simulation. Results: The transition from protective ventilation to ultraprotective ventilation in a patient with severe acute respiratory distress syndrome and a static respiratory compliance of 20mL/cm H2O reduced the energy transfer from the ventilator to the lungs from 35.3 to 2.6 joules/minute. A hypothetical patient, hyperdynamic and slightly anemic with VO2 = 200mL/minute, can reach an arterial oxygen saturation of 80%, while maintaining the match between the oxygen transfer by ECMO and the VO2 of the patient. Carbon dioxide is easily removed, and normal PaCO2 is easily reached. Venous blood oxygenation through the ECMO circuit may drive the PO2 stimulus of pulmonary hypoxic vasoconstriction to normal values. Conclusion: Ultraprotective ventilation largely reduces the energy transfer from the ventilator to the lungs. Severe hypoxemia on venous-venous-ECMO support may occur despite the matching between the oxygen transfer by ECMO and the VO2 of the patient. The normal range of PaCO2 is easy to reach. Venous-venous-ECMO support potentially relieves hypoxic pulmonary vasoconstriction.

Angioplastía con balón para el tratamiento de la hipertensión arterial pulmonar por enfermedad tromboembólica crónica. Resultados hemodinámicos y clínicos inmediatos / Balloon pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension

Background: Balloon pulmonary angioplasty (BPA) is a therapeutic alternative for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Aim: To report the initial experience with the "refined BPA technique" with the use of intravascular images. Patients and Methods: Between June 2015 and June 2016 we selected fourteen patients with CTEPH who were considered candidates for BPA. Lesions targeted for treatment were further analyzed using intravascular imaging with optical frequency domain imaging (OFDI). We report the immediate hemodynamic results and four weeks of follow-up of the first eight patients of this series. Results: We performed 16 BPA in eight patients aged 61 ± 14 years (88% women). Mean pulmonary artery pressure (PAPm) was 48.6 ± 5.8 mmHg. Success was achieved in seven patients (88%). A mean of 2.3 segments per patient were intervened in 11 sessions (1.6 sessions/ patient). Only one patient developed lung reperfusion injury. No mortality was associated with the procedure. After the last BPA session, PAPm decreased to 37.4 ± 8.6 mmHg (p=0.02). Pulmonary vascular resistance (RVP) decreased from 858,6 ± 377,0 at baseline to 516,6 ± 323,3 Dynes/sec/cm−5 (p<0.01) and the cardiac index increased from 2.4±0.6 at baseline to 2.8±0.3 L/min/m2 (p=0.01). At 4 weeks after the last BPA, WHO functional class improved from 3.3±0.5 to 2.5±0.5 (p<0,01) and six minutes walking distance from 331±92 to 451±149 m (p=0.01). Conclusions: BPA guided by OFDI for the treatment of inoperable CTEPH patients is a safe alternative with excellent immediate hemodynamic and clinical results.

Ventilation distribution as a contributor to the functional exercise capacity in patients with systemic sclerosis-associated interstitial lung disease without pulmonary hypertension

Phenotypic differences have been described between patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD) and SSc-associated pulmonary hypertension, including performance differences in the 6-min walk test (6MWT). Moreover, the correlations between the 6MWT and traditional pulmonary function tests (PFTs) are weak, indicating the need to search for new parameters that explain exercise performance. Thus, our objective was to evaluate the impact of ventilation distribution heterogeneity assessed by the nitrogen single-breath washout (N2SBW) test and peripheral muscle dysfunction on the exercise capacity in patients with SSc-ILD and limited involvement of the pulmonary parenchyma. In this cross-sectional study, 20 women with SSc-ILD and 20 matched controls underwent PFTs (including spirometry, diffusing capacity for carbon monoxide (DLco), and the N2SBW test) and performed the 6MWT and knee isometric dynamometry. The 6-min walking distance (6MWD, % predicted) was strongly correlated with the phase III slope of the single-breath nitrogen washout (phase III slopeN2SBW) (r=−0.753, P<0.0001) and reasonably correlated with the forced vital capacity (FVC) (r=0.466, P=0.008) and DLco (r=0.398, P=0.011). The peripheral oxygen saturation (SpO2) during exercise was not significantly correlated with any of the pulmonary or muscle function parameters. The phase III slopeN2SBW was the only predictive variable for the 6MWD, whereas quadriceps strength and FVC/DLco were predictive variables for SpO2. Ventilation distribution heterogeneity is one factor that contributes to a lower 6MWD in SSc-ILD patients. In addition, muscle dysfunction and abnormal lung diffusion at least partly explain the decreased SpO2 of these patients.

Disability and its clinical correlates in pulmonary hypertension measured through the World Health Organization Disability Assessment Schedule 2 0: a prospective, observational study / Deficiência e seus correlatos clínicos na hipertensão pulmonar medidos pelo World Health Organization Disability Assessment Schedule 2 0: um estudo prospectivo e observacional

ABSTRACT Objective: To characterise the degree of disability in pulmonary hypertension (PH) patients based on the World Health Organisation Disability Assessment Schedule 2.0 (WHODAS 2.0). Method: A prospective and observational study of patients with documented PH (N = 46). Patients completed the WHODAS 2.0 questionnaire during a scheduled routine clinical visit, and their demographic and clinical characteristics were retrieved from electronic medical records (EMR). In subsequent visits, selected clinical variables were registered to assess disease progression. Results: WHODAS 2.0 scores were indicative of mild to moderate disability for the domains of mobility (22.0 ± 23.2), life activities (23.7 ± 25.5), and participation in society (17.2 ± 15.9), as well as total WHODAS 2.0 score (15.3 ± 15.2). For the domains of cognition (9.1 ± 14.1), self-care (8.3 ± 14.4), and interpersonal relationships (11.7 ± 15.7), scores were lower. Disability scores were, generally, proportional to the PH severity. The main baseline correlates of disability were World Health Organisation (WHO) functional class, fatigue, dyspnoea, 6-minute walking distance (6MWD), and N-terminal pro b-type natriuretic peptide (NTproBNP). Baseline WHODAS 2.0 scores showed significant associations with disease progression. However, this effect was not transversal to all domains, with only a few domains significantly associated with disease progression variables. Conclusions: This PH population shows mild disability, with higher degree of disability in the domains of mobility and life activities. This study is the first one to assess disability in PH using WHODAS 2.0. Further studies should apply this scale to larger PH populations with suitable representations of more severe PH forms.

RESUMO Objetivo: Caracterizar o nível de deficiência em pacientes com hipertensão pulmonar (HP) com base no World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Método: Estudo prospectivo e observacional em pacientes com HP documentada (N = 46). Os pacientes completaram o questionário WHODAS 2.0 durante uma consulta de rotina, e seus dados demográficos e clínicos foram retirados de prontuários médicos eletrônicos. Nas visitas subsequentes, variáveis clínicas específicas foram registradas para avaliar a progressão da doença. Resultados: a pontuação no WHODAS 2.0 indicaram deficiência leve a moderada para os domínios de mobilidade (22,0 ± 23,2), atividades da vida (23,7 ± 25,5) e participação em sociedade (17,2 ± 15,9), assim como a pontuação total do WHODAS 2.0 (15,3 ± 15,2). Para os domínios de cognição (9,1 ± 14,1), autocuidado (8,3 ± 14,4) e relações interpessoais (11,7 ± 15,7), a pontuação foi mais baixa. Os pontos referentes à deficiência foram, em geral, proporcionais à gravidade da HP. Os principais parâmetros da deficiência foram a classificação de funcionalidade da Organização Mundial da Saúde (OMS), fatiga, dispneia, teste de caminhada de 6 minutos (TC6M), e a porção N-terminal do pró-hormônio do peptídeo natriurético do tipo B (NT-proBNP). Os valores de parâmetro do WHODAS 2.0 mostraram associações significativas com a progressão da doença. Porém, este efeito não foi transversal a todos os domínios; apenas alguns estiveram significativamente associados às variáveis da progressão da doença. Conclusão: Esta população com HP mostra deficiência leve, com níveis mais altos nos domínios de mobilidade e atividades da vida diária. Este estudo é o primeiro a avaliar a deficiência em HP usando o WHODAS 2.0. Outros estudos devem aplicar esta escala em populações maiores com HP, com representações de formas mais graves da HP.

Cross-cultural adaptation of the Cambridge Pulmonary Hypertension Outcome Review for use in patients with pulmonary hypertension in Colombia / Adaptación transcultural de la escala Cambridge Pulmonary Hypertension Outcome Review en pacientes con hipertensión pulmonar en Colombia

ABSTRACT Objective: To conduct a cross-cultural adaptation of the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) as an instrument to evaluate the perception of symptoms, functional limitation, and health-related quality of life (HRQoL) in subjects diagnosed with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) in Colombia. Methods: The adaptation process involved 3 phases: translation, cognitive debriefing interviews, and a validation survey. To evaluate the psychometric properties, we recruited individuals ≥ 18 years of age who had been diagnosed with PAH or CTEPH to take part in the latter two stages of the adaptation process. All individuals were being followed on an outpatient basis by the pulmonary hypertension programs at Hospital Universitario San Ignacio, Fundación Clínica Shaio,and Clínicos IPS, all located in the city of Bogotá, Colombia. Results: A Spanish-language version of the CAMPHOR was developed for use in Colombia. The internal consistency was excellent for the symptoms, functioning, and quality of life scales (Cronbach's alpha coefficients of 0.92, 0.87, and 0.93, respectively). Test-retest reliability was above 0.70. The evaluation of the convergent validity and known group validity of the CAMPHOR scales confirmed that there were moderate and strong correlations with the related constructs of the Medical Outcomes Study 36-item Short-Form Health Survey, version 2, as well as showing their capacity to discriminate disease severity. Conclusions: The Spanish-language version of the CAMPHOR developed for use in Colombia was the result of a translation and cultural adaptation process that allows us to consider it equivalent to the original version, having shown good psychometric properties in the study sample. Therefore, its use to assess the impact of interventions on the HRQoL of patients with PAH or CTEPH is recommended, in research and clinical practice.

RESUMEN Objetivo: Realizar la adaptación transcultural del cuestionario Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) como instrumento para evaluar la percepción de síntomas, la limitación funcional y la calidad de vida relacionada con la salud (CVRS) en una población colombiana de sujetos con diagnóstico de hipertensión arterial pulmonar (HAP) e hipertensión pulmonar tromboembólica crónica (HPTEC). Métodos: Estudio de validación de pruebas de determinación de precisión y propiedades psicométricas desarrollado en 3 fases: traducción con adaptación cultural mediante panel bilingüe, aplicación inicial y general para la evaluación de características psicométricas en una cohorte de pacientes > 18 años, con diagnóstico de HAP e HPTEC, en seguimiento por consulta externa de programas de hipertensión pulmonar del Hospital Universitario San Ignacio, Fundación Clínica Shaio y Clínicos IPS. Resultados: Se obtuvo una versión en castellano de la escala CAMPHOR. La consistencia interna observada para los dominios de síntomas, actividades y calidad de vida (valores del coeficiente alfa de Cronbach de 0,92, 0,87 y 0,93 respectivamente) fue adecuada. La confiabilidad prueba-reprueba estuvo por encima de 0,70 y la evaluación de la validez convergente y de grupos conocidos de las subescalas confirmó las correlaciones moderadas y fuertes con constructos relacionados del SF36v2, así como la capacidad discriminatoria según la severidad de la enfermedad. Conclusiones: La versión en castellano de la escala CAMPHOR presentó un proceso de traducción lingüística y adaptación cultural que permite considerarla equivalente a la versión original, demostrando adecuadas propiedades psicométricas en la muestra estudiada. Por ello se recomienda su utilización tanto en la investigación como en la práctica clínica, con el fin de evaluar el impacto de las intervenciones en la CVRS.

Hipertensión pulmonar como presentación en mieloma múltiple / Pulmonary hypertension as presentation in multiple myeloma

El mieloma múltiple es una enfermedad oncohematológica, que representa el 15% de las enfermedades hematológicas malignas. La edad media de aparición es entre los 65-70 años, siendo muy poco frecuente en pacientes jóvenes; 2% son menores de 40 años. Presentamos el caso de una mujer de 36 años con antecedente de tabaquismo de 20 paquetes año. Consultó por disnea asociada a signos de insuficiencia cardíaca derecha, anemia, proteinuria, elevación de reactantes de fase aguda y patrón sugestivo de restricción moderadamente grave en la espirometría y caída de la capacidad de difusión de monóxido de carbono (DLco). El ecocardiograma doppler evidenció dilatación de cavidades derechas y signos de hipertensión pulmonar que se confirmó con cateterismo cardiaco derecho. En busca de la etiología se arribó al diagnóstico de mieloma múltiple.

Multiple myeloma is a hematologic disease, which accounts for 15% of hematologic malignancies. The average age of onset is between 65-70 years and is very rare in young patients, as 2% are under 40 years old. We present a case of 36-year-old women with history of 20 pack years (p/y) smoking, who complaints of dyspnea associated with signs of right cardiac overload, anemia, proteinuria, elevated acute phase reactants and spirometry pattern suggestive of moderately-severe restriction and severe drop in diffusing capacity for carbon monoxide (DLCO). Echocardiogram evidence dilated right heart cavities and signs of pulmonary hypertension which is confirmed by right heart catheterization. In search of the etiology we arrive to the diagnosis of multiple myeloma.

Hipertensión arterial pulmonar asociada al virus de inmunodeficiencia humana. A 3 décadas de su descripción / Pulmonary arterial hypertension associated with human immunodeficiency virus: thirty years after its description

Resumen El desarrollo de hipertensión arterial pulmonar asociada al virus de inmunodeficiencia humana reduce la probabilidad de sobrevivencia en el paciente afectado en comparación con el que no presenta esta alteración cardiopulmonar. La fisiopatogenia aún es incierta. Existen varias líneas de investigación para asociar las diferentes proteínas del virus en la lesión endo- telial. Desde el punto de vista terapéutico, existen modalidades de tratamiento que permiten una expectativa de vida aceptable.

Abstract The development of pulmonary arterial hypertension associated with human immunodeficiency virus reduces the probability of survival in the patient affected compared to those without cardiopulmonary disease. The pathophysiology is uncertain. There are several lines of research to associate the different proteins of the virus in the endothelial lesion. From a therapeutic point of view there are treatment modalities that allow an acceptable life expectancy.

Insights on the epigenetic mechanisms underlying pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH), characterized by localized increased arterial blood pressure in the lungs, is a slow developing long-term disease that can be fatal. PAH is characterized by inflammation, vascular tone imbalance, pathological pulmonary vascular remodeling, and right-sided heart failure. Current treatments for PAH are palliative and development of new therapies is necessary. Recent and relevant studies have demonstrated that epigenetic processes may exert key influences on the pathogenesis of PAH and may be promising therapeutic targets in the prevention and/or cure of this condition. The aim of the present mini-review is to summarize the occurrence of epigenetic-based mechanisms in the context of PAH physiopathology, focusing on the roles of DNA methylation, histone post-translational modifications and non-coding RNAs. We also discuss the potential of epigenetic-based therapies for PAH.

Evaluating respiratory musculature, quality of life, anxiety, and depression among patients with indeterminate chronic Chagas disease and symptoms of pulmonary hypertension

Abstract INTRODUCTION: Chagas disease (CD) is progressive and incapacitating, especially when cardiopulmonary function is affected. For example, respiratory muscle weakness can cause dyspnea upon exertion and fatigue, which may be exacerbated when it is associated with pulmonary hypertension (PH). The present study aimed to evaluate respiratory musculature, quality of life, anxiety, and depression among patients with indeterminate chronic CD and symptoms of PH. METHODS: All individuals completed a clinical evaluation, spirometry, a 6-min walking test, respiratory musculature testing using maximum inspiratory pressure (PImax) and maximum expiratory pressure (PEmax), the Hospital Anxiety and Depression Scale, and the SF-36 questionnaire. RESULTS: We evaluated 107 patients who were assigned to a control group with only CD (G1, 8 patients), a group with CD and possible PH (G2, 93 patients), and a group with CD and echocardiography evidence of PH (G3, 6 patients). The three groups had similar values for PImax and PEmax. Compared to the G1 and G2 groups, the G3 group covered significantly less distance during the 6-min walking test and had a significantly shorter predicted distance (p < 0.05 vs. the G1 group). All three groups had similar values for their spirometry results, Hospital Anxiety and Depression Scale scores, and SF-36 questionnaire results. CONCLUSIONS: Patients with indeterminate chronic CD and symptoms of PH did not experience significant impairment in the studied variables, with the exception of the 6-min walking test, which suggests a low exercise tolerance.

De la tromboembolia pulmonar aguda a la hipertensión pulmonar tromboembólica crónica: implicaciones en la patobiología y fisiopatología / From acute pulmonary embolism to chronic thromboembolic pulmonary hypertension: Pathobiology and pathophysiology

Resumen: La hipertensión pulmonar tromboembólica crónica (HPTEC) es un subtipo de hipertensión pulmonar (HP) caracterizada por la obstrucción mecánica de las arterias pulmonares causada por una tromboembolia pulmonar. Sin tratamiento es una enfermedad progresiva y devastadora, y es el único subgrupo de HP potencialmente curable mediante la endarterectomía pulmonar. La magnitud, así como la recurrencia de la embolia pulmonar, son determinantes y contribuyen al desarrollo de la HPTEC aun cuando está asociada solo a algunos factores trombofílicos. Una hipótesis es que la enfermedad es consecuencia de la resolución incompleta y la organización del trombo, favorecido por fenómenos de inflamación, inmunitarios y/o genéticos que promueven el desarrollo de estenosis de tipo fibroso que culminan con el remodelado vascular oclusivo de vasos proximales y distales. Los mecanismos involucrados en la fallida resolución del trombo aún no están esclarecidos. Los pacientes con HPTEC con frecuencia exhiben HP severa que no puede ser explicada por el grado de obstrucción vascular demostrada en estudios por imagen. En tales casos la arteriopatía pulmonar y las lesiones trombóticas obstructivas, distales al nivel subsegmentario, pueden contribuir al incremento fuera de proporción de las resistencias vasculares pulmonares. Los procesos que llevan al desarrollo de la arteriopatía pulmonar y los cambios microvasculares que ocurren en la HPTEC explican el comportamiento progresivo de la HP y el deterioro clínico gradual con pobre pronóstico para los pacientes, así como también la falta de correlación entre la magnitud de la obstrucción vascular y la medición de parámetros hemodinámicos, aun en ausencia de tromboembolismo venoso recurrente. Esta revisión resume los aspectos más relevantes y actuales de la patobiología y fisiopatología de la HPTEC.

Abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) represents a unique subtype of pulmonary hypertension characterized by the presence of mechanical obstruction of the major pulmonary vessels caused by venous thromboembolism. CTEPH is a progressive and devastating disease if not treated, and is the only subset of PH potentially curable by a surgical procedure known as pulmonary endarterectomy. The clot burden and pulmonary embolism recurrence may contribute to the development of CTEPH however only few thrombophilic factors have been found to be associated. A current hypothesis is that CTEPH results from the incomplete resolution and organization of thrombus modified by inflammatory, immunologic and genetic mechanisms, leading to the development of fibrotic stenosis and adaptive vascular remodeling of resistance vessels. The causes of thrombus non-resolution have yet to be fully clarified. CTEPH patients often display severe PH that cannot be fully explained by the degree of pulmonary vascular obstruction apparent on imaging studies. In such cases, the small vessel disease and distal obstructive thrombotic lesions beyond the sub-segmental level may contribute for out of proportion elevated PVR. The processes implicated in the development of arteriopathy and microvascular changes might explain the progressive nature of PH and gradual clinical deterioration with poor prognosis, as well as lack of correlation between measurable hemodynamic parameters and vascular obstruction even in the absence of recurrent venous thromboembolism. This review summarizes the most relevant up-to-date aspects on pathobiology and pathophysiology of CTEPH.

Tyrosine phosphorylation of Kv1. 5 is upregulated in intrauterine growth retardation rats with exaggerated pulmonary hypertension

Intrauterine growth retardation (IUGR) is associated with the development of adult-onset diseases, including pulmonary hypertension. However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular dysfunction later in life is not fully understood. Here, we investigated the role of tyrosine phosphorylation of voltage-gated potassium channel 1.5 (Kv1.5) in this prenatal event that results in exaggerated adult vascular dysfunction. A rat model of chronic hypoxia (2 weeks of hypoxia at 12 weeks old) following IUGR was used to investigate the physiological and structural effect of intrauterine malnutrition on the pulmonary artery by evaluating pulmonary artery systolic pressure and vascular diameter in male rats. Kv1.5 expression and tyrosine phosphorylation in pulmonary artery smooth muscle cells (PASMCs) were determined. We found that IUGR increased mean pulmonary artery pressure and resulted in thicker pulmonary artery smooth muscle layer in 14-week-old rats after 2 weeks of hypoxia, while no difference was observed in normoxia groups. In the PASMCs of IUGR-hypoxia rats, Kv1.5 mRNA and protein expression decreased while that of tyrosine-phosphorylated Kv1.5 significantly increased. These results demonstrate that IUGR leads to exaggerated chronic hypoxia pulmonary arterial hypertension (CH-PAH) in association with decreased Kv1.5 expression in PASMCs. This phenomenon may be mediated by increased tyrosine phosphorylation of Kv1.5 in PASMCs and it provides new insight into the prevention and treatment of IUGR-related CH-PAH.