RESUMEN
BACKGROUND: Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene. Based on expert consensus, guidelines recommend annual screening echocardiography in asymptomatic BMPR2 mutation carriers. The main objectives of this study were to evaluate the characteristics of asymptomatic BMPR2 mutation carriers, assess their risk of occurrence of PAH and detect PAH at an early stage in this high-risk population. METHODS: Asymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of 2â years (DELPHI-2 study; ClinicalTrials.gov: NCT01600898). Annual screening included clinical assessment, ECG, pulmonary function tests, 6-min walk distance, cardiopulmonary exercise testing, chest radiography, echocardiography and brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP level. Right heart catheterisation (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline. RESULTS: 55 subjects (26 males; median age 37â years) were included. At baseline, no PAH was suspected based on echocardiography and NT-proBNP levels. All subjects accepted RHC at inclusion, which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension (21.8%). At long-term follow-up (118.8â patient-years of follow-up), three additional cases were diagnosed, yielding a PAH incidence of 2.3% per year (0.99% per year in males and 3.5% per year in females). All PAH cases remained at low-risk status on oral therapy at last follow-up. CONCLUSIONS: Asymptomatic BMPR2 mutation carriers have a significant risk of developing incident PAH. International multicentre studies are needed to confirm that refined multimodal screening programmes with regular follow-up allow early detection of PAH.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Adulto , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Hipertensión Pulmonar Primaria Familiar/genética , Femenino , Humanos , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/genética , Masculino , Mutación , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: Long-term outcomes in portopulmonary hypertension (PoPH) are poorly studied in the current era of pulmonary hypertension management. We analysed the effect of pulmonary arterial hypertension (PAH)-targeted therapies, survival and predictors of death in a large contemporary cohort of patients with PoPH. METHODS: Data from patients with PoPH consecutively enrolled in the French Pulmonary Hypertension Registry between 2007 and 2017 were collected. The effect of initial treatment strategies on functional class, exercise capacity and cardiopulmonary haemodynamics were analysed. Survival and its association with PAH- and hepatic-related characteristics were also examined. RESULTS: Six hundred and thirty-seven patients (mean age 55 ± 10 years; 58% male) were included. Fifty-seven percent had mild cirrhosis, i.e. Child-Pugh stage A. The median model for end-stage liver disease (MELD) score was 11 (IQR 9-15). Most patients (n = 474; 74%) were initiated on monotherapy, either with a phosphodiesterase-5 inhibitor (n = 336) or with an endothelin-receptor antagonist (n = 128); 95 (15%) were initiated on double oral combination therapy and 5 (1%) on triple therapy. After a median treatment time of 4.5 months, there were significant improvements in functional class (p <0.001), 6-minute walk distance (6MWD) (p <0.0001) and pulmonary vascular resistance (p <0.0001). Overall survival rates were 84%, 69% and 51% at 1, 3 and 5 years, respectively. Baseline 6MWD, sex, age and MELD score or Child-Pugh stage were identified as independent prognostic factors. Survival from PoPH diagnosis was significantly better in the subgroup of patients who underwent liver transplantation (92%, 83% and 81% at 1, 3 and 5 years, respectively). CONCLUSION: Survival of patients with PoPH is strongly associated with the severity of liver disease. Patients who underwent liver transplantation had the best long-term outcomes. LAY SUMMARY: Portopulmonary hypertension is defined by the presence of pulmonary arterial hypertension in the context of chronic liver disease and is characterized by progressive shortness of breath and exercise limitation. The presence of severe pulmonary arterial hypertension in liver transplant candidates represents a contraindication for such a surgery; however, treatments targeting pulmonary arterial hypertension are efficacious, allowing for safe transplantation and conferring good survival outcomes in those who undergo liver transplantation.
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Antagonistas de los Receptores de Endotelina/uso terapéutico , Hipertensión Portal , Cirrosis Hepática , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Hipertensión Arterial Pulmonar , Sistema Cardiovascular/fisiopatología , Tolerancia al Ejercicio , Femenino , Francia/epidemiología , Estado Funcional , Humanos , Hipertensión Portal/diagnóstico , Hipertensión Portal/mortalidad , Hipertensión Portal/fisiopatología , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/fisiopatología , Cirrosis Hepática/cirugía , Trasplante de Hígado/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Manejo de Atención al Paciente/métodos , Pronóstico , Hipertensión Arterial Pulmonar/mortalidad , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/terapia , Índice de Severidad de la Enfermedad , Análisis de SupervivenciaRESUMEN
CONTEXT: The left ventricular filling pressure (LVFP) is correlated to right atrial pressure (RAP) in heart failure. We compared diagnostic value of the inferior vena cava (IVC) measurements to the one of the 2016 echocardiographic recommendations to estimate LVFP in patients with suspected heart failure with preserved ejection fraction (HFpEF). METHODS: Invasive hemodynamics and echocardiography were obtained within 48 hours in 132 consecutive patients with left ventricular ejection fraction ≥50%, and suspected pulmonary hypertension. Increased LVFP was defined by a pulmonary artery wedge pressure (PAWP) >15 mmHg. RESULTS: Of 83 patients in sinus rhythm, a score of the 2016 recommendations ≥ 2 (E/e' ratio >14 and/or tricuspid regurgitation velocity >2.8 m/s and/or indexed left atrial volume>34 mL /m²) had a positive predictive value (PPV) of 63% for PAWP>15 mmHg, whereas a dilated IVC (>2.1 cm) and/or non-collapsible (≤50%) had a PPV of 82%. The net reclassification improvement was 0.39 (P < .05). In atrial fibrillation (AF), a dilated and/or non-collapsible IVC had an 86% PPV for PAWP>15 mmHg. The correlation between RAP and PAWP was 0.60, with 75.7% concordance (100/132) between dichotomized pressures (both RAP>8 mmHg and PAWP>15 mmHg and vice versa). CONCLUSION: The IVC size and collapsibility is valuable to identify patients with HFpEF with high LVFP in both sinus rhythm and AF.
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Insuficiencia Cardíaca , Cateterismo Cardíaco , Ecocardiografía , Insuficiencia Cardíaca/diagnóstico por imagen , Humanos , Volumen Sistólico , Vena Cava Inferior/diagnóstico por imagen , Función Ventricular Izquierda , Presión VentricularRESUMEN
BACKGROUND: Hemodynamic variables such as cardiac index and right atrial pressure have consistently been associated with survival in pulmonary arterial hypertension (PAH) at the time of diagnosis. Recent studies have suggested that pulmonary arterial compliance may also predict prognosis in PAH. The prognostic importance of hemodynamic values achieved after treatment initiation is less well established. METHODS: Our objective was to evaluate the prognostic importance of clinical and hemodynamic variables during follow-up, including pulmonary arterial compliance, after initial management in PAH. We evaluated incident patients with idiopathic, drug- and toxin-induced, or heritable PAH enrolled in the French pulmonary hypertension registry between 2006 and 2016 who had a follow-up right-sided heart catheterization (RHC). The primary outcome was death or lung transplantation. We used stepwise Cox regression and the Kaplan-Meier method to assess variables obtained at baseline and at first follow-up RHC. RESULTS: Of 981 patients, a primary outcome occurred in 331 patients (33.7%) over a median follow-up duration of 2.8 years (interquartile range, 1.1-4.6 years). In a multivariable model considering only baseline variables, no hemodynamic variables independently predicted prognosis. Median time to first follow-up RHC was 4.6 months (interquartile range, 3.7-7.8 months). At first follow-up RHC (n=763), New York Heart Association functional class, 6-minute walk distance, stroke volume index (SVI), and right atrial pressure were independently associated with death or lung transplantation, adjusted for age, sex, and type of PAH. Pulmonary arterial compliance did not independently predict outcomes at baseline or during follow-up. The adjusted hazard ratio for SVI was 1.28 (95% confidence interval, 1.11-1.49; P<0.01) per 10-mL/m2 decrease and for right atrial pressure was 1.05 (95% confidence interval, 1.02-1.09; P<0.01) per 1-mm Hg increase. Among patients who had 2 (n=355) or 3 (n=193) low-risk prognostic features at follow-up, including a cardiac index ≥2.5 L·min-1·m-2, 6-minute walk distance >440 m, and New York Heart Association class I or II functional class, lower SVI was still associated with higher rates of death or lung transplantation (P<0.01). CONCLUSIONS: SVI and right atrial pressure were the hemodynamic variables that were independently associated with death or lung transplantation at first follow-up RHC after initial PAH treatment. These findings suggest that the SVI could be a more appropriate treatment target than cardiac index in PAH.
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Presión Sanguínea , Cateterismo Cardíaco , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/fisiopatología , Trasplante de Pulmón , Sistema de Registros , Anciano , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Francia/epidemiología , Humanos , Hipertensión Pulmonar/etiología , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
OBJECTIVE: To compare the respiratory workload using the diaphragm thickening fraction (DTf) determined by sonography during high-flow nasal oxygen (HFNO), standard oxygen therapy (SOT), and noninvasive bilevel positive airway pressure support (BIPAP) in patients with acute respiratory failure (ARF) after cardiothoracic surgery. DESIGN: Prospective controlled clinical trial. SETTING: A French 23-bed cardiothoracic surgical intensive care unit. PARTICIPANTS: Nonintubated patients with ARF after cardiothoracic surgery or while awaiting lung transplantation. INTERVENTIONS: HFNO (50 L/min), SOT via a standard facemask, and BIPAP (pressure support, 4 cmH2O; positive end-expiratory pressure [PEEP], 4 cmH2O), with FIO2 kept constant were successively applied and compared. With BIPAP, pressure support or PEEP increments up to 8 cmH2O were compared with baseline settings. Each measurement was made after stable breathing for 5 minutes. MEASUREMENTS AND MAIN RESULTS: Fifty patients aged 60.0 ± 12.2 years were enrolled, including 14 (28%) with obesity. Mean PaO2/FIO2 was 153 ± 55 mmHg. DTf was lower with HFNO and BIPAP than with SOT (respectively 21.2% ± 15.1% v 30.9% ± 21.1% and 17.8% ± 19.1% v 30.9% ± 21.1%, p < 0.001) and was not different with HFNO versus BIPAP (pâ¯=â¯0.22). With BIPAP, increasing pressure support to 8 cmH2O decreased DTf (21.0% ± 14.3% v 28.8% ± 19.8%, pâ¯=â¯0.009), whereas increasing PEEP to 8 cmH2O did not (25.2% ± 17.2% v 28.8% ± 19.8%, pâ¯=â¯0.79). Tidal volume increased to 10.6 ± 3.4 mL/kg with 8 cmH2O pressure support v 8.8 ± 2.7 mL/kg with 4 cmH2O pressure support (p < 0.001). CONCLUSION: HFNO provides a comparable respiratory workload decrease compared with BIPAP at lower levels of pressure support and PEEP compared with SOT. Increasing BIPAP pressure support may provide higher levels of assistance but carries a risk of overdistension.
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Diafragma/diagnóstico por imagen , Oxígeno/metabolismo , Respiración con Presión Positiva/métodos , Síndrome de Dificultad Respiratoria/terapia , Mecánica Respiratoria/fisiología , Procedimientos Quirúrgicos Torácicos/métodos , Ultrasonografía/métodos , Diafragma/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Nariz , Terapia por Inhalación de Oxígeno/métodos , Periodo Posoperatorio , Estudios Prospectivos , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/fisiopatología , Volumen de Ventilación PulmonarRESUMEN
Portopulmonary hypertension (PoPH) is diagnosed in 2-6% of liver transplantation (LT) candidates. We studied outcomes of candidates for LT suffering from PoPH. Data were collected retrospectively from a prospective registry. Pulmonary hemodynamic variables were collected at the time of PoPH diagnosis, at last evaluation before LT, and within 6 months and beyond 6 months after LT. Forty-nine patients (35 males, 48 ± 8 years) were analyzed (median Model for End-Stage Liver Disease score 20). At baseline, mean pulmonary artery pressure (mPAP) was 44 ± 10 mm Hg (range 26-73 mm Hg), cardiac index was 3.5 ± 0.9 L/min/m2 , and pulmonary vascular resistance was 5.6 ± 2.8 Wood units. Hemodynamic reassessment performed in 35 patients who were treated with pulmonary arterial hypertension-targeted therapies before LT resulted in significant decreases in both mPAP (36 ± 7 versus 47 ± 10 mm Hg, P < 0.0001) and pulmonary vascular resistance (3.0 ± 1.4 versus 6.1 ± 3.1 Wood units, P < 0.0001). Fourteen patients (29%) died without having had access to LT. Thirty-five patients underwent LT and were followed up for a median of 38 months. Eight patients (23%) died after LT including 5 due to PoPH (after 1 day to 6 months). Among survivors (n = 27), all patients treated with intravenous epoprostenol were weaned off post-LT, and endothelin receptor antagonist or phosphodiesterase type 5 inhibitors were continued in 15/27 patients (55%). At last evaluation, 20/27 patients (74%) had mPAP <35 mm Hg and 8 of them (30%) had mPAP <25 mm Hg. Overall survival estimates after LT were 80%, 77%, and 77% at 6 months, 1 year, and 3 years, respectively. CONCLUSION: Stabilization or reversibility of PoPH seems to be an attainable goal using the combination of pulmonary arterial hypertension-targeted therapies and LT in patients who are transplantation candidates. (Hepatology 2017;65:1683-1692).
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Hipertensión Portal/terapia , Hipertensión Pulmonar/terapia , Trasplante de Hígado/mortalidad , Adulto , Femenino , Francia/epidemiología , Humanos , Hipertensión Portal/mortalidad , Hipertensión Pulmonar/mortalidad , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
There is growing recognition of the clinical importance of pulmonary haemodynamics during exercise, but several questions remain to be elucidated. The goal of this statement is to assess the scientific evidence in this field in order to provide a basis for future recommendations.Right heart catheterisation is the gold standard method to assess pulmonary haemodynamics at rest and during exercise. Exercise echocardiography and cardiopulmonary exercise testing represent non-invasive tools with evolving clinical applications. The term "exercise pulmonary hypertension" may be the most adequate to describe an abnormal pulmonary haemodynamic response characterised by an excessive pulmonary arterial pressure (PAP) increase in relation to flow during exercise. Exercise pulmonary hypertension may be defined as the presence of resting mean PAP <25â mmHg and mean PAP >30â mmHg during exercise with total pulmonary resistance >3â Wood units. Exercise pulmonary hypertension represents the haemodynamic appearance of early pulmonary vascular disease, left heart disease, lung disease or a combination of these conditions. Exercise pulmonary hypertension is associated with the presence of a modest elevation of resting mean PAP and requires clinical follow-up, particularly if risk factors for pulmonary hypertension are present. There is a lack of robust clinical evidence on targeted medical therapy for exercise pulmonary hypertension.
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Gasto Cardíaco , Prueba de Esfuerzo , Hipertensión Pulmonar/diagnóstico , Resistencia Vascular , Disfunción Ventricular Izquierda/diagnóstico por imagen , Comités Consultivos , Cateterismo Cardíaco/efectos adversos , Ecocardiografía Doppler , Europa (Continente) , Humanos , Hipertensión Pulmonar/fisiopatología , Guías de Práctica Clínica como Asunto , Sociedades MédicasRESUMEN
A resting mean pulmonary artery pressure (mPAP) of 21-24â mmHg is above the upper limit of normal but does not reach criteria for the diagnosis of pulmonary hypertension (PH). We sought to determine whether an mPAP of 21-24â mmHg is associated with an increased risk of developing an abnormal pulmonary vascular response during exercise.Consecutive patients (n=290) with resting mPAP <25â mmHg who underwent invasive exercise haemodynamics were analysed. Risk factors for pulmonary vascular disease or left heart disease were present in 63.4% and 43.8% of subjects. An abnormal pulmonary vascular response (or exercise PH) was defined by mPAP >30â mmHg and total pulmonary vascular resistance >3â WU at maximal exercise.Exercise PH occurred in 74 (86.0%) out of 86 versus 96 (47.1%) out of 204 in the mPAP of 21-24â mmHg and mPAP <21â mmHg groups, respectively (OR 6.9, 95% CI: 3.6-13.6; p<0.0001). Patients with mPAP of 21-24â mmHg had lower 6-min walk distance (p=0.002) and higher New York Heart Association functional class status (p=0.03). Decreasing levels of mPAP were associated with a lower prevalence of exercise PH, which occurred in 60.3%, 38.7% and 7.7% of patients with mPAP of 17-20, 13-16 and <13â mmHg, respectively.In an at-risk population, a resting mPAP between 21-24â mmHg is closely associated with exercise PH together with worse functional capacity.
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Ejercicio Físico/fisiología , Hemodinámica/fisiología , Arteria Pulmonar/fisiopatología , Adulto , Anciano , Presión Sanguínea , Gasto Cardíaco/fisiología , Femenino , Humanos , Hipertensión Pulmonar/fisiopatología , Masculino , Persona de Mediana Edad , Fenotipo , Descanso , Factores de Riesgo , Resistencia Vascular/fisiologíaRESUMEN
The impact of bone morphogenetic protein receptor 2 (BMPR2) gene mutations on vascular remodelling in pulmonary arterial hypertension (PAH) is unknown. We sought to identify a histological profile of BMPR2 mutation carriers.Clinical data and lung histology from 44 PAH patients were subjected to systematic analysis and morphometry.Bronchial artery hypertrophy/dilatation and bronchial angiogenesis, as well as muscular remodelling of septal veins were significantly increased in PAH lungs carrying BMPR2 mutations. We found that patients displaying increased bronchial artery remodelling and bronchial microvessel density, irrespective of the mutation status, were more likely to suffer from severe haemoptysis. History of substantial haemoptysis (>50â mL) was significantly more frequent in BMPR2 mutation carriers. 43.5% of BMPR2 mutation carriers, as opposed to 9.5% of noncarriers, displayed singular large fibrovascular lesions, which appear to be closely related to the systemic lung vasculature.Our analysis provides evidence for the involvement of the pulmonary systemic circulation in BMPR2 mutation-related PAH. We show that BMPR2 mutation carriers are more prone to haemoptysis and that haemoptysis is closely correlated to bronchial arterial remodelling and angiogenesis; in turn, pronounced changes in the systemic vasculature correlate with increased pulmonary venous remodelling, creating a distinctive profile in PAH patients harbouring a BMPR2 mutation.
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Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Arterias Bronquiales/patología , Hipertensión Pulmonar Primaria Familiar/genética , Pulmón/patología , Remodelación Vascular/genética , Adolescente , Adulto , Niño , Preescolar , Hipertensión Pulmonar Primaria Familiar/cirugía , Femenino , Francia , Hemoptisis/etiología , Heterocigoto , Humanos , Trasplante de Pulmón , Masculino , Persona de Mediana Edad , Mutación , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The exercise definition of pulmonary hypertension using a mean pulmonary artery pressure threshold of greater than 30âmmHg was abandoned following the 4th World Pulmonary Hypertension Symposium in 2008, as this definition was not supported by evidence and healthy individuals frequently exceed this threshold. Meanwhile, the clinical value of exercise pulmonary hemodynamic testing has also been questioned. RECENT FINDINGS: Recent data support the notion that an abnormal pulmonary hemodynamic response during exercise (or exercise pulmonary hypertension) is associated with symptoms and exercise limitation. Pathophysiologic mechanisms accounting for the development of exercise pulmonary hypertension include increased vascular resistance, excessive elevation in left atrial pressure and/or increased volume of trapped air during exercise, resulting in a steep rise in pulmonary artery pressure relative to cardiac output. Recent evidence suggests that exercise pulmonary hypertension may be defined by a mean pulmonary artery pressure surpassing 30âmmHg together with a simultaneous total pulmonary resistance exceeding 3âWU. SUMMARY: Exercise pulmonary hypertension is a clinically relevant entity and an improved definition has been suggested based on new evidence. Exercise pulmonary hemodynamics may help unmask early or latent disease, particularly in populations that are at high risk for the development of pulmonary hypertension.
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Ejercicio Físico/fisiología , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/fisiopatología , Pulmón/fisiología , Prueba de Esfuerzo , Tolerancia al Ejercicio , Hemodinámica , Humanos , Hipertensión Pulmonar/etiología , Pulmón/fisiopatología , Pruebas de Función RespiratoriaRESUMEN
Right ventricular adaptation to the increased pulmonary arterial load is a key determinant of outcomes in pulmonary hypertension (PH). Pulmonary vascular resistance (PVR) and total arterial compliance (C) quantify resistive and elastic properties of pulmonary arteries that modulate the steady and pulsatile components of pulmonary arterial load, respectively. PVR is commonly calculated as transpulmonary pressure gradient over pulmonary flow and total arterial compliance as stroke volume over pulmonary arterial pulse pressure (SV/PApp). Assuming that there is an inverse, hyperbolic relationship between PVR and C, recent studies have popularised the concept that their product (RC-time of the pulmonary circulation, in seconds) is "constant" in health and diseases. However, emerging evidence suggests that this concept should be challenged, with shortened RC-times documented in post-capillary PH and normotensive subjects. Furthermore, reported RC-times in the literature have consistently demonstrated significant scatter around the mean. In precapillary PH, the true PVR can be overestimated if one uses the standard PVR equation because the zero-flow pressure may be significantly higher than pulmonary arterial wedge pressure. Furthermore, SV/PApp may also overestimate true C. Further studies are needed to clarify some of the inconsistencies of pulmonary RC-time, as this has major implications for our understanding of the arterial load in diseases of the pulmonary circulation.
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Hipertensión Pulmonar/fisiopatología , Resistencia Vascular , Presión Sanguínea , Elasticidad , Ventrículos Cardíacos/fisiopatología , Humanos , Pulmón/fisiopatología , Pronóstico , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Circulación Pulmonar , Neumología/métodos , Presión Esfenoidal Pulmonar , Valores de Referencia , Reproducibilidad de los Resultados , Volumen Sistólico , Sístole , Disfunción Ventricular Derecha/fisiopatologíaRESUMEN
The previous definition of exercise pulmonary hypertension (PH) with a mean pulmonary artery pressure (mPAP) >30â mmHg was abandoned because healthy individuals can exceed this threshold at high cardiac output (CO). We hypothesised that incorporating assessment of the pressure-flow relationship using the mPAP/CO ratio, i.e. total pulmonary resistance (TPR), might enhance the accuracy of diagnosing an abnormal exercise haemodynamic response.Exercise haemodynamics were evaluated in 169 consecutive subjects with normal resting mPAP ≤20â mmHg. Subjects were classified into controls without heart or lung disease (n=68) versus patients with pulmonary vascular disease (PVD) (n=49) and left heart disease (LHD) (n=52).TPR and mPAP at maximal exercise produced diagnostic accuracy with area under the receiver operating curve of 0.99 and 0.95, respectively, for discriminating controls versus patients with PVD and LHD. The old criterion of mPAP >30â mmHg had sensitivity of 0.98 but specificity of 0.77. Combining maximal mPAP >30â mmHg and TPR >3â mmHg·min·L(-1) retained sensitivity at 0.93 but improved specificity to 1.0. The accuracy of the combined criteria was high across different age groups, sex, body mass index and diagnosis (PVD or LHD).Combining mPAP >30â mmHg and TPR >3â mmHg·min·L(-1) is superior to mPAP >30â mmHg alone for defining a pathological haemodynamic response of the pulmonary circulation during exercise.
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Prueba de Esfuerzo , Hemodinámica/fisiología , Hipertensión Pulmonar/diagnóstico , Resistencia Vascular/fisiología , Disfunción Ventricular Izquierda/diagnóstico , Adulto , Anciano , Análisis de Varianza , Área Bajo la Curva , Gasto Cardíaco/fisiología , Estudios de Casos y Controles , Femenino , Humanos , Hipertensión Pulmonar/fisiopatología , Masculino , Persona de Mediana Edad , Curva ROC , Valores de Referencia , Estudios Retrospectivos , Medición de Riesgo , España , Volumen SistólicoRESUMEN
OBJECTIVES: Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. METHODS: To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. RESULTS: The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. CONCLUSION: Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations.
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Condrodisplasia Punctata/diagnóstico por imagen , Fenotipo , Índice de Severidad de la Enfermedad , Ultrasonografía Prenatal , Condrodisplasia Punctata/genética , Femenino , Marcadores Genéticos , Pruebas Genéticas , Humanos , Recién Nacido , Mutación , Embarazo , Segundo Trimestre del Embarazo , Radiografía , Estudios Retrospectivos , Esteroide Isomerasas/genética , Inactivación del Cromosoma XRESUMEN
The aim of the study was to investigate the prognostic value of right heart catheterisation variables measured during exercise. 55 incident patients with idiopathic, familial or anorexigen-associated pulmonary arterial hypertension (PAH) underwent right heart catheterisation at rest and during exercise and 6-min walk testing before PAH treatment initiation. Patients were treated according to recommendations within the next 2 weeks. Right heart catheterisation was repeated 3-5 months into the PAH treatment in 20 patients. Exercise cardiac index decreased gradually as New York Heart Association (NYHA) functional class increased whereas cardiac index at rest was not significantly different across NYHA groups. Baseline 6-min walk distance correlated significantly with exercise and change in cardiac index from rest to exercise (r=0.414 and r=0.481, respectively; p<0.01). Change in 6-min walk distance from baseline to 3-5 months under PAH treatment was highly correlated with change in exercise cardiac index (r=0.746, p<0.001). The most significant baseline covariates associated with survival were change in systolic pulmonary artery pressure from rest to exercise and exercise cardiac index (hazard ratio 0.56 (95% CI 0.37-0.86) and 0.14 (95% CI 0.05-0.43), respectively). Change in pulmonary haemodynamics during exercise is an important tool for assessing disease severity and may help devise optimal treat-to-target strategies.
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Ejercicio Físico , Hipertensión Pulmonar Primaria Familiar/diagnóstico , Hipertensión Pulmonar/diagnóstico , Adulto , Anciano , Área Bajo la Curva , Cateterismo Cardíaco , Prueba de Esfuerzo , Hipertensión Pulmonar Primaria Familiar/fisiopatología , Femenino , Estudios de Seguimiento , Hemodinámica , Humanos , Hipertensión Pulmonar/fisiopatología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Sensibilidad y Especificidad , Resultado del Tratamiento , CaminataRESUMEN
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial dysfunction and vascular remodeling. Recently, bone marrow progenitor cells have been localized to PAH lungs, raising the question of their role in disease progression. Independently, serotonin (5-HT) and its receptors have been identified as contributors to the PAH pathogenesis. We hypothesized that 1 of these receptors, 5-HT(2B), is involved in bone marrow stem cell mobilization that participates in the development of PAH and pulmonary vascular remodeling. A first study revealed expression of 5-HT(2B) receptors by circulating c-kit(+) precursor cells, whereas mice lacking 5-HT(2B) receptors showed alterations in platelets and monocyte-macrophage numbers, and in myeloid lineages of bone marrow. Strikingly, mice with restricted expression of 5-HT(2B) receptors in bone marrow cells developed hypoxia or monocrotaline-induced increase in pulmonary pressure and vascular remodeling, whereas restricted elimination of 5-HT(2B) receptors on bone marrow cells confers a complete resistance. Moreover, ex vivo culture of human CD34(+) or mice c-kit(+) progenitor cells in the presence of a 5-HT(2B) receptor antagonist resulted in altered myeloid differentiation potential. Thus, we demonstrate that activation of 5-HT(2B) receptors on bone marrow lineage progenitors is critical for the development of PAH.
Asunto(s)
Médula Ósea/fisiología , Hipertensión Pulmonar/genética , Receptor de Serotonina 5-HT2B/fisiología , Animales , Sangre/metabolismo , Análisis Químico de la Sangre , Médula Ósea/metabolismo , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/fisiología , Diferenciación Celular/genética , Células Cultivadas , Hipertensión Pulmonar Primaria Familiar , Femenino , Humanos , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/inmunología , Hipertensión Pulmonar/metabolismo , Pulmón/metabolismo , Masculino , Ratones , Ratones Noqueados , Modelos Biológicos , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptor de Serotonina 5-HT2B/genética , Receptor de Serotonina 5-HT2B/metabolismoRESUMEN
BACKGROUND: Exercise hemodynamics are recommended for early detection of pulmonary arterial hypertension (PAH) and have been suggested to be predictive of future development of PAH in high-risk populations such as BMPR2 mutation carriers. However, the optimal exercise hemodynamic screening parameter remains to be determined. Recent data suggest that pulmonary vascular distensibility coefficient (α) may serve as a useful parameter for early detection of PAH. RESEARCH QUESTION: What is the value of exercise hemodynamics, including α, for predicting the occurrence of PAH during long-term follow-up in BMPR2 mutation carriers? STUDY DESIGN AND METHODS: Fifty-two asymptomatic BMPR2 mutation carriers who underwent symptom-limited exercise hemodynamic assessment were followed up for a median of 10 years. The impact of hemodynamics at rest and exercise, presence of exercise pulmonary hypertension, and α on occurrence of PAH during long-term follow-up were assessed. RESULTS: During long-term follow-up, five patients demonstrated PAH. Patients who demonstrated PAH showed a significantly lower α (0.8 ± 0.4%/mm Hg) than patients without PAH (1.8 ± 0.8%/mm Hg; P = .008). The only hemodynamic parameter that predicted the occurrence of PAH during long-term follow-up at regression analysis was α. Receiver operating characteristic analysis showed that α ≤ 1.5%/mm Hg predicted PAH occurrence with a specificity of 75% and sensitivity of 100%. INTERPRETATION: Before development of PAH in BMPR2 mutation carriers, α is reduced markedly and may serve as a useful parameter in the setting of early disease detection. Given the low event rate, caution is warranted in interpreting these results, highlighting the need for validation studies.
RESUMEN
The contribution of heart rate (HR) to pulmonary artery hemodynamics has been suggested in pulmonary hypertension (PH). Our high-fidelity pressure, retrospective study tested the hypothesis that HR explained the majority of mean pulmonary artery pressure (mPAP) and pulse pressure (PApp) variation in 12 severe precapillary PH patients who performed incremental-load cycling while in the supine position. Seven idiopathic pulmonary arterial hypertension patients and five chronic thromboembolic PH patients were studied. Four to five PAP-thermodilution cardiac output (CO) points (mean: 4.4) were obtained. At rest, mPAP was 57 ± 9 mmHg, PApp was 51 ± 11 mmHg, HR was 90 ± 12 beats/min, and stroke volume (SV) was 50 ± 22 ml. At peak exercise, mPAP was 76 ± 10 mmHg, PApp was 67 ± 11 mmHg, and HR was 123 ± 18 beats/min (i.e., 71 ± 10% of maximum HR, each P < 0.05), whereas SV was 51 ± 20 ml (P = not significant). The input resistance did not change (mPAP/CO = 14.1 ± 4.1 vs. 13.5 ± 4.4 mmHg·min·l(-1)). The relative increase in mPAP was related to the relative increase in HR (n = 12, r(2) = 0.74) but not in CO. mPAP was linearly related to CO in 8 of 12 patients (median r(2) = 0.83) and to HR in 12 of 12 patients (median r(2) = 0.985). The parsimony principle favored the latter fit. PApp was linearly related to mPAP in 12 of 12 patients (median r(2) = 0.985), HR in 10 of 12 patients (median r(2) = 0.97), CO in 7 of 12 patients (median r(2) = 0.87), and SV in 1 of 12 patients. A strong linear relationship between HR and mPAP was consistently documented in severe precapillary PH patients who performed supine exercise. The limited value of thermodilution CO to predict mPAP could be explained by unavoidable precision errors in CO measurements, unchanged/decreased SV on exercise, curvilinearity of the mPAP-CO relationship at high flow, or flow-independent additional mechanisms increasing mPAP on exercise.