RESUMEN
RATIONALE: Whether pulmonary hypertension at high altitude limits exercise capacity remains uncertain. OBJECTIVES: To gain further insight into the pathophysiology of hypoxia induced pulmonary hypertension and the resulting reduction in exercise capacity, we investigated if the reduction in hypoxic pulmonary vasoconstrictive response with corticosteroids or phosphodiesterase-5 inhibition improves exercise capacity. METHODS: A cardiopulmonary exercise test and echocardiography to estimate systolic pulmonary artery pressure were performed in 23 subjects with previous history of high altitude pulmonary edema, known to be associated with enhanced hypoxic vasoconstriction. Subjects were randomized to dexamethasone 8 mg twice a day, tadalafil 10 mg twice a day, or placebo (double-blinded), starting the day before ascent. MEASUREMENTS AND MAIN RESULTS: Measurements were performed at low and high (i.e., 4,559 m) altitude. Altitude exposure decreased maximum oxygen uptake and oxygen saturation, increased pulmonary artery pressure, and altered oxygen uptake kinetics. Compared with placebo, dexamethasone improved maximum oxygen uptake (% predicted 74 +/- 13%; tadalafil 63 +/- 13%, placebo 61 +/- 11%; P < 0.05), oxygen kinetics (mean response time 41 +/- 13 s; tadalafil 46 +/- 6 s, placebo 45 +/- 10 s; P < 0.05), and reduced the ventilatory equivalent for CO(2) (42 +/- 4; tadalafil 49 +/- 4, placebo 50 +/- 5; P < 0.01). Peak oxygen saturation did not differ significantly between the three groups (dexamethasone 66 +/- 7%, placebo 62 +/- 7%, tadalafil 69 +/- 5%; P = 0.08). During echocardiography at low-intensity exercise (40% of peak power), dexamethasone compared with placebo resulted in lower pulmonary artery pressure (47 +/- 9 mm Hg; tadalafil 57 +/- 11 mm Hg, placebo 68 +/- 23 mm Hg; P = 0.05) and higher oxygen saturation (74 +/- 7%; tadalafil 67 +/- 3%, placebo 61 +/- 20; P < 0.02). CONCLUSIONS: Corticosteroids, but not phosphodiesterase-5 inhibition, partially prevented the limitation of exercise capacity in subjects with intense hypoxic pulmonary vasoconstriction at high altitude.
Asunto(s)
Mal de Altura/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Carbolinas/uso terapéutico , Dexametasona/uso terapéutico , Prueba de Esfuerzo/efectos de los fármacos , Inhibidores de Fosfodiesterasa/uso terapéutico , Edema Pulmonar/tratamiento farmacológico , Adulto , Antiinflamatorios/efectos adversos , Carbolinas/efectos adversos , Dióxido de Carbono/sangre , Dexametasona/efectos adversos , Método Doble Ciego , Ecocardiografía , Femenino , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Pulmón/irrigación sanguínea , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Inhibidores de Fosfodiesterasa/efectos adversos , Presión Esfenoidal Pulmonar/efectos de los fármacos , Tadalafilo , Vasoconstricción/efectos de los fármacosRESUMEN
BACKGROUND: The prognosis of pulmonary hypertension (PH), especially idiopathic pulmonary arterial hypertension (IPAH), has improved during the recent years. The Swiss Registry for PH represents the collaboration of the various centres in Switzerland dealing with PH and serves as an important tool in quality control. The objective of the study was to describe the treatment and clinical course of this orphan disease in Switzerland. METHODS: We analyzed data from 222 of 252 adult patients, who were included in the registry between January 1999 and December 2004 and suffered from either PAH, PH associated with lung diseases or chronic thromboembolic PH (CTEPH) with respect to the following data: NYHA class, six-minute walking distance (6-MWD), haemodynamics, treatments and survival. RESULTS: If compared with the calculated expected figures the one, two and three year mean survivals in IPAH increased from 67% to 89%, from 55% to 78% and from 46% to 73%, respectively. Most patients (90%) were on oral or inhaled therapy and only 10 patients necessitated lung transplantation. Even though pulmonary endarterectomy (PEA) was performed in only 7 patients during this time, the survival in our CTEPH cohort improved compared with literature data and seems to approach outcomes usually seen after PEA. The 6-MWD increased maximally by 52 m and 59 m in IPAH and CTEPH, respectively, but in the long term returned to or below baseline values, despite the increasing use of multiple specific drugs (overall in 51% of IPAH and 29% of CTEPH). CONCLUSION: Our national registry data indicate that the overall survival of IPAH and presumably CTEPH seems to have improved in Switzerland. Although the 6-MWD improved transiently, it decreased in the long term despite specific and increasingly combined drug treatment. Our findings herewith underscore the progressive nature of the diseases and the need for further intense research in the field.
Asunto(s)
Antihipertensivos/uso terapéutico , Hipertensión Pulmonar/epidemiología , Trasplante de Pulmón/métodos , Presión Esfenoidal Pulmonar/fisiología , Adulto , Distribución por Edad , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/terapia , Incidencia , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Distribución por Sexo , Tasa de Supervivencia/tendencias , Suiza/epidemiología , Factores de TiempoRESUMEN
BACKGROUND: Altitude-induced pulmonary hypertension has been suggested to cause left ventricular (LV) diastolic dysfunction due to ventricular interaction. In this study, we evaluate the effects of exercise- and altitude-induced increase in pulmonary artery pressures on LV diastolic function in an interventional setting investigating high-altitude pulmonary edema (HAPE) prophylaxis. METHODS: Among 39 subjects, 29 were HAPE susceptible (HAPE-S) and 10 served as control subjects. HAPE-S subjects were randomly assigned to prophylactic tadalafil (10 mg), dexamethasone (8 mg), or placebo bid, starting 1 day before ascent. Doppler echocardiography at rest and during submaximal exercise was performed at low altitude (490 m) and high altitude (4,559 m). The ratio of early transmitral inflow peak velocity (E) to atrial transmitral inflow peak velocity (A), pulmonary venous flow parameters, and tissue velocity within the septal mitral annulus during early diastole (E') were used to assess LV diastolic properties. LV filling pressures were estimated by E/E'. Systolic right ventricular to atrial pressure gradients (RVPGs) were measured in order to estimate pulmonary artery pressures. RESULTS: At 490 m, E/A decreased similarly with exercise in HAPE-S and control subjects (HAPE-S, 1.5 +/- 0.3 to 1.3 +/- 0.3; control, 1.7 +/- 0.4 to 1.3 +/- 0.3; p = 0.12 between groups) [mean +/- SD], whereas RVPG increased significantly more in HAPE-S subjects (20 +/- 5 to 43 +/- 9 mm Hg vs 18 +/- 3 to 28 +/- 3 mm Hg, p < 0.001). Changes in RVPG levels during exercise did not correlate with changes in E/A (p > 0.1). From 490 to 4,559 m, no correlations between changes in RVPG and changes in E/A or atrial reversal (both p > 0.1) were observed. Neither of the groups showed an increase in E/E' from 490 to 4,559 m. CONCLUSION: Increased pulmonary artery pressure associated with exercise and acute exposure to 4,559 m appears not to cause LV diastolic dysfunction in healthy subjects. Therefore, ventricular interaction seems not to be of hemodynamic relevance in this setting.