Exercise tolerance improves within a few weeks after prostacyclin initiation in patients with primary pulmonary hypertension even in the absence of significant changes in resting pulmonary vascular resistance and/or in patients who fail to respond to an acute vasodilator challenge. We tested the hypothesis that this early effect of prostacyclin may be ascribable to an improved pressure–flow response of the pulmonary circulation to exercise. Pulmonary hemodynamic variables at rest and during exercise and the 6-min walking distance were determined before and after 6 wk of continuous intravenous prostacyclin treatment (11 ± 1.5 ng/kg/min) in seven patients unresponsive to an acute nitric oxide vasodilator test. Mean pulmonary arterial pressure/cardiac index coordinates obtained during exercise were pooled, and the slopes of these plots were compared using covariance analysis. All hemodynamic variables at rest were unchanged after prostacyclin. By contrast, the 6-min walking distance improved in all patients (mean increase, 81 m) and the slope of the mean pulmonary artery pressures/cardiac indexes plot decreased with prostacyclin, from 18.2 to 13.1 mm Hg/L/min/m2 (p < 0.01). These results suggest that the improvement in exercise tolerance seen after 6 wk of prostacyclin therapy may be ascribable to a decrease in incremental pulmonary vascular resistance during exercise.
Keywords: primary pulmonary hypertension; prostacyclin; epoprostenol; exercise testing
The recent introduction of chronic intravenous prostacyclin therapy in patients with primary pulmonary hypertension (PPH) has substantially improved the outcome of this devastating disease. Long-term prostacyclin therapy improves exercise tolerance, quality of life, and survival (1-3). The mechanisms underlying the improvement in exercise tolerance are unclear, although a decrease in the pulmonary vascular resistance (PVR) has been implicated. However, pulmonary hemodynamics during exercise have not been evaluated in patients under prostacyclin therapy. Moreover, an early improvement in exercise capacity has been reported in the absence of significant changes in resting pulmonary hemodynamics and in patients unresponsive to an acute vasodilator challenge (4-6).
In patients with pulmonary vascular diseases, PVR measurement alone may not reflect the effects of a pharmacological agent on the pulmonary circulation: the extrapolated pressure intercept of the pressure–flow plot is positive in patients with PPH (7), and consequently PVR is no longer a constant value independent of the absolute level of pulmonary artery pressure and pulmonary blood flow. Because prostacyclin increases pulmonary blood flow in most patients with PPH, a reduction in a single calculated resting PVR value can occur in the absence of an effect on the pressure–flow curve. A more reliable means of investigating pulmonary vasculature function in patients with PPH consists in establishing multipoint curves of pressure versus flow in the pulmonary arteries. We compared relations between mean pulmonary artery pressure (Ppa) and cardiac index (CI) during exercise in patients with PPH before and after 6 wk of continuous intravenous prostacyclin therapy.
The study was approved by the ethics committee of the Paris-South University, and informed consent was obtained from all the patients. Seven consecutive patients (four males and three females, mean age ± SD = 46 ± 14 yr) were studied. The diagnosis of PPH was based on the criteria of the NIH Patient Registry for Catheterization in Primary Pulmonary Hypertension (8). All patients were in (NYHA) functional class III. All patients were treated with warfarin without oral vasodilators. Patients with right-to-left interatrial shunting were excluded.
Hemodynamic evaluation was carried out with the patient supine and breathing room air, according to our standard protocol (9-11). The right heart catheter (Cordis/Sentron, Roden, the Netherlands) (12) was a 7.5-Fr, two-lumen, thermodilution, micromanometer tipped catheter with a high-fidelity transducer with a frequecy bandwith of 0 to 180 Hz (11). Cardiac output (CO) was measured in triplicate by thermodilution. Mean systemic arterial pressure was monitored continuously using an external automated blood pressure cuff (Dynamap 1800; Critikon, Tampa, FL). CI was calculated as CO divided by the body surface area. Total PVR (TPVR) was calculated as mean pulmonary artery pressure (Ppa) divided by CI. Systolic and diastolic Ppa were also determined. Pulmonary artery blood samples were taken for measurement of mixed oxygen venous saturation (SvO2 ) in resting condition. Hemodynamic variables were assessed before (baseline) and after 6 wk of prostacyclin treatment. At baseline, values were measured at rest, and before and after inhalation of an air/nitric oxide (NO, 10 ppm) mixture (11). Patients with greater than 20% reductions in TPVR and Ppa were classified as responders, as previously defined (13). After a 5-min washout period, patients were instructed to pedal at a rate of 60 rpm, the workload being increased stepwise to 15, 30, 45, and 60 W (Figure 1). Pulmonary arterial occlusion pressure (Ppao) was measured at each workload in only four patients. A 6-min walking test was performed at baseline, at 1 wk, at 6 wk, and long-term evaluations after initiation of prostacyclin.
All seven patients received a continuous infusion of prostacyclin (14). The seven patients were reevaluated after a 6-wk infusion. The mean prostacyclin dosages at 6 wk was 11 ± 1.5 ng/kg/min.
The data are expressed as means ± SD. The Wilcoxon test was used to compare resting variables at baseline and 6-wk treatment. Ppa and CI at rest and at each workload were plotted for each patient after the Ppa values were transformed using the method developed by Poon (15, 16). The best-fit line was determined by linear regression. Comparisons of the Ppa/CI slopes and zero-flow extrapolated pressure intercepts at baseline and after 6 wk of prostacyclin were done by applying covariance analysis to the transformed variables in each patient and after pooling the Ppa/CI values of the seven patients. p Values smaller than 0.05 were considered significant.
The hemodynamic variables at baseline are shown in Table 1. All patients had severe pulmonary hypertension; Ppa was 56.3 ± 5.1 mm Hg (range, 50–66 mm Hg), mean CI was 2.45 ± 0.47 L/ min/m2 (range, 1.6–3.3 L/min/m2), and mean TPVR was 23.5 ± 3.6 mm Hg/L/min/m2 (range, 20.1–30.6 mm Hg/L/min/m2). None of these patients was a responder to the NO inhalation test.
|Baseline (n = 7)||6-wk Prostacyclin (n = 7)|
|RAP, mm Hg||12.6 ± 6.5||12.5 ± 4.2|
|Psa, mm Hg||94.6 ± 8.2||91.7 ± 11.8|
|Ppa, mm Hg||56.3 ± 5.1||52.3 ± 8.2|
|Ppao, mm Hg||12.2 ± 3.4||11.3 ± 3|
|CI, L/min/m2||2.45 ± 0.47||2.62 ± 0.57|
|TPVR, mm Hg/L/min/m2||23.5 ± 3.6||20.9 ± 5.7|
|SvO2 , %||60 ± 5||64 ± 6|
|6-min walk test, m||398 ± 59||478 ± 72†|
At 6 wk, Ppa, CI, TPVR, and SvO2 measured in resting conditions showed small nonsignificant improvements (Table 1) as compared with baseline. By contrast, after 1 and 6 wk of prostacyclin therapy, exercise tolerance was significantly improved in all seven patients, and the mean distance walked in 6 min was increased by 67 ± 52 m (p = 0.046, versus baseline) and 81 ± 54 m (p = 0.0012, versus baseline), respectively (Table 1).
Four to nine data points were recorded in each patient during exercise. The relationship between Ppa and CI was rectilinear in each of the seven patients at baseline and after 6 wk of prostacyclin. The zero-flow extrapolated pressure intercepts at baseline and after 6 wk of prostacyclin were positive and superior to the Ppao in six patients. The slopes of the Ppa/CI plot significantly decreased in six patients after 6 wk of prostacyclin. When the data points from the seven patients were pooled the relations between Ppa and CI were rectilinear (Figure 2) both at baseline and after 6 wk of prostacyclin (y = 18.2x + 13.8; r = 0.95, p < 0.0001; y = 13.1x + 20.1; r = 0.96, p < 0.0001). The slope of the Ppa/CI plot was significantly decreased (Figure 2) after 6 wk of prostacyclin (18.2 versus 13.1 mm Hg/L/min/m2; p < 0.01) indicating a decrease in incremental PVR. The zero-flow extrapolated pressure intercept after prostacyclin was not significantly modified as compared with baseline. Interestingly, similar linear relations were observed between diastolic Ppa or systolic Ppa and CI during exercise testing both at baseline and after 6 wk of prostacyclin (y = 10.52x + 14.6; r = 0.96, p < 0.001; y = 7.9x + 12.3; r = 0.94, p < 0.001, for the diastolic Ppa/CI plots, and y = 23.2x + 26.1; r = 0.88, p < 0.01; y = 17.9x + 32.2; r = 0.96, p < 0.001, for the systolic Ppa/CI plots) with a significant decrease in the slopes of these plots after 6 wk prostacyclin. In addition, systolic Ppa correlated with mean Ppa pressures during exercise both at baseline and after 6 wk of prostacyclin (y = 1.56x + 1.2; r = 0.96, p < 0.0001, and y = 1.4x + 0.96; r = 0.98, p < 0.0001, respectively).
The mechanisms by which continuous intravenous prostacyclin therapy improves exercise tolerance in patients with PPH are unclear (1-3). A decrease in PVR has been reported during long-term prostacyclin therapy, and it has been suggested that this effect may explain the improved exercise tolerance (1, 4). However, the improvement in exercise tolerance begins within the first few weeks after prostacyclin initiation (3) antedating changes in resting pulmonary hemodynamics (3). In addition, exercise tolerance increases even in patients showing no acute response to NO or prostacyclin (3, 17). In our study, the patients were unresponsive to acute NO inhalation, a feature associated with unresponsiveness to acute prostacyclin (11), yet consistently showed an improvement in the 6-min walking test as early as after 1 wk of prostacyclin therapy. In keeping with earlier data (3), and in contrast to this improvement in exercise tolerance with prostacyclin, no changes were noted in TPVR or other pulmonary hemodynamic variables at rest.
This apparent discordance suggested to us that prostacyclin may affect the Ppa/CI relation during exercise without decreasing resting TPVR. In patients with PPH, TPVR values calculated as the ratio of Ppa divided by CI are misleading because the extrapolated pressure intercept of the linear portion of the pulmonary artery pressure–flow plot is positive (7, 18), and TPVR is no more a constant value independent of the levels of Ppa and CI. Therefore, the pulmonary vasculature functional state in patients with PPH is probably better described by the slope of multipoint Ppa versus CI curves (true PVR) than by a single TPVR determination at rest (18).
In each patient, as well as in the pooled data analysis, the Ppa–CI relations were linear, with a positive extrapolated pressure intercept that was consistently greater than the Ppao (Figure 2). This is consistent with previous data obtained by Janicki and coworkers (19), and suggests that Ppao should not be used as the downstream pressure in calculating PVR.
The present study is the first investigation of the pressure– flow response of the pulmonary circulation to exercise in patients with PPH treated with prostacyclin. By comparing the pressure–flow exercise response before and after 6 wk of prostacyclin therapy, we were able to demonstrate that prostacyclin consistently decreased the slope of the Ppa/CI plot, which is taken as the incremental PVR upstream from the site of the closing pressure (7, 15, 18). Because prostacyclin affected only the slope of the pressure–flow plot without changing resting pressures and flows, the extrapolated pressure intercept, which is commonly taken as the mean closing pressure (7, 15, 18), increased slightly.
These findings suggest that 6 wk of prostacyclin therapy may have affected the slope of the pressure–flow relation predominantly through a vasodilator effect. An alternative possibility may include a greater decrease in left atrial pressure during exercice with prostacyclin, than at baseline.
The correlation between systolic Ppa and Ppa during exercise suggests that noninvasive estimates of systolic Ppa during exercise might be done at intervals, to reveal whether these changes develop sooner than 6 wk.
In conclusion, this study showed that continuous prostacyclin therapy given for 6 wk to patients with PPH decreased the slope of the Ppa–CI relation in the pulmonary circulation. This may explain the early improvement in exercise tolerance seen in patients with PPH receiving prostacyclin therapy.
|1.||Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, et al.. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med3341996296302|
|2.||Higenbottam T, Wheeldon D, Wells F, Wallwork JLong-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet1198410461047|
|3.||Rubin LJ, Mendoza J, Hood M, McGoon M, Barst R, Williams WB, Diehl JH, Crow J, Long WTreatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med1121990485491|
|4.||McLaughlin VV, Genthner DE, Panella MM, Rich SReduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension [see comments]. N Engl J Med3381998273277|
|5.||Higenbottam T, Spiegelhalter D, Scott JP, Fuster V, Dinh-Xuan AT, Caine N, Wallwork JProstacyclin (epoprostenol) and heart-lung transplantation as treatments for severe pulmonary hypertension. Br Heart J701993366370|
|6.||Galie N, Ussia G, Passarelli P, Parlangeli R, Branzi A, Magnani BRole of pharmacologic tests in the treatment of primary pulmonary hypertension. Am J Cardiol75199555A62A|
|7.||Fishman AP. The respiratory system: circulation and non respiratory functions. In: Handbook of Physiology. Bethesda, MD: American Physiology Society; 1985. p. 93–166.|
|8.||Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, et al.. Primary pulmonary hypertension. A national prospective study. Ann Intern Med1071987216223|
|9.||Brenot FPrimary pulmonary hypertension. Case series from France. Chest105199433S36S|
|10.||Raffy O, Azarian R, Brenot F, Parent F, Sitbon O, Petitpretz P, Herve P, Duroux P, Dinh-Xuan AT, Simonneau GClinical significance of the pulmonary vasodilator response during short-term infusion of prostacyclin in primary pulmonary hypertension. Circulation931996484488|
|11.||Castelain V, Herve P, Lecarpentier Y, Duroux P, Simonneau G, Chemla DPulmonary artery pulse pressure and wave reflection in chronic pulmonary thromboembolism and primary pulmonary hypertension. J Am Coll Cardiol37200110851092|
|12.||Chemla D, Hebert JL, Coirault C, Salmeron S, Zamani K, Lecarpentier YMatching dicrotic notch and mean pulmonary artery pressures: implications for effective arterial elastance. Am J Physiol2711996H1287H1295|
|13.||Kneussl MP, Lang IM, Brenot FPMedical management of primary pulmonary hypertension. Eur Respir J9199624012409|
|14.||Humbert M, Sanchez O, Fartoukh M, Jagot JL, Le Gall C, Sitbon O, Parent F, Simonneau GShort-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: results of a pilot study. Eur Respir J13199913511356|
|15.||Kafi SA, Melot C, Vachiery JL, Brimioulle S, Naeije RPartitioning of pulmonary vascular resistance in primary pulmonary hypertension. J Am Coll Cardiol31199813721376|
|16.||Poon CSAnalysis of linear and mildly nonlinear relationships using pooled subject data. J Appl Physiol641988854859|
|17.||Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PSSurvival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin [see comments]. Ann Intern Med1211994409415|
|18.||McGregor M, Sniderman AOn pulmonary vascular resistance: the need for more precise definition. Am J Cardiol551985217221|
|19.||Janicki JS, Weber KT, Likoff MJ, Fishman APThe pressure-flow response of the pulmonary circulation in patients with heart failure and pulmonary vascular disease. Circulation72198512701278|