Effects of inhaled iloprost on right ventricular contractility, right ventriculo-vascular coupling and ventricular interdependence: a randomized placebo-controlled trial in an experimental model of acute pulmonary hypertension

Abstract

Introduction: Prostacyclin inhalation is increasingly used to treat acute pulmonary hypertension and right ventricular failure, although its pharmacodynamic properties remain controversial. Prostacyclins not only affect vasomotor tone but may also have cAMP-mediated positive inotropic effects and modulate autonomic nervous system tone. We studied the role of these different mechanisms in the overall haemodynamic effects produced by iloprost inhalation in an experimental model of acute pulmonary hypertension.

Methods: In this prospective, randomized, placebo-controlled animal study, twenty-six pigs (mean weight 35 +/- 2 kg) were instrumented with biventricular conductance catheters, a pulmonary artery flow probe and a high-fidelity pulmonary artery pressure catheter. The effects of inhaled iloprost (50 microg) were studied in the following groups: animals with acute hypoxia-induced pulmonary hypertension, and healthy animals with and without blockade of the autonomic nervous system.

Results: During pulmonary hypertension, inhalation of iloprost resulted in a 51% increase in cardiac output compared with placebo (5.6 +/- 0.7 versus 3.7 +/- 0.8 l/minute; P = 0.0013), a selective reduction in right ventricular afterload (effective pulmonary arterial elastance: 0.6 +/- 0.3 versus 1.2 +/- 0.5 mmHg/ml; P = 0.0005) and a significant increase in left ventricular end-diastolic volume (91 +/- 12 versus 70 +/- 20 ml; P = 0.006). Interestingly, right ventricular contractility was reduced after iloprost-treatment (slope of preload recruitable stroke work: 2.2 +/- 0.5 versus 3.4 +/- 0.8 mWatt.s/ml; P = 0.0002), whereas ventriculo-vascular coupling remained essentially preserved (ratio of right ventricular end-systolic elastance to effective pulmonary arterial elastance: 0.97 +/- 0.33 versus 1.03 +/- 0.15). In healthy animals, inhaled iloprost had only minimal haemodynamic effects and produced no direct effects on myocardial contractility, even after pharmacological blockade of the autonomic nervous system.

Conclusions: In animals with acute pulmonary hypertension, inhaled iloprost improved global haemodynamics primarily via selective pulmonary vasodilatation and restoration of left ventricular preload. The reduction in right ventricular afterload is associated with a paradoxical decrease in right ventricular contractility. Our data suggest that this reflects an indirect mechanism by which ventriculo-vascular coupling is maintained at the lowest possible energetic cost. We found no evidence for a direct negative inotropic effect of iloprost.

Figure 1

Assessment of right ventricular contractility by pressure-volume loop analysis. Presented are RV pressure-volume loops (dotted lines) in one representative animal at (a) baseline, in (b) pulmonary hypertension, and (c) 5 minutes after inhalation of iloprost. These were obtained during a controlled preload reduction by occlusion of the inferior caval vein. The end-systolic pressure-volume relationship is obtained by fitting a regression line (solid line) through the points of maximal (end-systolic) elastance, delineated for each cardiac cycle with grey circles. The induction of pulmonary hypertension elicits an immediate increase in RV contractility (as indicated by the increase in the slope of the end-systolic pressure-volume relationship), which serves the right ventricle to preserve pump performance without changing preload in the face of high afterload conditions (homeometric autoregulation). Conversely, treatment of pulmonary hypertension with inhaled iloprost obviates the need for homeometric autoregulation and allows the right ventricle to return to its baseline (lower) contractile state. RV, right ventricular.

Figure 2

The effects of inhaled iloprost on MPAP. The panels show the characteristic experimental time course, with a maximum pulmonary vasodilating effect immediately after inhalation and a duration of action of approximately 30 minutes. The data are expressed as mean ± standard deviation. *P < 0.05 versus BL; ^†P < 0.05 versus before inhalation; ^‡P < 0.05, ILO versus C (adjusted for multiple comparisons). In addition, P values of the repeated measures analysis of variance are shown separately for the time, group and interaction (time × group) effects. BL, baseline; C, control; ILO, iloprost; INT, interaction; MPAP, mean pulmonary artery pressure; PHT, pulmonary hypertension.

Figure 3

The effects of inhaled iloprost on RV afterload and contractility in animals with PHT. (a) RV afterload is illustrated with effective pulmonary arterial elastance (PA-Ea), and (b) the slopes of the PQ relationships in the PA. RV contractility is shown as (c) Mw and (d) Emax. Data are expressed as mean ± standard deviation. *P < 0.05 versus BL; ^†P < 0.05 versus before inhalation; ^‡P < 0.05, ILO versus C (adjusted for multiple comparisons). In addition, P values of the repeated measures analysis of variance are shown separately for the time, group and INT (time × group) effects. BL, baseline; C, control; Ea, effective arterial elastance; Emax, slope of the end-systolic pressure-volume relationship; ILO, iloprost; INT, interaction; Mw, slope of the preload-recruitable stroke work relationship; PHT, pulmonary hypertension; PA, pulmonary artery; PQ, pressure-flow; RV, right ventricular.

Figure 4

The effects of inhaled iloprost on ventricular interdependence. Shown are the effects of inhaled iloprost on end-diastolic and endsystolic volumes in the (a) right ventricle and (b) left ventricle in animals with PHT. Data are expressed as mean ± standard deviation. *P < 0.05 versus BL; ^†P < 0.05 versus before inhalation; ^‡P < 0.05, ILO versus C (adjusted for multiple comparisons). In addition, P values of the repeated measures analysis of variance are shown separately for the time, group and INT (time × group) effects. BL, baseline; EDV, end-diastolic volume; ESV, end-systolic volume; ILO, iloprost; INT, interaction; LV, left ventricular; PHT, pulmonary hypertension; RV, right ventricular.

Figure 5

The effects of inhaled iloprost on RV afterload and contractility in animals with and without blockade of the ANS. RV afterload is illustrated by (a) effective pulmonary arterial elastance (PA-Ea) and (b) the slopes of the PQ relationships in the PA. RV contractility is shown as (c) Mw and (d) Emax. Data are expressed as mean ± standard deviation. *P < 0.05 versus BL (adjusted for multiple comparisons). In addition, P values of the repeated measures analysis of variance are shown separately for the time, group and INT (time × group) effects. ANS, autonomous nervous system; BL, baseline; Ea, effective arterial elastance; Emax, slope of the end-systolic pressure-volume relationship; INT, intraction; Mw, slope of the preload-recruitable stroke work relationship; PA, pulmonary artery; PQ, pressure-flow; RV, right ventricular.