Published ahead of print on February 1, 2007, doi:10.1164/rccm.200611-1615OC
American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 846-850, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200611-1615OC
How Prostacyclin Improves Cardiac Output in Right Heart Failure in Conjunction with Pulmonary Hypertension
François Kerbaul*,1,
Serge Brimioulle*,2,
Benoît Rondelet1,
Céline Dewachter1,
Ives Hubloue1 and
Robert Naeije1
1 Laboratory of Physiology, Faculty of Medicine of the Free University of Brussels, Brussels, Belgium; and 2 Department of Intensive Care, Erasme University Hospital, Brussels, Belgium
Correspondence and requests for reprints should be addressed to Dr. R. Naeije, M.D., Ph.D. Department of Physiology, Faculty of Medicine of the Free University of Brussels, Erasme Campus, CP 604, Lennik Road 808, B-1070 Brussels, Belgium. E-mail: rnaeije{at}ulb.ac.be
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ABSTRACT
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Rationale: Prostacyclin therapy improves patients with pulmonary arterial hypertension, but whether this is attributable to an improved inotropic state of the right ventricle in addition to a decreased pulmonary arterial pulmonary vascular resistance remains unclear.
Objectives: We measured the effects of prostacyclin on load-independent measurements of right ventricular contractility in a model of load-induced acute right ventricular failure.
Methods and Results: Persistent right ventricular failure was induced in dogs by a transient (90 min) pulmonary arterial constriction. After constriction release and stabilization, intravenous prostacyclin (epoprostenol) was given at doses of 6 and 12 ng/kg/minute for 30 minutes. Pulmonary vascular resistance was assessed by pressure–flow relationships and right ventricular afterload by effective pulmonary arterial elastance. Right ventricular contractility was estimated by end-systolic elastance and right ventriculoarterial coupling efficiency by the ratio of these elastances. Transient pulmonary arterial constriction persistently increased pulmonary vascular resistance, increased arterial elastance from 1.00 ± 0.07 to 2.86 ± 0.26 mm Hg/ml, decreased end-systolic elastance from 1.11 ± 0.07 to 0.54 ± 0.02 mm Hg/ml, decreased the ratio of elastances from 1.14 ± 0.08 to 0.20 ± 0.02, and cardiac output from 4.6 ± 0.1 to 2.3 ± 0.1 L/min (p < 0.05). Epoprostenol did not affect end-systolic elastance; however, it decreased arterial elastance to 1.84 ± 0.33 mm Hg/ml, and increased the ratio of elastances to 0.46 ± 0.17 and cardiac output to 3.4 ± 0.3 L/min (p < 0.05).
Conclusions: In this model of afterload-induced right ventricular failure, prostacyclin improves right ventriculoarterial coupling and cardiac output because of vasodilating effects.
Key Words: right heart failure • contractility • heart failure • pulmonary hypertension • prostaglandins
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AT A GLANCE COMMENTARY
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Scientific Knowledge on the Subject
Prostacyclin improves pulmonary arterial hypertension, but whether this is partly explained by positive inotropic effects remains unclear.
What This Study Adds to the Field
In experimental afterload right heart failure, prostacyclin improves cardiac output and right ventricular contractility because of vasodilating effects.
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Prostacyclin therapy improves functional state, exercise capacity, quality of life, and pulmonary hemodynamics in pulmonary arterial hypertension (PAH); in addition, it has been shown to increase the survival rate in the idiopathic form of the disease (1). Beneficial effects of prostacyclin therapy in PAH are attributed to a decrease in pulmonary arterial (PA) resistance because of a decreased tone and possibly reversal of arteriolar remodeling (1). However, the decrease in PA pressures with prostacyclin therapy is modest in most studies, in contrast to significant improvements in cardiac output and exercise capacity (1–3). In addition, excessive prostacyclin dosing may induce high-output states (4). It has therefore been hypothesized that prostacyclin therapy would also benefit patients with PAH through positive inotropic effects, allowing for the afterloaded right ventricle to generate higher flow outputs, and thereby improve oxygen delivery to the tissues (4). However, the effects of prostacyclin have been reported to be variable in isolated myocardial tissue preparations (5–7). In experimental shunt-induced PAH in piglets, prostacyclin did not affect right ventricular (RV) end-systolic elastance (Ees), a load-independent parameter of myocardial contractility (8). However, in that study, RV function was well adapted to afterload as assessed by preserved Ees to effective arterial elastance (Ea) ratio (8). This may not necessarily translate to patients with PAH who present with an RV function that is decoupled from the pulmonary circulation, with typically increased Ees but a decreased Ees/Ea ratio (9). We therefore believed it to be of interest to investigate the effects of intravenous prostacyclin on RV–arterial coupling in an animal model of load-induced RV failure (10). We previously used this model to differentiate inotropic from inodilating pharmacologic effects on RV–arterial coupling (11).
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METHODS
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All experiments were approved by the Animal Ethics Committee of the Brussels Free University School of Medicine, and were done in accordance with the "Guiding Principles in the Care and Use of Animals" of the American Physiological Society.
Preparation
The study included seven mongrel dogs (mean weight, 25 kg) that were premedicated with 20 mg/kg intramuscular ketamine, anesthetized with 10 mg/kg followed by 20 mg/kg/hour intravenous propofol, and paralyzed for thoracotomy with 0.2 mg/kg followed by 0.2 mg/kg/hour intravenous pancuronium bromide. Sufentanil 20 µg was given intravenously at time of induction and again at the beginning of surgery, and 5- to 20-µg boluses were added to prevent increases in heart rate or blood pressure. Other details of the preparation have been published previously (11, 12). Briefly, the dogs were ventilated with an inspired oxygen fraction of 0.4, a positive end-expiratory pressure of 5 cm H2O, a tidal volume of 15 to 25 ml/kg, and a respiratory rate to achieve a PaCO2 of 35 to 40 mm Hg. A PA catheter (131H–7F; Baxter-Edwards, Irvine, CA) was inserted and normal saline was infused to maintain the occluded PA pressure between 5 and 10 mm Hg. Thrombus formation was prevented by 100 U/kg of intravenous heparin. A balloon catheter (Percor; Datascope Corp., Paramus, NJ) was advanced into the inferior vena cava to decrease cardiac output by reducing venous return. A left thoracotomy was performed and a 16- to 24-mm ultrasonic flow probe (T206; Transonic, Ithaca, NY) was positioned around the main pulmonary artery. Manometer-tipped catheters (SPC 350; Millar, Houston, TX) were introduced into the right ventricle and proximal pulmonary artery. Snares were placed around the right and left pulmonary arteries. The pericardium and the chest were closed.
Data Analysis
Instantaneous pressures and flow were sampled at 200 Hz. PA resistance was assessed by pressure–flow relationships obtained by rapid flow reduction (12). PA pressure values were interpolated at flows of 2 and 4 L/minute/m2 from individual regressions, and were averaged to obtain composite pressure–flow plots. A single-beat method was applied to compute RV Ees as the slope of the end-systolic pressure–volume line, PA effective elastance (Ea) as the absolute slope of the end-systolic to end-diastolic line, and ventriculoarterial coupling efficiency as the Ees/Ea ratio (13). The method is based on the nonlinear extrapolations of early and late isovolumic portions of the RV pressure curve. A maximum pressure (Pmax) is calculated that corresponds to the pressure which would generate a nonejecting RV at the same end-diastolic volume. The instantaneous PA flow is integrated to measure relative changes in RV volume. Representative recordings and derived calculations in a dog with acute RV failure before and after the institution of an infusion of prostacyclin are shown in Figure 1.
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Figure 1. Instantaneous right ventricular pressure curve, with maximum pressure calculated from nonlinear extrapolation of its isovolumic portions, and systolic portion of the right ventricular pressure–volume curve, with end-systolic elastance (Ees) and arterial elastance (Ea) lines, before (A) and after (B) an infusion of epoprostenol at 12 ng · kg–1 · minute–1 in a dog with acute right ventricular failure induced by transient pulmonary artery constriction. Prostacyclin improved ventriculoarterial coupling (Ees/Ea) essentially because of a decrease in Ea.
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Protocol
Each dataset included flow and pressure values collected at steady state for calculation of impedance and RV–PA coupling, and collected during a flow reduction maneuver for construction of pressure–flow relations. A first dataset was obtained after 30 minutes of postoperative stabilization. The two snares were then gradually pulled to constrict the pulmonary arteries and to achieve a doubling of RV systolic pressure over 15 minutes. A second dataset was obtained after 90 minutes of ensnarement. The snares were released, and a third dataset was obtained 30 minutes later. Intravenous prostacyclin (epoprostenol, Flolan; GlaxoSmithKline, Paris, France) was infused at the rate of 6 ng · kg–1 · minute–1 for 30 minutes and of 12 ng · kg–1 · minute–1 for 30 minutes, in a random sequence. The fourth and fifth datasets were obtained at the end of each 30-minute period. At the end of the experiment, an autopsy was performed to verify the position of the snares and to confirm the absence of any residual PA constriction.
Statistics
Data were expressed as mean ± SE. Results were analyzed by a repeated-measures analysis of variance followed by Fisher's exact tests. p < 0.05 was considered as statistically significant.
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RESULTS
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Arterial pH was 7.39 ± 0.01, PaCO2 was 37 ± 1 mm Hg, and PaO2 was 170 ± 25 mm Hg at baseline, and remained stable during the entire observation period.
PA Constriction
PA constriction increased PA pressure, pulmonary vascular resistance, right atrial pressure, and heart rate, and decreased cardiac output and systemic arterial pressure (Table 1). Pressure–flow plots were shifted to higher pressures (Figure 2). Ea increased from 1.00 to 5.82 mm Hg/ml, Ees decreased from 1.11 to 0.65 mm Hg/ml, and Ees/Ea markedly decreased from 1.13 to 0.12 (all p < 0.05) (Figure 3).
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Figure 2. Pulmonary arterial (PA) pressure versus cardiac output relations at baseline, during PA constriction, after PA release, and during epoprostenol infusion at 12 ng · kg–1 · minute–1 (n = 7, means ± SE). *p < 0.05 versus baseline.
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Figure 3. Right ventricular afterload (pulmonary arterial effective elastance [Ea], upper panel), right ventricular contractility (end-systolic elastance [Ees], middle panel), and ventriculoarterial coupling efficiency (Ees to Ea ratio [Ees/Ea], lower panel) at baseline, during pulmonary artery constriction (Constr.), after pulmonary artery release, and during epoprostenol infusion at 6 (Dose 1) and 12 (Dose 2) ng · kg–1 · minute–1 (n = 7, means ± SE). #p < 0.05 versus baseline;  p < 0.05 versus release.
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PA Release
PA release was associated with a correction of PA pressure (vs. baseline), whereas right atrial pressure and pulmonary vascular resistance remained increased (Table 1). Systemic arterial pressure improved but did not return to baseline. Pressure–flow plots went downwards but did not normalize (Figure 1). Ea also showed a partial reversal to 2.86 mm Hg/ml (p < 0.05), whereas Ees remained low at 0.54 mm Hg/ml. Ees/Ea also remained significantly altered (Figure 3).
Effects of Epoprostenol
Epoprostenol progressively decreased PA and right atrial pressures back to baseline values, but also decreased systemic arterial pressure, and increased heart rate and cardiac output by about 50% (Table 1). The pressure–flow relationship went further downward but did not normalize (Figure 2). Ea progressively decreased to 1.84 mm Hg/ml (p < 0.05) but did not normalize, whereas Ees remained low and unchanged. Ees/Ea remained decreased even at the higher dose of epoprostenol (Figure 2). An representative experiment showing the effects of epoprostenol is shown in Figure 1.
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DISCUSSION
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The present results show that, in acute afterload-induced RV failure, epoprostenol improves RV–arterial coupling and increases cardiac output by decreasing PA resistance, without a detectable effect on contractility.
Experimental Model
Greyson and colleagues reported that transient PAH could be used to induce a persistent RV failure in pigs (10). We confirmed this observation in dogs, and showed that RV failure was associated with an RV–arterial uncoupling resulting both from an increase in RV afterload and a decrease in RV contractility (11, 14). In this setting, dobutamine restored RV–PA coupling and cardiac output better than norepinephrine, because of more potent inotropic effect (14). Levosimendan restored RV–arterial coupling better than dobutamine, because it increased RV contractility but also reduced RV afterload (11). By allowing the separate investigation of arterial and ventricular function, the model appeared suitable to determine whether prostacyclin has positive inotropic effects in addition to its well-documented pulmonary vasodilating effects.
PA Changes
In addition to conventional measurements of PA pressure and resistance, we used pressure–flow curves to refine the measurements of resistance changes (12). In the present study, PA pressure returned close to baseline after release of PA constriction. However, the reduction of PA pressure mainly resulted from the low flow, because pressure–flow plots remained shifted to higher pressures, and Ea remained abnormal, indicating a persistent increase in RV afterload. Similar resistance and elastance changes have been reported previously, and are believed to result from an activation of stretch receptors due to the PA constriction (14).
RV Changes
In addition to conventional hemodynamic measurements, we used a single-beat method to measure Ees as a load-independent parameter of contractility, and Ees/Ea to assess the ventricular adaptation to afterload (13, 15). RV contractility decreased markedly during PA constriction, and remained altered after PA release (Ees change from 1.11 to 0.54 mm Hg/ml). Because RV afterload also remained increased after PA release (Ea change from 1.00 to 2.86 mm Hg/ml), the combination of both factors resulted in a severe and persisting deterioration of RV–PA coupling efficiency (Ees/Ea change from 1.13 to 0.20), confirming previous observations on the same model (14).
As previously discussed (10, 14), the mechanisms of persistently depressed RV function after a brief period of pressure overload remain unknown. In the present experiments, no attempt was made to maintain coronary perfusion pressure by the infusion of phenylephrine in order to exclude RV ischemia, which was previously reported to improve RV function in a model of severe acute embolic pulmonary hypertension (16). This intervention has actually been shown to worsen RV failure in patients with pulmonary hypertension, probably due to coronary or PA constriction offsetting the benefit of increased coronary driving pressure (17) Whether the decrease in systemic blood pressure relative to RV diastolic pressure was sufficient to compromise RV perfusion in the present experiments is uncertain (10, 14). Activation of enzymes or disruption of myocardial structural elements have been proposed as other possible explanations of pressure load-induced RV failure (10, 14).
Effects of Prostacyclin in Experimental Models
The effects of prostacyclin on in vitro myocardial tissue preparations have been reported to be variable with no changes (5, 7), decreases (7), or, more often, increases in contractility (6, 18–20). In intact dogs, intravenous prostacyclin decreased systemic vascular resistance and increased cardiac output, but these effects were not different from those of hydralazine, suggesting an exclusive vasodilating effect (21). However, in intact normal pigs, prostacyclin increased RV ejection fraction and Ees, suggesting a positive inotropic effect (22). But in pigs with shunt-induced PAH, prostacyclin at doses of up to 12 ng/kg/minute had no effect on RV Ees or on Ees/Ea, suggesting no intrinsic effect on RV contractility. In that study, RV–arterial coupling was maintained in the face of increased afterload, suggesting well-preserved RV function, and in keeping with the notion that ventricular adaptation to increased afterload is essentially systolic (8).
Effects of Prostacyclin in Patients with Pulmonary Hypertension
In patients with PAH, chronic intravenous prostacyclin has been shown to reduce RV size, septal displacement, and tricuspid insufficiency, indicating an improvement in RV function, but this could be entirely explained by a decreased RV afterload (23). In patients with PAH due to end-stage heart failure, prostacyclin decreased PA resistance and elastance, and systemic vascular resistance, and increased cardiac output, together with an increased left ventricular contractile element maximal velocity (24). This was interpreted by the authors as indicative of a positive inotropic effect of prostacyclin, but maximal velocity is derived from pressure differences over time (dP/dt), and is therefore similarly preload and afterload sensitive. All changes could thus be explained by pulmonary and systemic vasodilation. In prostacyclin-treated patients with idiopathic PAH, and who developed a high cardiac output, a decrease in prostacyclin dose was associated with an increase in PA resistance and a return of cardiac output to normal (4). The authors believed that these changes revealed a positive inotropic effect of prostacyclin (4). However, an alternative explanation would relate this observation to the effects of prostacyclin on PA resistance. Patients with PAH have been shown to present with RV–arterial decoupling (decreased Ees/Ea ratio) despite increased contractility (increased Ees) related to RV remodeling (9). A remodeled hypercontractile RV would be most sensitive to changes in PA resistance and associated change in afterload, thus more prone to excessive flow output with decreased PA resistance.
Prostacyclin in the Present Study
In the present study, prostacyclin decreased PA resistance and elastance, but did not affect RV contractility, so that RV–arterial coupling efficiency improved markedly (mean Ees/Ea increase from 0.20 to 0.46). This likely accounted for the observed increase in cardiac output. It is to be noted that coupling efficiency and cardiac output did not return to baseline values, because of the persistent depression in RV contractility. This is in contrast with the effects of levosimendan, an inodilating drug that has been observed in the same experimental model of afterload-induced RV failure to completely restore coupling efficiency and cardiac output (11).
Limitations
In the present study, the dose of epoprostenol was limited to 12 ng/kg/minute, in the range of the maximum tolerated dose without systemic hypotension or intolerable side effects of short-term administrations in experimental animals (8) and in patients (1–3). Markedly higher doses could have presented with direct or indirect, sympathetic nervous system–mediated effects on the RV myocardium. Also, persistent acute RV failure on sudden increases in PA pressure may not perfectly mimic end-stage failure of a remodeled ventricle in patients with end-stage PAH. Therefore, although unlikely in view of the present and previous (8) absence of detectable intrinsic RV inotropic effects of the highest tolerable dose of prostacyclin, some inotropic effect in chronically treated patients cannot be excluded. Finally, the present study did not include a placebo-treated control group. However, we and others have previously shown RV failure on a brisk increase in afterload to persist for several hours (10, 14), with no significant changes in Ees and Ea up to 90 minutes after PA constriction release (14).
Clinical Perspectives
Patients with PAH and no clinical signs of RV failure present with an increased RV contractility, but that is not sufficient to match the increased afterload caused by pulmonary vascular remodeling and tone (9). This situation is similar to that of the RV connected to the systemic arterial system in patients with congenitally corrected transposition of the great arteries, where chronic RV–systemic arterial decoupling probably heralds overt RV failure (25). Although this has not been yet investigated, it is likely that clinical RV failure in PAH would be due to aggravated RV–arterial decoupling, and eventually a decrease in RV contractility. Together, these observations may provide a rationale for inotropic interventions added to prostacyclin therapy in patients with PAH who present with RV decompensation.
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Acknowledgments
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The authors thank P. Jespers for help in the statistical analysis. Prostacyclin was kindly supplied by GlaxoSmithKline, Paris, France.
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FOOTNOTES
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Supported by the Association pour le Développement des Recherches Biologiques et Médicales (ADEREM), Marseilles, France; the Foundation for Cardiac Surgery, Brussels, Belgium; and the Fonds de la Recherche Scientifique Médicale, Brussels, Belgium (grant 3.4516.02).
* These authors contributed equally to this article. 
Originally Published in Press as DOI: 10.1164/rccm.200611-1615OC on February 1, 2007
Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
Received in original form November 9, 2006;
accepted in final form January 30, 2007
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Copyright © 2007 American Thoracic Society
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ABSTRACT
AT A GLANCE COMMENTARY