This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hinderliter, A. L. Articles by Long, W. A. Search for Related Content PubMed PubMed Citation Articles by Hinderliter, A. L. Articles by Long, W. A.

(Circulation. 1997;95:1479-1486.)
© 1997 American Heart Association, Inc.

Articles

Effects of Long-term Infusion of Prostacyclin (Epoprostenol) on Echocardiographic Measures of Right Ventricular Structure and Function in Primary Pulmonary Hypertension

Alan L. Hinderliter, MD; Park W. Willis, IV, MD; Robyn J. Barst, MD; Stuart Rich, MD; Lewis J. Rubin, MD; David B. Badesch, MD; Bertron M. Groves, MD; Michael D. McGoon, MD; Victor F. Tapson, MD; Robert C. Bourge, MD; Bruce H. Brundage, MD; Spencer K. Koerner, MD; David Langleben, MD; Cesar A. Keller, MD; Srinivas Murali, MD; Barry F. Uretsky, MD; Gary Koch, PhD; Shu Li, MS; Linda M. Clayton, PharmD; Maria M. Jöbsis, BA; Shelmer D. Blackburn, Jr, BA; James W. Crow, PhD; Walker A. Long, MD; for the Primary Pulmonary Hypertension Study Group¹

From the Departments of Medicine (A.L.H., P.W.W.), Pediatrics (W.A.L.), and Biostatistics (G.K., S.L.), University of North Carolina, Chapel Hill; Department of Pediatrics (R.J.B.), College of Physicians and Surgeons, Columbia University, New York, NY; Departments of Medicine, University of Illinois at Chicago (S.R.); University of Maryland (L.J.R.), Baltimore; University of Colorado Health Sciences Center (D.B.B., B.M.G.), Denver; Mayo Clinic Medical Center (M.D.M.), Rochester, Minn; Duke University Medical Center (V.F.T.), Durham, NC; University of Alabama (R.C.B.), Birmingham; Harbor-UCLA Medical Center (B.H.B.), Torrance, Calif; Cedars Sinai Medical Center (S.K.K.), Los Angeles, Calif; Sir Mortimer B. Davis Jewish General Hospital (D.L.), McGill University, Montreal, Quebec, Canada; Baylor College of Medicine (C.A.K.), Houston, Tex; and Presbyterian-University Hospital (S.M., B.F.U.), University of Pittsburgh, Pa; GlaxoWellcome Inc (L.M.C., M.M.J., S.D.B.), Research Triangle Park, NC; and Cato Research, Ltd (J.W.C.), Research Triangle Park, NC.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Background Right heart failure is an important cause of morbidity and mortality in primary pulmonary hypertension. In a recent prospective, randomized study of severely symptomatic patients, treatment with prostacyclin (epoprostenol) produced improvements in hemodynamics, quality of life, and survival. This article describes the echocardiographic characteristics of participants in this trial; the relationships of echocardiographic variables to hemodynamic parameters, exercise capacity, and quality of life; and the echocardiographic changes associated with prostacyclin therapy.

Methods and Results The 81 patients enrolled in this multicenter trial were randomized to treatment with a long-term infusion of prostacyclin in addition to conventional therapy (n=41) or conventional therapy alone (n=40) for 12 weeks. Echocardiograms and assessments of hemodynamics, exercise capacity, and quality of life were performed before and after the treatment phase. On baseline evaluation, patients had marked right ventricular dilatation and dysfunction, abnormal septal curvature, and significant tricuspid regurgitation with a high regurgitant velocity. Pericardial effusions were common. More pronounced abnormalities in right heart structure and function were associated with higher pulmonary arterial and mean right atrial pressures, lower cardiac index, and impaired exercise capacity but had no predictable relationship to quality-of-life indicators. The 12-week infusion of prostacyclin had beneficial effects on right ventricular size, curvature of the interventricular septum, and maximal tricuspid regurgitant jet velocity.

Conclusions The echocardiographic manifestations of severe primary pulmonary hypertension reflect abnormalities in hemodynamics and exercise capacity. Prostacyclin has beneficial effects on right heart structure and function that may contribute to the clinical improvement and prolonged survival observed with this drug.

Key Words: hypertension, pulmonary • heart failure • prostacyclin

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Primary pulmonary hypertension is a disease of uncertain origin characterized by increased pulmonary vascular resistance and elevated pulmonary arterial pressure. Morbidity and mortality are in large part due to the consequent abnormalities in cardiac structure and function.^{1 2} These abnormalities include right ventricular enlargement and hypertrophy, depressed right ventricular function and low cardiac output, elevated pulmonary arterial and right atrial pressures, tricuspid regurgitation, an abnormal interaction between right and left ventricles, and pericardial effusion.^{3 4 5 6} Ultimately, right heart failure is the cause of death in approximately two thirds of patients with primary pulmonary hypertension.^{2 7}

Several recent studies^{8 9 10 11} evaluated a potential role for prostacyclin (epoprostenol) in the treatment of primary pulmonary hypertension. Prostacyclin is the principal product of arachidonic acid in all vascular tissues¹² and mediates many important biological functions. In addition to acting as a potent vasodilator,¹³ it is an effective inhibitor of platelet aggregation^{14 15 16} and smooth muscle proliferation^{17 18} and may therefore inhibit the thrombosis and pulmonary vascular medial hypertrophy characteristic of primary pulmonary hypertension. In a prospective, randomized, parallel study of prostacyclin plus conventional therapy versus conventional therapy alone in severely symptomatic patients, prostacyclin resulted in improved hemodynamics, exercise capacity, quality of life, and survival.¹¹ In the present study, we describe the following: (1) the baseline echocardiographic indexes of right heart structure and function in patients enrolled in this trial; (2) the relationship of Doppler estimates to invasive measurements of pulmonary arterial systolic pressure; (3) the relationships of baseline echocardiographic variables to hemodynamic parameters, exercise capacity, functional class, and other quality-of-life indicators; and (4) the echocardiographic changes associated with prostacyclin therapy.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Patients
After giving their informed consent, 81 patients were enrolled in this multicenter, randomized, open-label comparison of the safety and efficacy of long-term prostacyclin infusion plus conventional therapy versus conventional therapy alone in the treatment of severe primary pulmonary hypertension. The clinical diagnosis of primary pulmonary hypertension was established in all patients before entry into the study by use of the criteria from the National Institutes of Health Patient Registry for the Characterization of Primary Pulmonary Hypertension.¹ All patients were markedly symptomatic (New York Heart Association [NYHA] class III or class IV) despite the attempted use of vasodilators.

Study Protocol
The study was approved by the institutional review committee of each participating center. Details of the protocol were described in a previous publication.¹¹ A baseline echocardiogram was performed on day 1 of the study. Exercise capacity was assessed by use of the unencouraged 6-minute walk test, an objective measure of functional status under conditions approximating daily living.¹⁹ Quality of life was evaluated by use of the Chronic Heart Failure Questionnaire,²⁰ the Nottingham Health Profile,²¹ and the dyspnea-fatigue rating,²² each of which generates scores in up to six categories of physical or emotional function. On day 2, catheterization of the right side of the heart and a dose-ranging study were performed to measure baseline hemodynamics and determine the maximal tolerated dose of prostacyclin for each patient.

After baseline measurements and the dose-ranging study, subjects were randomized to receive prostacyclin in addition to conventional therapy (n=41) or conventional therapy alone (n=40) for 12 weeks. Patients in the prostacyclin-treatment group received a continuous infusion of prostacyclin through a permanent intravenous catheter by use of a portable infusion pump. Those randomized to conventional therapy alone were treated with the optimal combination of oral vasodilators, supplemental oxygen, cardiac glycosides, and diuretics, as determined by individual investigators. Except for one patient in each treatment group, all subjects were given warfarin for anticoagulation. Repeat evaluations were performed after 12 weeks of therapy.

Imaging Protocol
Two-dimensional and Doppler ultrasound examinations were performed on the baseline evaluation and at the end of the 12-week treatment phase with the use of a defined imaging protocol. All studies were recorded on VHS videocassettes. To the extent possible, the studies from each individual center were performed on the same machine and by the same sonographer. Patients were imaged during quiet respiration in the left lateral decubitus position. Parasternal and apical two-dimensional views were obtained, with the transducer orientation and gain settings adjusted to optimally define the endocardial surface of each cardiac chamber. Color Doppler examinations were performed at a pulse-repetition frequency of 4 Hz, with gain adjusted so that static background noise was barely perceptible. Continuous-wave Doppler recordings of tricuspid regurgitation were obtained from the apical window.

All studies were digitized and analyzed with the use of an off-line quantification system. Interpretations were performed by a single observer from the core echocardiography laboratory who was unaware of each patient's clinical history or treatment assignment. Measurements were made on three representative beats and the results averaged.

The following variables were analyzed:

1. The right ventricular end-diastolic area was measured in the apical four-chamber view by tracing the endocardial edges of the right ventricle and the plane of the tricuspid valve at end diastole. This area was divided by height to correct for differences in body size. Images were considered technically adequate if no dropout in the endocardial outlines along the interventricular septum and right ventricular free wall was observed. Right ventricular size was characterized as a planar area rather than calculated volume because derivation of volumes would necessitate geometric assumptions about the right ventricle that may be inaccurate in patients with chronic pulmonary hypertension.

2. The right ventricular percent change in area was calculated from the areas of the right ventricle in end diastole (EDA) and end systole (ESA) as Right Ventricular Percent Change in Area=100x(EDA-ESA)/EDA. This measure of right ventricular function correlates closely with right ventricular ejection fraction as measured by radionuclide angiography.²³

3. The eccentricity index, a measure of the degree of septal displacement, was measured at end diastole and end systole from parasternal short-axis views of the left ventricle at the level of the chordae tendineae. This was calculated by the method of Ryan et al²⁴ as Eccentricity Index=D2/D1, where D2 is the minor-axis dimension of the left ventricle parallel to the septum and D1 is the minor-axis diameter perpendicular to and bisecting the septum.

4. The pericardial effusion size was determined from parasternal long-axis and short-axis views. Effusions were graded and assigned a score as follows: absent (score=0); trace (score=1; separation of pericardial layers in both systole and diastole); small (score=2; diastolic separation <1 cm); moderate (score=3; diastolic separation of 1 to 2 cm); or large (score=4; diastolic separation >2 cm).

5. The tricuspid regurgitant jet area was measured in the apical four-chamber view. Frame-by-frame analysis of each cardiac cycle was used to identify the maximum area of the color flow Doppler jet. The outline of the regurgitant signal was traced and the area determined by computerized planimetry. Previous investigators²⁵ demonstrated that this area is closely correlated with the severity of tricuspid regurgitation measured by a double thermodilution technique.

6. The maximal tricuspid regurgitant jet velocity, an index of the systolic pressure gradient between the right ventricle and right atrium,²⁶ was measured by determining the peak regurgitant velocity in the continuous-wave Doppler flow profile obtained from the cardiac apex. Only Doppler signals resulting in a clearly defined envelope of velocities were considered suitable for analysis. With the use of a modified Bernoulli equation and assumption of a right atrial systolic pressure of 14 mm Hg, pulmonary arterial systolic pressure was estimated as 4V²+14, where V is maximal tricuspid regurgitant jet velocity.

Measurements of right ventricular end-diastolic area, right ventricular percent change in area, diastolic and systolic eccentricity indexes, pericardial effusion size, and tricuspid regurgitant jet area were made on echocardiograms of 40 healthy young adults without significant cardiopulmonary disease who participated in an unrelated study. This normal control group consisted of 30 women and 10 men aged 34±1 years (mean±SE).

The reproducibility of individual measurements and derived variables at the core laboratory was determined from repeated interpretations of 17 baseline echocardiograms (one selected at random from each participating center). The difference (mean±SE) between the two interpretations was as follows: 1.4±0.2 cm²/m for indexed right ventricular end-diastolic area; 4.7±0.1% for right ventricular percent change in area; 0.15±0.02 for systolic eccentricity index; 0.07±0.01 for diastolic eccentricity index; 0.9±0.2 cm² for tricuspid regurgitant jet area; and 0.08±0.01 m/s for maximal tricuspid regurgitant jet velocity.

Data Analysis
Mean±SE values for baseline demographic features, hemodynamic measurements, and echocardiographic variables were calculated for the patients in the two treatment arms, and the significance levels of differences between groups were evaluated with two-sample t tests. Similarly, differences in echocardiographic measurements between normal control subjects and patients in each treatment arm were evaluated by two-sample t tests and Wilcoxon rank sum tests. A two-sided value of P<.05 was considered statistically significant.

The accuracy of noninvasive estimates of pulmonary arterial systolic pressure was evaluated by assessing the relation of Doppler estimates to invasive measurements with the use of a Pearson correlation and corresponding probability value. The associations of measures of right heart structure and function with the severity of primary pulmonary hypertension were evaluated through Spearman's rank correlations of baseline echocardiographic values with baseline hemodynamic parameters (pulmonary arterial mean pressure, mean right atrial pressure, and cardiac index), distance walked in 6 minutes, and quality-of-life scores. In addition, changes in echocardiographic variables between baseline and 12-week examinations were correlated with changes in hemodynamic measurements and 6-minute walk results. For correlational analyses with multiple comparisons (ie, echocardiographic measurements versus hemodynamic parameters or quality-of-life indicators), the significance was adjusted to P<.01. Differences in echocardiographic variables between NYHA class III and class IV patients were evaluated with two-sample t tests.

The strategy for analyzing differences in treatment effect was defined before enrollment of patients. Three patients (two assigned to conventional therapy and one treated with prostacyclin) underwent lung transplantation during the study and were excluded from this analysis. The changes from baseline to treatment values of each echocardiographic parameter were calculated for individual patients in whom technically adequate studies were available at baseline and at 12 weeks. Patients who died during the trial were assigned the least desirable change scores, ie, the largest negative changes for right ventricular percent change in area and the largest positive changes for the other measures. A second analysis excluded all patients who died. The median changes in each variable were calculated for the prostacyclin and conventional therapy groups. Comparisons between groups were made with the Wilcoxon rank sum test, with a two-sided value of P<.05 considered statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Baseline Demographic Characteristics, Hemodynamic Measurements, and Echocardiographic Values in Study Subjects
Forty-one patients were randomized to prostacyclin plus conventional therapy and 40 to conventional therapy alone. Baseline demographic features, hemodynamic values, and 6-minute walk results of the patients in each treatment arm are shown in Table 1. There were no significant differences between the two groups in any of these parameters.

View this table: [in this window] [in a new window]   Table 1. Baseline Demographic and Hemodynamic Characteristics by Treatment Group

Baseline echocardiographic values for patients in the two treatment groups and for normal control subjects are noted in Table 2. Echocardiograms were of adequate technical quality for quantification of right ventricular size and function, septal curvature, pericardial effusion size, and tricuspid regurgitation severity in at least 75 patients, and the maximal tricuspid regurgitant jet velocity was measurable in 70. In comparison to normal control subjects, patients with primary pulmonary hypertension had marked right ventricular dilatation, severely depressed right ventricular contractile function, marked septal displacement in both diastole and systole, and a greater likelihood of having a pericardial effusion. All but 2 patients with primary pulmonary hypertension had tricuspid regurgitation that could be detected by color Doppler imaging in the apical four-chamber view. The maximal tricuspid regurgitant jet velocity was markedly elevated, reflecting the high pulmonary arterial systolic pressure. There were no clinically important or statistically significant differences in any of these variables between patients randomized to prostacyclin plus conventional therapy and those who received conventional therapy alone.

View this table: [in this window] [in a new window]   Table 2. Baseline Echocardiographic Features of Patients (by Treatment Group) and Control Subjects

Relationship of Doppler Estimates to Invasive Measurements of Pulmonary Arterial Systolic Pressure
Doppler estimates and invasive measurements of pulmonary arterial systolic pressure were significantly correlated (r=.57, P<.0001; see Figure). When an assumed right atrial systolic pressure of 14 mm Hg was used, Doppler estimates tended to underestimate pulmonary arterial pressure; the mean difference between Doppler and invasive measurements was 11±2 mm Hg, and invasive measurements exceeded Doppler estimates by >20 mm Hg in 31% of patients.

View larger version (19K): [in this window] [in a new window]   Figure 1. Correlation of Doppler estimates of pulmonary arterial systolic pressure with measurements obtained during right heart catheterization. Doppler estimates were calculated as 4V2+14, where V is maximal tricuspid regurgitant jet velocity. The two measures were significantly correlated (r=.57, P<.001), although the Doppler method tended to underestimate pressures. The dotted line represents the line of identity. PA indicates pulmonary arterial.

To evaluate the accuracy of Doppler echocardiography in measuring changes in pulmonary arterial pressure associated with long-term therapy in individual patients, the Doppler estimate of the change in each patient's pulmonary arterial systolic pressure during the 12-week treatment period was compared with the change measured invasively. There was no significant correlation between Doppler and invasive measurements of this change in the 53 patients in whom the relevant values were available.

Relationships of Baseline Echocardiographic Measures to Baseline Hemodynamics, Exercise Capacity, and Quality of Life
The associations of echocardiographic variables with invasive hemodynamic measurements at baseline are illustrated in Table 3. Higher pulmonary arterial mean pressures were associated with more pronounced abnormalities in the septal curvature and depressed right ventricular contractile function. Weaker correlations of marginal statistical significance (P<.05) were noted between pulmonary arterial mean pressure and both right ventricular size and pericardial effusion size. Mean right atrial pressure was significantly related to right ventricular size, diastolic eccentricity index, pericardial effusion size, and tricuspid regurgitation severity. Cardiac index was inversely correlated with diastolic eccentricity index, pericardial effusion size, and tricuspid regurgitant jet area. There were no significant correlations between changes in hemodynamic parameters and changes in echocardiographic measures during the 12-week treatment phase.

View this table: [in this window] [in a new window]   Table 3. Spearman's Rank Correlation Coefficients Relating Baseline Echocardiographic Variables to Hemodynamic Parameters

Exercise capacity, expressed as the distance walked in 6 minutes, was correlated with several baseline echocardiographic measures. As shown in Table 4, subjects with a poor performance on the 6-minute walk before randomization were characterized by a greater degree of right ventricular dilatation, more pronounced septal displacement in diastole, larger pericardial effusions, and more severe tricuspid regurgitation. The change in 6-minute walk results between baseline and 12-week evaluations was inversely related to the changes in diastolic eccentricity index (r=-.32, P<.05) and pericardial effusion size (r=-.26, P<.05).

View this table: [in this window] [in a new window]   Table 4. Spearman's Rank Correlation Coefficients Relating Baseline Echocardiographic Variables to Distance Walked in 6 Minutes

Baseline quality-of-life indicators were not consistently related to echocardiographic variables. The dyspnea-fatigue score was correlated with pericardial effusion size (r=.36, P=.001), and patients with NYHA class IV symptoms were more likely to have pericardial effusions than those in NYHA class III (P<.01). Otherwise, no significant associations between quality-of-life measures and echocardiographic indexes of right heart structure and function were noted.

Effects of Treatment With Prostacyclin on Echocardiographic Measures
A comparison of changes in echocardiographic and Doppler variables during treatment in the prostacyclin and conventional therapy groups is shown in Table 5. Eight subjects in the conventional therapy group died during the treatment phase and were assigned the least desirable ranked changes from baseline. The causes of death in these patients were progressive right heart failure in 6, cardiac arrest in 1, and pulmonary hemorrhage in 1. None of the patients treated with prostacyclin plus conventional therapy died. Depending on the variable analyzed, echocardiographic data were available at baseline and after 12 weeks of therapy in 30 to 38 patients assigned to conventional therapy alone and in 32 to 36 subjects in the prostacyclin-treatment group.

View this table: [in this window] [in a new window]   Table 5. Changes in Echocardiographic Variables by Treatment Group

During the 12-week course of treatment, subjects in the conventional therapy group had a greater increase in right ventricular end-diastolic area than those treated with prostacyclin. Therapy with prostacyclin was also associated with improvement of the eccentricity index in both diastole and systole and with a decrease in the maximal tricuspid regurgitant jet velocity. There was a trend toward a beneficial effect of prostacyclin on the tricuspid regurgitant jet area, although this difference did not reach statistical significance (P=.1). No significant effects of treatment on right ventricular percent change in area or pericardial effusion size were noted.

When data were analyzed excluding the eight patients who died during the trial, the improvement in the diastolic eccentricity index associated with prostacyclin therapy remained statistically significant (P<.05), and directionally favorable differences were still present in right ventricular end-diastolic area, tricuspid regurgitant jet area, and maximal tricuspid regurgitant jet velocity.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Echocardiographic Features of Patients With Primary Pulmonary Hypertension
This is the largest reported series of patients with severe primary pulmonary hypertension with detailed echocardiographic assessments of right heart structure and function. Previous studies^{1 5 6} in patients with this disease described right ventricular enlargement on M-mode or two-dimensional echocardiograms. In the participants in the present trial, the indexed area of the right ventricle imaged from the apical window (a measure of right ventricular chamber size) was more than twice that observed in normal control subjects. Right ventricular contractile function was severely depressed, as evidenced by the low mean percent change in right ventricular area. These results suggest that severe primary pulmonary hypertension is usually accompanied by marked right ventricular dilatation and contractile dysfunction.

Abnormalities of the curvature of the interventricular septum are an echocardiographic hallmark of right ventricular pressure and volume overload. When the transseptal pressure gradient is altered by elevated right ventricular pressures, the left ventricular cavity is distorted by leftward displacement of the septum.²⁴ This alteration in ventricular geometry is associated with abnormal left ventricular filling dynamics in patients with primary pulmonary hypertension.⁴ The patients in the present study had marked abnormalities in the septal curvature, both at end diastole and at end systole, reflecting elevated right ventricular pressures in both phases of the cardiac cycle.

The majority of the patients in the present trial also had pericardial effusions. Similar findings have been reported by Park et al²⁷ in a group of patients with severe chronic pulmonary hypertension due primarily to thromboembolic disease and by Eysmann et al³ in patients with primary pulmonary hypertension. The cause of these effusions is uncertain, but they may result from impaired drainage of the myocardium due to high venous and lymphatic pressures, an explanation that is supported by the correlation of effusion size with mean right atrial pressure.

Functional tricuspid regurgitation is a manifestation of right ventricular and tricuspid annular dilatation and was detected in all but two of the study participants. The severity of tricuspid regurgitation was approximated as the maximal area of the color flow Doppler signal. Although the spatial distribution of regurgitant flow is influenced by flow velocity as well as by technical and methodological factors,^{28 29} previous investigators^{25 30} demonstrated a close correlation between the regurgitant jet area and independent measures of tricuspid regurgitation. On the basis of data from the study of Mugge et al,²⁵ the mean tricuspid regurgitant jet area of 9.3 cm² in patients with primary pulmonary hypertension corresponds to a regurgitant fraction >25%.

Doppler Estimates of Pulmonary Arterial Systolic Pressure
Several previous investigators^{26 31} reported very close correlations between direct measurements of pulmonary arterial systolic pressure and noninvasive estimates based on continuous-wave Doppler measurements of the maximal tricuspid regurgitant jet velocity. Other studies^{32 33} in subjects with chronic obstructive lung disease or with severe pulmonary hypertension of other causes suggest that technically adequate signals are difficult to obtain in some patients and that pulmonary arterial pressure is underestimated by the Doppler technique. The regurgitant velocity was measurable in 70 of the 81 patients enrolled in the present trial and permitted a reasonable quantitative assessment of pulmonary arterial systolic pressure. Nonetheless, pulmonary arterial pressure was significantly underestimated by this method in some patients. The discrepancy between Doppler and invasive measurements may have been due in part to the spontaneous variability of pulmonary arterial pressure. Doppler studies and pulmonary arterial catheterization were not performed simultaneously, and pulmonary arterial systolic pressure varies over a range exceeding 20 mm Hg in resting, unstimulated patients.^{34 35} Our results might also have been improved if the regurgitant jet velocity had been measured from multiple acoustic windows or if an angle correction had been applied.³⁶ The lack of a significant correlation between Doppler and invasive measurements of pulmonary arterial pressure changes during the 12-week treatment phase may be attributable to the narrow range of changes observed. The absolute change in pulmonary arterial systolic pressure averaged 9±1 mm Hg (equivalent to a change of <0.3 m/s in maximal tricuspid regurgitant jet velocity) and exceeded 20 mm Hg in only 4 of 53 patients. Our data suggest that Doppler echocardiography is useful in estimating the severity of pulmonary hypertension but may not reliably quantify small changes in pulmonary arterial pressure in individual patients.

Relationships of Right Heart Structure and Function to Hemodynamics, Exercise Capacity, and Quality of Life
Echocardiographic measures of right heart structure and function were examined in relation to hemodynamic indexes of the severity of primary pulmonary hypertension, exercise capacity, NYHA functional class, and quality-of-life indicators. Patients with higher pulmonary arterial and mean right atrial pressures and depressed cardiac index had echocardiographic evidence of more severe right heart disease. Similarly, significant inverse correlations were noted between the distance walked in 6 minutes and right ventricular size, diastolic eccentricity index, severity of tricuspid regurgitation, and pericardial effusion size. In general, however, functional class and quality-of-life indicators did not correlate with echocardiographic measures.

These results suggest that cardiac manifestations of primary pulmonary hypertension develop in parallel with increasing pulmonary arterial pressure and may be responsible in part for the impaired exercise capacity associated with this disease. In contrast, subjective perceptions of the impact of illness, as measured by quality-of-life scores, are influenced by a number of innate and environmental factors that may obscure small differences in the severity of physiological abnormalities. The lack of a strong association of quality-of-life scores with indexes of cardiac dysfunction has also been described in patients with congestive heart failure.³⁷

Effects of Treatment With Prostacyclin on Right Ventricular Structure and Function
Despite the interest in treatment of primary pulmonary hypertension with vasodilator therapy and the recognized importance of right ventricular dysfunction in determining the clinical manifestations of this disease, the effects of vasodilating agents on right heart structure and function have not been studied extensively. Rich and Brundage⁵ reported a reduction in right ventricular chamber size and normalization of the systolic interventricular septal curvature in a small, highly selected group of patients treated with calcium channel blockers. Similarly, Barst³⁸ observed an improvement in the curvature of the interventricular septum and demonstrable improvement in right ventricular function in selected patients treated with calcium antagonists or phenoxybenzamine.

The present study is the first to evaluate the cardiac effects of long-term intravenous prostacyclin in patients with primary pulmonary hypertension. Continuous infusion of prostacyclin for 12 weeks in patients with primary pulmonary hypertension resulted in improved hemodynamics, exercise capacity, quality of life, and survival.¹¹ Our data suggest that prostacyclin also had important beneficial effects on right heart structure and function. Compared with patients randomized to conventional therapy, patients treated with prostacyclin had a lower maximal tricuspid regurgitant jet velocity, less right ventricular dilatation, and an improved curvature of the interventricular septum and exhibited a trend toward less tricuspid regurgitation.

Summary
The present study demonstrates that severe primary pulmonary hypertension results in abnormalities of the right heart that reflect the degree of hemodynamic derangement and magnitude of impaired exercise capacity. Treatment with long-term intravenous prostacyclin, a potent vasodilator that also inhibits platelet aggregation and smooth muscle proliferation, results in beneficial changes in right heart structure and function. Because right ventricular failure is an important determinant of the morbidity and mortality associated with primary pulmonary hypertension, the effects of prostacyclin on cardiac function may contribute to the improved survival and exercise capacity observed in patients treated with this drug.

	Acknowledgments

 
This study was supported in part by GlaxoWellcome Inc, Research Triangle Park, NC. Dr Rubin is the recipient of an academic award in vascular disease from the National Heart, Lung, and Blood Institute. Dr Badesch is the recipient of a clinical investigator award from the National Institutes of Health. The authors gratefully acknowledge the contributions of the study coordinators, pharmacists, and sonographers who participated in this trial. We also thank Virginia Smith for preparation of the manuscript.

	Footnotes

 
Reprint requests to Alan L. Hinderliter, MD, Division of Cardiology, CB #7075, 338 Burnett-Womack, University of North Carolina, Chapel Hill, NC 27599-7075.

¹ For a complete list of participants in the Primary Pulmonary Hypertension Study Group, please see the "Appendix."

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Participants in the Primary Pulmonary Hypertension Study Group included: Robyn J. Barst, MD, Evelyn Horn, MD, and Jillian Kirkpatrick, RN, Columbia-Presbyterian Medical Center, New York, NY; David B. Badesch, MD, Bertron Groves, MD, and Kristine Wynne, RN, University of Colorado Health Sciences Center, Denver; Robert C. Bourge, MD, and Wanda Knight, RN, University of Alabama Medical Center, Birmingham; Bruce H. Brundage, MD, Demetrious Georgiou, MD, and Joy Beckman, RN, Harbor-UCLA Medical Center, Torrance, Calif; William R. Clarke, MD, David Ralph, MD, and Patsy Schrader, RN, MN, Children's Hospital and University Hospital, University of Washington, Seattle; Edgar J. Caldwell, MD, William Williams, MD, and Beth Vogel, RN, Maine Medical Center, Portland; Neil A. Ettinger, MD, and Denise Canfield, RN, Barnes Hospital, Washington University, St Louis, Mo; Nicholas S. Hill, MD, and Carol Carlisle, RN, Rhode Island Hospital, Providence; Alan Hinderliter, MD, and Park W. Willis IV, MD, University of North Carolina Hospitals, Chapel Hill; Cesar A. Keller, MD, Adaani E. Frost, MD, and Katie Chafizedah, RN, Methodist Hospital, Baylor College of Medicine, Houston, Tex; Spencer K. Koerner, MD, David Ross, MD, and Debbie Claire, RN, Cedars Sinai Medical Center, Los Angeles, Calif; David Langleben, MD, and Eileen Shalit, RN, Sir Mortimer B. Davis Jewish Hospital, McGill University, Montreal, Quebec, Canada; Michael D. McGoon, MD, Brooks Edwards, MD, Cathy Severson, RN, and Kay Kosberg, RN, Mayo Clinic Medical Center, Rochester, Minn; Srinivas Murali, MD, Barry F. Uretsky, MD, and Tammy Tokarczyk, RN, Presbyterian-University Hospital, University of Pittsburgh, Pa; Stuart Rich, MD, and Lisa Kaufman, RN, University of Illinois at Chicago; Lewis J. Rubin, MD, and Lori Hartle, RN, University of Maryland School of Medicine, Baltimore; Warren R. Summer, MD, Bennett deBoisblanc, MD, and Brenda Everett, RN, Charity Hospital, Louisiana State University Medical Center, New Orleans; and Victor F. Tapson, MD, and Abby Krichman, RRT, Duke University Medical Center, Durham, NC.

Participating sonographers included: Margaret Challenger, Columbia-Presbyterian Medical Center; Kathy Blanchard, University of Colorado Health Sciences Center; Po Phan, MD, University of Alabama Medical Center; John Linden, Harbor-UCLA Medical Center; Heidi Meida and Sarah Wright, Children's Hospital and University Hospital, University of Washington; Lenard Loiselle, Maine Medical Center; Al Wagoner and Julio Perez, MD, Barnes Hospital, Washington University; Kate Davis, Rhode Island Hospital; Laura Formella, Cedars Sinai Medical Center; George Honos, MD, and Roberta Yapp, Sir Mortimer B. Davis Jewish Hospital, McGill University; Barbara Nichols McAllister, Mayo Clinic Medical Center; Connie Matesic, Presbyterian-University Hospital, University of Pittsburgh; Theresa Biners, University of Illinois; Sharon White, University of Maryland School of Medicine; and Katherine Kisslo, Duke University Medical Center.

Received June 24, 1996; revision received November 4, 1996; accepted November 14, 1996.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 

1. Rich S, Dantzker DR, Ayres SM, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, Levy PC, Reid LM, Vreim CE, Williams GW. Primary pulmonary hypertension: a national prospective study. Ann Intern Med. 1987;107:216-223.
   
2. Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70:580-587.
   
3. Eysmann SB, Palevsky HI, Reichek N, Hackney K, Douglas PS. Two-dimensional and Doppler-echocardiographic and cardiac catheterization correlates of survival in primary pulmonary hypertension. Circulation. 1989;80:353-360.
   
4. Louie EK, Rich S, Levitsky S, Brundage BH. Doppler echocardiographic assessment of impaired left ventricular filling in patients with right ventricular pressure overload due to primary pulmonary hypertension. J Am Coll Cardiol. 1986;8:1298-1306.
   
5. Rich S, Brundage BH. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation. 1987;76:135-141.
   
6. Goodman DJ, Harrison DC, Popp RL. Echocardiographic features of primary pulmonary hypertension. Am J Cardiol. 1974;33:438-443.
   
7. D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, Levy PS, Pietra GG, Reid LM, Reeves JT, Rich S, Vreim CE, Williams GW, Wu M. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med. 1991;115:343-349.
   
8. Higenbottam T, Wells F, Wheeldon D, Wallwork J. Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet. 1984;1:1046-1047.
   
9. Rubin LJ, Mendoza J, Hood M, McGoon M, Barst R, Williams WB, Diehl JH, Crow J, Long W. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of a randomized trial. Ann Intern Med. 1990;112:485-491.
   
10. Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. 1994;121:409-415.
    
11. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn SD, Shortino D, Crow JW, for the Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996;334:296-301.
    
12. Bunting S, Gryglewski R, Moncada S, Vane JR. Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of mesenteric and coeliac arteries and inhibits platelet aggregation. Prostaglandins. 1976;12:897-913.
    
13. Moncada S, Vane JR. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A₂, and prostacyclin. Pharmacol Rev. 1978;30:293-331.
    
14. Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976;263:663-665.
    
15. Ubatuba FB, Moncada S, Vane JR. The effect of prostacyclin (PGI₂) on platelet behaviour: thrombus formation in vivo and bleeding time. Thromb Haemost. 1979;41:425-435.
    
16. Szczeklik A, Gryglewski RJ, Nizankowski R, Musial J, Pieton R, Mruk J. Circulatory and anti-platelet effects of intravenous prostacyclin in healthy men. Pharmacol Res Commun. 1978;10:545-556.
    
17. Willis AL, Smith DL, Vigo C, Kluge AF. Effects of prostacyclin and orally active stable mimetic agent RS-93427-007 on basic mechanisms of atherogenesis. Lancet. 1986;2:682-683.
    
18. Hajjar DP. Prostaglandins and cyclic nucleotides: modulators of arterial cholesterol metabolism. Biochem Pharmacol. 1985;34:295-300.
    
19. Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor DW, Berman LB. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J. 1985;132:919-923.
    
20. Guyatt GH, Nogradi S, Halcrow S, Singer J, Sullivan MJJ, Fallen E. Development and testing of a new measure of health status for clinical trials in heart failure. J Gen Intern Med. 1989;4:101-107.
    
21. Hunt SM, McEwen J, McKenna SP. The Nottingham Health Profile User's Manual: Measuring Health Status. London, UK: Croom Helm; 1986.
    
22. Feinstein AR, Fisher MB, Pigeon JG. Changes in dyspnea-fatigue ratings as indicators of quality of life in the treatment of congestive heart failure. Am J Cardiol. 1989;64:50-55.
    
23. Kaul S, Tei C, Hopkins JM, Shah PM. Assessment of right ventricular function using two-dimensional echocardiography. Am Heart J. 1984;107:526-531.
    
24. Ryan T, Petrovic O, Dillon JC, Feigenbaum H, Conley MJ, Armstrong WF. An echocardiographic index for separation of right ventricular volume and pressure overload. J Am Coll Cardiol. 1985;5:918-924.
    
25. Mugge A, Daniel WG, Herrmann G, Simon R, Lichtlen PR. Quantification of tricuspid regurgitation by Doppler color flow mapping after cardiac transplantation. Am J Cardiol. 1990;66:884-887.
    
26. Berger M, Haimowitz A, Van Tosh A, Berdoff RL, Goldberg E. Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound. J Am Coll Cardiol. 1985;6:359-365.
    
27. Park B, Dittrich HC, Polikar R, Olson L, Nicod P. Echocardiographic evidence of pericardial effusion in severe chronic pulmonary hypertension. Am J Cardiol. 1989;63:143-145.
    
28. Sahn DJ. Instrumentation and physical factors related to visualization of stenotic and regurgitant jets by Doppler color flow mapping. J Am Coll Cardiol. 1988;12:1354-1365.
    
29. Simpson IA, Valdes-Cruz LM, Sahn DJ, Murillo A, Tamura T, Chung KJ. Doppler color flow mapping of simulated in vitro regurgitant jets: evaluation of the effects of orifice size and hemodynamic values. J Am Coll Cardiol. 1989;13:1195-1207.
    
30. Rivera JM, Vandervoort PM, Vazquez de Prada JA, Mele D, Karson TH, Morehead A, Morris E, Weyman A, Thomas JD. Which physical factors determine tricuspid regurgitation jet area in the clinical setting? Am J Cardiol. 1993;72:1305-1309.
    
31. Chow LC, Dittrich HC, Hoit BD, Moser KM, Nicod PH. Doppler assessment of changes in right-sided cardiac hemodynamics after pulmonary thromboendarterectomy. Am J Cardiol. 1988;61:1092-1097.
    
32. Tramarin R, Torbicki B, Marchandise B, Laaban JP, Morpugo M. Doppler echocardiographic evaluation of pulmonary artery pressure in chronic obstructive pulmonary disease: a European multicentre study. Eur Heart J. 1991;12:103-111.
    
33. Brecker SJD, Gibbs JSR, Fox KM, Yacoub MH, Gibson DG. Comparison of Doppler derived haemodynamic variables and simultaneous high fidelity pressure measurements in severe pulmonary hypertension. Br Heart J. 1994;72:384-389.
    
34. Richards AM, Ikram H, Crozier IG, Nicholls MG, Jans S. Ambulatory pulmonary arterial pressure in primary pulmonary hypertension: variability, relation to systemic arterial pressure, and plasma catecholamines. Br Heart J. 1990;63:103-108.
    
35. Rich S, D'Alonzo GE, Dantzker DR, Levy PS. Magnitude and implications of spontaneous hemodynamic variability in primary pulmonary hypertension. Am J Cardiol. 1985;55:159-163.
    
36. Hamer HPM, Takens BL, Posma JL, Lie KI. Noninvasive measurement of right ventricular systolic pressure by combined color-coded and continuous-wave Doppler ultrasound. Am J Cardiol. 1988;61:668-671.
    
37. Gorkin L, Norvell NK, Rosen RC, Charles E, Shumaker SA, McIntyre KM, Capone RJ, Kostis J, Niaura R, Woods P, Hosking J, Garces C, Handberg E, Ahern DK, Follick MJ, for the SOLVD Investigators. Assessment of quality of life as observed from the baseline data of the Studies Of Left Ventricular Dysfunction (SOLVD) trial quality-of-life substudy. Am J Cardiol. 1993;71:1069-1073.
    
38. Barst RJ. Pharmacologically induced pulmonary vasodilation in children and young adults with primary pulmonary hypertension. Chest. 1986;89:497-503.
    

This article has been cited by other articles:

				C. E. Ventetuolo, R. L. Benza, A. J. Peacock, R. T. Zamanian, D. B. Badesch, and S. M. Kawut Surrogate and Combined End Points in Pulmonary Arterial Hypertension Proceedings of the ATS, July 15, 2008; 5(5): 617 - 622. [Abstract] [Full Text] [PDF]

				G. Reiter, U. Reiter, G. Kovacs, B. Kainz, K. Schmidt, R. Maier, H. Olschewski, and R. Rienmueller Magnetic Resonance-Derived 3-Dimensional Blood Flow Patterns in the Main Pulmonary Artery as a Marker of Pulmonary Hypertension and a Measure of Elevated Mean Pulmonary Arterial Pressure Circ Cardiovasc Imaging, July 1, 2008; 1(1): 23 - 30. [Abstract] [Full Text] [PDF]

				J.G. Coghlan and J. Davar How should we assess right ventricular function in 2008? Eur. Heart J. Suppl., December 1, 2007; 9(suppl_H): H22 - H28. [Abstract] [Full Text] [PDF]

				N. Galie, A. Manes, M. Palazzini, L. Negro, S. Romanazzi, and A. Branzi Pharmacological impact on right ventricular remodelling in pulmonary arterial hypertension Eur. Heart J. Suppl., December 1, 2007; 9(suppl_H): H68 - H74. [Abstract] [Full Text] [PDF]

				F. Kerbaul, S. Brimioulle, B. Rondelet, C. Dewachter, I. Hubloue, and R. Naeije How Prostacyclin Improves Cardiac Output in Right Heart Failure in Conjunction with Pulmonary Hypertension Am. J. Respir. Crit. Care Med., April 15, 2007; 175(8): 846 - 850. [Abstract] [Full Text] [PDF]

				A. Fischer, S. Misumi, D. Curran-Everett, R. T. Meehan, S. K. Ulrich, J. J. Swigris, S. K. Frankel, G. P. Cosgrove, D. A. Lynch, and K. K. Brown Pericardial Abnormalities Predict the Presence of Echocardiographically Defined Pulmonary Arterial Hypertension in Systemic Sclerosis-Related Interstitial Lung Disease Chest, April 1, 2007; 131(4): 988 - 992. [Abstract] [Full Text] [PDF]

				S. Dellegrottaglie, J. Sanz, M. Poon, J. F. Viles-Gonzalez, R. Sulica, M. Goyenechea, F. Macaluso, V. Fuster, and S. Rajagopalan Pulmonary Hypertension: Accuracy of Detection with Left Ventricular Septal-to-Free Wall Curvature Ratio Measured at Cardiac MR Radiology, April 1, 2007; 243(1): 63 - 69. [Abstract] [Full Text] [PDF]

				M. K. Steiner, I. R. Preston, J. R. Klinger, G. J. Criner, A. B. Waxman, H. W. Farber, and N. S. Hill Conversion to bosentan from prostacyclin infusion therapy in pulmonary arterial hypertension: a pilot study. Chest, November 1, 2006; 130(5): 1471 - 1480. [Abstract] [Full Text] [PDF]

				G B Bleeker, P Steendijk, E R Holman, C-M Yu, O A Breithardt, T A M Kaandorp, M J Schalij, E E van der Wall, J J Bax, and P Nihoyannopoulos Acquired right ventricular dysfunction Heart, April 1, 2006; 92(suppl_1): i14 - i18. [Full Text] [PDF]

				C. J. Lettieri, S. D. Nathan, S. D. Barnett, S. Ahmad, and A. F. Shorr Prevalence and Outcomes of Pulmonary Arterial Hypertension in Advanced Idiopathic Pulmonary Fibrosis Chest, March 1, 2006; 129(3): 746 - 752. [Abstract] [Full Text] [PDF]

				B. D. Hoit, N. D. Dalton, S. C. Erzurum, D. Laskowski, K. P. Strohl, and C. M. Beall Nitric oxide and cardiopulmonary hemodynamics in Tibetan highlanders J Appl Physiol, November 1, 2005; 99(5): 1796 - 1801. [Abstract] [Full Text] [PDF]

				J. G. Esposito, S. G. Thomas, L. Kingdon, and S. Ezzat Anabolic growth hormone action improves submaximal measures of physical performance in patients with HIV-associated wasting Am J Physiol Endocrinol Metab, September 1, 2005; 289(3): E494 - E503. [Abstract] [Full Text] [PDF]

				L. J. Rubin and D. B. Badesch Evaluation and Management of the Patient with Pulmonary Arterial Hypertension Ann Intern Med, August 16, 2005; 143(4): 282 - 292. [Abstract] [Full Text] [PDF]

				M. Oikawa, Y. Kagaya, H. Otani, M. Sakuma, J. Demachi, J. Suzuki, T. Takahashi, J. Nawata, T. Ido, J. Watanabe, et al. Increased [18F]Fluorodeoxyglucose Accumulation in Right Ventricular Free Wall in Patients With Pulmonary Hypertension and the Effect of Epoprostenol J. Am. Coll. Cardiol., June 7, 2005; 45(11): 1849 - 1855. [Abstract] [Full Text] [PDF]

				E. Bossone, B. D. Bodini, A. Mazza, and L. Allegra Pulmonary Arterial Hypertension: The Key Role of Echocardiography Chest, May 1, 2005; 127(5): 1836 - 1843. [Abstract] [Full Text] [PDF]

				Task Force members, N. Galie, A. Torbicki, R. Barst, P. Dartevelle, S. Haworth, T. Higenbottam, H. Olschewski, A. Peacock, G. Pietra, et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension: The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology Eur. Heart J., December 2, 2004; 25(24): 2243 - 2278. [Full Text] [PDF]

				O. Sitbon, V. Gressin, R. Speich, P. S. Macdonald, M. Opravil, D. A. Cooper, T. Fourme, M. Humbert, J.-F. Delfraissy, and G. Simonneau Bosentan for the Treatment of Human Immunodeficiency Virus-associated Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., December 1, 2004; 170(11): 1212 - 1217. [Abstract] [Full Text] [PDF]

<