(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
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.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
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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
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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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 studies8 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 aggregation14 15 16 and smooth muscle proliferation17 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.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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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.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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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
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There were no significant differences between the two groups in any of
these parameters.
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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.
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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.
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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.
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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).
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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.
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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.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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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 studies1 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 investigators25 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 investigators26 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 studies32 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.
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Acknowledgments |
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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.
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Footnotes |
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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." 
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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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.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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