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(Chest. 2004;125:572-579.)
© 2004 American College of Chest Physicians

Effects of Epoprostenol on Right Ventricular Hypertrophy and Dilatation in Pulmonary Hypertension*

Roald J. Roeleveld, MD; Anton Vonk-Noordegraaf, MD, PhD; J. Tim Marcus, PhD; Jean G. F. Bronzwaer, MD; Koen M. J. Marques, MD; Pieter E. Postmus, MD, PhD and Anco Boonstra, MD, PhD, FCCP

* From the Departments of Pulmonology (Drs. Roeleveld, Vonk-Noordegraaf, Postmus, and Boonstra), Physics and Medical Technology (Dr. Marcus), and Cardiology (Drs. Bronzwaer and Marques), VU University Medical Center, Amsterdam, The Netherlands.

Correspondence to: R. J. Roeleveld, MD, Department of Pulmonology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; e-mail: a.vonk{at}VUmc.nl


   Abstract
TOP
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objectives: To gain more knowledge of changes in main pulmonary artery flow and right ventricular mass and volumes in patients with pulmonary hypertension during epoprostenol therapy.

Methods: Eleven patients (9 women) were evaluated before the start of therapy and every 4 months thereafter. Right and left ventricular volumes and masses were measured by cine MRI. Flow was measured with MRI velocity quantification. At the same times, 6-min walking tests were performed. Right-heart catheterizations were performed at baseline and after 1 year.

Results: Right ventricular mass in the patient group was significantly higher from that in a control group of healthy volunteers (95 ± 26 g vs 42 ± 10 g, p < 0.05 [mean ± SD]), whereas the stroke volume was lower (34 ± 11 mL vs 81 ± 11 mL, p < 0.05). The greatest improvement in right ventricular stroke volume (to 41 ± 11 mL, p < 0.05) took place in the first 4 months. During the 1-year follow-up, right ventricular end-diastolic volume and mass did not change, and mean pulmonary artery pressure remained nearly stable at 55 mm Hg at baseline and 53 mm Hg after 1 year. Pulmonary vascular resistance decreased by 12.5% (p = 0.06).

Conclusions: From these data we conclude that epoprostenol lowers pulmonary vascular resistance, leading to an increase in pulmonary artery flow. This increase in pulmonary artery flow corresponds well with the increase in 6-min walking distance and can be noninvasively monitored by MRI (flow quantification). Right ventricular dilatation and hypertrophy are not reversed by epoprostenol therapy, but do not progress either.

Key Words: MRI • pulmonary hypertension • right ventricular function


   Introduction
TOP
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Primary pulmonary hypertension (PPH) is a rare, progressive, and fatal disease. Continuous administration of epoprostenol improves survival and exercise tolerance in patients with PPH.1 2 3 Clinical experience shows that most of the improvement takes place in the first few months of treatment. The mechanism underlying this improvement is not yet fully understood.

As reported by Barst et al,4 the clinical improvement induced by epoprostenol in patients with PPH is correlated to an increase in pulmonary blood flow and not to pulmonary artery pressures (PAPs). The increase in flow may be caused by a decreased afterload or an increased preload of the right ventricle (RV). Positive inotropic effects of epoprostenol must not be excluded.

Measurement of blood flow in the pulmonary artery to obtain right ventricular stroke volume (RVSV) may therefore be a valid way of monitoring the hemodynamic effects of epoprostenol in patients with PPH. Such measurements can be performed noninvasively using MRI velocity quantification. Cine MRI also yields information on the origin of changes in stroke volume by measuring end-diastolic and end-systolic ventricular volumes, and changes in ventricular mass during treatment. The aim of the study was to examine the effects of epoprostenol on RVSV, as well as the structure and function of the heart in a 1-year follow-up of 11 patients with PPH.


   Patients and Methods
TOP
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Study Subjects and Functional Status
The study protocol was approved by the institutional ethics review commission. Eleven consecutive patients (9 women; aged 31 to 74 years) with PPH gave informed consent to be included in our study. Multiple investigations, including transthoracic and transesophageal echocardiography, were performed to rule out any causes for a secondary pulmonary hypertension in these patients, following the algorithm of Gaine and Rubin.5

The functional status of the patients was assessed by the consulting pulmonologist using the New York Heart Association (NYHA) classification every 4 months. The unencouraged 6-min walking test was administered by a pulmonary function technician, and was performed just before the start of epoprostenol therapy and repeated every 4 months thereafter. MRI measurements were performed in 11 healthy age- and sex-matched control subjects to obtain reference values.

MRI Acquisition
A Siemens 1.5 T ‘Vision’ whole-body scanner (Siemens Medical Systems; Erlangen, Germany) was used, using a quadruple phased-array circularly polarized body coil with two receiver antennas locally applied on the anterior chest wall, and two on the posterior chest wall. RVSV was quantified by MRI velocity mapping in the main pulmonary artery. An image plane was positioned perpendicular to the main pulmonary artery. A two-dimensional, gradient-echo pulse sequence was used with excitation angle of 25° and echo time of 5 ms. One-dimensional velocity encoding was perpendicular to the image plane (and thus parallel to the flow in the main pulmonary artery). The phase encoding steps of two different acquisitions (repetition time of 12 ms) were interleaved, one with velocity encoding of phase and one without. Subtracting of the resulting phase maps compensated for phase changes caused by inhomogeneity of the magnetic field, leaving only phase changes related to velocity. The temporal resolution within the cardiac cycle was thus 2 x 12 ms = 24 ms. The velocity sensitivity was set at 150 cm/s, by proper adjustment of the amplitude of the velocity-encoding gradients. Field of view was 225 x 360 mm, and matrix size was 140 x 256. The R-R interval and heart rate were registered during the MRI acquisition of this flow map.

Additionally, short-axis (SA) cines were acquired covering the whole left ventricle (LV) and RV for volume and mass measurements. By using the end-diastolic cine frame of a four-chamber view, a series of parallel SA image planes was defined starting at the base of the LV and RV, and encompassing the entire LV and RV from base to apex. The most basal image plane was positioned close to the transition of ventricular myocardium to the atria, ensuring that also the most basal part of the ventricles was covered. At every SA plane, a breathhold cine acquisition was then performed. For the cine imaging, a gradient-echo pulse sequence was applied with segmented k space, 7 Ky lines per heartbeat, and a data-acquisition window of 80 ms. Echo sharing (or "view sharing") was used, yielding a temporal frame at every 40 ms. Slice thickness was 6 mm and interslice gap 4 mm, yielding a slice distance of 10 mm. The full protocol has been described in earlier studies6 7 8 and has proven its feasibility even in severely dyspneic patients. MRI scans were made in the same week as the first catheterizations, and after 4 months, 8 months, and 1 year of treatment.

MRI Postprocessing
RVSV was calculated as follows: in each time frame of the velocity images, the cross-sectional area of the artery was delineated by hand in order to account for translations of the artery with respect to the image plane. No aliasing due to high peak systolic velocities was encountered. Volumetric flow (in milliliters per second) was obtained in each time frame by multiplying the spatial mean velocity (in centimeters per second) with the cross-sectional area (centimeters squared). Finally, integrating the volumetric flow curve over systole yielded the RVSV (stroke volume in milliliters). Cardiac output measured by MRI velocity mapping (COMRI) is heart rate times stroke volume.

The SA images were processed using the MASS software package (Department of Radiology, Leiden University Medical Center; Leiden, the Netherlands). End diastole (ED) was defined as the first temporal frame directly after the R-wave of the ECG. End systole (ES) was defined as the temporal frame at which the image showed the smallest LV cavity area, usually 240 to 320 ms after the R-wave. Epicardial and endocardial contours were traced, and the papillary muscles were excluded from the ventricular volume and included with the ventricular mass. Because of the ventricular shortening, at least one more image slice at the base was needed at ED than at ES to encompass the complete ventricles. If the most basal image at ES was difficult to interpret (due to eg, partial volume effects), then this most basal plane was projected on the ES frame of the four-chamber cine images. The resulting projection line on this four-chamber image then provided the decisive clue, on whether or not to include the ES SA image as a part of the LV or RV.

For both ventricles, the end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated by summation of the product of area x slice distance for all slices. Ejection fraction (EF) was calculated as follows: EF = (EDV - ESV)/EDV x 100%. The LV and RV end-diastolic mass were obtained from the volume of the ventricular muscle tissue, multiplied with the specific weight of muscle tissue, which is 1.05 g/cm3. The septum was included with the LV mass, and thus RV mass refers to the mass of the RV free wall.

Invasive Measurements
All patients underwent right-heart catheterization to obtain the right ventricular EDP (RVEDP) and right ventricular systolic pressure (RVSP) and PAP. Cardiac output was measured invasively using the Fick method (COFICK). Oxygen consumption was measured within 24 h before or after the catheterization, using an on-line analyzer (max 6200; SensorMedics; Yorba Linda, CA) connected to a mouthpiece. Sampling took place over a period of 5 min, preceded by 10 min of absolute rest in a quiet room. During the measurement, the patients were wearing a nose clamp, and supplemental oxygen was temporarily discontinued. Blood samples were taken during the catheterization from the pulmonary and femoral arteries and saturation analyzed with a whole-blood oximeter (Oxicom 2000; Waters Instruments; Plymouth, MA) Total pulmonary vascular resistance (TPVR) was calculated from the COFICK and PAP.

Directly after the right-heart catheterization, all patients underwent acute vasodilator testing. The vasodilators used were oxygen (100%) and epoprostenol, in a dose-escalation scheme of 5-min periods with 2, 4, 6, 8, 10, and 12 ng/kg/min. At each step, PAP and systemic BP were recorded as well as COFICK and TPVR calculated. A drop in mean PAP of > 20% was considered reversible pulmonary hypertension. After 1 year (range, 11 to 15 months) of treatment, a second right-heart catheterization was performed.

Data Analysis
All analyses were performed using the SPSS statistical software package (Release 9.0.1; SPSS; Chicago, IL). Unless mentioned otherwise, all data were summarized as mean ± SD. The Wilcoxon signed rank test was used to compare baseline data with data obtained after 4, 8, and 12 months of treatment. Mann-Whitney U tests were used to compare study results with reference values; p < 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Clinical Status and Treatment
The baseline characteristics of the 11 patients are summarized in Table 1 . During the vasodilator test, none of the patients showed a >= 20% fall in PAP on epoprostenol. At the start of treatment, after the first catheterization and MRI scan, all patients received 4 ng/kg/min of epoprostenol. Additional therapy consisted of oral anticoagulation with a vitamin K antagonist, diuretics and, if required, oxygen to maintain an arterial PO2 > 60 mm Hg. The epoprostenol dose was adapted during the study period using a regime of linear increase in time, based on earlier studies9 and previous clinical experience. This lead to an average increase of 1.6 ng/kg/min/mo, which is a common regime.9 10 For the continuous IV drug delivery, permanently implanted port systems and cassette pumps were used (Port-a-Cath and CADD-1; SIMS-Deltec; St. Paul, MN).


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  		Table 1.. Clinical Status, Invasive Hemodynamics, and MRI Velocity Quantification-Based Pulmonary Artery Flow (n = 11)*

 
One patient died unexpectedly, shortly before completing the 1-year follow-up period. In a postmortem examination, a cerebral hemorrhage was considered the most likely cause of death. This patient was included in the study up to the 8-month follow-up measurements. The remaining 10 patients completed the 1-year follow-up period of this study.

At the start of the study, seven patients were NYHA class III and four were NYHA class IV. After 4 months, seven of the patients had improved one NYHA class, and the remaining four patients remained stable. Between 4 months and 8 months, three patients improved by one class. Between 8 months and 1 year, no further improvement was found. The distances covered during the 6-min walking test showed significant improvement in the first 4 months of treatment, with only minor changes thereafter (Table 1) .

Pulmonary Artery Flow
In total, 43 MRI scans were made. In two patients, the scans after 4 months and 8 months of follow-up could not be performed because of logistical reasons.

Figure 1 shows the flow patterns in the main pulmonary artery measured in one patient during 1-year follow-up. In all subjects, a biphasic flow pattern during systole was observed. At baseline, the mean RVSV was 34 ± 11 mL, considerably lower than the reference value of 70 mL (Fig 2 ). The stroke volume increased to 41 ± 11 mL (p < 0.05) within the first 4 months, to 45 ± 14 mL (p < 0.05) after 8 months, and 46 ± 14 mL (p < 0.05) after 1 year (significances when comparing each of the follow-up measurements with baseline; differences between the three follow-up measurements were not significant).



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  		Figure 1.. Changes in flow by MRI flow quantification in the main pulmonary artery during epoprostenol therapy in one patient. Each curve represents one cardiac cycle, and is an average of 140 heartbeats. The flow curve after 8 months of therapy was almost identical to the one after 1 year, and is therefore not shown.

 


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  		Figure 2.. Relationship between RVSV, by MRI velocity quantification, and 6MWD. Displayed are the mean values, the SEMs (error bars), and the correlation line (dotted). The error bars at the 8-month point are not drawn for reasons of legibility.

 
Without any significant change of mean heart rate throughout the study (Fig 3 , bottom left), this increase in stroke volume lead to an equal increase in COMRI. Within the first 4 months, COMRI increased from an average of 3.0 to 3.5 L/min (p < 0.05). COMRI increased further to 3.7 L/min after 8 months and 4.0 L/min after 1 year (both p < 0.05 compared to baseline). Again, there were no significant differences between the follow-up measurements.



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  		Figure 3.. Hemodynamic data. Each dot represents an individual patient; the horizontal lines represent the mean. Top left: RV-EDV changes during the study. Top right: RVSV by flow mapping changes in time. Bottom left: Heart rate as recorded during the acquisition of the RVSV flow maps. Bottom right: mPAP as found at the baseline catheterization and after 1 year of therapy.

 
Ventricular Masses and Volumes
Table 2 shows that the LV wall mass of 133 g was close to the normal value. The average RV wall mass of 95 g was significantly higher than the normal value of 41 g in healthy subjects (p < 0.05). The masses of both ventricles did not change during the follow-up period. Compared to the reference value, the LV showed a substantially decreased average EDV, whereas the average ESV was normal (Table 2) . In comparison to the reference values, the RV had a substantially increased EDV and ESV. An example of the large EDV is shown in Figure 4 . During the 1-year follow-up, RVEDV did not change significantly. Figure 3 shows the change in RVEDV (Fig 3 , top left) as well as RVSV (Fig 3 , top right).


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  		Table 2.. Calculations of Ventricular Volumes and Masses Based on the SA MRI Scans of the 10 Patients Who Completed the Study*

 


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  		Figure 4.. MRIs of the heart in SA orientation at ED. The images were made at baseline (top left) as well as 4 months (top right), 8 months (bottom left), and 1 year (bottom right) of therapy. At baseline, note the enlarged RV and the disturbed geometry of the interventricular septum. At 1 year of therapy, the septum shows a more normal shape with bowing to the right.

 
Invasive Measurements
At the initial catheterizations, mean PAP (mPAP) ranged from 46 to 64 mm Hg (average, 55 ± 7 mm Hg). At the second catheterization, average mPAP was 53 ± 9 mm Hg (p = not significant). However, changes in both directions were observed in individual patients (Fig 3 , bottom right).

COFICK at baseline was 4.1 ± 0.9 L/min, and 4.7 ± 1.5 L/min after 1 year (p < 0.05). Although COFICK was significantly higher than COMRI (p < 0.05), the correlation between both measurements was good (R = 0.81). Average TPVR was 1121 ± 373 dyne·s·cm-5 at baseline and 981 ± 401 dyne·s·cm-5 at the end of our study (p = 0.06).


   Discussion
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The performance of the heart per time unit is determined by four factors: heart rate, preload, afterload, and contractility. In patients with pulmonary hypertension, malperformance of the RV is the main cause of death, and improvement of this performance leads to a longer life expectancy. In our study population at baseline, heart rate, PAP, and TPVR were elevated, and RVSV was below normal. After 1 year of therapy with epoprostenol, heart rate and PAP had not changed, and TPVR showed a decrease of 12.5%, consistent with earlier studies.3 4 11 The increase of RVSV took place without increasing the RV EDV or RVEDP. In terms of cardiac performance, our findings imply that the increase in stroke volume cannot be explained by a change in preload.

In our patients, we found a significant increase in 6-min walking distance (6MWD) during the first 4 months of treatment. After the first 4 months, the clinical and hemodynamic status seemed to stabilize. Castelain et al12 showed that a decrease in incremental pulmonary vascular resistance during exercise, which is not automatically reflected by a decrease in TPVR measured during rest, might also contribute to the improved exercise tolerance during the first months of treatment. Although we did not measure the PAP/cardiac index relation during exercise in our patients, the significant increase in RVSV that appeared to be closely related to the improvement of the 6MWD indicate that RVSV measured during resting conditions reflects these changes in the pulmonary vascular bed.

Direct measurement of RVSV by MRI velocity quantification is a sensitive, noninvasive method of detecting hemodynamic changes in these patients. Pulmonary and tricuspid valve insufficiencies may result in a certain overestimation of the cardiac output when using invasive techniques13 14 or volumetric calculations by deducting ESV from EDV. These latter measurements are also complicated by the fact that placement of the most basal slice of the SA images has a large influence on the calculated volumes. Furthermore, the postprocessing steps of selecting the correct ES time frame and tracing the inner contours of the ventricles was done manually for each individual image, undoubtedly introducing some measurement error. Therefore, it is our opinion that the difference between RV EDV and RV ESV, calculated using the SA images, may not be seen as a reliable measurement of changes in stroke volume.

MRI velocity mapping in the main pulmonary artery yields the forward flow to the lungs, irrespective of tricuspid valve insufficiency, and can be corrected for any back flow due to pulmonary valve insufficiency. Because of the high accuracy both in vitro as in vivo, MRI velocity mapping has been proposed as the "gold standard" to quantify blood flow.15 The high reproducibility also enables studies to be performed on small patient groups,16 a great advantage in a rare disease as PPH.

The biphasic systolic flow patterns in the main pulmonary artery found in the PPH patients have earlier been identified by Bogren et al,17 and other studies18 19 state that abnormal flow patterns may be indicative for PH. The cause of this phenomenon is uncertain, but it may be related to a lack of compliance of the pulmonary vascular bed. Although pressure-wave analysis has been found to be of clinical value in pulmonary hypertension patients,15 17 18 19 20 extensive flow-wave analysis has not been performed in these patients until now. The clinical implications of the flow patterns in patients with pulmonary hypertension require further investigation.

RV EDV as well as RV ESV in our patients are significantly larger than the reference values, and do not change during 1 year of therapy; RV mass was found to be over twice the reference value. Neither RV EDV nor RV mass did increase further, as would have been expected in untreated patients. However, there are no historical data available on untreated patients followed over a 1-year period, based on the same methods.

The LV EDV is substantially decreased. LV ESV is within a normal range, indicating insufficient filling of the LV due to the small RVSV found in these patients. The left ventricular EF increased slightly, but the underlying mechanism remains unclear. Possible mechanisms are improved pump function by increased contractility, or complex systolic right-left ventricular interactions leading to an altered left systolic function.21

In conclusion, during 1 year of epoprostenol therapy in patients with pulmonary hypertension, the PAP as well as RV dilatation and hypertrophy did not change, whereas RVSV (measured by means of MRI velocity quantification) increased. Most improvement in RVSV, NYHA classification, and 6MWD took place in the first 4 months of therapy. The increase in RVSV corresponded well with the functional improvement, and was consistent with decreased pulmonary vascular resistance at 1-year follow-up.


   Acknowledgements
 
The authors thank Th. J. C. Faes, J-W. Lankhaar, and N. Westerhof for their valuable comments.


   Footnotes
 
Abbreviations: COFICK = cardiac output measured invasively using the Fick method; COMRI = cardiac output measured by MRI velocity mapping; ED = end diastole; EDV = end-diastolic volume; EF = ejection fraction; ES = end systole; ESV = end-systolic volume; LV = left ventricle; mPAP = mean pulmonary artery pressure; NYHA = New York Heart Association; PAP = pulmonary artery pressure; PPH = primary pulmonary hypertension; RV = right ventricle; RVEDP = right ventricular end-diastolic pressure; RVSP = right ventricular systolic pressure; RVSV = right ventricular stroke volume; SA = short axis; 6MWD = 6-min walking distance; TPVR = total pulmonary vascular resistance

This study was financially supported by GlaxoSmithKline Netherlands BV.

Received for publication March 19, 2003. Accepted for publication September 1, 2003.


   References
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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