Author + information
- Received March 26, 2013
- Revision received May 6, 2013
- Accepted May 6, 2013
- Published online August 1, 2013.
- Evan L. Brittain, MD∗∗ (, )
- Meredith E. Pugh, MD, MSCI†,
- Lisa A. Wheeler, BS†,
- Ivan M. Robbins, MD†,
- James E. Loyd, MD†,
- John H. Newman, MD†,
- Eric D. Austin, MD, MSCI‡ and
- Anna R. Hemnes, MD†
- ∗Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- †Division of Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- ‡Department of Pediatrics, Vanderbilt Children's Hospital, Nashville, Tennessee
- ↵∗Reprint requests and correspondence:
Dr. Evan L. Brittain, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 1215 21st Avenue South, Medical Center East, Nashville, Tennessee 37232.
Objectives This study hypothesized that right ventricular stroke work index (RVSWI) and pulmonary capacitance (PC) would increase after treatment for pulmonary arterial hypertension (PAH) and that prostanoids would have a stronger effect than oral therapy.
Background Right ventricular (RV) function is a major determinant of outcome in patients with PAH. Little is known about the response of RV function or its hemodynamic determinants to PAH-specific therapy.
Methods We reviewed hemodynamic and health data on 58 patients from an institutional registry and analyzed changes in hemodynamic status between diagnostic and first repeat catheterization after initiation of therapy for PAH.
Results The RVSWI and PC increased significantly after therapy (p = 0.007 and p = 0.02, respectively). Improvement in RV function was limited to patients treated with prostanoid-only therapy (p = 0.04); no improvement was found in patients treated with oral therapy (p = 0.25). Patients with the poorest baseline RV function (lowest tertile) had the greatest improvement post-therapy (p = 0.005 and p < 0.001 vs. middle and highest tertiles). The major determinant of RVSWI was change in stroke volume (rs = 0.54, p < 0.001), indicating RVSWI is an accurate reflection of RV function.
Conclusions Right ventricular function improves after therapy with regimens including prostanoids but not oral-only regimens. Patients with the least compensated RV function at diagnosis might derive the most benefit from therapy. Larger studies are needed to determine whether changes in RVSWI after therapy are associated with outcomes.
- pulmonary arterial hypertension
- pulmonary capacitance
- right ventricle
- right ventricular function
- right ventricular stroke work index
Pulmonary arterial hypertension (PAH) is an incurable disease characterized by progressive pulmonary vascular obliteration, right ventricular (RV) failure, and death (1). Evidence suggests that outcomes in PAH more closely mirror changes in RV function than improvement in pulmonary hemodynamic status (2–4). There are limited data that a direct beneficial effect of PAH therapy on RV function might occur (3), but differences among treatment regimens have not been studied. Availability of an accurate measure of RV function at the time of catheterization and knowledge of which medications are likely to improve RV function might influence clinician choice of therapy.
Conventional hemodynamic markers of RV function such as right atrial pressure (RAP), cardiac output (CO), and pulmonary pressure (PAP) can be integrated into a measure of RV function, the right ventricular stroke work index (RVSWI). Lower RVSWI is associated with worse outcome in PAH, left ventricular failure, and left ventricular assist device patients (5–7). Invasive hemodynamic status can also be used to measure pulmonary capacitance (PC), a measure of vascular resistance and elastic recoil. Depressed PC is a strong prognostic indicator of adverse outcome in idiopathic PAH (IPAH) (8). We have previously shown that RVSWI and PC are prognostic indicators in a cohort of familial (FPAH) and idiopathic pulmonary arterial hypertension (IPAH) (9). However, the effect of different PAH-specific therapies on RV function and PC has not been studied.
We studied the effect of therapy for PAH on RVSWI and PC from the time of diagnostic catheterization to the first repeat right heart catheterization (RHC). We hypothesized that RV function and PC would improve in response to therapy and that prostanoids would have a stronger effect than oral therapy.
Data for this study were retrospectively analyzed from an institutional registry. Patients in this study are consecutive patients seen in the Vanderbilt University Center for Pulmonary Vascular Disease and enrolled in the Vanderbilt Pulmonary Hypertension Research Cohort (VPHRC). The VPHRC also includes patients evaluated at outside institutions, but only patients seen at Vanderbilt were included in this study. Cases were restricted, to avoid confounding by treatment era, to those with diagnostic hemodynamic and clinical data between January 1, 1996 (when intravenous prostaglandins became commercially available) and March 1, 2011.
The diagnosis of PAH was made by experienced physicians according to consensus guidelines (10), including mean pulmonary artery pressure (mPAP) ≥25 mm Hg, pulmonary vascular resistance (PVR) >3 wood units (WU), and pulmonary wedge pressure (PWP) ≤15 mm Hg. Only patients with IPAH, FPAH, and connective tissue disease-associated PAH were included in the analysis. Patients were diagnosed with FPAH if they had at least 1 other family member within their bloodline confirmed with PAH.
Only patients who were treatment-naïve at the time of evaluation were included. Treatment regimens were categorized as prostanoid (intravenous or inhaled), oral (monotherapy or in combination), mixed prostanoid and oral therapy, and vasodilator (calcium channel blocker)-responsive. For purposes of analysis, vasodilator-responsive patients were not included in the oral therapy group, given the well-recognized favorable hemodynamic response in this group (11).
Heart rate (HR), RAP, PAP (mean, systolic, and diastolic), PWP, and CO were recorded from the diagnostic catheterization of the patient. Cardiac index, PVR, and stroke volume (SV) were calculated from standard formulas.
The physiological rationale for the calculation of PC has been described in detail elsewhere (8). The PC and RVSWI were calculated with the following formulas: PC (ml/mm Hg) = SV/pulmonary pulse pressure; and RVSWI (gm·m/m2/beat) = (mean PAP − mean RAP) × (cardiac index/HR) × 0.0136.
We included only patients who underwent repeat RHC within 3 years of diagnostic catheterization to allow enough time on therapy for pulmonary vascular and RV remodeling while providing a relatively homogenous cohort with regard to length of therapy. Pre- and post-treatment six minute walk test distance (6MWD) and New York Heart Association (NYHA) functional class were also recorded.
Continuous data are expressed as mean ± SD. The Mann-Whitney U or Kruskal-Wallis test was used to compare differences in continuous demographic, hemodynamic, and outcome variables, depending on the number of groups. Paired measurements of RVSWI and PC were compared with the Wilcoxon signed rank test. Categorical clinical and demographic variables were compared between groups with the chi-square test. Spearman correlation was used to show the relationship between continuous variables. A p value of <0.05 was considered statistically significant. Statistical analyses were performed with Prism software (version 5.0, Graph Pad Software, Inc., La Jolla, California) and SPSS software (version 20, SPSS, Inc., Chicago, Illinois).
Demographic and clinical characteristics
At the time of analysis, the VPHRC contained 616 unique cases, 183 of whom were seen at Vanderbilt, treatment-naïve, and had diagnostic and repeat RHC data available. Of those, 70 patients had a repeat RHC within 3 years of diagnostic catheterization during the time frame of the study; 12 of those 70 patients had either incomplete RHC data (n = 4) or PWP >15 mm Hg (n = 8). Fifty-eight patients were included in the analysis representing 3 subtypes: IPAH (n = 33), FPAH (n = 16), and connective tissue-associated PAH (n = 9).
Demographic and clinical characteristics of the 58 study patients divided into treatment regimen are shown in Table 1. The distribution of baseline RVSWI is shown in Figure 1. At the time of presentation, most patients (40 of 58, 69%) had supra-normal RVSWI, whereas 18 of 58 (31%) fell into the low or normal range.
Demographic data and clinical characteristics of the cohort divided into tertiles of baseline RV function are shown in Table 2. No differences in age or subtype of PAH were found among the tertiles. However, the lowest tertile contained a higher proportion of men compared with the other tertiles (p = 0.037). There was a strong trend toward better functional class in the tertile with the highest RVSWI (p = 0.07).
Medical therapy and hemodynamic status
The median time from starting medical therapy to the first follow-up clinic visit was 2.7 months (interquartile range 1.9 to 5.2 months). The median time between diagnostic and repeat RHC was 15.6 months (interquartile range 12.0 to 32.0 months). Seventeen patients were started on a regimen of oral therapy (monotherapy or any combination), and 21 patients were started on a regimen of prostanoid (intravenous or inhaled) therapy. Seven patients were started on a regimen of combination oral and prostanoid therapy, and an additional 7 patients were found to be vasodilator responsive and started on a regimen of calcium channel blockers; 6 patients were not started on a regimen of therapy, due to patient or physician preference.
Hemodynamic data at the time of diagnostic catheterization according to treatment regimen are shown in Table 3. The only difference among treatment groups was lower mixed venous oxygen saturation in the prostanoid group compared with the oral therapy group (58.2 ± 10.7 vs. 66.6 ± 5.6, respectively; p = 0.01). For the entire cohort, we found a significant increase in RVSWI (mean increase 3.4 ± 9.5 gm·m/m2/beat, p = 0.007) and PC (mean increase 0.4 ± 1.0 ml/mm Hg, p = 0.02) after medical therapy (Fig. 2). In the prostanoid group there was a significant increase in RVSWI (p = 0.04) and a trend toward improvement in PC (p = 0.06). However, in the 17 patients started on a regimen of oral therapy, neither RVSWI nor PC increased significantly after treatment (p = 0.25 and 0.46, respectively) (Fig. 3). In the 7 patients who were treated with calcium channel blockers, RVSWI (15.7 ± 4.0 gm·m/m2/beat vs. 19.4 ± 3.2 gm·m/m2/beat; p = 0.02) and PC (1.2 ± 0.3 ml/mm Hg vs. 2.3 ± 1.1 ml/mm Hg; p = 0.03) both increased after therapy.
Because only prostanoids and calcium channel blockers were available between 1996 and 2001, we repeated our analysis with a cutoff diagnosis date of January 2001 (n = 50). Improvement in RVSWI and PC remained significant in the prostanoid group (p = 0.04 and 0.01, respectively) and did not reach significance in the oral therapy group (p = 0.23 and 0.30, respectively).
Determinants of RV function
Change in RVSWI after therapy was driven more by change in CO (rs = 0.5, p = 0.002) than change in mPAP (rs = 0.36, p = 0.03) (Figs. 4A and 4B). The major determinant of RVSWI was change in SV (rs = 0.54, p < 0.001). Increase in CO after therapy was almost entirely due to an increase in SV (rs = 0.89, p < 0.001) with no contribution from change in HR (rs = 0.1, p = 0.3) (Figs. 4C and 4D). We found that change in PC was strongly influenced by change in PVR (rs = −0.6, p < 0.001) (Fig. 5).
Change in PVR was investigated as a possible explanation for the difference in RV function response between oral and prostanoid therapy groups. We found no difference in delta PVR between the oral-only and prostanoid groups (−0.4 ± 4.6 WU vs. −4.5 ± 7.9 WU, respectively; p = 0.07), although there was a strong trend toward statistical significance. Change in PVR and change in RVSWI did not correlate significantly in either the oral only (rs = −0.12, p = 0.66) or prostanoid group (rs = −0.20, p = 0.44).
When comparing the response to therapy by RVSWI tertile, we found a stepwise response with the highest improvement in RVSWI in the lowest tertile (Fig. 6). There was no association between tertile of baseline RVSWI and likelihood of being treated with prostanoid therapy (p = 0.67; 95% confidence interval: 0.4 to 1.7). A similar stepwise pattern in PC was seen in response to therapy with the lowest baseline tertile improving the most (Fig. 6).
Differences in change in 6MWD and functional class by group are shown in Table 4. Improvement in both 6MWD and functional class was significantly better in the prostanoid group, compared with the oral therapy group. For the cohort as a whole, no correlation was found between RVSWI at diagnosis and 6MWD (rs = −0.08, p = 0.59) or functional class (rs = −0.19, p = 0.16) at diagnosis, although improvement in RVSWI (net increase 3.4 ± 9.5 gm-m/m2/beat) was associated with improvement in both functional class (net decrease −0.8 ± 0.8; rs = −0.32, p = 0.016) and change in 6MWD (net increase 46 ± 103 m; rs = 0.52, p = 0.04) at first follow-up visit after initiation of therapy. Change in SV was an independent predictor of improvement in functional class when controlling for mPAP and HR with an odds ratio of 1.04/ml (p = 0.03; 95% confidence interval: 1.004 to 1.09).
In this study of 58 mixed-etiology PAH patients, we report the response of RV function and PC before and after PAH-specific therapy. For the entire cohort, we found that improvement in RV function was driven by patients treated with prostanoid therapy. Patients with the poorest baseline RV function had the greatest improvement post-therapy, a finding that might have implications for identifying patients with the greatest potential benefit from therapy. Improvement in PC was limited to patients treated with prostanoid therapy and vasodilator-responsive patients treated with calcium channel blockers. Finally, we showed that improvement in RVSWI predicts improvement in post-therapy 6MWD and functional class.
The RVSWI is a measure of RV function that can be readily calculated from the usual components of a diagnostic RHC. It is used clinically in patients with LV failure, but little is known about its natural history or ability to prognosticate in patients with PAH (12). We previously showed that, as judged by RVSWI, FPAH patients are less compensated at the time of diagnosis, compared with IPAH patients. In addition, RVSWI is lower in FPAH patients who die or undergo lung transplant within 5 years of diagnosis (9). In our cohort, most patients (69%) had supra-normal RVSWI at baseline, despite limited functional capacity measured by NYHA functional class and exercise capacity. This discrepancy might be explained by the subjective nature of NYHA functional class and variations in effort on 6MW testing, particularly in relation to obese patients as in our cohort (13,14).
To better understand why RVSWI changes in response to therapy, we analyzed the relationship between individual components (mPAP and CO) and the composite parameter. The CO had a stronger influence than mPAP in the response of RVSWI to PAH therapy, but both components provided a significant influence. Change in CO was almost entirely driven by improvement in SV, supporting our hypothesis that improvement in RVSWI in response to therapy is due to improved RV contractility, not increase in HR. The importance of RV function in PAH is further supported in our study by the independent value of SV in predicting improvement in functional class. The RVSWI might be superior to either CO or mPAP alone and might have a previously unrecognized role to play in the interpretation of invasive hemodynamic status in PAH.
Little is known about the response to therapy of RV function in PAH. Although RVSWI and PC increased post-therapy in the cohort as a whole, this finding was driven by an increase in RVSWI and PC in the 21 patients started on a regimen of prostanoid only therapy. Potential explanations for this difference include greater efficacy of prostanoids in therapy of PAH pulmonary vascular disease, a direct effect of prostaglandins on the RV (15,16), or differences in treatment as a function of disease severity reflected in RVSWI or other unfavorable hemodynamic predictors. The strong influence we found of SV on change in RVSWI suggests that prostanoids might exert an inotropic effect on the RV, but this requires further study.
Patients in the lowest tertile at diagnosis had the greatest improvement in RVSWI after treatment, reflecting the well-described ability of the RV to recover function with removal of load stress (17,18). Although signs and symptoms of RV dysfunction at diagnosis are often recognized by treating physicians, quantification of low RVSWI at diagnosis might help clinicians identify patients at risk for poor outcomes and the greatest potential benefit from aggressive therapy.
Pulmonary capacitance measures the ability of the pulmonary vasculature to receive blood during RV systole and then expel blood from the pulmonary tree during diastole. In the normal pulmonary circulation, resistance is nearly 0 (≤1 WU), and therefore elastic recoil is primarily responsible for capacitance. In contrast, in PAH, there is reduction in lumen size, dropout of vessels, and thickening of large arteries such that compliance is low, and PVR probably accounts for most of capacitance data. This is supported by our data showing that PVR has a strong inverse association with PC in our cohort. The prognostic value of PC, measured at RHC or echocardiography, in patients with IPAH is well-described (8,19). However, the response of PC to PAH therapy has not previously been studied. The increase in PC after therapy in our study was driven by the presence of prostanoids in the treatment regimen (either alone or in combination with oral therapy).
In patients with PAH, a decrease in PVR is thought to drive improvement in RV function by decreasing RV afterload; however, improvement or decline in RV function is often independent of the change in PVR after therapy (3). This is supported by our finding of no difference in change in PVR between patients with oral-only regimens and those treated with prostanoids; however, our study might have been underpowered to detect this difference, given that the p value was nearly significant (p = 0.07). Tedford et al. (20) recently showed that the influence of PVR on RV afterload is governed by the hyperbolic relationship between PVR and PC. The fixed relationship between PVR and PC and the flatness of the curve at elevated PVR means that patients with high baseline PVR require significant decreases in PVR (not often produced with current PAH therapy) to achieve a decrease in RV afterload. Thus, our findings suggest that improvement in RV function on a regimen of prostanoid therapy might represent a direct effect on RV contractility, not simply a decrease in resistance.
Our study has a relatively small sample size, compared with contemporary studies of hemodynamic variables in PAH, but it is the first to report the response of RVSWI and PC to therapy. Patients who died or were lost from the study before follow-up catheterization were excluded from this analysis, which might limit the prognostic value of our findings and bias to the null hypothesis.
The RVSWI is an imperfect measure of RV function and reflects influences from both afterload and preload. However, it is used clinically in patients with left heart disease and has prognostic value in patients with PAH (9,21). In addition, our detailed analysis suggests that it might add incremental value to interpretation of its individual components. Echocardiographic data would have provided an additional measure of RV function but were not available for analysis in our cohort over the extended period of the study.
In this study of serial hemodynamic measurements in patients with PAH we have shown that RV function improves after prostanoid therapy but not after therapy with oral medications. Patients with the least compensated RV function at diagnosis had the greatest post-therapy improvement in RV function and might derive the most benefit from therapy. Larger studies are needed to validate these findings and determine the clinical utility of RVSWI and PC versus conventional hemodynamic parameters. Further study is also needed to explore the potential of prostanoid therapy to directly improve RV function.
This work was supported by the National Institutes of Health (K08 HL093363 [to Dr. Hemnes], K23 HL0987431 [to Dr. Austin], 1PO HL108800-01A1 (to Drs. Loyd, Newman, Austin, and Hemnes), and NCRR/NIH 1 UL1 RR024975 [Vanderbilt]) and the American College of Cardiology Foundation/Merck Fellowship (to Dr. Brittain). Dr. Pugh has served as consultant to Gilead. Dr. Robbins has served as advisory board member for Actelion, Gilead, and United Therapeutics; and received grants from Actelion, Gilead, United Therapeutics, Geno, and Novartis. Dr. Hemnes has received grants from Pfizer and the National Institutes of Health; and has served as consultant to Pfizer and United Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- cardiac output
- familial pulmonary arterial hypertension
- heart rate
- idiopathic pulmonary arterial hypertension
- mean pulmonary artery pressure
- New York Heart Association
- pulmonary arterial hypertension
- pulmonary capacitance
- pulmonary vascular resistance
- pulmonary wedge pressure
- right atrial pressure
- right heart catheterization
- right ventricle/ventricular
- right ventricular stroke work index
- stroke volume
- Wood units
- 6-minute walk distance
- Received March 26, 2013.
- Revision received May 6, 2013.
- Accepted May 6, 2013.
- 2013 American College of Cardiology Foundation
- Voelkel N.F.,
- Quaife R.A.,
- Leinwand L.A.,
- et al.
- Humbert M.,
- Sitbon O.,
- Chaouat A.,
- et al.
- van de Veerdonk M.C.,
- Kind T.,
- Marcus J.T.,
- et al.
- Benza R.L.,
- Miller D.P.,
- Gomberg-Maitland M.,
- et al.
- Mahapatra S.,
- Nishimura R.A.,
- Sorajja P.,
- Cha S.,
- McGoon M.D.
- Brittain E.L.,
- Pugh M.E.,
- Wheeler L.A.,
- et al.
- Badesch D.B.,
- Champion H.C.,
- Sanchez M.A.,
- et al.
- Troosters T.,
- Gosselink R.,
- Decramer M.
- Reesink H.J.,
- Marcus J.T.,
- Tulevski I.I.,
- et al.
- Tedford R.J.,
- Hassoun P.M.,
- Mathai S.C.,
- et al.