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Pulmonary Arterial Capacitance Index Is a Strong Predictor for Adverse Outcome in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension
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Pulmonary Arterial Capacitance Index Is a Strong Predictor for Adverse Outcome in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension Shinichi Takatsuki, MD1, Tomotaka Nakayama, MD1, Satoshi Ikehara, MD1, Hiroyuki Matsuura, MD1, David Dunbar Ivy, MD2, and Tsutomu Saji, MD1 Objectives To evaluate the clinical utility of pulmonary artery capacitance index (PACi) in the assessment of disease severity and prognostic value in children with idiopathic and heritable pulmonary arterial hypertension (PAH). Study Design PACi is defined as the ratio of stroke volume index over pulmonary pulse pressure. A retrospective study was performed to compare PACi, brain natriuretic peptide (BNP), 6-minute walk distance, New York Heart association (NYHA) functional class, and adverse outcomes (hospitalization due to heart failure, lung transplantation, and cardiac mortality) in 72 Japanese children (10 ± 3.6 years) with idiopathic and heritable PAH. Results PACi had significant correlations with pulmonary vascular resistance index (r =−0.73, P < .0001), BNP levels (r = −0.40, P = .0008), and 6-minute walk distance (r = 0.57, P < .05). Statistically significant differences in PACi were observed between NYHA functional class II vs combined III and IV (median; 1.1 vs 0.6 mL/mm Hg/m2, respectively, P < .05). There were 25 of 72 (35%) children who had an adverse event including initiation of hospitalization due to heart failure, lung transplantation, and death. Cumulative event-free survival rate was significantly lower when PACi was <0.85 mL/mm Hg/m2 (log-rank test, P < .0001). Conclusions PACi correlated with BNP and NYHA functional class and may serve as a strong prognostic marker in children with idiopathic and heritable PAH. (J Pediatr 2016;■■:■■-■■).
P
ulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, leading to right ventricular (RV) failure and cardiac death.1-3 Obliteration of the pulmonary vascular bed by cell proliferation and thrombosis leads to increasing vascular stiffness, decreasing compliance, and worsening RV function.4-6 Pulmonary arterial capacitance index (PACi) is defined as stroke volume index divided by pulmonary artery pulse pressure. PACi reflects the pulmonary vascular compliance with each RV contraction and improves characterization of RV afterload beyond pulmonary vascular resistance. Therefore, PACi is a useful marker in the assessment of the RV-pulmonary arterial coupling and may be associated with RV failure. Recent published studies have demonstrated that reduced PACi was associated with cardiac mortality in adults with PAH.7-9 Although previous studies in pediatric patients with various forms of PAH have demonstrated the clinical application of PACi in children with idiopathic and heritable PAH,10,11 its prognostic value and correlation with disease severity have not been investigated fully. The aim of this study was to assess the clinical utility of PACi for evaluating disease severity and predicting outcomes in children with idiopathic and heritable PAH.
Methods We retrospectively reviewed hemodynamic data evaluated by cardiac catheterization and clinical data of 72 children diagnosed with idiopathic and heritable PAH. All children (18 years or younger of age at diagnosis) were followed at Toho University Omori Medical Center (Tokyo, Japan) between 1998 and 2015. Patients with associated PAH due to congenital heart disease, secondary to left-sided obstructive lesions (pulmonary venous hypertension), or persistent pulmonary hypertension of the From the 1Department of Pediatrics, Toho University newborn were excluded. The diagnosis of idiopathic and heritable PAH was 2 Omori Medical Center, Tokyo, Japan; and Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO
BNP NYHA PACi PAH PVR PVRi RV 6MWD
Brain natriuretic peptide New York Heart Association Pulmonary arterial capacitance index Pulmonary arterial hypertension Pulmonary vascular resistance Pulmonary vascular resistance index Right ventricular 6-minute walk distance
Supported by the Jayden DeLuca Foundation, the Leah Bult Foundation, Colorado Clinical Translational Science Institute (UL1 TR001082), National Center for Research Resources, and National Institutes of Health. The University of Colorado contracts with Actelion, Bayer, Lilly, and United Therapeutics. D.I. serves as a member of the Gilead Sciences Research Scholars Program. The other authors declare no conflicts of interest. 0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org10.1016/j.jpeds.2016.10.003
1 FLA 5.4.0 DTD ■ YMPD8720_proof ■ October 31, 2016
THE JOURNAL OF PEDIATRICS • www.jpeds.com established according to echocardiography, blood test including autoantibodies and liver function, pulmonary function tests, pulmonary ventilation-perfusion scans, genetic testing, and catheterization. All children were enrolled in a protocol approved by the institutional review board at Toho University Omori Medical Center. New York Heart Association (NYHA) functional class was evaluated in children who were 6 years of age or older, and a 6-minute walk distance (6MWD) was performed in children who were 5 years of age or older. Brain natriuretic peptide (BNP) levels, 6MWD, echocardiography, and assessment of NYHA functional class were evaluated within 3 days of right heart catheterization. At cardiac catheterization, the patients underwent mild sedation with the use of midazolam without mechanical ventilation. Right heart catheterization was performed with a balloon-tipped, flow-directed Swan-Ganz catheter and systemic arterial catheter for monitoring. Hemodynamic measurements included right atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, systemic blood pressure, and oxygen saturation. Accordingly, we calculated pulmonary vascular resistance index (PVRi) (mean pulmonary artery pressure minus pulmonary capillary wedge pressure divided by cardiac index) and pulmonary vascular resistance/ systemic vascular resistance index ratio. Cardiac output was obtained by the Fick method by use of the LaFarge estimation, and cardiac index was calculated. PACi was expressed as the stroke volume/pulmonary artery pulse pressure indexed to body surface area (mL/mm Hg/m2). Stroke volume was calculated as cardiac output divided by heart rate and pulmonary pulse pressure expressed as the difference between the systolic and diastolic pulmonary artery pressures. Acute pulmonary vasodilator testing also was tested with 100% of oxygen, and we evaluated response to oxygen as a vasodilator agent. Cardiac catheterization was performed at time of diagnosis except for 2 patients with NYHA functional class IV. For these patients, hemodynamic variables were evaluated at 2 and 3 months after diagnosis, respectively, because of disease severity. Statistical Analyses Categorical values are expressed as percentages and continuous variables as means with SDs for data with a normal distribution and median and range for non-normally distributed data. A composite outcome included hospitalization due to heart failure, lung transplantation, and cardiac mortality. Only the first adverse event was considered in each patient. The correlations with 6MWD, echocardiographic data, BNP levels, and hemodynamic variables were determined with the Pearson correlation coefficient. Mann-Whitney U test was used for PACi between NYHA functional class II and III or IV and PACi between patients with and without adverse events. Differences between the hemodynamic data including PACi before and after acute vasoreactivity testing were performed with a paired t test or Wilcoxon signed-rank test, as appropriate. The receiver operating characteristic curve was calculated from a logistic regression to assess optimal cut-off values for the prediction of the adverse outcome. The Kaplan-Meier method was
Volume ■■ used to approximate the adverse events with the log-rank test. The association between baseline variables and adverse events was evaluated with multivariable Cox proportional hazards analysis. The factors entered into the Cox regression models for composite outcomes included age, sex, idiopathic or familial, follow-up periods, BNP levels, 6MWD, NYHA functional class, treatment (use of epoprostenol), hemodynamic variables, and PACi at diagnosis. The level of statistical significance was defined as a P value of .05. Analyses were conducted with Statmate III for Windows (Atoms Co, Tokyo, Japan).
Results Table I presents the clinical characteristics of the pediatric patients. Overall, 55 patients with idiopathic PAH and 17 with heritable PAH were enrolled. The age at diagnosis was 9.8 ± 3.7 years, with 38 male and 34 female patients. In all, 50 children (69%) were administrated epoprostenol infusion therapy during follow-up, and the remaining 22 children received oral vasodilators. Correlation with BNP, 6MWD, Echocardiographic Measurements, and Hemodynamics All children had plasma BNP levels performed, and 6MWD was measured in 63 patients (Table I). Nine children were not evaluated for 6MWD because of severe PAH or age younger than 5 years. PACi had significant but weak correlations with plasma BNP levels and 6MWD (r = -0.40, P = .0008; r = 0.57, P = .005, respectively) (Figure 1; available at www.jpeds.com). Among echocardiographic measurements, only tricuspid regurgitation velocities had significant negative correlation with PACi (r = −0.59, P < .0001), whereas there were no significant associations between PACi and other measures, such as RV myocardial performance index, tricuspid annular plane systolic excursion, and tricuspid e′ velocity (r = −011, P = .45; r = 0.17, P = .22; r = 0.18, P = .20, respectively). In addition, PACi had a significant correlation with hemodynamic measurements
Table I. Demographic data of study populations Characteristics Idiopathic/heritable 55/17 Age at diagnosis, y, mean ± SD 9.8 ± 3.7 Age at evaluation, y, mean ± SD 10 ± 3.6 Sex, male/female 38/34 Laboratory data Median (range) BNP, pg/mL 53.6 (3.5-1380) 6MWD, m, ≥5 y (n = 63) 407 (165-595) NYHA functional class, ≥6 y (n = 63) Class II; 19 III; 42, IV; 2 Hemodynamics by right heart catheterization Mean ± SD, median (range) Mean right atrial pressure, mm Hg 8±4 Systolic pulmonary artery pressure, mm Hg 96 ± 25 Diastolic pulmonary artery pressure, mm Hg 51 ± 17 Mean pulmonary artery pressure, mm Hg 68 ± 19 2 19.9 (7.1-43.0) PVRi, unit·m Pulmonary/systemic vascular resistance ratio 0.92 (0.27-1.77) 3.0 (2.0-5.2) Cardiac index, L/min/m2
2
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2016
Figure 2. PACi had negative significant correlations with PVRi, mean pulmonary artery pressure, and pulmonary/systemic vascular resistance (Rp/Rs) ratio, whereas there was a significant positive correlation between PACi and cardiac index.
including mean pulmonary artery pressure (r = −0.63, P < .0001), PVRi (r = −0.73, P < .0001), pulmonary/systemic vascular resistance ratio (r = −0.61, P < .0001), and cardiac index (r = 0.56, P < .0001) (Figure 2). NYHA Functional Class At initial evaluation, 19 patients were in NYHA functional class II, and the remaining 44 were class III or IV (Table I). In 9 children, the NYHA functional class was not assessed because of
their age. There were statistically significant differences in PACi between NYHA functional class II and III or IV (median and range; 1.1 [0.3-1.8] mL/mm Hg/m2 vs 0.6 [0.2-2.0] mL/mm Hg/m 2 , respectively, P = .0005) (Figure 3; available at www.jpeds.com). Response to Vasodilators All patients underwent acute vasoreactivity testing. PACi was significantly increased during acute vasoreactivity testing
Pulmonary Arterial Capacitance Index Is a Strong Predictor for Adverse Outcome in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension FLA 5.4.0 DTD ■ YMPD8720_proof ■ October 31, 2016
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THE JOURNAL OF PEDIATRICS • www.jpeds.com (median and range, before and after acute vasoreactivity testing; 0.74 [0.24-1.96] mL/mm Hg/m2 vs 0.90 [0.31-2.25] mL/mm Hg/m2, P = .0001). In addition, PVRi and pulmonary/systemic vascular resistance index ratio significantly improved (median and range, 19.9 [7.1-43.0] unit·m2 vs 15.5 [4.9-48.0] unit·m2; 0.92 [0.27-1.77] vs 0.76 [0.29-1.45], P < .0001, respectively), although mean right atrial pressure, mean pulmonary artery pressure, and cardiac index were not significantly different after acute vasoreactivity testing (7.6 ± 3.9 mm Hg vs 7.0 ± 3.6 mm Hg, P = .05; 68 ± 18 mm Hg vs 62 ± 18 mm Hg, P = .06; 3.0 [2.0-5.2] L/min/m 2 vs 3.2 [1.9-5.9] L/min/m 2 , P = .08, respectively). Outcomes During follow-up period (median and range; 24 months, 1-60 months), 25 of 72 (35%) children had an adverse event including hospitalization due to heart failure (n = 9), lung transplantation (n = 4), and death (n = 12). The PACi in patients without adverse events was significantly greater than the PACi in patients with adverse events (median and range; 1.0 [0.32.0] mL/mm Hg/m2 vs 0.5 [0.2-1.2] mL/mm Hg/m2, respectively, P < .0001). When a receiver operating characteristic curve was used, a PACi cutoff value of 0.85 mL/mm Hg/m2 for prediction of adverse outcomes yielded an area under the curve of 0.78, which was greater than mean pulmonary artery pressure, mean right atrial pressure, PVRi, pulmonary/systemic vascular resistance index ratio, and cardiac index (Figure 4; available at www.jpeds.com). Thirty-three of 72 children (46%) with greater PACi (≥0.85 mL/mm Hg/m2) had only 1 event (1/33 cases; 3%), and the remaining 39 children with lower PACi (<0.85 mL/mm Hg/m2) had 24 events (24/39 cases; 62%) during follow-up. The cutoff value of 0.85 mL/mm Hg/m2 corresponds to a sensitivity of 96% and a specificity of 68%. The cumulative event-free rate was significantly lower when the PACi was lower than 0.85 mL/mm Hg/m2 (log-rank test, P < .0001; Figure 5).
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Table II. Cox regression analysis for the adverse events Variables
HR (95% CI)
Age at diagnosis Sex Follow-up periods Heritable BNP 6MWD NYHA functional class III and IV Initiation of epoprostenol Mean right atrial pressure Mean pulmonary artery pressure PVRi Pulmonary/systemic vascular resistance ratio Cardiac index PACi
0.93 0.63 1.55 1.28 1.00 0.99 2.86 1.27 1.01 1.05 1.22 1.02 0.98 10.8
(0.79-1.09) (0.20-1.98) (1.23-3.15) (0.82-1.99) (0.99-1.01) (0.23-1.13) (0.15-25.6) (0.37-4.3) (0.89-1.25) (0.95-1.12) (0.97-1.32) (0.88-2.22) (0.56-1.33) (2.3-49.4)
P value .36 .43 .09 .06 .20 .29 .85 .70 .67 .83 .45 .41 .32 .002
HR, hazard ratio.
Multiple Regression Analysis Cox regression models were conducted for the composite outcome of hospitalization due to heart failure, lung transplantation, and cardiac mortality (Table II). We found that lower PACi was an independent predictor of cardiac mortality, lung transplantation, and hospitalization due to heart failure (hazard ratio 10.8; 95% CI 2.3-49.4; P = .002) whereas age, sex, BNP, 6MWD, NYHA functional class, treatment (epoprostenol use), hemodynamics such as PVRi, mean pulmonary artery pressure, and cardiac index were not associated with adverse events.
Discussion We found that PACi had a significant correlation with disease severity including hemodynamic variables, BNP levels, 6MWD, and NYHA functional class and predicted adverse outcomes. The capacitance is the distensibility of the pulmonary arterial
Figure 5. PACi <0.85 mL/mm Hg/m2 was associated with an adverse outcome in 72 children with idiopathic and heritable PAH. 4
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2016 tree and is an important component of RV workload. Although normal pulmonary vessels have the capacity to dilate, in PAH pulmonary arterial capacitance is diminished or lost, leading to increased pulmonary artery pressure and RV hypertrophy. As RV hypertrophy progresses, RV diastolic pressure increases and RV failure occurs. RV failure leads to progressive decrease in cardiac output and eventually cardiac death.12,13 Therefore, the lower capacitance is associated with disease severity and lower survival rate. Previous studies demonstrated that PACi was superior to pulmonary vascular resistance (PVR) in assessing RV dysfunction and may be a strong independent prognostic factor for worse survival in adult patients with PAH.8,9 In our study population, PACi correlated with PVRi, but PACi had better predictive value compared with PVRi. Although PVRi has been used to assess severity in children with PAH, PVR does not reflect the entire RV load.11,14,15 In this study, PACi cutoff value of 0.85 mL/mm Hg/m2 predicted adverse event in children with idiopathic and heritable PAH. Other studies demonstrated that PACi was the best marker for predicting cardiac mortality among other hemodynamic variables in pediatric patients with various forms of PAH, including PAH associated with congenital heart disease.10,11 Although congenital heart disease is a common cause of PAH in children, PAH due to large left-to-right systemic-topulmonary shunts has relatively lower PVR compared with idiopathic and heritable PAH.10,16-18 The etiologic difference may translate into different characteristics of the pulmonary vasculature.10 Therefore, in the studies including PAH associated with congenital heart disease, there was some potential bias of treatment effectiveness and survival. Thus, this report builds on previous evidence by focusing on PACi for predicting outcome only in children with idiopathic and heritable PAH. Our study was limited by relatively small numbers. Therefore, a larger study involving children with idiopathic and heritable PAH is needed to determine whether our results can be generalized to the larger population. In addition, previous studies demonstrated that survival rate in children with heritable PAH was lower than in idiopathic PAH, and we did not separate these 2 populations. Despite these limitations, this study demonstrated that PACi at diagnosis was associated with disease severity and prognosis in pediatric patients. We conclude that PACi correlates with BNP levels, 6MWD, and NYHA functional class as indicators of disease severity and may serve as a useful prognostic marker in children with idiopathic and heritable PAH. ■ Submitted for publication Mar 30, 2016; last revision received Aug 3, 2016; accepted Oct 3, 2016
References 1. Farrar JF. Idiopathic pulmonary hypertension. Am Heart J 1963;66:12835. 2. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:1117. 3. Galie N, Manes A, Uguccioni L, Serafini F, De Rosa M, Branzi A, et al. Primary pulmonary hypertension: insights into pathogenesis from epidemiology. Chest 1998;114:184S-94S. 4. Edwards WD, Edwards KE. Clinical primary pulmonary hypertension: three pathologic types. Circulation 1977;56:884-8. 5. Humbert M, Morrell N, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:S13-24. 6. Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004;43:25S-32S. 7. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. Relationship of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial hypertension. J Am Coll Cardiol 2006;47:799-803. 8. Dragu R, Rispler S, Habib M, Sholy H, Hammerman H, Galie N, et al. Pulmonary arterial capacitance in patients with heart failure and reactive pulmonary hypertension. Eur J Heart Fail 2015;17:74-80. 9. Al-Naamani N, Preston IR, Paulus JK, Hill NS, Roberts KE. Pulmonary arterial capacitance is an important predictor of mortality in heart failure with a preserved ejection fraction. JACC Heart Fail 2015;3:467-74. 10. Sajan I, Manlhiot C, Reyes J, McCrindle BW, Humpl T, Friedberg MK. Pulmonary arterial capacitance in children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease: relation to pulmonary vascular resistance, exercise capacity, and survival. Am Heart J 2011;162:562-8. 11. Douwes JM, Roofthooft MT, Bartelds B, Talsma MD, Hillege HL, Berger RM. Pulsatile haemodynamic parameters are predictors of survival in paediatric pulmonary arterial hypertension. Int J Cardiol 2013;168:1370-7. 12. Boxt LM, Katz FJ, Kolb T. Direct quantitation of right and left ventricular volumes with nuclear magnetic resonance imaging in patients with primary pulmonary hypertension. J Am Coll Cardiol 1992;19:1508-15. 13. Tanaka H, Tei C, Nakao S, Tahara M, Sakurai S, Kashima T, et al. Diastolic bulging of the interventricular septum toward the left ventricle. An echocardiographic manifestation of negative interventricular pressure gradient between left and right ventricles during diastole. Circulation 1980;62:558-63. 14. Mahapatra S, Nishimura RA, Oh JK, McGoon MD. The prognostic value of pulmonary vascular capacitance determined by Doppler echocardiography in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr 2006;19:1045-50. 15. Hunter KS, Lee PF, Lanning CJ, Ivy DD, Kirpy KS, Claussen LR, et al. Pulmonary vascular input impedance is a combined measure of pulmonary vascular resistance and stiffness and predicts clinical outcomes better than pulmonary vascular resistance alone in pediatric patients with pulmonary hypertension. Am Heart J 2008;155:166-74. 16. Wagenvoort C, Wagenvoort N. Primary pulmonary hypertension. A pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970;42:1163-84. 17. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S55-66. 18. Rosenzweig EB, Widlitz AC, Barst RJ. Pulmonary arterial hypertension in children. Pediatr Pulmonol 2004;38:2-22.
Pulmonary Arterial Capacitance Index Is a Strong Predictor for Adverse Outcome in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension FLA 5.4.0 DTD ■ YMPD8720_proof ■ October 31, 2016
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Figure 1. PACi had significant correlations with 6MWD and BNP levels by Pearson correlation coefficient test.
Figure 3. Sixty-three children who were ≥6 years old could be evaluated. PACi of the children with NYHA functional class II (n = 19) was significantly greater compared with those of class III and IV (n = 44) by the Mann-Whitney U test. 5.e1
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Figure 4. Receiver operating characteristic curve corresponded to a c-index (area under the curve) of 0.78. The cutoff value of 0.85 mL/mm Hg/m2 corresponds to a sensitivity of 96% and a specificity of 68%.
Pulmonary Arterial Capacitance Index Is a Strong Predictor for Adverse Outcome in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension FLA 5.4.0 DTD ■ YMPD8720_proof ■ October 31, 2016
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ORIGINAL ARTICLES
Pulmonary Arterial Capacitance Index Is a Strong Predictor for Adverse Outcome in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension Shinichi Takatsuki, MD1, Tomotaka Nakayama, MD1, Satoshi Ikehara, MD1, Hiroyuki Matsuura, MD1, David Dunbar Ivy, MD2, and Tsutomu Saji, MD1 Objectives To evaluate the clinical utility of pulmonary artery capacitance index (PACi) in the assessment of disease severity and prognostic value in children with idiopathic and heritable pulmonary arterial hypertension (PAH). Study Design PACi is defined as the ratio of stroke volume index over pulmonary pulse pressure. A retrospective study was performed to compare PACi, brain natriuretic peptide (BNP), 6-minute walk distance, New York Heart association (NYHA) functional class, and adverse outcomes (hospitalization due to heart failure, lung transplantation, and cardiac mortality) in 72 Japanese children (10 ± 3.6 years) with idiopathic and heritable PAH. Results PACi had significant correlations with pulmonary vascular resistance index (r =−0.73, P < .0001), BNP levels (r = −0.40, P = .0008), and 6-minute walk distance (r = 0.57, P < .05). Statistically significant differences in PACi were observed between NYHA functional class II vs combined III and IV (median; 1.1 vs 0.6 mL/mm Hg/m2, respectively, P < .05). There were 25 of 72 (35%) children who had an adverse event including initiation of hospitalization due to heart failure, lung transplantation, and death. Cumulative event-free survival rate was significantly lower when PACi was <0.85 mL/mm Hg/m2 (log-rank test, P < .0001). Conclusions PACi correlated with BNP and NYHA functional class and may serve as a strong prognostic marker in children with idiopathic and heritable PAH. (J Pediatr 2016;■■:■■-■■).
P
ulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling, leading to right ventricular (RV) failure and cardiac death.1-3 Obliteration of the pulmonary vascular bed by cell proliferation and thrombosis leads to increasing vascular stiffness, decreasing compliance, and worsening RV function.4-6 Pulmonary arterial capacitance index (PACi) is defined as stroke volume index divided by pulmonary artery pulse pressure. PACi reflects the pulmonary vascular compliance with each RV contraction and improves characterization of RV afterload beyond pulmonary vascular resistance. Therefore, PACi is a useful marker in the assessment of the RV-pulmonary arterial coupling and may be associated with RV failure. Recent published studies have demonstrated that reduced PACi was associated with cardiac mortality in adults with PAH.7-9 Although previous studies in pediatric patients with various forms of PAH have demonstrated the clinical application of PACi in children with idiopathic and heritable PAH,10,11 its prognostic value and correlation with disease severity have not been investigated fully. The aim of this study was to assess the clinical utility of PACi for evaluating disease severity and predicting outcomes in children with idiopathic and heritable PAH.
Methods We retrospectively reviewed hemodynamic data evaluated by cardiac catheterization and clinical data of 72 children diagnosed with idiopathic and heritable PAH. All children (18 years or younger of age at diagnosis) were followed at Toho University Omori Medical Center (Tokyo, Japan) between 1998 and 2015. Patients with associated PAH due to congenital heart disease, secondary to left-sided obstructive lesions (pulmonary venous hypertension), or persistent pulmonary hypertension of the From the 1Department of Pediatrics, Toho University newborn were excluded. The diagnosis of idiopathic and heritable PAH was 2 Omori Medical Center, Tokyo, Japan; and Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO
BNP NYHA PACi PAH PVR PVRi RV 6MWD
Brain natriuretic peptide New York Heart Association Pulmonary arterial capacitance index Pulmonary arterial hypertension Pulmonary vascular resistance Pulmonary vascular resistance index Right ventricular 6-minute walk distance
Supported by the Jayden DeLuca Foundation, the Leah Bult Foundation, Colorado Clinical Translational Science Institute (UL1 TR001082), National Center for Research Resources, and National Institutes of Health. The University of Colorado contracts with Actelion, Bayer, Lilly, and United Therapeutics. D.I. serves as a member of the Gilead Sciences Research Scholars Program. The other authors declare no conflicts of interest. 0022-3476/$ - see front matter. © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org10.1016/j.jpeds.2016.10.003
1 FLA 5.4.0 DTD ■ YMPD8720_proof ■ October 31, 2016
THE JOURNAL OF PEDIATRICS • www.jpeds.com established according to echocardiography, blood test including autoantibodies and liver function, pulmonary function tests, pulmonary ventilation-perfusion scans, genetic testing, and catheterization. All children were enrolled in a protocol approved by the institutional review board at Toho University Omori Medical Center. New York Heart Association (NYHA) functional class was evaluated in children who were 6 years of age or older, and a 6-minute walk distance (6MWD) was performed in children who were 5 years of age or older. Brain natriuretic peptide (BNP) levels, 6MWD, echocardiography, and assessment of NYHA functional class were evaluated within 3 days of right heart catheterization. At cardiac catheterization, the patients underwent mild sedation with the use of midazolam without mechanical ventilation. Right heart catheterization was performed with a balloon-tipped, flow-directed Swan-Ganz catheter and systemic arterial catheter for monitoring. Hemodynamic measurements included right atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, systemic blood pressure, and oxygen saturation. Accordingly, we calculated pulmonary vascular resistance index (PVRi) (mean pulmonary artery pressure minus pulmonary capillary wedge pressure divided by cardiac index) and pulmonary vascular resistance/ systemic vascular resistance index ratio. Cardiac output was obtained by the Fick method by use of the LaFarge estimation, and cardiac index was calculated. PACi was expressed as the stroke volume/pulmonary artery pulse pressure indexed to body surface area (mL/mm Hg/m2). Stroke volume was calculated as cardiac output divided by heart rate and pulmonary pulse pressure expressed as the difference between the systolic and diastolic pulmonary artery pressures. Acute pulmonary vasodilator testing also was tested with 100% of oxygen, and we evaluated response to oxygen as a vasodilator agent. Cardiac catheterization was performed at time of diagnosis except for 2 patients with NYHA functional class IV. For these patients, hemodynamic variables were evaluated at 2 and 3 months after diagnosis, respectively, because of disease severity. Statistical Analyses Categorical values are expressed as percentages and continuous variables as means with SDs for data with a normal distribution and median and range for non-normally distributed data. A composite outcome included hospitalization due to heart failure, lung transplantation, and cardiac mortality. Only the first adverse event was considered in each patient. The correlations with 6MWD, echocardiographic data, BNP levels, and hemodynamic variables were determined with the Pearson correlation coefficient. Mann-Whitney U test was used for PACi between NYHA functional class II and III or IV and PACi between patients with and without adverse events. Differences between the hemodynamic data including PACi before and after acute vasoreactivity testing were performed with a paired t test or Wilcoxon signed-rank test, as appropriate. The receiver operating characteristic curve was calculated from a logistic regression to assess optimal cut-off values for the prediction of the adverse outcome. The Kaplan-Meier method was
Volume ■■ used to approximate the adverse events with the log-rank test. The association between baseline variables and adverse events was evaluated with multivariable Cox proportional hazards analysis. The factors entered into the Cox regression models for composite outcomes included age, sex, idiopathic or familial, follow-up periods, BNP levels, 6MWD, NYHA functional class, treatment (use of epoprostenol), hemodynamic variables, and PACi at diagnosis. The level of statistical significance was defined as a P value of .05. Analyses were conducted with Statmate III for Windows (Atoms Co, Tokyo, Japan).
Results Table I presents the clinical characteristics of the pediatric patients. Overall, 55 patients with idiopathic PAH and 17 with heritable PAH were enrolled. The age at diagnosis was 9.8 ± 3.7 years, with 38 male and 34 female patients. In all, 50 children (69%) were administrated epoprostenol infusion therapy during follow-up, and the remaining 22 children received oral vasodilators. Correlation with BNP, 6MWD, Echocardiographic Measurements, and Hemodynamics All children had plasma BNP levels performed, and 6MWD was measured in 63 patients (Table I). Nine children were not evaluated for 6MWD because of severe PAH or age younger than 5 years. PACi had significant but weak correlations with plasma BNP levels and 6MWD (r = -0.40, P = .0008; r = 0.57, P = .005, respectively) (Figure 1; available at www.jpeds.com). Among echocardiographic measurements, only tricuspid regurgitation velocities had significant negative correlation with PACi (r = −0.59, P < .0001), whereas there were no significant associations between PACi and other measures, such as RV myocardial performance index, tricuspid annular plane systolic excursion, and tricuspid e′ velocity (r = −011, P = .45; r = 0.17, P = .22; r = 0.18, P = .20, respectively). In addition, PACi had a significant correlation with hemodynamic measurements
Table I. Demographic data of study populations Characteristics Idiopathic/heritable 55/17 Age at diagnosis, y, mean ± SD 9.8 ± 3.7 Age at evaluation, y, mean ± SD 10 ± 3.6 Sex, male/female 38/34 Laboratory data Median (range) BNP, pg/mL 53.6 (3.5-1380) 6MWD, m, ≥5 y (n = 63) 407 (165-595) NYHA functional class, ≥6 y (n = 63) Class II; 19 III; 42, IV; 2 Hemodynamics by right heart catheterization Mean ± SD, median (range) Mean right atrial pressure, mm Hg 8±4 Systolic pulmonary artery pressure, mm Hg 96 ± 25 Diastolic pulmonary artery pressure, mm Hg 51 ± 17 Mean pulmonary artery pressure, mm Hg 68 ± 19 2 19.9 (7.1-43.0) PVRi, unit·m Pulmonary/systemic vascular resistance ratio 0.92 (0.27-1.77) 3.0 (2.0-5.2) Cardiac index, L/min/m2
2
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Figure 2. PACi had negative significant correlations with PVRi, mean pulmonary artery pressure, and pulmonary/systemic vascular resistance (Rp/Rs) ratio, whereas there was a significant positive correlation between PACi and cardiac index.
including mean pulmonary artery pressure (r = −0.63, P < .0001), PVRi (r = −0.73, P < .0001), pulmonary/systemic vascular resistance ratio (r = −0.61, P < .0001), and cardiac index (r = 0.56, P < .0001) (Figure 2). NYHA Functional Class At initial evaluation, 19 patients were in NYHA functional class II, and the remaining 44 were class III or IV (Table I). In 9 children, the NYHA functional class was not assessed because of
their age. There were statistically significant differences in PACi between NYHA functional class II and III or IV (median and range; 1.1 [0.3-1.8] mL/mm Hg/m2 vs 0.6 [0.2-2.0] mL/mm Hg/m 2 , respectively, P = .0005) (Figure 3; available at www.jpeds.com). Response to Vasodilators All patients underwent acute vasoreactivity testing. PACi was significantly increased during acute vasoreactivity testing
Pulmonary Arterial Capacitance Index Is a Strong Predictor for Adverse Outcome in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension FLA 5.4.0 DTD ■ YMPD8720_proof ■ October 31, 2016
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THE JOURNAL OF PEDIATRICS • www.jpeds.com (median and range, before and after acute vasoreactivity testing; 0.74 [0.24-1.96] mL/mm Hg/m2 vs 0.90 [0.31-2.25] mL/mm Hg/m2, P = .0001). In addition, PVRi and pulmonary/systemic vascular resistance index ratio significantly improved (median and range, 19.9 [7.1-43.0] unit·m2 vs 15.5 [4.9-48.0] unit·m2; 0.92 [0.27-1.77] vs 0.76 [0.29-1.45], P < .0001, respectively), although mean right atrial pressure, mean pulmonary artery pressure, and cardiac index were not significantly different after acute vasoreactivity testing (7.6 ± 3.9 mm Hg vs 7.0 ± 3.6 mm Hg, P = .05; 68 ± 18 mm Hg vs 62 ± 18 mm Hg, P = .06; 3.0 [2.0-5.2] L/min/m 2 vs 3.2 [1.9-5.9] L/min/m 2 , P = .08, respectively). Outcomes During follow-up period (median and range; 24 months, 1-60 months), 25 of 72 (35%) children had an adverse event including hospitalization due to heart failure (n = 9), lung transplantation (n = 4), and death (n = 12). The PACi in patients without adverse events was significantly greater than the PACi in patients with adverse events (median and range; 1.0 [0.32.0] mL/mm Hg/m2 vs 0.5 [0.2-1.2] mL/mm Hg/m2, respectively, P < .0001). When a receiver operating characteristic curve was used, a PACi cutoff value of 0.85 mL/mm Hg/m2 for prediction of adverse outcomes yielded an area under the curve of 0.78, which was greater than mean pulmonary artery pressure, mean right atrial pressure, PVRi, pulmonary/systemic vascular resistance index ratio, and cardiac index (Figure 4; available at www.jpeds.com). Thirty-three of 72 children (46%) with greater PACi (≥0.85 mL/mm Hg/m2) had only 1 event (1/33 cases; 3%), and the remaining 39 children with lower PACi (<0.85 mL/mm Hg/m2) had 24 events (24/39 cases; 62%) during follow-up. The cutoff value of 0.85 mL/mm Hg/m2 corresponds to a sensitivity of 96% and a specificity of 68%. The cumulative event-free rate was significantly lower when the PACi was lower than 0.85 mL/mm Hg/m2 (log-rank test, P < .0001; Figure 5).
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Table II. Cox regression analysis for the adverse events Variables
HR (95% CI)
Age at diagnosis Sex Follow-up periods Heritable BNP 6MWD NYHA functional class III and IV Initiation of epoprostenol Mean right atrial pressure Mean pulmonary artery pressure PVRi Pulmonary/systemic vascular resistance ratio Cardiac index PACi
0.93 0.63 1.55 1.28 1.00 0.99 2.86 1.27 1.01 1.05 1.22 1.02 0.98 10.8
(0.79-1.09) (0.20-1.98) (1.23-3.15) (0.82-1.99) (0.99-1.01) (0.23-1.13) (0.15-25.6) (0.37-4.3) (0.89-1.25) (0.95-1.12) (0.97-1.32) (0.88-2.22) (0.56-1.33) (2.3-49.4)
P value .36 .43 .09 .06 .20 .29 .85 .70 .67 .83 .45 .41 .32 .002
HR, hazard ratio.
Multiple Regression Analysis Cox regression models were conducted for the composite outcome of hospitalization due to heart failure, lung transplantation, and cardiac mortality (Table II). We found that lower PACi was an independent predictor of cardiac mortality, lung transplantation, and hospitalization due to heart failure (hazard ratio 10.8; 95% CI 2.3-49.4; P = .002) whereas age, sex, BNP, 6MWD, NYHA functional class, treatment (epoprostenol use), hemodynamics such as PVRi, mean pulmonary artery pressure, and cardiac index were not associated with adverse events.
Discussion We found that PACi had a significant correlation with disease severity including hemodynamic variables, BNP levels, 6MWD, and NYHA functional class and predicted adverse outcomes. The capacitance is the distensibility of the pulmonary arterial
Figure 5. PACi <0.85 mL/mm Hg/m2 was associated with an adverse outcome in 72 children with idiopathic and heritable PAH. 4
Takatsuki et al FLA 5.4.0 DTD ■ YMPD8720_proof ■ October 31, 2016
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2016 tree and is an important component of RV workload. Although normal pulmonary vessels have the capacity to dilate, in PAH pulmonary arterial capacitance is diminished or lost, leading to increased pulmonary artery pressure and RV hypertrophy. As RV hypertrophy progresses, RV diastolic pressure increases and RV failure occurs. RV failure leads to progressive decrease in cardiac output and eventually cardiac death.12,13 Therefore, the lower capacitance is associated with disease severity and lower survival rate. Previous studies demonstrated that PACi was superior to pulmonary vascular resistance (PVR) in assessing RV dysfunction and may be a strong independent prognostic factor for worse survival in adult patients with PAH.8,9 In our study population, PACi correlated with PVRi, but PACi had better predictive value compared with PVRi. Although PVRi has been used to assess severity in children with PAH, PVR does not reflect the entire RV load.11,14,15 In this study, PACi cutoff value of 0.85 mL/mm Hg/m2 predicted adverse event in children with idiopathic and heritable PAH. Other studies demonstrated that PACi was the best marker for predicting cardiac mortality among other hemodynamic variables in pediatric patients with various forms of PAH, including PAH associated with congenital heart disease.10,11 Although congenital heart disease is a common cause of PAH in children, PAH due to large left-to-right systemic-topulmonary shunts has relatively lower PVR compared with idiopathic and heritable PAH.10,16-18 The etiologic difference may translate into different characteristics of the pulmonary vasculature.10 Therefore, in the studies including PAH associated with congenital heart disease, there was some potential bias of treatment effectiveness and survival. Thus, this report builds on previous evidence by focusing on PACi for predicting outcome only in children with idiopathic and heritable PAH. Our study was limited by relatively small numbers. Therefore, a larger study involving children with idiopathic and heritable PAH is needed to determine whether our results can be generalized to the larger population. In addition, previous studies demonstrated that survival rate in children with heritable PAH was lower than in idiopathic PAH, and we did not separate these 2 populations. Despite these limitations, this study demonstrated that PACi at diagnosis was associated with disease severity and prognosis in pediatric patients. We conclude that PACi correlates with BNP levels, 6MWD, and NYHA functional class as indicators of disease severity and may serve as a useful prognostic marker in children with idiopathic and heritable PAH. ■ Submitted for publication Mar 30, 2016; last revision received Aug 3, 2016; accepted Oct 3, 2016
References 1. Farrar JF. Idiopathic pulmonary hypertension. Am Heart J 1963;66:12835. 2. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:1117. 3. Galie N, Manes A, Uguccioni L, Serafini F, De Rosa M, Branzi A, et al. Primary pulmonary hypertension: insights into pathogenesis from epidemiology. Chest 1998;114:184S-94S. 4. Edwards WD, Edwards KE. Clinical primary pulmonary hypertension: three pathologic types. Circulation 1977;56:884-8. 5. Humbert M, Morrell N, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:S13-24. 6. Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, et al. Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 2004;43:25S-32S. 7. Mahapatra S, Nishimura RA, Sorajja P, Cha S, McGoon MD. Relationship of pulmonary arterial capacitance and mortality in idiopathic pulmonary arterial hypertension. J Am Coll Cardiol 2006;47:799-803. 8. Dragu R, Rispler S, Habib M, Sholy H, Hammerman H, Galie N, et al. Pulmonary arterial capacitance in patients with heart failure and reactive pulmonary hypertension. Eur J Heart Fail 2015;17:74-80. 9. Al-Naamani N, Preston IR, Paulus JK, Hill NS, Roberts KE. Pulmonary arterial capacitance is an important predictor of mortality in heart failure with a preserved ejection fraction. JACC Heart Fail 2015;3:467-74. 10. Sajan I, Manlhiot C, Reyes J, McCrindle BW, Humpl T, Friedberg MK. Pulmonary arterial capacitance in children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease: relation to pulmonary vascular resistance, exercise capacity, and survival. Am Heart J 2011;162:562-8. 11. Douwes JM, Roofthooft MT, Bartelds B, Talsma MD, Hillege HL, Berger RM. Pulsatile haemodynamic parameters are predictors of survival in paediatric pulmonary arterial hypertension. Int J Cardiol 2013;168:1370-7. 12. Boxt LM, Katz FJ, Kolb T. Direct quantitation of right and left ventricular volumes with nuclear magnetic resonance imaging in patients with primary pulmonary hypertension. J Am Coll Cardiol 1992;19:1508-15. 13. Tanaka H, Tei C, Nakao S, Tahara M, Sakurai S, Kashima T, et al. Diastolic bulging of the interventricular septum toward the left ventricle. An echocardiographic manifestation of negative interventricular pressure gradient between left and right ventricles during diastole. Circulation 1980;62:558-63. 14. Mahapatra S, Nishimura RA, Oh JK, McGoon MD. The prognostic value of pulmonary vascular capacitance determined by Doppler echocardiography in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr 2006;19:1045-50. 15. Hunter KS, Lee PF, Lanning CJ, Ivy DD, Kirpy KS, Claussen LR, et al. Pulmonary vascular input impedance is a combined measure of pulmonary vascular resistance and stiffness and predicts clinical outcomes better than pulmonary vascular resistance alone in pediatric patients with pulmonary hypertension. Am Heart J 2008;155:166-74. 16. Wagenvoort C, Wagenvoort N. Primary pulmonary hypertension. A pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970;42:1163-84. 17. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S55-66. 18. Rosenzweig EB, Widlitz AC, Barst RJ. Pulmonary arterial hypertension in children. Pediatr Pulmonol 2004;38:2-22.
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Figure 1. PACi had significant correlations with 6MWD and BNP levels by Pearson correlation coefficient test.
Figure 3. Sixty-three children who were ≥6 years old could be evaluated. PACi of the children with NYHA functional class II (n = 19) was significantly greater compared with those of class III and IV (n = 44) by the Mann-Whitney U test. 5.e1
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Figure 4. Receiver operating characteristic curve corresponded to a c-index (area under the curve) of 0.78. The cutoff value of 0.85 mL/mm Hg/m2 corresponds to a sensitivity of 96% and a specificity of 68%.
Pulmonary Arterial Capacitance Index Is a Strong Predictor for Adverse Outcome in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension FLA 5.4.0 DTD ■ YMPD8720_proof ■ October 31, 2016
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