Feb 1, 2017 - Reserve: Toward Early Detection of Pulmonary. Vascular .... disease course, whereas in more severe PAH, âright ventricularâ reserve may also ...
CORRESPONDENCE Noninvasive Assessment of Cardiopulmonary Reserve: Toward Early Detection of Pulmonary Vascular Disease
RHC (invasive arm) and CMR (noninvasive arm) were performed within 48 hours. Measurements (RHC: mean pulmonary arterial pressure [mPAP], mPAWP, CO by thermodilution, and pulmonary vascular resistance; CMR: phase-contrast imaging through the pulmonary trunk to calculate average blood flow velocity [meanPAvel]; Figure 1) were taken at rest and during intravenous adenosine (after 2 min at each dose: 70, 140, and 210 mg/kg/min). PAH was confirmed (PAH group) or excluded (high-risk group) using standard resting hemodynamic criteria (1). Healthy volunteers underwent CMR only (control group). Normally distributed continuous variables are expressed as means 6 SDs. Pearson correlation coefficients investigated the association between invasive and noninvasive measures at rest and during adenosine infusion. Between-group differences were assessed using Student’s t test or one-way analysis of variance where appropriate. Receiver operating characteristic (ROC) curve analyses investigated detection of participant groups using meanPAvel, with areas under the curves compared (2). Statistical analyses were performed (GraphPad Prism, La Jolla, CA), with a P value , 0.05 considered significant.
To the Editor: Pulmonary arterial hypertension (PAH) represents a late stage of progressive microcirculatory remodelling, or pulmonary vascular disease (PVD). Earlier detection of PVD should improve prognosis with current therapies, although validated, noninvasive methods to do so remain elusive. We postulated that changes in pulmonary arterial blood flow velocity in response to standardized intravenous adenosine infusion, measured using cardiac magnetic resonance imaging (CMR), would provide a novel and noninvasive means to measure “cardiopulmonary reserve,” providing proof of concept for the detection of preclinical PVD. Methods
Patients with known or suspected PAH and a clinical indication for a right heart catheter (RHC) and matched healthy volunteers were studied. Exclusion criteria were younger than 18 years old, pregnancy, a high cardiac output (CO) state, mean pulmonary arterial wedge pressure (mPAWP) greater than 15 mm Hg, or a contraindication to CMR or adenosine.
Results
Forty-one participants were enrolled and five excluded (four with mPAWP . 15 mm Hg, one with claustrophobia). Demographics are presented in Table 1.
B
C
D
120
120
100
100
80 60
Rest meanPAvel =19cm/s
40 20
Velocity, cm/s
Velocity, cm/s
A
60
Hyperemic meanPAvel = 33cm/s
40 20 0
0 –20
80
500 Time, ms
1000
–20
500 Time, ms
1000
Figure 1. (A) Reference sequences for phase-contrast images were two double-oblique orthogonal views along the main axis of the pulmonary trunk. (B) Flow imaging was performed using a velocity-encoded gradient echo sequence with an upper velocity limit of 150 cm/s 1.5 to 2 cm above the pulmonary valve. (C and D) A typical flow velocity profile is shown at rest (C) and during hyperemia (D). meanPAvel = mean pulmonary arterial blood flow velocity.
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CORRESPONDENCE Table 1. Demographic and Clinical Characteristics of Participants
PAH (n = 17) Female, n (%) Age, yr, mean 6 SD BSA, m2, mean 6 SD Diabetes mellitus, n (%) Smoker, n (%) Hypertension, n (%)
High Risk (n = 9)
13 (76) 7 (78) 54.3 6 14 60.2 6 14 1.78 6 0.25 1.84 6 0.14 4 (24) 0 (0) 2 (12) 0 (0) 1 (6) 1 (11)
Healthy Control (n = 10) 8 (80) 46.9 6 12 1.78 6 0.16 0 (0) 0 (0) 0 (0)
Definition of abbreviations: BSA = body surface area; PAH = pulmonary arterial hypertension.
PAH cases were idiopathic (n = 12) or connective tissue disease–associated (n = 5). New York Heart Association class III symptoms predominated (n = 12 vs. n = 5 with class II). Prevalent cases were on PAH-specific therapy (78% combination therapy, 22% single-agent therapy). Participants with suspected but excluded PAH (n = 9) were considered “high risk” for incident PAH on the basis of: nine had unaccounted-for breathlessness (class II) with an estimated pulmonary arterial systolic pressure greater than or equal to 40 mm Hg by transthoracic echocardiography; six had connective tissue disease (five with scleroderma, one with systemic lupus erythematosus); mean serum N-terminal pro b-type natriuretic peptide levels were elevated (normalized ratio, 7.7 6 4.8); diffusing capacity of the lung for carbon monoxide (DLCO) was disproportionately reduced (% FVC/% DLCO = 1.4 6 0.18); four had resting mPAP outside the accepted “normal” range (21–24 mm Hg); and none had epicardial coronary artery stenosis greater than 50% or left ventricular myocardial disease.
Invasively, the high-risk group had greater dose-dependent hemodynamic changes with adenosine (Table 2, Figure 2) (greater pulmonary vascular resistance index reduction [18 6 8% greater, P , 0.05] due predominantly to cardiac index [CI] augmentation [27 6 13% greater, P , 0.05] rather than transpulmonary gradient reduction [transpulmonary gradient = mPAP 2 mPAWP; 5.7 6 9% greater, P = 0.57]). Correlation between CMR-derived meanPAvel and hemodynamic measurements (positive with CI, negative with mPAP/pulmonary vascular resistance index) was moderate–strong at rest and throughout adenosine infusion (R2 . 0.32, P , 0.05 for all). MeanPAvel at peak hyperemia correlated strongly with minimum mPAP/pulmonary vascular resistance index and maximum CI during hyperemia (R = 20.75 [20.88 to 20.51], 20.61 [20.81 to 20.29], and 0.69 [0.06 to 0.73], respectively; P , 0.001 for all). Intraobserver and interobserver variability for meanPAvel was small (mean bias, 20.01 and 20.0000238; 95% limits of agreement, 20.21 to 0.19 and 20.27 to 0.27, respectively). Differences between group average meanPAvels were smallest at rest (9.7 6 2.2 cm/s vs. 14.9 6 2.7 cm/s vs. 18 6 2.5 cm/s; PAH vs. high risk, P , 0.0001; high risk vs. control, P = 0.02) and largest at peak hyperemia (11.9 6 3 cm/s vs. 22 6 3.4 cm/s vs. 33.7 6 4.4 cm/s; P , 0.0001 between all), reflecting dose-dependent changes up to 127 6 24%, 148 6 29%, and 186 6 26% for PAH, high-risk, and control groups, respectively (P = 0.052 for PAH vs. high risk; P = 0.01 for high risk vs. control) (Table 2, Figure 3). ROC analyses revealed excellent capacity to differentiate between PAH and high-risk participants using meanPAvel at rest and during hyperemia (area under the ROC [AUC] with 95% confidence intervals: 0.98 [0.94–1.02] and 0.99 [0.96–1.01], respectively; P . 0.05). More overlap in meanPAvel at rest between high-risk and control groups resulted in a lower AUC (0.81 [0.61–1.02]). This improved significantly with meanPAvel at peak hyperemia (AUC, 1.0 [1.0–1.0]; P = 0.03). Discriminatory capacity was inferior using the relative change in meanPAvel.
Table 2. Right Heart Catheter– and Cardiac Magnetic Resonance Imaging–derived Parameters at Rest and during Adenosine-induced Hyperemia PAH
PVRI, WU/m2 mPAP, mm Hg CI, L/min/m2 mPAWP, mm Hg meanPAvel, cm/s RVEF, % LVEF, %
High Risk
Rest
Hyperemia
Change (%)
6.7 6 6 47 6 17 2.3 6 0.8 10 6 2 9.7 6 2.2 40 6 18 66 6 10
5.6 6 6.4 45 6 16 2.9 6 1.2 11 6 4 11.9 6 3
229 6 16 27 6 11 132 6 30 122 6 35 127 6 24
Healthy Control
Rest
Hyperemia
Change (%)
1.0 6 0.5* 19 6 4* 3 6 1.2 10 6 3 14.9 6 2.7* 61 6 8* 69 6 3
0.5 6 0.2* 20 6 3* 4.7 6 1† 13 6 2 22 6 3.4‡
247 6 23* 15 6 14 159 6 30* 131 6 30 148 6 29
Rest
Hyperemia
Change (%)
18 6 2.5x 63 6 6* 67 6 4
33.7 6 4.4jj
186 6 26jj
Definition of abbreviations: CI = cardiac index; LVEF = left ventricular ejection fraction; meanPAvel = mean pulmonary arterial blood flow velocity; mPAP = mean pulmonary arterial pressure; mPAWP = mean pulmonary arterial wedge pressure; PAH = pulmonary arterial hypertension; PVRI = pulmonary vascular resistance index; RVEF = right ventricular ejection fraction. Data are mean 6 SD. *P , 0.05 for high risk compared with PAH. † P , 0.005 for high risk compared with PAH. ‡ P , 0.0001 for high risk compared with PAH. x P , 0.05 for control compared with high risk. jj P , 0.0001 for control compared with high risk.
Correspondence
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CORRESPONDENCE
% change with hyperemia
100
*
*
**
50
0
PAH
–50
High Risk
–100
ΔPVRI
ΔCI
ΔTPG
ΔSVI
ΔHR
Figure 2. Hemodynamic changes at peak hyperemia compared with rest. *P , 0.05; **P , 0.005. DCI = change in cardiac index; DHR = change in heart rate; DPVRI = change in pulmonary vascular resistance index; DSVI = change in stroke volume index; DTPG = change in transpulmonary gradient (mean pulmonary arterial pressure 2 mean pulmonary arterial wedge pressure); PAH = pulmonary arterial hypertension.
Infusion was stopped before completion in two participants (one with sinus bradycardia, one with nausea). Side effects included facial flushing (84%), dyspnea (81%), and chest tightness (76%). Discussion
Adenosine, administered intravenously, promotes preferential pulmonary over systemic vasodilation via endothelial-independent mechanisms at the proximal microcirculatory level where PVD predominates, causing CO augmentation without direct inotropic effect (3–7). Hemodynamic changes during intravenous adenosine infusion therefore reflect microcirculatory dilatation/recruitment, the capacity of the right ventricle to augment flow in response to
A
afterload reduction, or a combination. “Microcirculatory reserve” is likely to govern the magnitude of hemodynamic response early in the disease course, whereas in more severe PAH, “right ventricular” reserve may also contribute (inotropic/chronotropic). Both are important and intricately linked, hence the term cardiopulmonary reserve. Invasively, average hemodynamic changes in response to adenosine in the high-risk group exceeded those in the PAH group, confirming greater cardiopulmonary reserve. Noninvasively, these differences were mirrored by a strong trend toward a more significant dose-dependent increase in meanPAvel in the high-risk group (148 6 29% vs. 127 6 24%, P = 0.052; Figure 3) and, moreover, a significantly greater response in healthy control subjects compared with both other groups (meanPAvel change, 186 6 26%, P , 0.0001 compared with other groups). MeanPAvel at peak hyperemia showed better diagnostic performance than relative change in meanPAvel, possibly due to the impact of ventilation–perfusion matching, hypoxic vasoconstriction, or anxiety, which were ameliorated at peak hyperemia. MeanPAvel at peak hyperemia was therefore an excellent functional correlate for cardiopulmonary reserve across a spectrum of clinical risk phenotypes, as determined by “traditional” hemodynamic, clinical, and biomarker characteristics. The key limitation was the small sample size. Participants with suspected but excluded PAH were labeled high risk, which can only be validated by long-term follow-up. We demonstrated safety, feasibility, and proof of concept for a novel, noninvasive method to assess cardiopulmonary reserve as it pertains to PVD and its sequela, PAH. Sound rationale, noninvasive acquisition, ease of measurement, robust inter- and intraobserver variability, and potential for adaptation to transthoracic
B 40
Controls
* High Risk
meanPAvel, cm/s
30
*** PAH 20 0 10
10
20 30 Rest meanPAvel, cm/s
40
50
C Controls
****
0 0
70
140
Adenosine dose, μg/kg/min
210
High Risk
****
PAH
0
10
20 30 40 Hyperemic meanPAvel, cm/s
50
Figure 3. (A) Change in mean pulmonary arterial blood flow velocity (meanPAvel) during adenosine infusion (group-average meanPAvel and SD at each dose). Blue = control; green = high risk; red = PAH. (B and C) Between-group differences were smallest at rest (B) and greatest at peak hyperemia (C) (each data point represents a study participant; bars represent the group mean and SD). *P , 0.05; ***P , 0.0005; ****P , 0.0001. PAH = pulmonary arterial hypertension.
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CORRESPONDENCE echocardiography should facilitate larger derivation and validation trials. If confirmed, such a tool should afford the earliest possible detection of PVD, which may prove an attractive time point for therapy. n Author disclosures are available with the text of this letter at www.atsjournals.org. Acknowledgment: The authors thank Kerry Williams, CMR radiographer, and Peta King, pulmonary hypertension nurse. Timothy J. Baillie, B.M. B.S., F.R.A.C.P. Samuel Sidharta, B.M. B.S., F.R.A.C.P. Royal Adelaide Hospital Adelaide, South Australia, Australia and University of Adelaide Adelaide, South Australia, Australia Peter M. Steele, B.M. B.S., F.R.A.C.P. Royal Adelaide Hospital Adelaide, South Australia, Australia Stephen G. Worthley, B.M. B.S., Ph.D., F.R.A.C.P. Royal Adelaide Hospital Adelaide, South Australia, Australia and University of Adelaide Adelaide, South Australia, Australia Scott Willoughby, Ph.D. South Australian Health and Medical Research Institute Adelaide, South Australia, Australia Karen Teo, B.M. B.S., Ph.D., F.R.A.C.P. Royal Adelaide Hospital Adelaide, South Australia, Australia Prashanthan Sanders, B.M. B.S., Ph.D., F.R.A.C.P. Royal Adelaide Hospital Adelaide, South Australia, Australia and University of Adelaide Adelaide, South Australia, Australia Stephen J. Nicholls, B.M. B.S., Ph.D., F.R.A.C.P. Royal Adelaide Hospital Adelaide, South Australia, Australia University of Adelaide Adelaide, South Australia, Australia and South Australian Health and Medical Research Institute Adelaide, South Australia, Australia Matthew I. Worthley, B.M. B.S., Ph.D., F.R.A.C.P. Royal Adelaide Hospital Adelaide, South Australia, Australia and University of Adelaide Adelaide, South Australia, Australia
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67–119. 2. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143:29–36. 3. Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of adenosine on human coronary arterial circulation. Circulation 1990;82: 1595–1606. 4. Zuo XR, Zhang R, Jiang X, Li XL, Zong F, Xie WP, Wang H, Jing ZC. Usefulness of intravenous adenosine in idiopathic pulmonary arterial hypertension as a screening agent for identifying long-term responders to calcium channel blockers. Am J Cardiol 2012;109:1801–1806. 5. Morgan JM, McCormack DG, Griffiths MJ, Morgan CJ, Barnes PJ, Evans TW. Adenosine as a vasodilator in primary pulmonary hypertension. Circulation 1991;84:1145–1149. 6. Nootens M, Schrader B, Kaufmann E, Vestal R, Long W, Rich S. Comparative acute effects of adenosine and prostacyclin in primary pulmonary hypertension. Chest 1995;107:54–57. 7. Schrader BJ, Inbar S, Kaufmann L, Vestal RE, Rich S. Comparison of the effects of adenosine and nifedipine in pulmonary hypertension. J Am Coll Cardiol 1992;19:1060–1064.
Copyright © 2017 by the American Thoracic Society
Serially Measured Uric Acid Levels Predict Disease Severity and Outcome in Pediatric Pulmonary Arterial Hypertension To the Editor: Pediatric pulmonary arterial hypertension (PAH) is a serious disease, ultimately causing the early death of affected individuals (1). To ensure optimal monitoring and clinical decision-making, reliable markers of disease severity and outcome are needed. Previous observations have suggested that serum uric acid, a degradation product of purine metabolism (2), has potential as a noninvasive, inexpensive, and easily obtainable biomarker in PAH (3, 4). Uric acid is increased in oxidative stress conditions such as vascular and cardiac dysfunction, including chronic heart failure, cyanotic congenital heart disease, and also PAH (2–5). In cross-sectional observations of children with PAH, baseline levels of uric acid have previously been shown to correlate with outcome in two independent pediatric cohorts (6–8). Because a reliable biomarker should reflect the disease process and fluctuate according to the course of the disease, additional long-term follow-up data on longitudinal trends and time-dependent associations are required. In this study, we therefore evaluated the association of serially measured uric acid levels with disease severity and outcome in children with PAH. We analyzed longitudinal uric acid data from 81 children who were consecutively enrolled in the prospective clinical registry of the national referral center of the Dutch National Network for
ORCID ID: 0000-0003-1949-1359 (T.J.B.).
References 1. Galie` N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, et al.
Correspondence
Supported by the Sebald Fund and by the Netherlands CardioVascular Researsch Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON No. 2012-08 - PHAEDRA).
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