Abstract
Introduction:
Identification of elevated pulmonary artery (PA) pressures during exercise has important diagnostic, prognostic, and therapeutic implications. Stress echocardiography is frequently used to estimate PA pressures during exercise testing, but data supporting this practice are limited. This study examined the accuracy of Doppler echocardiography for the estimation of PA pressures at rest and during exercise.
Methods:
Simultaneous cardiac catheterization-echocardiographic studies were performed at rest and during exercise in 97 subjects with dyspnea. Echocardiography-estimated PA systolic pressure (ePASP) was calculated from the right ventricular to right atrial pressure gradient (eRV-RA) and estimated RA pressure (eRAP), and then compared with directly measured PASP and RAP.
Results:
Estimated PASP was obtainable in 57% of subjects at rest, but feasibility decreased to 15–16% during exercise, due mainly to an inability to obtain eRAP during stress. Estimated PASP correlated well with direct PASP at rest (r=0.76, p<0.0001; bias −1 mmHg) and during exercise (r=0.76, p=0.001; bias +3 mmHg). When assuming eRAP of 10 mmHg, ePASP10 correlated with direct PASP (r=0.70, p<0.0001), but substantially underestimated true values (bias +9 mmHg), with the greatest underestimation among patients with severe exercise-induced pulmonary hypertension (EIPH). Estimation of eRAP during exercise from resting eRAP improved discrimination of patients with or without EIPH (AUC=0.81), with minimal bias (5 mmHg), but wide limits of agreement (−14 mmHg to 25 mmHg).
Conclusions:
The RV-RA pressure gradient can be estimated with reasonable accuracy during exercise when measurable. However, RA hypertension frequently develops in patients with EIPH, and the inability to noninvasively account for this leads to substantial underestimation of exercise PA pressures.
Trial Registration:
clinicaltrials.gov Identifier: NCT01418248.
Keywords: Echocardiography, exercise, pulmonary hypertension, stress testing
Subject Codes: Pulmonary hypertension, exercise testing, hemodynamics, echocardiography
INTRODUCTION
Pulmonary hypertension (PH) is common in patients with a variety of cardiopulmonary diseases and is associated with increased morbidity and mortality.1–4 Because the lungs display remarkable circulatory reserve, the presence of PH at rest actually represents a rather advanced stage of pulmonary vascular disease, where changes in the left heart and pulmonary microcirculation have progressed dramatically.5, 6 In patients with less advanced cardiopulmonary disease, pulmonary artery (PA) pressures increase only during physiological stresses such as exercise.7 Like PH at rest, the presence of exercise-induced PH (EIPH) is associated with impaired aerobic capacity, worse hemodynamics, impaired ventricular-arterial coupling, and poor clinical outcomes.8–12 Accurate identification of patients with EIPH may allow for more effective diagnosis and delivery of interventions to treat and prevent PH-associated diseases.5, 13, 14
Invasive hemodynamic exercise testing represents the gold standard to make this assessment, but technical complexity and cost may be barriers to widespread utilization in practice.14–16 Doppler echocardiography allows for non-invasive estimation of PA pressures at rest based upon the velocity of tricuspid regurgitation and appearance and collapsibility of the inferior vena cava.17 However, the assumptions upon which those estimations are based may be violated during exercise, particularly where right atrial pressures may increase dramatically. While commonly performed, data regarding the accuracy of estimated PA pressure during exercise compared with invasive hemodynamic measurements are limited.18 Accordingly, we performed a simultaneous cardiac catheterization-echocardiographic study to determine the accuracy of Doppler echocardiography for the estimation of PA pressures at rest and during exercise.
METHODS
Subjects referred to the Mayo Clinic catheterization laboratory for invasive hemodynamic exercise stress testing were prospectively enrolled between August 2011 and July 2013. Some participant data from this study has been published,19–24 but not as it relates to the evaluation of PH. The study was approved by the Mayo Clinic Institutional Review Board and the study was registered (NCT01418248). Written informed consent was provided by all patients prior to participation in study-related procedures. The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
Study Population
We prospectively enrolled 99 subjects who referred for a simultaneous echo-catheterization testing with exercise in the evaluation of exertional dyspnea and fatigue. One participant withdrew following consent and another developed complete heart block during right heart catheterization (RHC), allowing for 97 subjects that completed the study. Subjects were divided into patients with and without EIPH, defined as a mean PA pressure (mPAP) >30 mmHg during exercise with a total pulmonary resistance (TPR) of >3 mmHg･min/l.25, 26 Post capillary PH was defined by EIPH with high left heart filling pressures (pulmonary capillary wedge pressure, PCWP) at rest (>15mmHg) and/or with exercise (≥25mmHg).15, 22
Study Protocol
After providing consent, subjects underwent a history and physical examination, and comprehensive resting echocardiogram to familiarize the sonographer with optimal acoustic windows in the pre-procedure area. Cardiac catheterization was then performed with simultaneous echocardiography and expired gas analysis at rest and during supine ergometer exercise. The first stage of exercise (20 Watts, W) was performed for 5 minutes to allow greater time for image acquisition, and was followed by graded 10W increments in workload (3-minute stages) to subject-reported exhaustion, which was held as long as possible to allow for imaging.
Catheterization Protocol
Patients were studied on their chronic medications in the fasted state after minimal sedation in the supine position as previously described.19–24 Right heart catheterization was performed through a 9 Fr sheath via the right internal jugular vein. Pressures in the right atrium (RA), right ventricular (RV), PA, and PCWP were measured at end expiration (mean of ≥3 beats) using 2 Fr high fidelity micromanometer-tipped catheters (Millar Instruments, Houston, TX) advanced through the lumen of a 7 Fr fluid-filled catheter (Balloon wedge, Arrow). Pressure tracings from the entire study were digitized and stored for offline analysis by one investigator with extensive experience in exercise hemodynamic assessment (BAB).
Mean RA and PCWP were taken at mid A wave. The PCWP position was verified by typical waveforms, appearance on fluoroscopy, and direct oximetry (PCWP blood saturation≥94%). Arterial blood pressure (BP) was measured through a 4–6 Fr radial arterial cannula. Oxygen consumption (VO2) was measured from the expired gas analysis (MedGraphics, St. Paul, MN). Arterial-venous O2 content difference (AVO2diff) was measured directly as the difference between systemic arterial and PA O2 contents equal to the product of O2 saturation*hemoglobin*1.34. Cardiac output or pulmonary blood flow (QP) was determined by the Fick method (VO2/ AVO2diff) at baseline, 20W and peak exercise.
Echocardiography
Two-dimensional, M-mode, Doppler and tissue Doppler echocardiography was performed according to current guidelines by experienced sonographers.17, 27, 28 Echocardiographic data were obtained simultaneously with invasive assessment at rest and during all stages of exercise. All studies were interpreted offline and in a completely blinded fashion by a single investigator with extensive experience in resting and exercise echocardiographic assessment (GCK). Estimated RV-RA pressure gradient (eRV-RA gradient) was measured from the velocity of the tricuspid regurgitation (TR) jet using the modified Bernoulli formula (=4*velocity2).17, 29 All patients had continuous-wave Doppler assessment through the right ventricular outflow tract to exclude obstruction to flow and allow the equation of eRVSP to estimated PA systolic pressure (ePASP).
Estimated RA pressure (eRAP) was determined from the size and collapsibility of the inferior vena cava (IVC) and hepatic vein Doppler profile, coded as 5 mmHg (normal sized IVC with >50% respiratory collapse and systolic forward predominant flow on hepatic vein Doppler), 10 mmHg (borderline/normal sized IVC with >50% respiratory collapse and equal degrees of systolic and diastolic forward flow on hepatic vein Doppler), 15 mmHg (enlarged IVC with >25% respiratory collapse and predominant diastolic forward flow on hepatic vein Doppler), or 20 mmHg (enlarged IVC with minimal or no collapse and solely diastolic forward flow or systolic flow reversal on hepatic vein Doppler), according to the Mayo Clinic protocol.29 ePASP was then calculated as the sum of eRAP and eRV-RA gradient.
The reproducibility of eRV-RA gradient and eRAP at rest, 20W, and peak exercise was assessed in 15 randomly selected patients. Intra- and inter-observer agreement was evaluated after the same observer and another experienced reader repeated the analysis using intra-class correlation coefficients (ICCs).
Statistical Analysis
Results are reported as mean (SD), median (IQR) or number (%). Between-group differences were compared by unpaired t test, Wilcoxon rank sum test, or χ2, as appropriate. Correlations between invasive hemodynamics and echocardiographic estimates were assessed using Pearson’s correlation. The Bland-Altman method was used to assess agreement and bias between invasive and estimated, noninvasive hemodynamic measures.
RESULTS
Subject Characteristics
EIPH was present in 73 subjects (75%). Of participants with EIPH, 49 (67%) had heart failure (HF) with preserved ejection fraction (EF), 8 (11%) had dilated cardiomyopathy, 3 (4%) had HF with reduced EF, 5 (7%) had primary valvular heart disease, 7 (10%) had precapillary PH (6 had Group I and 1 had Group V PH), and one (1%) had constrictive pericarditis. Compared to subjects without EIPH, subjects with EIPH were older, more obese, hypertensive, and anemic, and had higher NT-proBNP levels (Table 1). There were no differences in sex and other comorbidities. Subjects with EIPH were more likely to be treated with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, beta blockers, and loop diuretics. Jugular vein distention and peripheral edema were more prevalent in EIPH compared to the non-EIPH group, while rales and gallop sounds were rare in both groups. LV size, mass, and EF were similar between the groups, but E/e’ and left atrial volume index were higher in subjects with EIPH (Table 1). RV size and systolic function and TR severity were similar between the groups.
Table 1:
Baseline Characteristics
| Exercise-induced PH | |||
|---|---|---|---|
| No (n=24) | Yes (n=73) | P value | |
| Age (years) | 57±11 | 68±12 | <0.0001 |
| Female, n (%) | 9 (38) | 42 (58) | 0.09 |
| Body mass index (kg/m2) | 28.2±5.5 | 32.2±7.4 | 0.02 |
| Comorbidities | |||
| Coronary disease, n (%) | 6 (25) | 23 (32) | 0.55 |
| Diabetes mellitus, n (%) | 5 (21) | 21 (29) | 0.45 |
| Hypertension, n (%) | 17 (74) | 68 (93) | 0.01 |
| Medications | |||
| ACEI or ARB, n (%) | 8 (33) | 47 (64) | 0.008 |
| Beta-blocker, n (%) | 10 (42) | 49 (67) | 0.03 |
| Calcium channel blocker, n (%) | 5 (21) | 17 (23) | 0.80 |
| Loop diuretic, n (%) | 5 (21) | 35 (48) | 0.02 |
| Laboratories | |||
| Hemoglobin (gm/dl) | 13.9±1.2 | 12.4±1.4 | <0.0001 |
| NT-proBNP (pg/ml) | 87 (36, 473) | 681 (239,1661) | 0.0006 |
| Physical exam | |||
| JVP (<8/8–12/12–16/>16 cm), (%) | 92/8/0/0 | 52/25/4/19 | 0.006 |
| Rales, n (%) | 0 (0) | 2 (3) | 0.41 |
| S3 gallop, n (%) | 0 (0) | 3 (4) | 0.31 |
| Edema (none/mild/mod-sev), (%) | 92/8/0 | 66/21/14 | 0.04 |
| LV structure and function | |||
| LV diastolic dimension (mm) | 49±8 | 48±7 | 0.69 |
| LV mass index (gm/m2) | 93±24 | 89±25 | 0.53 |
| LV ejection fraction (%) | 56±14 | 59±13 | 0.32 |
| LA volume index (ml/m2) | 29 (20, 50) | 40 (32, 54) | 0.04 |
| E/e’ ratio | 8 (7, 11) | 15 (10,18) | <0.0001 |
| RV end-diastolic area (cm2) | 20±6 | 20±6 | 0.7 |
| FAC (%) | 45±10 | 43±10 | 0.3 |
| TAPSE (mm) | 21±6 | 20±6 | 0.7 |
| TR severity (%) no/mild/moderate/severe | 17/79/0/4 | 8/84/3/5 | 0.6 |
Data are mean ± SD, median (interquartile range), or n (%). ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin-receptor blockers; E/e’ ratio, the ratio of early diastolic mitral inflow to mitral annular tissue velocities; FAC, fractional area change; JVP, jugular venous pressure; LA, left atrial; LV, left ventricular; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PH, pulmonary hypertension; RV, right ventricular; and TAPSE, tricuspid annular plane systolic excursion.
Resting Hemodynamics and Echocardiographic-Invasive Relationships
Subjects with EIPH had higher right and left heart filling pressures, higher PA pressures, and lower QP by invasive assessment compared to those without EIPH (Table 2). Heart rate and systolic BP were similar between the groups.
Table 2:
Baseline Invasive and Noninvasive Hemodynamics
| Exercise-induced PH | |||
|---|---|---|---|
| No (n=24) | Yes (n=73) | P value | |
| Invasive data | |||
| Heart rate (bpm) | 71±14 | 68±11 | 0.29 |
| Systolic BP (mmHg) | 138±27 | 144±24 | 0.26 |
| RA pressure (mmHg) | 5±2 | 10±5 | <0.0001 |
| PASP (mmHg) | 26±6 | 40±11 | <0.0001 |
| PA mean pressure (mmHg) | 16±4 | 27±8 | 0.0001 |
| RV-RA gradient (mmHg) | 22±5 | 30±9 | <0.0001 |
| PCWP (mmHg) | 8±3 | 17±6 | <0.0001 |
| Cardiac output (l/min) | 5.6±1.7 | 4.8±1.3 | 0.02 |
| Echocardiographic data | |||
| IVC diameter at expiration (mm) | 18±5 | 20±6 | 0.06 |
| IVC diameter at inspiration (mm) | 10±5 | 11±6 | 0.3 |
| Hepatic Vein Doppler profile 0/1/2/3a, n | 19/1/2/1 | 28/15/13/3 | 0.02 |
| eRV-RA gradient (mmHg), (n=10,45) | 25±8 | 31±9 | 0.06 |
| eRA pressure (mmHg), (n=24, 70) | 6±3 | 9±5 | 0.001 |
| ePASP (mmHg), (n=10,45) | 33±8 | 40±11 | 0.04 |
| eCardiac output (l/min), (n=20,66) | 5.9±1.6 | 5.6±1.7 | 0.46 |
Data are mean ± SD. BP, blood pressure; PA; pulmonary artery; PASP, pulmonary artery systolic pressure; PCWP, pulmonary capillary wedge pressure; RA, right atrial; RV, right ventricular; and other abbreviations as in Table 1.
Hepatic vein Doppler profile characteristics defined as: 0-predominant systolic flow, profile, 1-equal systolic and diastolic flow, 2-predominant diastolic flow, and 3-solely diastolic forward flow or systolic flow reversal.
Estimated RA pressure, RV-RA gradient, and PASP were obtainable at rest in 97%, 57%, and 57% of participants, respectively. The intra- and inter-observer agreement was consistently good at all stages (Supplemental Table 1). Resting eRAP and ePASP were higher in the EIPH group compared to the non-EIPH group (Table 2). Significant correlations were observed between the simultaneous invasive and echocardiographic measurements for RA pressure (r=0.70, p<0.0001), RV-RA gradient (r=0.73, p<0.0001), and PASP (r=0.76, p<0.0001; Figure 1). Bland-Altman analyses showed little bias for RAP (bias 0.2mmHg, 95% limits of agreement ranging from −7mmHg to 8mmHg), RV-RA gradient (bias −1 mmHg, 95% limits of agreements from −14mmHg to 12mmHg), and PASP (−1mmHg, 95% limits of agreement from −17mmHg to 14mmHg; Figure 1).
Figure 1. Correlations and Bland-Altman plots between invasive and noninvasive hemodynamic parameters at rest.
Modest correlations were observed between the simultaneous invasive and echocardiographic measurements for right atrial (RA) pressure (r=0.70, p<0.0001), right ventricular-right atrial gradient (RV-RA gradient)(r=0.73, p<0.0001), and pulmonary artery systolic pressure (PASP)(r=0.76, p<0.0001). Bland-Altman analyses showed little bias for these estimates.
In the pre-procedure area, where patient position could be modified more than in the catheterization lab, estimated RA pressure, RV-RA gradient, and PASP were obtainable at rest in 97%, 81%, and 80% of participants, respectively. Correlations between these non-simultaneous invasive and echocardiographic measurements remained robust for RA pressure (r=0.72, p<0.0001), RV-RA gradient (r=0.70, p<0.0001), and PASP (r=0.74, p<0.0001).
The criteria for eRAP as suggested by the American Society of Echocardiography,(17) which differs to that used at the Mayo Clinic, also correlated with invasive RAP, but less well (r=0.45, p<0.0001). A Bland-Altman plot showed little bias between the ASE-based eRAP and invasively-measured RAP, but wider limits of agreement (Supplemental figure 1, bias 0.6 mmHg, 95% limits of agreement ranging from −11 mmHg to 12 mmHg) than those between eRAP estimated by the criteria used at the Mayo Clinic and true RAP (Figure 1). The superiority of the Mayo criteria as compared to the ASE criteria was consistently observed across different categories of eRAP (Supplemental Table 2). The lateral tricuspid valve annulus E/e’ ratio correlated only weakly with RAP (r=0.34, p=0.003), with a lateral TV E/e’ ratio > 6 having a sensitivity of 73% and specificity of 56% for a RAP≥15 mm Hg.
Echocardiographic-Invasive Relationships during Exercise
Peak exercise workload (37±14 vs. 71±26 W, p<0.0001) and peak VO2 (8.2±2.7 vs. 14.1±4.3 ml/min/kg, p<0.0001) were both markedly impaired in subjects with EIPH as compared to those without EIPH. During submaximal (20W) and peak exercise, subjects with EIPH displayed higher left and right heart filling pressures, with lower QP compared to non-EIPH subjects (Tables 3).
Table 3:
Submaximal and peak exercise Invasive and Noninvasive Hemodynamics among patients with obtainable ePASP10
| Exercise-induced PH | |||
|---|---|---|---|
| No (n=24) | Yes (n=73) | P value | |
| Submaximal exercise (20W) | |||
| Invasive data | |||
| Heart rate (bpm) | 88±16 | 90±17 | 0.64 |
| Systolic BP (mmHg) | 163±31 | 170±29 | 0.33 |
| RA pressure (mmHg) | 9±4 | 21±7 | <0.0001 |
| PASP (mmHg) | 35±10 | 64±13 | <0.0001 |
| PA mean pressure (mmHg) | 24±7 | 45±9 | <0.0001 |
| RV-RA gradient (mmHg) | 26±8 | 44±11 | <0.0001 |
| PCWP (mmHg) | 14±6 | 30±7 | <0.0001 |
| Cardiac output (l/min) | 8.6±2.1 | 6.4±2.0 | <0.0001 |
| Echocardiographic data | |||
| eRV-RA gradient measurable (n/%) | 11 (46%) | 41 (56%) | |
| eRV-RA gradient (mmHg) | 32±12 | 41±10 | 0.01 |
| eRA pressure (mmHg), (n=0/16) | - | 15±5 | - |
| ePASP (mmHg), (n=0/16) | - | 54±13 | - |
| ePASP10 (mmHg) | 42±12 | 51±10 | 0.01 |
| eCardiac output (l/min) | 8.4±2.1 | 7.8±2.3 | 0.34 |
| Peak exercise | |||
| Invasive data | |||
| Heart rate (bpm) | 117±23 | 100±20 | 0.0006 |
| Systolic BP (mmHg) | 179±30 | 180±32 | 0.95 |
| RA pressure (mmHg) | 10±5 | 22±8 | <0.0001 |
| PASP (mmHg) | 40±8 | 68±13 | <0.0001 |
| PA mean pressure (mmHg) | 27±7 | 47±9 | <0.0001 |
| RV-RA gradient (mmHg) | 31±7 | 46±12 | <0.0001 |
| PCWP (mmHg) | 15±6 | 33±8 | <0.0001 |
| Cardiac output | 12.4±4.0 | 7.4±2.4 | <0.0001 |
| Echocardiographic data | |||
| eRV-RA gradient measurable (n/%) | 7 (29%) | 38 (52%) | |
| eRV-RA gradient (mmHg) | 33±14 | 46±11 | 0.005 |
| eRA pressure (mmHg), (n=0/15) | - | 16±4 | - |
| ePASP (mmHg), (n=0/15) | - | 64±14 | - |
| ePASP10 (mmHg) | 43±14 | 56±11 | 0.009 |
| eCardiac output (l/min) | 12.3±3.7 | 8.6±2.4 | 0.002 |
The number of subjects with obtainable ePASP during 20W and peak exercise substantially decreased to 16 (16%) and 15 (15%), respectively. This was largely caused by an inability to determine eRAP during exercise (68% both during 20W and peak exercise). In a subset of patients with obtainable eRAP (n=31 and n=30 during 20W and peak exercise, respectively), eRAP correlated with invasively-obtained RA pressure during exercise (r=0.73, p<0.001), with an underestimation of true RA pressure by 5 mmHg (Supplemental Figure 2). In this smaller cohort with both eRAP and eRV-RA assessment (n=16 and n=15), estimated PASP was correlated with invasive measurements, but underestimated true PASP by 3–6 mmHg on average, with wide limits of agreement (Supplemental Figure 3).
In contrast, the eRV-RA gradient was obtainable in 54% and 45% of subjects at 20W and peak exercise (Table 3). Correlations between invasive and echocardiographic measurements for RV-RA gradient during 20W and peak exercise were moderately strong (r=0.73, p<0.0001 and r=0.72, p<0.0001), with little bias (20W, bias −0 mmHg, 95% limits of agreement −16mmHg to 16mmHg; peak exercise, bias −1mmHg, 95% limits of agreement −19mmHg to 16mmHg, respectively; Figure 2).
Figure 2. Correlations and Bland-Altman plots between the simultaneous invasive and echocardiographic measurements for RV-RA gradient.
Correlation between RV-RA gradient remained significant during 20W and peak exercise (r=0.73, p<0.0001 and r=0.72, p<0.0001, respectively), with little bias. Abbreviations as in Figure 1.
Given the inability to assess eRAP during exercise in the majority of subjects, a common assumed RA pressure value of 10 mmHg was next used to provide an estimate of exercise PASP (ePASP10). While ePASP10 correlated well with invasively-measured PASP during exercise (20W r=0.68, p<0.0001 during 20W and r=0.70, p<0.0001 during peak exercise), it systematically underestimated invasive PASP, with wide 95% limits of agreement (20W, bias 7mmHg, 95% limits of agreement −15mmHg to 30mmHg; peak exercise, bias 9mmHg, 95% limits of agreement −13mmHg to 30mmHg, respectively; Figure 3).
Figure 3. Correlations and Bland-Altman plots between the simultaneous invasive and echocardiographic measurements for PASP during exercise.
While ePASP10 correlated well with direct PASP during 20W and peak exercise (r=0.68, p<0.0001 and r=0.70, p<0.0001, respectively), it underestimated true PASP, with wide 95% limits of agreement. ePASP10 was determined from an assumed exercise RA pressure of 10 mmHg. Abbreviations as in Figure 1.
We further investigated whether estimated RA pressure at rest could predict eRA pressure during peak exercise. Echocardiographic RA pressure at rest was correlated with eRA pressure during peak exercise (r=0.66, p<0.0001), allowing for prediction of peak eRA pressure using rest eRA pressure (peak eRAPpredict = 0.83*Baseline eRAP + 5.4 mmHg, r2=0.43, p<0.001). Peak ePASPpredict (calculated as eRV-RA gradient during peak + peak eRAPpredict) was correlated with direct PASP (r=0.75, p<0.0001, n=45) with relatively little bias (5.3 mmHg) but wide limits of agreement (−14 mmHg to 25 mm Hg; Supplemental figure 4).
Contributions of Right Atrial Hypertension to PASP during Exercise
PASP is equal to the sum of the RV-PA pressure gradient and RAP. The individual contributions of changes in RAP and the RV-RA gradient to total change in PASP during exercise are shown in Figure 4. On average, the change in RV-RA gradient accounted for 59% of the change in PASP, while the change in RAP during exercise accounted for 41% of the increase. The underestimation of PASP using assumed RAP values was more pronounced in EIPH subjects and in those with higher RAP during exercise (Figure 4 and Supplemental figure 5).
Figure 4. Changes in direct and echocardiographic PASP, RV-RA gradient, and RAP during exercise.
(A) Echocardiography could reasonably estimate direct change in RV-RA during exercise (black and gray bars). However, it underestimated direct change in RAP either using measured peak RAP or assumed RAP (orange, gold, and yellow bars). This led to substantial underestimation of direct change in PASP by echocardiography (red and pink bars). (B) The underestimation of true PASP using assumed RAP values was more pronounced in exercise-induced pulmonary hypertension (EIPH) subjects and in those with higher RAP during exercise.
Diagnostic Implications
Finally, we examined the diagnostic ability of exercise stress echocardiography for identification of EIPH. When restricted to the subset of patients with obtainable ePASP, resting ePASP as a continuous variable demonstrated a modest diagnostic accuracy for EIPH (AUC 0.70) with a sensitivity of 62% and a specificity of 70% at the optimal cutoff value of 37 mmHg (Table 4). Within the subgroup of patients with measurable data during exercise (54% at 20W and 46% at peak) exercise ePASP10 >40 mmHg increased sensitivity to detect the development of EIPH, but reduced specificity, with no improvement in discrimination (AUC 0.72 and 0.67, Table 4). Applying ePASP10 as a continuous variable also displayed moderate discrimination of the groups, with AUC of 0.70 and 0.76 at 20W and peak exercise (Table 4). The diagnostic ability of peak PASPpredict (prediction of peak RA pressure using eRAP at rest) was slightly improved (AUC 0.81; Table 4) Results were similar when excluding EIPH patients with PH at rest (Supplemental Table 3).
Table 4:
Diagnostic Accuracy for Identification of Exercise-induced PH
| Optimal Cutoff |
Sensitivity (%) |
Specificity (%) |
PPV (%) |
NPV (%) |
AUC | N | |
|---|---|---|---|---|---|---|---|
| Echocardiographic Data | |||||||
| Rest ePASP (mmHg) | 37 | 62 | 70 | 90 | 29 | 0.70 | 55 (57%) |
| 20W ePASP10 >40 mmHg | - | 90 | 55 | 88 | 60 | 0.72 | 52 (54%) |
| Peak ePASP10 >40 mmHg | - | 92 | 43 | 90 | 50 | 0.67 | 45 (46%) |
| 20W ePASP10 (mmHg) (continuous) | 40 | 90 | 55 | 88 | 60 | 0.70 | 52 (54%) |
| Peak ePASP10 (mmHg) (continuous) | 41 | 84 | 57 | 100 | 25 | 0.76 | 45 (46%) |
| Peak ePASPpredict (mmHg) (continuous) | 57 | 61 | 100 | 100 | 32 | 0.81 | 45 (46%) |
DISCUSSION
In this simultaneous echocardiographic-cardiac catheterization study we observed that Doppler-estimated ePASP at rest was well correlated with invasively-measured PASP, with little bias, but ePASP was not obtainable in more than 40% of subjects due to inability to image the TR Doppler envelope. During exercise, there was a progressive increase in the number of patients with incomplete echocardiographic data to determine PASP (approximately 85%), mainly due to the inability to determine eRAP. Using an assumed RAP of 10 mmHg during exercise increased the feasibility of obtaining estimated PASP, but resulted in a significant underestimation of true PASP, especially among patients with more severe EIPH, with wide limits of agreement, due to the fact that marked RA hypertension develops in many patients with EIPH during exercise. Among the 46–54% of subjects where TR Doppler could be performed during exercise, exertional ePASP10 improved sensitivity to identify the development of EIPH, but decreased specificity, with no improvement in overall discrimination compared to resting data, but estimation of eRAP during exercise from resting eRAP improved discrimination. These data confirm that the RV-RA gradient can be accurately estimated in many patients during exercise, but failure to account for the severity of RA hypertension during stress, which is often dramatic, leads to marked underestimation of EIPH severity in many patients.
Accuracy of Non-invasive Estimates of PA Pressures at Rest
PH is associated with worsening exercise capacity, increased mortality and greater morbidity in patients with a variety of cardiopulmonary diseases.1–4 Doppler-derived PASP is often used in the noninvasive evaluation of PH. Several studies have reported modest correlations between ePASP and directly measured PASP at rest,30, 31 but simultaneous echocardiographic-catheterization assessments are more limited.18, 32–35 Except for one study examining group I PH,33 ePASP has been found to be well-correlated with invasively-measured PASP at rest (r=0.72–0.97) with acceptable limits of agreement.18, 32, 34, 35 The current data confirm and extend upon the utility of ePASP as a non-invasive tool to estimate PASP at rest. However, even with highly-trained research sonographers, a significant proportion of subjects (>40%) did not have a reliable measurement of ePASP at rest, due to inability to obtain TR velocity. The proportion of patients with missing data in this study is very similar to a previous meta-analysis.31 Even when TR spectra are obtainable, it has been reported that accuracy of ePASP depends vitally on the quality of the TR Doppler envelope.18 In the current study, a greater proportion of participants had evaluatable data when evaluated in the pre-procedure area, where greater freedom is available to change positions, and the inabilty to change from the supine position in the invasive laboratory likely contributed to the lower number of participants with adequate data.
Estimating the RV-PA Pressure Gradient during Exercise
The importance of identifying exercise-induced PH has been increasingly recognized in view of its diagnostic, prognostic, and potentially, therapeutic utilities.8–12 Like resting PH,1–4 exercise-induced elevation in PA pressures due to pre- and post-capillary etiologies is associated with increased morbidity and mortality,36–38 and has recently been adopted as an important therapeutic target for both drug and device therapies.39–42 Invasive exercise hemodynamic testing provides a direct measurement of PA pressures with exertion and thus serves as the gold standard, but is difficult to apply as broadly given its invasive nature, technical complexity and cost.
There is increasing enthusiasm for more broad utilization of exercise stress echocardiography studies for clinical purposes, including evaluation for exertional dyspnea.13 However, few studies have examined the reliability of PASP estimates during exercise.34, 43 Only one study has reported assessments using simultaneous catheterization-echocardiographic evaluation at rest and during exercise.18 In this study, van Riel and colleagues observed that despite wide limits of agreement (−30 to 34 mmHg), non-invasive PASP was modestly well-correlated with invasive PASP (r=0.57) with small bias (1.9 mmHg). However, in this study the authors compared invasive and noninvasive RV-RA gradient, not absolute PASP, which is the clinical variable of interest that determines RV afterload. The current data demonstrate how even with robust correlations between invasive and noninvasive RV-RA gradients, there may be substantial error in the estimation of PASP owing to the difficulty with noninvasively assessing RAP.
The Importance of Right Atrial Hypertension
Consistent with van Riel et al.,18 we found a reasonable correlation between invasive and echocardiographic measurements for the RV-RA gradient during exercise (r=0.72–0.73), with little bias. However, we observed that it was very difficult to obtain diagnostic quality imaging of both the TR spectrum and IVC to allow for estimation of PASP, obtainable in only 15% of participants during exercise.
An important observation from this study was that people with EIPH frequently develop substantial RA hypertension during exercise, and this contributes substantially to the total PASP, often exceeding the pressure elevation attributable to the RV-RA gradient (Supplemental Figure 6). Exertional RA hypertension frequently develops from abnormalities in RV-PA coupling, common in patients with pulmonary vascular disease, as well as in patients with increased pericardial restraint, such as patients with obesity.11, 44 There may also be greater redistribution of blood from the capacitance veins to the right heart during exercise that contributes to worsening RA hypertension.45
To explore whether use of an assumed RAP might produce acceptable results, we next estimated ePASP using a fixed eRAP of 10 mmHg (abbreviated as ePASP10), and observed a modest correlation with directly-measured PASP during exercise. However, this estimation systematically underestimated true PASP, especially among patients with EIPH (Figures 4). Thus, an important clinical implication from this study is that Doppler-echo assessments of PASP during exercise may substantially underestimate the severity of PH, and this underestimation is greatest in the population that is most afflicted by PH and abnormalities in RV-PA coupling during exercise. Using assumed values of RAP during exercise was associated with robust sensitivity to detect EIPH (Table 4), but at the cost poor specificity (43–57%), which would increase the risk of diagnosing normal patients with EIPH.
An estimation of PASP by the addition of the Doppler derived RV-RA gradient and exercise eRAP predicted by resting eRAP correlated with the true measured exercise PASP, and provided an improved metric to discriminate EIPH from no PH, underscoring the potential clinical value for an accurate estimate of exercise RAP in the assessment of pulmonary vascular hemodynamics, though limits of agreement were wide. Other modalities to estimate RAP during exercise, such as imaging of the internal jugular vein or superior vena cava warrant future study to address this problem.46
Limitations
This is a single-center study from a tertiary referral center and as such has inherent flaws relating to selection and referral bias. The sample size is moderate, but this is the largest study for a comparison of simultaneous catheterization and echocardiography during exercise, and the only study to also estimate simultaneous right atrial pressure to calculate PASP. Although echocardiography was performed by rigorously trained, dedicated research sonographers, the requirement for imaging in the supine, draped patient in the catheterization laboratory may have limited the availability of Doppler data and IVC assessment.
Conclusions
In patients with obtainable echocardiographic images, the RV-RA pressure gradient can be estimated with reasonable accuracy and precision during exercise. However, RA hypertension develops frequently in patients being evaluated for PH during exercise, and the inability to noninvasively account for high RAP leads to substantial underestimation of exercise PASP, which may lead to underappreciation of the burden of pulmonary vascular disease. Further study is necessary to identify methods to accurately estimate RAP during exercise to improve assessment of EIPH.
Supplementary Material
Supplemental Figure 1. A Bland-Altman plot between the ASE-guided RAP and invasively-measured RAP at rest. A Bland-Altman plot between the ASE-guided RAP and invasively-measured RAP at rest showed a little bias, but relatively wider limits of agreement (bias 0.6 mmHg, 95% limits of agreement −11 mmHg to 12 mmHg)(n=85). ASE, American Society of Echocardiography; and RAP, right atrial pressure.
Supplemental Figure 4. Correlations and Bland-Altman plots between the predicted peak PASP using eRAP at rest and simultaneous invasively-measured PASP
Echocardiographic RAP at rest was highly correlated with eRAP during peak exercise (r=0.66, p<0.0001), allowing for a prediction of peak eRAP using eRAP at rest (peak eRAPpredict = 0.83*Baseline eRAP + 5.4 mmHg). Peak ePASPpredict (eRV-RA gradient during peak + peak eRAPpredict) was correlated with direct PASP (r=0.75, p<0.0001, n=45) with little bias though limits of agreement were relatively wide (5.3 mm Hg, LOA −14 mmHg to 25 mm Hg). Abbreviations as in Supplemental Figures 1 and 3.
Supplemental Figure 2. Correlations and Bland-Altman plots between the simultaneous invasive and echocardiographic measurements for RAP during exercise
In a subset of patients with obtainable estimated right atrial pressure (eRAP)(n=31 and n=30 during 20W and peak exercise, respectively), eRAP correlated with invasively-obtained RA pressure during exercise (r=0.73, p<0.001), with an underestimation of true RA pressure by 5 mmHg. Abbreviations as in Supplemental Figure 1.
Supplemental Figure 3. Correlations and Bland-Altman plots between the simultaneous invasive and echocardiographic measurements for PASP during exercise
In the smaller cohort with both eRAP and eRV-RA assessment (n=16 and n=15), estimated pulmonary artery systolic pressure (ePASP) was correlated with invasive measurements, but underestimated true PASP by 3–6 mmHg on average, with wide limits of agreement. Abbreviations as in Supplemental Figure 1.
Supplemental Figure 5. Baseline, submaximal (20W), and peak exercise for simultaneous invasive and echocardiographic measurements for RAP, RV-RA gradient, and PASP
The underestimation of PASP using assumed RAP values (ePASP10) was more pronounced in exercise-induced pulmonary hypertension (EIPH) subjects. Data are mean ± SE. Abbreviations as in Supplemental Figures 1 and 3.
Supplemental Figure 6. Representative case for the underestimation of true PASP by stress echocardiography
Exercise hemodynamics and echocardiography in a patient presenting exertional dyspnea and normal EF. Pulmonary artery (red) and RA (blue) pressures were moderately elevated at rest. Echocardiography could accurately estimate both RV-RA gradient and RAP at rest. During exercise RAP increased dramatically to 38 mmHg, without an increase in RV-RA gradient (direct PASP 67 mmHg). While exercise RV-RA gradient could be estimated by echocardiography, inferior vena cava image was unobtainable during exercise. Estimated PASP (39 mmHg) using assumed RAP of 10 mmHg substantially underestimated direct PASP by 28 mmHg. This underestimation could even misclassify this patient as having normal pulmonary hemodynamics response with exercise. Abbreviations as in Supplemental Figures 1 and 3.
Acknowledgements
The authors thank the staff of the Earl Wood Catheterization Laboratory and patients who agreed to participate in this study to be completed. This study was supported by an award from the Mayo Department of Cardiovascular Diseases. BAB is supported by R01 HL128526, R01 HL 126638, U01 HL125205 and U10 HL110262.
Footnotes
Disclosures
None.
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Associated Data
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Supplementary Materials
Supplemental Figure 1. A Bland-Altman plot between the ASE-guided RAP and invasively-measured RAP at rest. A Bland-Altman plot between the ASE-guided RAP and invasively-measured RAP at rest showed a little bias, but relatively wider limits of agreement (bias 0.6 mmHg, 95% limits of agreement −11 mmHg to 12 mmHg)(n=85). ASE, American Society of Echocardiography; and RAP, right atrial pressure.
Supplemental Figure 4. Correlations and Bland-Altman plots between the predicted peak PASP using eRAP at rest and simultaneous invasively-measured PASP
Echocardiographic RAP at rest was highly correlated with eRAP during peak exercise (r=0.66, p<0.0001), allowing for a prediction of peak eRAP using eRAP at rest (peak eRAPpredict = 0.83*Baseline eRAP + 5.4 mmHg). Peak ePASPpredict (eRV-RA gradient during peak + peak eRAPpredict) was correlated with direct PASP (r=0.75, p<0.0001, n=45) with little bias though limits of agreement were relatively wide (5.3 mm Hg, LOA −14 mmHg to 25 mm Hg). Abbreviations as in Supplemental Figures 1 and 3.
Supplemental Figure 2. Correlations and Bland-Altman plots between the simultaneous invasive and echocardiographic measurements for RAP during exercise
In a subset of patients with obtainable estimated right atrial pressure (eRAP)(n=31 and n=30 during 20W and peak exercise, respectively), eRAP correlated with invasively-obtained RA pressure during exercise (r=0.73, p<0.001), with an underestimation of true RA pressure by 5 mmHg. Abbreviations as in Supplemental Figure 1.
Supplemental Figure 3. Correlations and Bland-Altman plots between the simultaneous invasive and echocardiographic measurements for PASP during exercise
In the smaller cohort with both eRAP and eRV-RA assessment (n=16 and n=15), estimated pulmonary artery systolic pressure (ePASP) was correlated with invasive measurements, but underestimated true PASP by 3–6 mmHg on average, with wide limits of agreement. Abbreviations as in Supplemental Figure 1.
Supplemental Figure 5. Baseline, submaximal (20W), and peak exercise for simultaneous invasive and echocardiographic measurements for RAP, RV-RA gradient, and PASP
The underestimation of PASP using assumed RAP values (ePASP10) was more pronounced in exercise-induced pulmonary hypertension (EIPH) subjects. Data are mean ± SE. Abbreviations as in Supplemental Figures 1 and 3.
Supplemental Figure 6. Representative case for the underestimation of true PASP by stress echocardiography
Exercise hemodynamics and echocardiography in a patient presenting exertional dyspnea and normal EF. Pulmonary artery (red) and RA (blue) pressures were moderately elevated at rest. Echocardiography could accurately estimate both RV-RA gradient and RAP at rest. During exercise RAP increased dramatically to 38 mmHg, without an increase in RV-RA gradient (direct PASP 67 mmHg). While exercise RV-RA gradient could be estimated by echocardiography, inferior vena cava image was unobtainable during exercise. Estimated PASP (39 mmHg) using assumed RAP of 10 mmHg substantially underestimated direct PASP by 28 mmHg. This underestimation could even misclassify this patient as having normal pulmonary hemodynamics response with exercise. Abbreviations as in Supplemental Figures 1 and 3.