Evaluation of Right Ventricular Systolic Pressure During Incremental Exercise by Doppler Echocardiography in Adults With Atrial Septal Defect

Evaluation of Right Ventricular Systolic Pressure During Incremental Exercise by Doppler Echocardiography in Adults With Atrial Septal Defect* David A. Oelberg , MD; Fran9ois Marcotte, MD; Harvey Kreisman, MD, FCCP; Norman Wolkove, MD, FCCP; David Langleben, MD; and David Small, MD, FCCP

Study objectives: Pulmonary hypertension is the most important complication in patients with atrial septal defect (ASD), but its role in limiting exercise has not been examined. This study sought to evaluate exercise performance in adults with ASD and determine the contribution of elevated pulmonary artery pressure in limiting exercise capacity. Design: We used Doppler echocardiography during exercise in 10 adults (aged 34 to 70 years) with isolated ASD (New York Heart Association class I, II) and an equal number of matched control subjects. Incremental exercise was performed on an electrically braked upright cycle ergometer. Expired gases and VE were measured breath-by-breath. Two-dimensional and Doppler echocardiographic images ~ere obtained at rest prior to exercise to determine ASD size, stroke volume (SV), shunt ratio (Qp:Qs), right ventricular outflow tract (RVOT) size, and right ventricular systolic pressure at rest (RVSPr). Doppler echocardiography was repeated at peak exercise to measure right ventricular systolic pressure during exercise (RVSPex). Results: Resting echocardiography revealed that RVOT was larger (21±4 vs 35±8 mm, mean±SD; p=0.0009) and RVSPr tended to be higher (17±8 vs 31±8 mm Hg; p=0.08) in ASD; however, left ventricular SV was not different (64±23 vs 58±23 mL; p>0.05), compared with control subjects. Despite normal resting left ventricular function, ASD patients had a significant reduction in maximum oxygen uptake (Vo2 max) (22.9±5.4 vs 17.3±4.2 mUkglmin; p=0.005). RVSPex was higher (19±8 vs 51±10 mm Hg; p=0.001) and the mean RVSP-Vo2 slope (1±2 vs 18±3 mm Hg!Umin; p=0.003) and intercept (17±4 vs 27±4 mm Hg; p=0.05) were higher in the ASD group. Vo2 max correlated inversely with both RVSPr (r= -0.69; p=0.007) and RVSPex (r= -0.67; p=O.Ol). Conclusion: These fmdings suggest that adults with ASD have reduced exercise performance, which may be associated with an abnormal increase in pulmonary artery pressure during exercise. (CHEST 1998; 113:1459-65) Key words: atrial septal defect; echocardiography; exercise; pulmonary hype1tension Abbreviations: ASD=atrial septal defect; BR=breathing resezve; CI=confidence intezval; HR = ~eart rate; LVOT=left ventricular outflow tract; MPA=main pulmonary artery; NYHA = New York Heart Association; Qp=pulmonary cardiac output; Qp:Qs=shunt ratio; Qs =systemic cardiac output; RA=right atrial; RVOT=right ventricular outflow tract; RVSP = right ventricular systolic pressure; RVSPex = right ventricular systolic pressure during exercise; RVSPr= right ventricular systolic pressure a t rest; Sa02 =arterial saturation of oxygen; SV=systemic str
I solated atrial septal defect (ASD ) is the second most frequently encountered form of congenitalheart disease after childhood, accounting for approx-

*From the Pulmonary and Cardiology Divisions, Department of Inte rnal Medicine, Sir Mortimer B. Davis-Jewish General Hospital and McGill University, Montreal, Canada. Supported by Canadian Lung Association/Medical Research Council Fellowship 9611 JN9-l020-38948 (Dr. Oelberg). Manuscript received July 14, 1997; revision accepted November 18, 1997. Reprint requests: David A Oelberg , MD, Pulmonary and Critical Care Division, Danbury Hospital, Danbury, C T 06810

imately 22% of cases.l Although some patients with uncorrected ASD survive to an advanced age, 2 •3 overall life expectancy is thought to be shortened. 4 For editorial comment see page 1436 Pulmonary hypertension, the most important complication, is associated with increased morbidity and mortality.5 -7 At present, a majority of adults with ASD are advised to undergo surgical repair before th e onset of pulmonary hypertension in order to CHEST I 113 I 6 I JUNE, 1998

1459

increase longevity and limit the deterioration of functional capacity. 8 Once pulmonary hypertension develops, irreversible right ventricular failure may result. Detecting pulmonary hypertension during exercise, before the onset of sustained resting pulmonmy hypertension, may be of value when considering operative repair in adults vvith ASD . Doppler echocardiography provides an accurate noninvasive approach to determine right ventricular systolic pressure (RVSP) at rest9 and has been validated against direct measurements of pulmona1y systolic pressure during exercise .10 · 11 This technique has not been utilized in this patient population, however. We conducted a prospective, controlled study to determine if adults with uncorrected ASD develop pulmonary hypertension during exercise, and to examine the importance of elevated pulmonary arte1y pressure during exercise in limiting overall performance.

MATERIALS AND METHODS Study Population

Ten patients with isolated ASD (New York Heart Association [NYHA] functional class I, II ), 'Nith a mean age of 52.9±11.2 years (range, 34 to 70 years) , and an equal number of matched healthy control subjects gave informed consent to participate in the study. All study subjects (patients and controls) were selected from th e echocardiographic laboratory database (UpBeat Syste ms lnc; Montreal, Canada) of the Sir Mortimer B. Davis-Jewish General Hospital. Between S epte mber 1989 and April 1993, 10,725 patients were enrolled in this database. From this group, 63 individuals with ASD were identified. Twenty patients who had previously undergon e surgical repair were excluded. An additional 17 patients were excluded because of known coronary artery disease, other valvular cardiac abnormalities, or vascular, otihopedic, neurologic, or other systemic disease; seven patients were excluded because of age > 70 years, and six were classified as NYHA class III or IV. Of the 13 remaining ASD patients who fulfill ed all entry criteria, 10 agreed to participate in the study. Ten consecutive patients from this database who had a normal echocardiogram , no clinical histmy of cardiopulmonaty disease, and matched ASD patient characteristics with respect to age, sex, height, and smoking history, were recruited as co ntrol subjects .. one of the ASD patients or controls had any evidence of pulmonary stenosis by echocardiography. This study was approved by our institutional review board for human studies. H eight and weight were measured, and resting spirometry (DS 560; Collins; Braintree, Mass ) perform ed on all study paliicipants within two weeks of the exercise study.

Exercise P1·otocol Exercise studies were perform ed at th e Sir Mortimer B. Davis-Jewish General Hospital Cardiopulmonary Exercise Laboratmy. Subjects were seated on an upright cycle ergometer (CPE 2000; Medical Graphics Cmp; St. Paul, Minn ). A mouthpiece and noseclips were placed and a 12-lead ECG was perform ed. \TE, \To 2 , and \Tco 2 were measured breath by breath using a 1460

commercially available metabolic cart (Cardio II System; Medical Graphics Cmp). The pneumotachograph was calibrated using a 3-L syringe at fi ve different flow rates, with errors of ±2% accepted. A zirconia cell 0 2 analyzer and single-beam infrared C0 2 analyzer were calibrated with room air and a 5% C
Echocardiogmphy Supine resting and upright res ting and exe rcise echocardiographic studies were performed on all subjects with an ultrasonograph (Hewlett-Packard 1.500; Hewlett-Packard; Andover, Mass ), eq uipped with a standard imaging 2.5-MHz probe. B efore exercise, a co mplete resting echocardiographic study was perform ed in the supine position in all standard views to dete rmine cardiac chambe r and great vessel dimensions, cardiac output, and shunt ratios. All echocardiograms were reco rded on high-quality VHS videocassettes and interpreted blindly, without knowledge of patien t identity. The subjects were positioned in the left lateral dec ubitus position for parastemal and apical views and dorsal decubitus for subcostal images. Images were obtained during held midexpiration to enhance the definition of the right ventricular outflow tract (RVOT) and main pulmonary mie1y (MPA). Cardiac dimensions were obtained by parasternal long-axis M-mode echocardiography, according to th e American Society of Echocardiography standards. 12 These dim ensions included left ventricular end-diastolic diamete r, interventricular septal wall and posterior wall thickness, right ventricular outflow diastolic diam eter, and left ventricular end-systolic diame te r. Right ventricular inlet diam eter was obtained b y th e apical four-chamber view, just b elow the tricuspid valve leaflet insertion. Atlial septal defect dimensions were calculated by color flow imaging in the subcostal views. 13· 14 Each parameter was measured off-line in triplicate ;md averaged. High resolution images of the left ventricular outflow tract (LVOT), immediately below the insertion of th e aortic valve leaflets were obtained by freeze-frame two-dimensional echocardiography in the left parasternal window. The LVOT area was calcu lated as d 2 ·0.785, where dis th e LVOT diameter. Using th e same calculations, the RVOT area and proximal MPA area were meas ured, res pectively, immediately below the pulmonic valve leaBet insertion and distal to the pulmonic valve leaflets. The pulsed Doppler cursor was carefully positioned parallel to the RVOT and MPA to measure flow velocity time integral at both sites and obtain the right ventricular stroke volume (SV).1.s The pulmona1y cardiac output (Qp) was calculated as th e average of SV obtained at the RVOT and the MPA, multiplied by the resting HR For each patient. The LVOT flow was meas ured by the apical four-chamber view, immediately below th e aoliic valve leafl ets. The systemic cardiac output (Qs) was obtain ed b ymultiplying the LVOT area by the LVOT velocity time integral and HR. For patie nts in sinus rhythm, each p aramete r was measured in triplicate and averaged; for patients with atrial fibrillation, seven measurements were averaged. The RVSP was calculated from the tricuspid regurgitation (TR) jet obtained under color flow imaging guidance 16 In all patients, Clinical Investigations

the best TR Doppler signal quality was obtained from the apical or modified low left parasternal four-chamber view. The chest was carefully marked with a felt-tip pen at the site providing the best TR Doppler signal for quick localization during exercise testing. In the patients with atrial fibrillation, the largest and most complete pansystolic TR signals were considered for analysis. Technically adequate TR Doppler signals were obtained at rest in eight patients and six control subjects, and during exercise in seven patients and seven control subjects; complete rest and exercise data were available for six patients and six control subjects. Using the simplified Bernoulli formula (peak gradient=4·V2 , where V is the peak TR velocity into the right atrium), the RVSP was obtained by adding the peak TR gradient to the estimated right atrial (RA) pressure. RA pressure was estimated at rest by the response of the inferior vena cava to deep inspiration and was assumed to be constant throughout exercise. With the trailing-edge to leading-edge technique, maximum inferior vena cava diameters before inspiration and minimum diameters after inspiration were measured in the subcostal view within 2 em of the entrance to the right atrium. When the diameter of the inferior vena cava decreased by less than 50% after deep inspiration, RA pressure was defined as 15 mm Hg; when the diameter decreased by more than 50%, RA pressure was defined as 5 mm Hgn All patients and control subjects showed more than a 50% decrease in vena cava diameter at rest. This technique, which assumes that the estimated RA pressure remains constant during exercise, has been validated against simultaneous measurements of pulmonary artety systolic pressure during incremental exercise. 16 Data Analysis

Resting ventilatory and gas exchange data were averaged over the last 2 min of rest. During exercise, they were averaged over contiguous 30-s intervals. VE, Vo 2 , and Vco 2 were calculated from standard formulas. Vo 2 max was defined as the highest Vo 2 measured during the last minute of the symptom-limited exercise test. The ventilatory threshold was defined as the Vo 2 corresponding to the inflection point of the Vco 2 vs Vo2 plot or V-slope method, 18 and was determined by two blinded physicians experienced in exercise testing. Predicted maximum HR was estimated as 220-[age in years]. 19 The breathing reserve (BR) was calculated as the difference between maximum voluntary ventilation and maximum VE. A pulmonary mechanical limit to exercise was defined as a BR <11 Umin. A significant 0 2 desaturation was defined by a decrease in Sa0 2 2:4%. Predicted values for Vo 2 max and normal values for the BR were those of Hansen et aJ.2° A significant left-to-right shunt was defined as Qp:Qs2:l.5. All values are expressed as mean±SD. Discrete rest and exercise variables were compared using Student's two-tailed t test. Continuous data were analyzed by simple linear regression. Computations were made with the Statview 4.0 statistical program (Abacus Concepts; Berkeley, Calif). A p value of ~0.05 was considered significant.

RESULTS

Baseline Characteristics

The baseline data for ASD patients and control subjects are presented in Table l. A secundum-type ASD was present in six, a sinus venosus-type ASD in three, and a primum-type ASD in one. Seven ASD patients were in functional class I (NYHA), and three were in NYHA class II. No differences were found in

Table !-Baseline Characteristics*

Age, yr Sex (M/F) Height, em Weight, kg FEV 1 , L ASD size, mm RVOT size, mm SV, mL Qs, Umin Qp:Qs RVSPr, mm Hg

Control Subjects

ASD Patients

52.3±10.9 6/4 167±8 69.9±14.7 3.02±0.55

52.9±11.2 6/4 167±7 82.7±20.6 1 2.51±0.46 13.9±4.6 35±8 1 58±23 4.6±1.3 2.4±1.5 1 31±8

21±4 64±23 5.1±1.4 1.0±0.2 17±8

*RVOT, SV, and Qs data not obtained for one control subject. RVSPr data not obtained for four control subjects and two patients. RVSPr=resting right ventricular systolic pressure. 1 p<0.05 compared with control subjects.

age and height, however, weight was higher and FEV 1 tended to be lower in the ASD group. Two ASD patients had chronic atrial fibrillation; one of them was being treated with a f3-blocker, while the other was receiving nifedipine. A third ASD patient was receiving prazosin for the treatment of hypertension. All of the other patients and control subjects were in normal sinus rhythm, and none were receiving f3-blockers, calcium-channel blockers, digitalis, or other systemic vasodilators. Baseline echocardiography demonstrated an increase in right ventricular size in the ASD group, and a significant left-to-right shunt (Qp:Qs2::1.5) in all but one of the ASD patients. Despite these abnormalities, SV was no different from that of control subjects (64:::':::23 vs 58:::':::23 mL; p>0.05), suggesting normal resting left ventricular function. Incremental Exercise

Vo 2 max was reduced (22.9:::':::5.4 vs 17.3:::':::4.2 mU min/kg; p=0.005) in ASD patients (Table 2). No subject in either group reached a pulmonary mechanical limit to exercise (BR <11 L/min) or sustained a drop in Sa0 2 during exercise. In addition, no ischemic ECG changes or new arrhythmias occurred during exercise. Maximum HR tended to be lower in ASD patients, but this difference did not reach statistical significance. The trend remained after eliminating the ASD patient receiving a f3-blocker (163:::':::8 vs 144:::':::23 beats/min; p=0.12). A ventilatory threshold was identified in all 10 control subjects and in nine ASD patients, but was not different in the two groups. RVSP tended to be increased at rest, and was markedly higher at peak exercise in ASD patients (Tables 1 and 2). The mean RVSP-Vo 2 slope (1:::':::2 vs 18:::':::3 mm Hg/Limin; p=0.003) and intercept (17:::':::4 CHEST/113/6/JUNE, 1998

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Table 2-Exercise Results*

Vo 2 max, mUrnin/kg (% predicted) VT, mUmin/kg (% predicted Vo 2 max) Maximum I-IR, beats/min (% predicted) BR, Umin Peak exerdse Sa0 2 , % RVSPex, mm Hg

30

Control Subjects

ASD Patients

22.9:+:5.4 (87:+: 20) 11.7:+:2.4 (44:+: 7) 158:+:9 (95 :+: 15) 58:+:17 98:+:1 19:+:8

17.3:+:4.2 1 (75 :+: 13) 1 11.5:+: 1.7 (48:+:8) 147:+:20 (87:+: 17) 53:+:14 98:+:2 51:+:10 1

*A ventilatory threshold could not be determined for one ASD patient. Maximum HR not included for two ASD patients "~th atlial fibrillation during exerci se. HVSPex was not obtained for four control subjects and three patients. VT =ventilatmy threshold. 1 p <0.05 compared \vith control subjects.

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vs 27:±::4 mm Hg; p=0.05) were higher in the ASD group (Fig 1). In all subjects, an inverse correlation was noted between Vo2 max and RVSP at both rest (r= -0.69; p=0.007; Fig 2) and peak exercise (r= -0.67; p=0.01 ; Fig 3) , but Vo 2 max did not correlate with shunt ratio, RVOT, ASD size, or maximum HR.

DISCUSSION

In the current investigation, 10 minimally symptomatic adults with ASD (NYHA class I, II) and normal resting left ventricular function demon-

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and peak exercise using by closed circles; control group by open circles . Complete data available for six patients and six control subjects . The mean RVSP-Vo2 slope (1:+: 2 vs 18 ±.3 mm Hg!Umin; p=0.003 ) and intercept (17:+:4 vs 27:+:4 mm Hg; p=0.05 ) were higher in the ASD group. 1462

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RVSPr (mm Hg) FIGURE 2. Curve flt of Vo2 max vs right ventricular systolic pressure at rest (RVSPr) in all study subjects. ASD patients represented by closed circles; control group by open circles. Data not obtained for two patients and four control subjects. Slope=- 0.4 mUmin/kglmm Hg (95% confidence interval [CI], -0.6 to -0.1). Intercept = 30.0 mUminlkg (95% CI, 23.2 to 36.8) . Correlation coefficient= -0.69 (p=0.007 ).

strated a significant reduction in Vo 2 max during incremental exercise compared with matched controls. RVSP, measured noninvasively by exercise Doppler echocardiography, tended to be increased at rest and rose inappropriately during exercise in patients with ASD, whereas no significant rise in RVSP occurred in control subjects. Peak RVSP during exercise (RVSPex) was inversely correlated with Vo 2max in all patients. These findings suggest that (1) functional capacity is overestimated by subjective measures in this group; and (2) reduced exercise tolerance may be associated with an abnormal rise in pulmonary artery pressure during exercise. Reports characterizing the physiologic response to exercise in adults vvith ASD are few, and they have mainly focused on postoperative patients. When compared with matched healthy control subjects, asymptomatic children with ASD may have significantly diminished maximal exercise endurance.2 1 .22 In adults with corrected ASD, several studies have shown that exercise capacity remains normal if surgery was performed at an early age; 23 -25 however, a blunted HR response during exercise was found in some. 23·24 If surgery is delayed beyond early childhood, most reports show exercise performance to be reduced; 24 ·26 surgical repair may permit some improvement, however. 26 •27 Epstein et al2 6 reported on the exercise results of 12 patients with ASD, age 14 to 56 years. Preoperative and postoperative exercise Clinical Investigations

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RVSPex (mm Hg) FIGURE 3. Curve fit of \ To 2 max vs RVSPex in all study subjects. ASD p atients represented b y closed circles; control group by open circles. D ata not obtained f or three patients and four CI, -0.4 ( control subjects. Slope = - 0.2 m Umi n/kglm m H g 95% to - 0. 1). lntercept= 28.8 mUmi n!kg (95% CI, 22.0 t o35 ..5). Correlation coefficient= - 0.67 (p = O.Ol ).

tests were performed on seven. Although preoperative Vo 2 max was higher than in our group (23.2:±: 1.9 vs 17.9:±: 4.4 mUmin/kg), a 23% increase in Vo 2 max occurred in six of seven patients after surgery.26 Both a chronotropic abnormality and pulmonary hypertension may have contributed to the e xercise limitation in our patients. Although ASD patients were heavier than control subjects, deconditioning probably did not contribute to the reduction in Vo 2 max since no diffe rence in the ventilatory threshold was found between groups.28 Maximum HR tended to be lower in ASD patients, but this did not reach statistical significance. As mentioned previously, a blunted HR response to exercise has been described in patients with ASD,23 •24 however, the mechanisms remain ill-defined. No correlation was identified b etween p eak exercise HR and Vo 2 max, suggesting that a chronotropic abnormality, if present, is probably not the major determinant of overall exercise performance. In two older studies of adults with uncorrected ASD,29 •30 pulmonary vascular r esistance appeared to be a n important dete rminant of cardiac function during e xercise. More recently, Hirata et a]3 1 used radionuclide ventriculography during exercise in seven patients with ASD (mean age, 40:±: 17 years) to de monstrate an a ssociation between r educed right ventricular ejection fraction during exercise and elevated r esting pulmonmy vascular resistance . Although suggestive of a pulmonary vascular limit to exercise, the submaximal exercise protocols used in these studies precluded a link with Vo 2 max.

To our knowledge, the current investigation is the first r eport in which the abnormal elevation in pulmonary artery pressure during e xercise was related to a reduction in Vo 2 max in adults with uncorrected ASD . The absence of oxygen desaturation at peak exercise excludes shunt reversal as a m echanism limiting e xercise in this group. This suggests that the abnormal rise in pulmonary artery pressure limited exercise by an inability to adequately augment systemic cardiac output. Although we were un able to simultaneously measure pulmonary arte ry pressure and systemic cardiac output during e xercise using Doppler echocardiography, abnormal left ventricular performance in association with right heart dysfunction during e xercise in ASD has been r eported previously. 32 Three possible mechanisms may have contributed to an abnormality in left ventricular performance during exercise : (1) red uced pulmonary venous return due to a poorly recruitable pulmonary circulation incapable of handling the large increase se; (2) red uced in blood flow demanded b y e xerci blood flow from the left atrium to left ventricle because of augmented l eft-to-right interatrial shunting; and/or (3) interventricular septal shift due to right ventricular volume overload. Although all these mechanisms would limit systemic cardiac output by underfilling the left ventricle, one would expect left ventricular end-diastolic pressure to be reduced, unless the latter mechanism predominated. At rest, reduced systemic cardiac output in ASD patients has been noted in association with either normaP 3 or below-normal values for left ventricular end-diastolic pressure; 32 during e xercise, however, left ventricular end-diastolic pressure was elevated in some individuals. 3 2 In a study using radionuclide cineangiography at rest and during exercise in 11 patients with ASD before and after surgical repair, an improve ment in postoperative left ventricular function appeared to be related to a r eduction in right ventricular volume overload and improved interventricular septal motion.27 It remains unknown wh ether the improve ment in septal motion caused the left ventricle to function better or simply occurred as aconsequence of improved left ventricular filling postoperatively. Clearly, more work is needed to elucidate the precise mechanisms that limit exercise in this patient population. The importance of findin g abnormal and possibly limiting e levations in pulmonary artery pressure during e xercise in ASD lies in the decision regarding the timing of surgical closure. In young individuals with uncomplicated ASD, operative closure is usually recommended regardless of symptoms, because surgical mortality is low, medical complications can be obviated,25 and long-term survival returns to that of a n age-matched control population.7 In older CHEST / 113 / 6 / JUNE, 1998

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patients, especially those older than 40 years at the time of surgical repair, the prognosis appears to be less favorable, with higher operative mortality7·34 and an increased incidence of late cardiac failure, stroke, and atrial fibrillation.' However, long-term survival in patients over 40 years of age appears to be improved and the decline in functional status reduced more by operative repair than by medical managements In an older patient vvith severe pulmonmy hypertension, the operative risks are higher and long-term outcome may not be improved. 6·7 Once pulmonmy hypertension is established, it may progress after surgery. 35 However, a subgroup of affected patients may still be candidates for surgery if favorable pathologic changes are identifled36 or if pulmonaty vasodilatory capacity can be demonstrated.37 Once irreversible pulmonary hypertension has developed, isolated ASD repair may no longer be possible without concomitant lung transplantation. Therefore, early detection of exercise-induced pulmonary hypertension can guide the decision about surgical repair. Until recently, the measurement of pulmonary artery pressure during exercise required the invasive method of right heart catheterization. In the absence of pulmonic valve stenosis, the measurement of RVSP by Doppler echocardiography can be used to closely approximate pulmonary artery systolic pressure at restY This technique has also been validated during incremental exercise by studies with simultaneous hemodynamic monitoring.l0·11 In fact, in 10 patients with chronic lung disease, Himelman et al 10 showed a very tight correlation (r=0.98; p
with ASD can be obtained by noninvasive Doppler echocardiography, and should be considered in all patients being evaluated for surgical repair. A larger, long-term prospective study with both pre- and postoperative exercise testing would likely shed more light on the appropriate indications and timing of surgical closure in adults with ASD, and could determine the value of exercise testing in ASD patients prior to surgical repair. ACKNOWLEDGMENTS: The authors are indebted to Pierre Kupfer, William Klebanskyj , and Rosemmy Mattoscio for their technical assistance in the pulmonary function laboratory at S.M.B.D.-Jewish General Hospital. The authors also wish to thank Carole Daoust, RDCS, for her technical assistance.

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