Right ventricular systolic function during exercise with and without significant coronary artery disease

Right Ventricular Systolic Function During Exercise With and Without Significant Coroviary Artery Disease J. Thomas Heywood, MD, Joerg Grimm, PhD, Otto M. Hess, MD, Markus Jakob, and Hans P. Krayenbuehl, MD

To evaluate the effects of exercise and coronary artery disease on right ventricular (RV) systolic function, rest and exercise biplane RV angiograms were recorded in 20 patients undergoing diagnostic cardiac catheterization. Thirteen patients had exercise angiograms of sufficient quality to undergo analysis and were classified into 2 groups. Group 1 had no or only mild coronary artery disease; group 2 had significant coronary artery disease as manifested by new, exercise-induced, left ventricular regional wall motion abnormalities. RV systolic pressure increased in both groups during exercise: 33 to 57 mm Hg in group 1 (p = 0.0002) and 33 to 55 mm Hg in group 2 (p = 0.0004). Pulmonary resistance did not change in group 1 during exercise but increased in group 2 (3.2 to 4.8 Wood units, p = 0.04). RV ejection fraction increased slightly, but not significantly, during exercise in group 1, but decreased in group 2 (73 vs 58% with exercise [p = O.Ol]). The change in RV ejection fraction from rest to exercise correlated closely with the change in pulmonary resistance from rest to exercise (r = -0.89, p
From the Medical Policlinic, Cardiology University Hospital, Zurich, Switzerland. This study was supported in part by a grant from the Swiss National Science Foundation, Bern, Switzerland. Manuscript received May 8, 1990; revised manuscript received and accepted November 26, 1990. Address for reprints: J. Thomas Heywood, MD, Jerry L. Pettis Memorial Veterans Administration Hospital, 11201 Benton Street, Loma Linda, California 92357.

he left ventricular response to exercise has been the object of intense study for decades. Right ventricular (RV) function during exercise has also been evaluated, although to a lesser extent.1-3 Frequently, these investigations have reported the hemodynamic response to exercise or RV volumetric changes as assessedby radionuclide techniques.4-6 Angiographic RV evaluation during exercise has been infrequent.7,8 Because contrast angiography remains the “gold standard” for ventricular volumetric analysis,sJO we studied the RV systolic response to exercise as evaluated with biplane angiography.

T

METHODS Patients: Twenty men underwent right- and left-sid-

ed diagnostic cardiac catheterization with biplane right ventriculography at rest and during supine bicycle exercise. Seven patients were excluded from analysis because of poor ventricular opacification during exercise, frequent ventricular premature complexes, unsuspected noncoronary heart disease, or prior coronary artery bypass surgery. The 13 remaining patients are the subject of this report. The patients were subdivided according to coronary anatomy and left ventricular regional wall motion analysis. Six patients (group 1, mean age f standard deviation 52 f 6 years) had no or only functionally mild coronary artery disease (2 with no coronary disease, 2 with 150% stenoses in major coronary branches, and 2 with occlusions of small diagonal or obtuse marginal branches but no disease in the major coronary vessels). None of these patients had significant LV regional wall motion abnormalities with exercise (Table I). Seven patients (group 2, mean age 52 f 8 years) had significant coronary artery disease, defined as 170% narrowing in a major coronary branch (3 had lvessel, 2 had 2-vessel and 2 had 3-vessel disease). Additionally, 6 of the 7 patients in group 2 had a prior myocardial infarction (3 with inferior, 2 with anterior, and 1 patient with both inferior and anterior infarctions). All patients in group 2 had new or worsening LV wall motion abnormalities with exercise (Table I). Cardiac catheterization: All patients gave informed consent and the Institutional Review Committee for Human Research approved the exercise portion of the protocol. Cardiovascular medications were withheld, except for sublingual nitroglycerin, 12 to 24 hours before the investigation. One hour before catheterization, 10 mg of oral chlordiazepoxide was given to the patients for sedation. All catheters were introduced transfemoTHE AMERICAN

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TABLE Anterior Fraction

Group 1 Group 2

I Regional Left Ventricular Wall Motion Analysis Oblique Projection) Change in Regional kjection from Rest to Exercise

(Right

Post. Basal

Diaphrag.

Apical

Ant. Lat.

Ant. Basal

10.0 -4.0

12.8 -0.5

4.5 -6.4

3.4 -2.6

0.2 3.0

Regional ejection fraction for 5 sectors of the right anterior oblique left ventriculogram were calculated at rest and for exercise. The data represent the difference (exerciserest) in ejection fraction (%) for each sector. Ant. = anterior: Diaphrag. = diaphragmatic: Lat. = lateral; Post. = posterior,

rally. RV pressures were measured with an 8Fr Millar micromanometer pigtail catheter calibrated against a fluid-filled system. Simultaneous left ventricular pressure was obtained from a standard pigtail angiographic catheter. These pressures were recorded (Electronics for Medicine VR 16) at a paper speed of 250 mm/s. A simultaneous electrocardiogram, right and left ventricular pressures and an intracavitary RV phonocardiogram were transcribed. Biplane right ventriculograms were filmed in the 30° right anterior oblique and 60’ left anterior oblique projections at 50 frames/s. Fifty ml of iopamidol (Iopamire@), a nonionic contrast medium, was injected at a rate of 12 ml/s. A nonionic contrast agent was chosen so that repeat ventriculography would not unduly affect RV hemodynamics.l l Filming was continued to obtain a levophase left ventriculogram. Cine frames were numbered, with corresponding tine markers on the pressure tracing. Routine left ventriculography and coronary angiography were performed before right ventriculography in order to select patients appropriate for the study as well as to exclude patients with severe or unstable lesions from a prolonged investigation. Exercise protecel: Standard bicycle exercise ergometry was performed in all patients before catheterization to determine exercise tolerance and angina threshold. During catheterization the patients’ feet were elevated and strapped to the pedals of a bicycle ergometer on the catheterization table. All pressures and volumes at rest and during exercise were thus obtained with the legs in the elevated position. There was a 1Zminute waiting period between the resting angiogram and the initiation of exercise. Exercise consisted of 2 exercise periods of 2 minutes beginning at 50 to 80 W (mean 68) and con-

FIGURE 1. Right ventricular regional wall moth analysis was pehrnml tly subdiWing enddiastolic and end-systolic projections into 4 equiangular sectors, exdudlng the tricuspid and pulmonic valves. LAO = Ml anterior obiiqw; RAO = righi anterior oblique.

Anterior

Anteiior

Inferior

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tinuing at 70 to 150 W (mean 93). These exercise steps were chosen according to the prior exercise test. At the end of the second period RV angiography was immediately performed. Seventy ml of contrast material was injected at a rate of 14 to 16 ml/s for the exercise ventriculogram. Righi ventricular v&me analysis: To determine RV volume angiographically, 15 acrylic radiopaque casts of canine and human right ventricles were constructed. The water displacement volume of these casts were paired with their angiographically derived volume using Simpson’s method. A regression equation from this comparison (volume,,,(,t) = 0.77*angiographic 12) was then used to correct the angiographically derived volumes. The details of this procedure are published elsewhere.r2 H@mbdynamk data: Peak RV systolic pressure, RV pressure during each tine frame (every 20 ms) and left ventricular end-diastolic pressure were measured. Because it was not possible to measure RV and pulmonary artery pressures simultaneously, these were estimated in the following fashion: Peak RV pressure was substituted for pulmonary artery systolic pressure since no patient had evidence of pulmonic stenosis. Left ventricular enddiastolic pressure was used as an approximation of pulmonary artery diastolic pressure. Mean pulmonary artery pressure was then calculated as: mean pulmonary artery disease = [peak right ventricular systolic pressure + 2 (left ventricular end-diastolic pressure)]/3. This value was divided by the stroke volume multiplied by the heart rate to calculate an estimate of pulmonary resistance. The systolic portion of the pressure curve was digitized for the determination of the maximal rate of pressure change (dP/dt) which was calculated every 3 to 5 ms depending on the heart rate. Frame-by-frame RV volume analysis was performed from end diastole to end systole at rest and during exercise. End diastole was defined as the onset of the rapid pressure increase in the RV pressure tracing. End systole was determined as the point of closure of the pulmonic valve as determined angiographically or from the phonocardiogram. RV ejection fraction was calculated in the standard fashion. Additionally, RV ejection rates were calculated for every 20 ms period during systole. To reduce error due to “noise” in the ventricular tracings,13 the volumes were initially smoothed with a fifth grade moving average:

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TABLE

II Hemodynamic

Pt. No.

(HbReats/min) R

Data RVSP (mm W EX

R

LVEDP (mm W EX

Pul. Resis. (mm H&m/liter)

R

Ex

MaxdP/dt (mm M/s)

R

EX

R

Ex

Group 1 100 76 60 71 85 55

147 115 102 119 125 107

28 34 31 32 35 36

47 59 58 57 52 70

14 18 16 26 21 20

17 30 28 30 30 32

2.6 2.7 2.8 3.7 2.9 3.5

2.2 2.8 3.0 2.6 3.9 4.1

315 394 267 239 474 336

842 648 790 776 590 911

75f17 0.0001

119zlz16

33f3 0.0002

57f8

19f4 0.004

28zk5

3.0 f .5 NS

3.1 f .5

338 f 86 0.003

760f

29 35 29 36 26 37 37

51 70 39 52 57 61 58

18 21 21 10 12 8 16

17 43 32 29 42 35 25

2.6 3.6 3.7 3.2 2.6 3.0 3.5

2.3 5.5 3.7 4.4 6.7 6.5 4.2

539 482 289 566 316 448 478

3345 0.0004

55410

15f5 0.026

3219

3.2 -+ .5 0.04

4.8f

NS

0.04

120

Group 2 1 2 3 4 5 6 7

79 88 65 88 71 61 86

127 137 90 131 112 147 122

77fll 0.0006

124f

P

19

1.6

1,492 969 567 766 1,029 784 1,030

445 f 106 0.0006

948 f 293

Group 1 Versus Group 2 NS

NS

NS

NS

Hemodynamic data for groups 1 and 2 at rest and exercise. Parameters EX = exercise; HR = heart rate; LVEDP = left ventricular end-diastolic resistance; RVSP = right ventricular systolic pressure.

NS

NS

NS

NS

for each patient are given along with the mean f standard deviations and p values of the differences. pressure; MaxdP/dt = maximal rate of pressure change; NS = not significant; Pul. Resis. = pulmonary

V(t) = [v(t - 40) + 2 v(t - 20) + 3 v(t) + 2 v(t + 20)

+ v(t + 40)] /9, where t is the time from pulmonic valve opening in ms and v(t) and V(t) are raw and smoothed RV volumes, respectively. These data were then normalized for body surface area. The ejection rate was calculated as: ejection rate (ml/m2/s) = [V(t + 20) V(t - 20)]/40 ms. The peak ejection rate was taken as the maximal flow velocity during the ejection period. Regional ejection fraction was calculated from RV tine frames at rest and during exercise. Both the right anterior oblique and left anterior oblique projections were subdivided into 4 equiangular quadrants (Figure 1) through the center of gravity of each silhouette. The area of each quadrant was measured and the reduction in area from end diastole to end systole was divided by the end-diastolic area to obtain the regional ejection fraction. In a similar fashion, the right anterior oblique left ventricular end-diastolic and end-systolic tine frames were subdivided into 6 areas and regional ejection fractions were calculated at rest and during exercise to evaluate left ventricular wall motion abnormalities (Table 1). Statistical methods: Intragroup comparisons were obtained using a paired Student’s t test, and intergroup comparisons with the unpaired t test. Linear regression analysis was performed using StatviewTm software. RESULTS

Hemodynamic and volumetric data for the 2 groups are listed in Tables II and III. There were no significant differences between resting values in the 2 groups, al-

though there was a tendency for RV ejection fraction to be lower in group 2. In groups 1 and 2, heart rate, peak RV systolic pressure, peak dP/dt and peak ejection rate increased with exercise. There were significant differences between groups 1 and 2 with exercise. Stroke volume index was significantly different between groups 1 and 2 (p = 0.02) during exercise. Pulmonary resistance was higher during exercise in group 2 than in group 1 (p = 0.04). RV ejection fraction was substantially different between the 2 groups. Finally, peak ejection rate during exercise was higher in group 1 than in group 2 (p = 0.03). The results of RV regional wall motion analysis are summarized in Table IV. In group 1, there tended to be a generalized increase in regional ejection fraction from rest to exercise. Conversely, in group 2, regional ejection fraction was generally lower with exercise, decreasing or remaining the same in 8 of 8 sectors. The change in RV ejection fraction from rest to exercise correlated closely with the change in pulmonary resistance in the 2 groups (r = -0.89, p CO.0001) (Figure 2). DISCUSSION

In this study we evaluated angiographically the effects of exercise on RV function in patients with and without coronary artery disease. In both groups, RV systolic pressure and peak dP/dt increased similarly with exercise. However, patients with coronary artery disease had a significantly lower stroke volume and ejection fraction with exercise than the normal group. THE AMERICAN

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TABLE III Volumetric

Data

Pt.

EDVI

ESVI

SVI

RVEF

PER

No.

(ml/m’)

(mP+)

OWm2)

W)

(ml/m2/s)

R

Ex

R

Ex

R

Ex

R

Ex

R

Ex

47 71 67 62 37 54

77 65 77 70 72 69

81 70 86 76 65 61

184 258 271 211 147 293

282 388 345 330 203 283

56hl3

72k5

73flO

227 f 56

305 f 64

Group 1 1 2 3 4 5 6

52 102 87 74 69 108 82f21

P

58 101 78 82 57 89 78f17

NS

12 36 20 22 19 34

11 30 11 20 35

40 66 67 52 50 74

24*9

21 f 10

58f

20

NS

13

NS

0.01

N’s

I

Group 2 85 65 79 55 79 79 57

80 74 82 58 76 59 51

33 20 31 21 23 23 19

26 35 34 26 36 32 15

52 45 48 34 56 56 38

54 39 48 32 40 27 36

61 69 61 62 71 71 67

68 53 59 55 53 46 71

276 213 170 219 266 246 236

362 209 198 147 211 129 201

71 f 12

69hl2

24f5

29f7

47z.t.9

39f9

66f5

58&9

232 f 36

208 -+ 75

NS

NS

NS

NS

NS

Group 1 Versus Group 2 NS

NS

NS

0.12

NS

0.02

0.05

0.01

VolUmetric data for groups 1 and 2 at rest and during exercise. Mean f standard deviations and p values are given below each column. ED/VI * right ventricular enddiastolic volume index: ESVI = right ventricular end-systolic volume index; PER = peak right ventricular ejection fraction: SVI = stroke volume index: other abbreviations as in Table II.

RV ejection fraction correlated closely with changes in RV afterload from rest to exercise. The hemodynamic changes produced by exercise in the right ventricle and pulmonary circulation have been well described.1,14-16 In evaluating these data, it is important to be cognizant of body position during the exercise (supine with legs down or elevated, or sitting) and also the age of the patient group studied. In most studies, pulmonary artery systolic pressure increases significantly in both normal subjects and patients with coronary artery disease during supine exercise.16 Peak dP/dt has been infrequently evaluated in the right ventricle. Bussmann et al* reported a mean peak dP/dt of 490 mm Hg/s in 17 patients with left anterior descending coronary artery disease and 350 mm Hg/s in 9 patients with right coronary artery disease. In both groups, peak dP/dt increased significantly with exercise. However, there are theoretical concerns when peak dP/dt is used as an index of RV contractility.17 Contrary to peak left ventricular dP/dt, which precedes aortic valve opening, peak dP/dt of the right ventricle customarily occurs after the pulmonic valve opens. Moreover, it is an “impure signal” influenced by the timing of left ventricular contraction.‘* A number of investigators have determined RV volumes angiographically. They have employed Simpson’s rule,1992oas in our own study, or geometrical approximations of RV shape.21*22 Radionuclide determined RV end-systolic and enddiastolic volumes have generally been reported to be larger, and the ejection fraction smaller, than those 684

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NS

0.03

rata; RVEF = right ventricular

ejection

found with contrast angiography.5,6 This discrepancy has been thoroughly evaluated by Marving et al.1° They conclude that a major reason for this is the difficulty in discerning the RV-right atria1 border, and therefore only right anterior oblique projections should be used in radionuclide RV investigations. Dell’Italia et a123found a close correlation, r = 0.91, between angiographic and radiotmclide-determined RV volumes; however, a geometric correction for attenuation was applied and a close correlation would not exclude a consistent overestimation in ventricular volume. Determinants of right veritricular ejection performance during exercise: What is the mechanism for the

decline in RV ejection fraction during exercise in patients with coronary artery disease? Many factors may be involved, including RV ischemia, septal shifting and loading of the right ventricle. In radionuclide exercise studies reported by Johnson5 and Maddah@ and their co-workers, RV ejection fraction failed to increase during exercise when there were significant right coronary artery lesions. RV ejection fraction has been shown to decline when the right coronary artery is occluded during percutaneous transluminal coronary angioplasty.24 In 5 of the 7 patients in group 2, there were significant lesions involving the right coronary artery, so exerciseinduced ischemia could result in RV dysfunction. However, in the 2 other patients (patients 3 and 5, group 2, Table III) without significant right coronary artery disease, RV ejection fraction also decreased during exercise. Septal asynergy was not seen in group 2 (Table IV), so it is unlikely that septal ischemia is responsible.

TABLE

IV Right Ventricular Right Anterior

Pt. No.

ANT

Wall Motion

Analysis Left Anterior Oblique

Oblique ANT-API

INF-API

INF BSL

ANT

ANT-API

INF-API

SUP-SEP

4 31 10 -14 -8 2.3f 17

-2 -1 27 10 2 -13 3.8f 14

40 -62 27 -3 -15 7 -1f36

10 -8 6 6 -14 -12 -3 -2.1 f 9.6

8 -15 -1 ’ 0 -4 -30 3 -5.6 f 13

13 -5 -3 -1 -9 -25 30 Of7

NS

NS

NS

Group 1 9 2 20 4 0 -15 3.3fll

-1 9 2 8 8 9 5.8 f 4.3

4 0 16 6 15 5 7.7 f 6.4

23 -6 15 4 -1 -8 4.5 f 12.2

5 17 31 19 -8 -13 8.5& 17

-9

Group 2 6 -21 -10 -3 -22 -22 10 -8.9 f 14

-10 -19 8 -21 -38 -28 21 -12.4f21

3 2 13 2 -23 -25 -22 -7.1 f 16

0.11

0.06

0.05

-9 -2 -11 -10 -17 -24 -10 -11.9*23

3 -17 5 -10 -54 -43 -8 -17f23

Group 1 Versus Group 2 0.01

0.04

Regional wall motion analysis for the right ventricle at rest and during exercise for each of the 8 sectors in both projection. Mean f standard deviations and p values are given be low each column. Note that in group 1, mean regional ejection fraction (“IO) increased in all sectors as opposed to group 2 where it decreased in 7 of the 8 sectors. ANT = anterior: ANT-API = anterior apical: INF-API = inferior apical; INF-BSL = inferior basal; NS = not significant; SUP-SEP = superior septal. See Figure 1.

Regional wall motion analysis showed reduced function of the RV free wall during exercise even in patients without significant right coronary artery disease. Ventricular interaction should also be considered in this reduction of RV systolic function. The left ventricular end-diastolic volume increases with significant ischemia,25 and this may impede RV filling and thus reduce systolic performance. RV. end-diastolic volume was mildly, although not significantly, reduced with exercise in group 2. However, there was a similar nonsignificant decline in group 1 without a change in RV ejection fraction. Another explanation for the decline in RV ejection fraction during exercise is an acute increase in afterload. In group 1, afterload, measured by pulmonary resistance, did not change with exercise, whereas ejection fraction increased slightly but not significantly. However, in group 2, afterload increased and ejection fraction tended to decrease with exertion. There was a close correlation between the change in ejection fraction with exercise and the change in pulmonary resistance (Figure 2). The correlation between RV ejection fraction and pulmonary hemodynamics during exercise has been reported before, although only in patients with pulmonary or valvular heart disease. Cohen et al2 studied 8 patients with mitral stenosis by radionuclide imaging. They found a moderate correlation (r = -0.71, p = 0.05) between the change in RV ejection fraction from rest to exercise, corrected for duration of exercise, and peak exercise pulmonary pressure. In patients with chronic obstructive pulmonary disease, Morrison et a126noted a weak correlation (r = -0.51, p <0.05) between the change in ejection fraction with exercise and the change in total pulmonary resistance. However, this same

group27 failed to find such a correlation when a mixed group of patients with mitral or aortic stenosis underwent exercise. The difficulties inherent in using radionuelide imaging for RV ejection fraction determination, especially during exercise, may explain the somewhat higher correlation found in our patients. The influence of pulmonary artery pressures on RV function is a form of ventricular interaction that may have important clinical implications. Even with significant left ventricular failure and elevated resting systemic vascular resistance, systemic vascular resistance de-

- -. -2 CHANGE

-1

0

IN PULMONARY

1

2 RESISTANCE

3

4

(WOOD’S

5 UNITS)

FtGURE 2. Relation of UK change in right ventdab (RV) ejectionfmctionwiththedmngein resistoncs hm resttoexerciseforgroupsland2.Ri&t fractientendedtodecreae aspulmoniwyresi!3tencolncrea~ with exercise. THE AMERICAN

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clines with exercise.28 When significant pulmonary, valvular or -coronary artery disease is present, however, pulmonary resistance may increase with exercise and thus impair RV systolic function. In an intriguing report regarding patients with left ventricular dysfunction, Baker et a129 found no correlation between maximum oxygen uptake during exercise and resting left ventricular ejection fraction. Yet there was a good correlation between resting RV ejection fraction and maximal oxygen uptake (r = 0.70, p
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