1111JUDY 1011 W01410, MD, MASAMI SHIMIZZ DAD, YOSIM11TO A, MD, HIDEKAZU INO, MD, RNIC111 TAKI, MD, RYOYU TAKEDA, MD Kanazawa, Japan

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1 JACC Vol. 22, No. 5 November : Ilef I Ventricularr Functional Reserve in Patients With S on by Continuous Ventricular Function Monitorin 1111JUDY 111 W141, MD, MASAMI SHIMIZZ DAD, YOSIM11TO A, MD, HIDEKAZU INO, MD, RNIC111 TAKI, MD, RYOYU TAKEDA, MD Kanazawa, Japan Objectives. The objective of this study was to evaluate cardiac functional reserve in patients with syndrome X. Background. Syndrome X is characterized by stress-induced anginal pain and ST segment depression, normal findings on coronary angiography and normal left ventricular function at rest. Reduced coronary vasodilotive reserve and abnormal myocardial lactate metabolism have been described hi such patients. Methods. To assess left ventricular functional reserve in patients with syndrome X, continuous radionuclide monitoring of left ventricular end-diastolic volume, end-systolic volume and ejection fraction was performed in 12 patients and 13 normal control subjects during supine bicycle ergometer exercise. Results. In control subjects, end-diastolic volume increased at peak exercise from 1% to 16.5% (r <.1), end-systolic volume decreased from 39.1 % to 22.6% (p <.1) and ejection fraction increased from 6.9% to 78.6% (p <.1). In patients with syndrome X, end-diastolic volume increased at peak exercise from 1% to 16% (p <.1), and end-systolic volume decreased at ST segment deprission 5.5 mm ',the ST point) from 37% to 28.8% (p <.1) but increased at peak exercise to 44.7% (p <.1 vs. the ST point). Thus, ejection fraction increased at the ST point from 63% to 72.7% (p <.1) but decreased at peak exercise to 57.7% (p <.1 vs. the ST point and control subjects) in proportion to the degree of ST segment depression. In nine patients (75%), ejection fraction at peak exercise was lower than baseline values. All patients and control subjects showed a rapid ejection fraction increase just after exercise during the recovery period. The degree of ejection fraction "overshoot" in patients was similar to that in control subjects, but the interval from the end of exercise to the overshoot in patients was significantly longer than that in control subjects (118 vs. 65 s, p <.1). Conclusions. In patients with syndrome X subjected to exercise stress, left ventricular function remained normal before the onset of ST segment depression. Once ST segment depression appeared, left ventricular function deteriorated in proportion to the degree of depression, and reduced left ventricular function persisted into the recovery period. Continuous ventricular function monitoring is thus a useful predictor of reduced left ventricular functional reserve in patients with syndrome X. (J Am Coll Cardiol 1993,22 :146S-9) Syndrome X is defined as stress-induced anginal pain and ST segment depression with normal findings on coronary arteriography and normal left ventricular function at rest (1,2). Previous studies have demonstrated abnormal myocardial lactate metabolism (3-5), small vessel coronary artery disease (6) or absent small vessel coronary artery disease (5) on histologic examination of endomyocardial biopsy specimens and impaired endothelium-dependent vasodilation (7) in these patients. Using gated blood pool scintigraphy, several investigators (8-1) have suggested that 2% to 5% of all patients with syndrome X have reduced left ventricular functional reserve during exercise, probably because of reduced coronary blood flow. However, to validate ejection fraction calculations, the interval required for data acquisition in gated blood pool imaging is at least 9 to 12 s (11). From The Second Department of Internal Medicine and Nuclear Medicine, School of Medicine, Kanazawa University, Kanazawa, Japan. Manuscript received December 8, 1992 ; revised manuscript received April 24, 1993, accepted April 29, Address for comogo*kqg : Hiroyuki Yoshio, MD, The Second Department of Internal Medicine, School of Medicine, Kanazawa University, Takara-machi 13-1, Kanazawa 92, Japan by the American College of Cardiology The difficulty in assessing left ventricular function during rapid changes of heart rate during stress may explain the variability of these results. Therefore, the pathophysiologic characteristics of this disorder remain elusive. In this study, we evaluated left ventricular functional reserve in patients with syndrome X using the continuous ventricular function monitor (VEST) (12,13) to estimate the precise response of the left ventricle at the time of ST segment depression, peak exercise and recovery. Methods Study patients. Twelve patients (1 women, 2 men, 37 to 64 years old [mean 51]) were studied. All had typical stress-induced angina and a positive exercise test limited by angina with >I -mm horizontal or downsloping ST segment depression 8 ms after the J point. All patients had angiographically normal coronary arteries, normal global and regional ventricular function at rest and no coronary artery spasm on ergonovine or acetylcholine provocative testing Patients with systemic hypertension, diabetes mellitus or valvular heart disease were excluded from the study /93/S6.

2 1466 YOSHIO ET AL. This study also included 13 control patients (7 women, 6 men, 36 to 69 year., old [mean 51]) with angiographically normal coronary arteries. All underwent diagnostic cardiac catheterization because of an atypical chest pain syndrome. Treadmill exercise testing was performed before catheterization, and ischemia was not induced in any of the patients. Continuous ventricular function monitor (VEST). The VEST (Aloka, Inc.) consists of a cadmium telluride detector, preamplifier, portable acquisition unit and battery (13). The patient's red blood cells were labeled in vivo with 74 to 92.5 MBq (2 to 25 mci) of technetium-99m by the modified method of Callahan et al. (14). The electrocardiographic (ECG) electrodes were positioned to record a standard 12-lead ECG. Under gamma camera monitoring in the supine position, the plastic vestlike garment was placed on the patient's chest, and the VEST detector was positioned over the left ventricular blood pool and locked into the garment. The VEST records sequential 5-ms radionuclide emissions from the left ventricle through the detector, and the data are transferred to a laptop personal computer (LTl 1 NEC, Inc.). During data sampling, a beat to beat 3-point left ventricular smoothed time-activity curve is displayed in real time. A fixed percent of the background value (7% of end-diastolic counts) was used as a baseline. Nuclear data were summed at 2-s intervals to calculate the end-diastolic and endsystolic counts. In the determination of relative left ventricular volume, end-diastolic volume at the beginning of the measurement in the supine position at rest was designated as 1%. All other end-diastolic volumes and all end-systolic volumes were calculated relative to the initial end-diastolic volume. Ejection fraction was calculated by dividing the relative stroke volume by the relative end-diastolic volume. Taki et al. (13) have demonstrated good correlation (r =.9) between VEST detector measurements of ejection fraction and those recorded with the gamma camera in cardiac phantom studies. Exercise stress; testing. After the VEST detector was Positioned appropriately under gamma camera monitoring in the supine position and after a 5-min rest, patients performed supine bicycle ergometer exercise with an initial work load of 25 W and increasing increments of 25 W every 2 min. A 12-lead ECG and systolic and diastolic blood pressure were recorded at 1-min intervals during the test. Criteria for terminating the test were 1) X4.-mm ST segment depression 8 ms after the J point, or 2) severe chest pain or muscular exhaustion or maximal heart rate for age, alone or in combination. All data were recorded within 1 min after the termination of exercise. We de the following five points during the time course of exercise testing : 1) rest; 2) the ST point, defined as ST segment depression s.5 mm ; 3) the midpoint, defined as the midpoint of the ST point and the end point ; 4) the end point ; and 5) overshoot, defined as a rapid ejection fraction increase just after exercise (13,15,16). Additionally, the ST point in control subjects was designated the point at which JACC Vol. 22, No. 5 November : their heart rate-systolic blood pressure products increased to the same degree as that of the ST point in patients with syndrome X. Cardiac catheterization. Selective coronary angiography was performed by the Judkins technique. After initial coronary angiography, provocative testing was done by injection of ergonovine (4 µg) or acetylcholine (1 jig) into the coronary artery. Repeat coronary angiography was performed 2 min after the intracoronary injection of isosorbide dinitrate (2 mg). Statistical analysis. Values are expressed as mean value 1 SE. The differences in the mean values among the 5 points were assessed by two-way repeated measures analysis of variance followed by the Tukey-Kramer method (17). Significant differences were recognized at p <.5. Results Clinical and hemodynamic findings (Table 1). The average exercise duration was 6.4 ±.6 min in patients with syndrome X and 7.2 ±.3 min in the control group (p = NS). The average rate-pressure product at each of the 5 points was similar in both groups. The average ejection fraction at rest and at the ST and overshoot points were similar in both groups. However, ejection fraction at the mid and end points in the syndrome X group was significantly depressed compared with that in the control group (65.2 * 3.3% vs ± 2%,p<.1,and57.7±3.4%vvs.78.6±2.3%,p<.1, respectively). Nine (75%) of 12 patients with syndrome X showed decreased ejection fraction at the end point compared with that at rest. The average time to overshoot in the syndrome X group was significantly delayed compared with that in the control group (118 ± 13 vs. 65 ± 8 s, p <.1). Plot of the time course in ejection fraction (Fig. 1). In the control group, ejection fraction at the ST, mid and end points increased significantly compared with ejection fraction at rest (p <.1). Ejection fraction at overshoot increased beyond ejection fraction at the end point. In the syndrome X group, ejection fraction at the ST point increased significantly compared with ejection fraction at rest (1, <.1), but ejection fraction at the mid and end points, conversely, decreased significantly compared with ejection fraction at the ST point (p <.5 and p <.1, respectively). End-diastolic and end-systolic volume responses (Table 2). In the control group, end-diastolic volume at the ST, mid and end points increased significantly compared with the value at rest (p <.1), whereas end-systolic volume at these points decreased significantly compared with the value at rest (p <.1). In the syndrome X group, the end-diastolic volume response was similar to that in the control group, but the end-systolic volume response differed considerably. Conversely, the end-systolic volume at the mid and end points increased significantly compared with the end-systolic volume at the ST point (p <.5 and p <.1, respectively).

3 JACC Vol. 22, No. 5 November 1, 1991 : YOSHIO ET AL % Co 91 NS r--j e 1 fv i.5 U VD +I +I rs W 9 On, ! Sn' or-5 CS F-.V 4 Ir.- eh nl +I +I O 1: In.1~ Ir", 5 1, 16 1'z In +P 'hl A Rest ST MP EP S Figure 1. Changes in ejection fraction (EF) in control subjects and in patients with syndrome X. EP = end point ; MP = midpoint; OS overshoot ; ST = ST segment depression SO.5 mm. p -,.1. In 1"; 17~ In C'~ ~ PA S ~z 5, S V '= "P, Relation between ejection fraction and exercise-induced ST segment depression (Pig. 2), Ejection fraction decreased from the maximum in proportion to the degree of ST segment depression at the ST, mid and end points in patients with syndrome X (r =.74, p <.1). X X : -. OS M d' n N N N I- A A A A O 7 +j +1 I n 1-4 e-4 4l O " T +I +I ' , M J' ~r. 'O Cn O+ 'O n O5 D O' n.7 qj +I PI PJ M hl.n O v, +I J = Q in 1 C2 ' 'n 'C in 'n 'D 'C >1 w F 1 I 'O n 4' P_ M W ;7 "n,i TO (5 U Ei CC. O vi LU A N 5 > z 5 g M In 3 II 4 V 4 Discussion In this study we showed that in patients with syndrome X, left ventricular function is well preserved before ST segment depression in stress testing but becomes increasingly depressed in proportion to the degree of ST segment depression. This depressed left ventricular function persists into the recovery period. Impaired left ventricular functional reserve. Our results demonstrated significant impairment of left ventricular contractile reserve in 75% of patients with syndrome X. During the early phase of exercise, in the absence of ST segment depression, left ventricular contractility remained well preserved but became increasingly impaired in proportion to the degree of ST segment depression. Using gated blood pool scintigraphy, several investigators (5-1) have demonstrated a wide range in ejection fraction response to exercise. Our findings appear to differ markedly from these results. The reason for this discrepancy may be that the earlier studies used various criteria in patient selection. Patients in the present study were selected strictly to ensure that all had a reproducible positive exercise test limited by angina, with typical ischemic ST segment depression, angiographically normal coronary arteries, normal global and regional ventricular function at rest and absent coronary artery spasm on provocative testing. Furthermore, the earlier studies were performed with gated blood pool imaging techniques, each time point being the average of at least a 9- to 12-s period (11). Rapid changes in left ventricular function in response to heart rate and afterload during dynamic stress may also explain the variability of their results. In addition, this discrepancy may be related to the methodology used in our study : the supine position during exercise and the lack of

4 t o 1468 YOSHIO ET AL. VENTRICULAR FUNCTION IN ;;YNDROME X JACC Vol. 22, No. 5 November 1, 1993 : Table 2. Left Ventricular Responses in Control Subjects and Patients With Syndrome X Rest ST 'MP EP OS Control subjects EDV (%) 1. ± ± 1.3* 16.3±1.4* 16.5±1.7* 12.3±1.6t ESV (%) 39.1 ± ± 1.8* 23.7±2.* 22.6±2.3* 11.7 ± 2.6t Syndrome X EDV (%) 1. ± ± 1.2* 16. ± 1.1 * 15.9 ± 1.1 * 12.8 ±.8t ESV (%) 37. ± ± 2.9* 36.7±3.4# 44.7± ± 2.3t "p <.1 versus rest. tp <.1 versus EP. rp <.5 versus S1. p <.1 versus ST. Values presented are mean value ± SE. EDV = end-diastolic volume ; ESV = end-systolic volume ; other abbreviations as in Table 1. absolute end-systolic and end-diastolic left ventricular volumetric data. Recent two-dimensional echocardiographic stress studies perf' nted la patients with syndrome X revealed the absence of impaired left ventricular functional reserve (18, 19). Picano et al. (18) used dipyridamole infusion rather than exercise, which may be an inadequate stimulus to reveal left ventricular wall motion abnormalities (2). Nihoyannopoulos et al. (19) used treadmill exercise testing as the stress and immediately recorded echocardiographic images on videotape. In their study, images were obtained within an average time of 54.1 ± 11.3 s, while the ST segment was still almost completely depressed. In our study there was a rapid ejection fraction overshoot (13,15,16) just after exercise, while the ST segment was still depressed. The average degree of ejection fraction overshoot in syndrome X was similar to that seen in the control group. Thus, the initially reduced ejection fraction recovered and exceeded the baseline value within the initial 5 s of the recovery period. 'The shorter interval between exercise termination and assessment of left ventricular function may contribute to the explanation of our apparently different results. d the recovery period. Earlier investigators found a rapid ejection fraction increase just after exercise using ted blood pool scintigraphy (15,16). The VEST is a suitable device to assess this phenomenon (13,21). The mechanism of ejection fraction over- 2. Relation between ejection fraction and exercise-induced ST segment depression. AEF = change of ejection fraction from maximal ejection fraction.,%ef.to ST segment depression 1 4. mm shoot was suspected to be due to the afterload decrease. The persistence of catecholamine-stimulated left ventricular contractility further decreases the end-systolic volume and the maximal increase in ejection fraction. A delayed response in ejection fraction overshoot is thought to be a useful predictor of myocardial ischemia (13,15). In this study the average,ime to election fraction overshoot was delayed significantly in patients with syndrome X compared with the control group. These results suggest that the reduced left ventricular function in patients with syndrome X persists into the recovery period. Pathophyslologic considerations. The pathophysiologic reason for the reduced left ventricular ejection fraction in patients with syndrome X during exercise has been suspected to be myocardial ischemia resulting from decreased coronary vasodilator reserve (3,4). Maseri et al. (22) demonstrated that abnormal coronary prearteriolar constriction could be caused by the absence of endothelium-derived relaxation factor, and they su ested that a dynamic constriction of prearteriolar vessels may cause a limitation of coronary flow reserve and, possibly, multifocal myocardial ischemia. A decrease in ejection fraction is a sensitive indicator of myocardial ischemia (12,23). Thus, the results of our study are in agreement with these previous findings. Limitations of the study. With the VEST technique, volume as calculated with nuclear data was relative. Thus, comparison between individual values other than the ejection fraction was not applicable. The VEST can evaluate global ejection fraction, but regional ejection fraction cannot be assessed. Although this VEST-based study was performed with the subjects supine, several other studies (12,24,25) have been performed with the subjects in various positions, including upright, thereby imposing theoretic limitations on reproducibility unless consideration is given to the hemodynamic changes induced by posture. Clinical implications. In this study, continuous, precise ventricular monitoring demonstrated that patients with syndrome X have more significantly reduced left ventricular functional reserve than was evident in previous studies. The VEST clearly demonstrates the overshoot phenomenon, a rapid ejection fraction increase just after exercise. Future studies using gated blood pool scintigraphy and stress twodimensional echocardiography must be mindful of the overshoot phenomenon in assessing left ventricular function. The

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