Left ventricular response to exercise in coronary artery disease: relation to myocardial ischaemia and effects of nifedipine

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1 European Heart Journal (1985) 6, Left ventricular response to exercise in coronary artery disease: relation to myocardial ischaemia and effects of nifedipine W. F. SHEN*, G. S. ROUBIN*, C. Y.-P. CHOONG*, B. F. HuiTONt, P. J. HARRIS*, P. J. FLETCHER* AND D. T. KELLY* *Hallstrom Institute of Cardiology and ^Department of Nuclear Medicine, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia KEY WORDS: LV function, myocardial ischaemia, nifedipine. To assess the relationship between left ventricular (LV) response to exercise and myocardial ischaemia, 40 patients with coronary artery disease (CAD) and 17 control subjects underwent radionuclide ventriculography at rest and during semiupright exercise. In 14 of the 40 patients with CAD, radionuclide exercise studies were repeated 20 min after 20 mg of sublingual nifedipine. Patients with CAD had increases in both L V end-diastolic and end-systolic volumes and no change in ejection fraction during exercise. End-systolic volume increased and ejection fraction decreased significantly more in patients with multivessel disease, exercise-induced angina and/or ischaemic ST segment depression. Nifedipine reduced angina and STsegment depression during exercise, attenuated exercise-induced increase in end-diastolic and end-systolic volumes and improved ejection fraction. This study suggests that in patients with CAD, the response of LV volumes and ejection fraction to exercise is related to the degree of exercise-induced myocardial ischaemia and nifedipine improves exercise LV performance. Introduction In patients with coronary artery disease (CAD), left ventricular (LV) functional response to exercise during myocardial ischaemia is usually described by alterations in ejection fraction' 1 ' 2 '. As the changes in ejection fraction depend on the alterations in both end-diastolic and end-systolic volumes, measurement of LV volumes is helpful to characterize exercise performance in such patients' 3 " 3 '. The purpose of this study was to examine the relationship between myocardial ischaemia and LV response to exercise, and to determine if the vasodilator nifedipine could alter the LV volume changes and thus ejection fraction during exercise in patients with CAD. Received for publication on 11 March Address for reprints: Professor David T Kelly, Hallstrom Institute of Cardiology, Royal Prince Alfred Hoipital, Camperdown N.S.W. 2050, Australia. Methods STUDY POPULATION The study group consisted of 40 patients (38 men and 2 women, mean age 52 years, range 37-64) with angiographically documented CAD, defined as > 70% decrease in luminal diameter in one or more of the coronary arteries' 6 '. Twentyone patients had multivessel disease and 19 had single vessel disease. Twenty patients had a documented myocardial infarction (inferior 9 and anterior 11, mean LV ejection fraction 46 ± 13%) at least 6 months before the radionuclide exercise study. No patient had valvular heart disease or was taking propranolol or digoxin at the time of study. All patients were in sinus rhythm and had no clinical or radiographic evidence of pulmonary disease, and none had undergone coronary artery or LV surgery. Seventeen age-matched subjects (14 men and 3 women, mean age 47 years, range 30-59) with 0I95-668X/85/ $02.00/ The European Society of Cardiology

2 1026 W.F.Shen etal. angiographically normal LV function and coronary arteries served as a control group. All control subjects were previously studied because of atypical chest pain. None had medication and all were in sinus rhythm. STUDY PROTOCOL was performed in a semiupright position (45 degree) on a bicycle exercise table (Atomic Products, N.Y.) mounted with an electronically braked ergometer (Siemens Elema). The initial workload of 15 W was increased by 15 W every 3 min, and the pedal speed was held at a constant rate of 60 rpm. was continued until the development of either symptoms (limiting fatigue or angina) or ischaemic ST segment changes (>lmm horizontal or downsloping depression). Radionuclide counts were collected for 6 min at rest and during the last 2 min of each exercise level. Blood pressure was measured with a standard sphygmomanometer cuff by a single observer. A CM 5 electrocardiographs lead was monitored throughout the study and a 12-lead electrocardiogram was recorded at rest and every minute during exercise on an Avionics Exerstress 4000 System. In 14 patients with CAD and exercise-induced angina and ST-segment depression, 20 mg of nifedipine was administered sublingually 2 h after the first exercise study; 20 min later, heart rate, blood pressure, and radionuclide measurements were repeated at rest and during exercise with identical workloads. Table 1 Haemodynamic and left ventricular response to exercise in control subjects and in patients with coronary artery disease (mean ± SD) RADIONUCLIDE VENTRICULOGRAPHY Red blood cells were labelled in vivo with 25 mci of technetium-99m. Gated equilibrium radionuclide ventriculography was performed using a single-crystal gamma camera (Technicare Ohio Sigma 420) fitted with a 30 degree slant-hole, highsensitivity collimator and interfaced to a digital computer system (PDP 11/34). Radionuclide data were processed by a semiautomatic edge-detection program and the LV region of interest at enddiastole and end-systole was defined by a standard method' 7 ' 81. We have shown that LV ejection fraction measured by the radionuclide technique correlated well with that derived from contrast angiography' 8 '. LV volumes were measured by a nongeometric method, and absolute end-diastolic volume was determined by a regression equation validated previously in our laboratory 19 '. Endsystolic volume and stroke volume were derived from end-diastolic volume and ejection fraction. Although the use of a fixed attenuation correction factor for all patients may introduce some error in individual volume estimates, our findings were based upon changes in volumes; this small error should not, therefore, affect our conclusions. STATISTICAL ANALYSIS Data are expressed as mean ± standard deviation (SD). Comparison between rest and exercise measurements in each group were made using a paired t-test and difference between groups was analysed using an unpaired t-test. Data before and Control group (jv= 17) CAD group (#=40) HR (beat min" 1 ) MAP (mmhg) RPP(x 100) SV(ml) COCmin" 1 ) EDV (ml) ESV(ml) EF(%) 72±13 93±9 91 ± 19 77±11 5-7±O-9 I12±13 42±8 62±7 147 ±20* 132±14* 304±64* 100±18* 14-5±2-9* 129 ±20* 29 ±8* 77 ±5* 71 ±9 90±ll 87± ± ± ±43 73 ±38 51 ± ±16* 120±18* 225 ±47' 82±2I* 101 ±2-8* 175±51* 93 ±49* 5O±15 CAD-coronary artery disease; CO-Cardiac output; EDV-end-diastolic volume; EF-ejection fraction; ESV-end-systolic volume; HR-heart rate; MAP-mean arterial pressure; RPP-rate-pressure product; SV-stroke volume.*p<0-001 vscorresponding resting values.

3 Left ventricular response to exercise in coronary artery disease 1027 Table 2 Comparison between patients with single vessel disease and those with multivessel disease (mean ± SD) EXHR(beatmin-') EXMAP(mmHg) EDV (ml) ESV (ml) EF (%) Change in EDV (ml) Change in ESV (ml) Change in EF (%) SVD (N= 19) 130 ± ±I8 146±46 74 ±43 52±13 20±17 7±14 1±7 MVD (JV-21) 1I8±14* 116± ±41 73 ±35 50±12 42 ± ±25* ^t±8" EX-exercise; MVD-multivessel disease; SVD-single vessel disease; */ > <005, *P<00\ vs single vessel disease. Otherwise are as in Table 1. after nifedipine were analysed by two-way analysis of variance. When there was a significant difference among the 4 treatments (rest and exercise, before and after nifedipine), the treatment means were compared using a modified t statistic incorporating the pooled error mean square, with significance levels for 4 planned comparison derived from the Bonferroni two-tailed / table" 01. A P of <005 was considered significant.!60 r 120 Results p<oo\ P< 0-01 P<0O5 l40r 20 r 105 CONTROL GROUP The haemodynamic and LV functional responses to exercise in both groups are summarized in Table 1. All control subjects stopped exercise by fatigue, and no angina and ischaemic ST-segment changes were noted. On exercise, heart rate, mean arterial pressure, rate-pressure product, stroke volume and cardiac output increased significantly. LV end-diastolic volume increased significantly. LV end-diastolic volume increased by 15% and end-systolic volume decreased by 31%, resulting in an increase in ejection fraction. The individual increments in ejection fraction ranged from 5-26%. PATIENTS WITH CAD Of the 40 patients with CAD, 26 exercised to an endpoint of ST segment depression ^ lmm and 18 of these had angina during exercise. The other 14 patients were limited by fatigue. On exercise, heart rate, mean arterial pressure, rate-pressure product, stroke volume and cardiac output increased. LV end-diastolic and end-systolic volumes increased by 22% and 27% respectively, resulting in no change in ejection fraction. Thirty-three (83%) patients had an abnormal ejection fraction E > o = 70 ~ 0 : e- 40 :.^ «35 : HO L -35 L SVD MVD SVO MVD Figure I Comparison of changes in left ventricular end-diastolic (AEDV) and end-systolic volumes (AESV) and ejection fraction (AEF) from rest to exercise between patients with single vessel disease (SVD) and those with multivessel disease (MVD). -30 L SVD MVD

4 1028 W. F. Shen eta.1 Table 3 Comparison between patients with and those withoutpatients with single vessel disease (/ > <001). LV exercise-induced angina (mean ± SD) ejection fraction decreased in patients with multivessel disease, but was unchanged in those with No angina angina single vessel disease (Table 2, Fig. 1). (AT = 22) (#=18) In the 18 patients with exercise-induced angina, LV end-diastolic volume increased by 27% during exercise, and did not differ significantly from 18% in the 22 patients who exercised to endpoint fatigue. However, end-systolic volume increased EXHR(bcatmin"') EX MAP (mmhg) EXRPP(xlOO) EDV (ml) ESV (ml) EF (%) Change in EDV (ml) Change in ESV (ml) Change in EF (%) 127± ± ±48 140±44 74 ±39 50±12 25±21 9±14 2±6 121 ± ± ±48 147±42 73 ±38 53±13 4O±33 33 ±32* -6 ±8* Table 4 Comparison between patients with and those without exercise-induced ST-segment depression (mean ± SD) *P<00\ compared with patients with exercise-induced angina. Otherwise are as in Table 2. response to exercise (decreased, or increased <5%). Overall, an ischaemic ST-segment change and/or abnormal ejection fraction response to exercise were observed in 36 (90%) patients. COMPARISON BETWEEN SUBGROUPS IN CAD In the 21 patients with multivessel disease, LV end-diastolic volume increased by 30% and endsystolic volume increased by 42%; both were significantly greater than those (14% and 11%) in !40r 105 EXHR(beatmin-') EX MAP (mmhg) EXRPP(x 100) EDV (ml) ESV (ml) EF (%) Change in EDV (ml) Change in ESV (ml) Change in EF (%) NoST depression (#=14) 131 ± IV 125± ± ±53 78±48 49±14 16±17 5±13 2±7 ST depression (#=26) 120± 14** 120± ±46 142±38 71 ±33 52±12 40±29* 28 ±28* ^»±8" **/ > <005 vj patients with ST depression. Otherwise are as in Table 2. P< O-Ol P< r 10 I > o E g. ^ L -35 L No ongino Angina No angina Angina Noangina Angino Figure 2 Comparison of changes in left ventricular volumes and ejection fraction from rest to exercise between patients with and those without angina during exercise. Abbreviations are as in Figure 1.

5 :. «Left ventricular response to exercise in coronary artery disease 1029 l60 r l40r P<0-0\ 20 r P< I > 80-40>~ i..: -e- I 1 70 in UJ 35.«!: L -30 L NoST* ST* NoST* ST* NoST* ST* Figure 3 Comparison of changes in left ventricular volumes and ejection fraction from rest to exercise between patients with and those without exercise-induced ischaemic ST-segment depression. Abbreviations are as in Figure 1. Table 5 Effects ofnifedipine on left ventricular response in 14 patients with coronary artery disease (mean ± SD) HR (beat/min) MAP (mmhg) RPP(xlOO) SV(ml) C0(l/min) EDV (ml) ESV(ml) EF(%) Before nifedipine 74±12 104±12 94±26 62±I1 4-6 ± ± ±37 53±14 111±13* 127±12* 240 ±63* 76±17* 8-4±21* 156 ±38* 80±41* 52± 15 After nifedipine 89±14f 87±8f 88±21 68±lltt 61±l-3t 126±36 59 ±36 57±14ft ±17*f 104±10*f 205±5Ott 84±17*t I0-6±2-6*t 146±31*tt 62±33f 6O±13t I-.- Abbreviations: fp<0-01, ff<0"05 effects ofnifedipine at rest and during exercise. / > <0-01, **/ > <005 effects of exercise before and after nifedipine. Otherwise are as in Table 1. significantly more in patients with angina (45%) than in those without angina (12%) (/ > <001). On exercise, ejection fraction decreased in patients with angina, but was unchanged in those without angina (Table 3, Fig. 2). In the 26 patients with exercise-induced ischaemic ST-segment depression, both LV enddiastolic and end-systolic volumes increased during exercise. In the other 14 patients without ST-segment depression, end-diastolic volume increased and end-systolic volume was unchanged on exercise. The changes in end-diastolic and endsystolic volumes from rest to exercise were significantly greater in patients with, than in those without ischaemic ST-segment changes (/ > <001). On exercise, ejection fraction decreased in patients

6 1030 W. F. Shen et al. with ST-segment depression, but was unchanged in those without ST-segment depression (Table 4, Fig. 3). When patients with and without previous myocardial infarction were compared, there were no significant differences in changes in LV volumes and ejection fraction from rest to exercise EFFECTS OF NIFEDIP1NE In 14 patients, after nifedipine maximal workloads achieved increased from 49 ± 19 to 58 ± 18 W (/ > <001), and maximal ST-segment depressio'n decreased from 2-5± 1-2 to l-7± l-5mm(/><0-01). At workloads identical to the maximum during the control exercise, angina did not occur in 7 patients after nifedipine. The changes in haemodynamics and LV function are shown in Table 5. After nifedipine, at rest heart rate increased by 20% and mean arterial pressure decreased by 16%, but the rate-pressure product was unaltered. Stroke volume and cardiac output increased significantly. Both LV enddiastolic and end-systolic volumes were unchanged, but ejection fraction was slightly but significantly increased. During exercise at identical workloads to maximal exercise in the control studies, heart rate, stroke volume and cardiac output were higher, but mean arterial pressure and the ratepressure product were lower. LV end-diastolic and end-systolic volumes were smaller and ejection fraction was higher. Discussion LV RESPONSE TO EXERCISE The LV volume and ejection fraction responses to exercise in our control subjects were similar to those previously reported in normals' 11 ', suggesting that the normal heart adapts to semiupright exercise by increasing myocardial contractility and utilizing the Frank-Starling mechanism. In patients with CAD, LV end-diastolic volume increased more than stroke volume, resulting in an increase in end-systolic volume and no significant change in ejection fraction from rest to exercise. The failure to increase ejection fraction and to decrease end-systolic volume with exercise separated patients with CAD from control subjects' 31. When patients with CAD were examined, the degree of exercise-induced LV dysfunction was related to the number of stenotic coronary arteries, and this agrees with previous reports' 3 '. Almost one-third of patients in this study developed ischaemic ST-segment depression but no angina, confirming previous findings that asymptomatic myocardial ischaemia may occur in patients with CAD' 51. Of 40 patients with CAD, 26 (65%) had exercise-induced ischaemic ST segment depression with or without angina, but 33 (83%) developed LV dysfunction during exercise. This suggests that the changes in LV function were more sensitive to ischaemia than either clinical symptoms or the electrocardiogram, and agrees with previous findings' 5 ' 131. Although the LV functional response to exercise was abnormal in patients without exercise-induced angina or ischaemic ST-segment depression, when angina and/or ST-segment depression developed, LV function was worse as indicated by a greater increase in end-systolic volume and decrease in ejection fraction. These findings suggest that the degree of change in LV volumes and ejection fraction during semiupright exercise in patients with CAD may be related to the extent of myocardial ischaemia. BENEFICIAL EFFECTS OF NIFEDIPINE In this study, the 14 patients who were given nifedipine developed angina, ST-segment depression, and LV dysfunction during the control exercise. After nifedipine, exercise-induced angina did not occur in 7 of 14 patients and ST-segment depression was reduced at a workload identical to that on control exercise. LV end-diastolic volume was smaller and stroke volume was higher, resulting in a smaller end-systolic volume and a higher ejection fraction. Nifedipine may improve abnormal LV volume and ejection fraction responses to exercise in patients with CAD by combined effects of afterload reduction and amelioration of the balance between myocardial oxygen supply and demand' 12 '. During exercise after nifedipine, mean arterial pressure was lower and LV volumes were smaller than those during the control exercise, thus LV wall stress (afterload) wad reduced' 14 '. Lichtlen et a/.' 15 'demonstrated that nifedipine increased post-stenotic perfusion of ischaemic areas induced by exercise, and Zacca and coworkers' 16 ' found that nifedipine improved thallium-201 uptake during exercise. These findings suggest that both total and the distribution of coronary blood flow were improved, resulting from the direct vasodilator effects of nifedipine on coronary arteries. In summary, this study shows that in patients

7 Left ventricular response to exercise in coronary artery disease 1031 with CAD, the degree of change in LV volumes and ejection fraction during exercise may be related to the extent of exercise-induced myocardial ischaemia, and nifedipine exerted a beneficial effect on LV performance during exercise. References [1] Borer JS, Kent KM, Bacharach SL et al. Sensitivity, specificity and predictive accuracy of radionuclide cineangiography during exercise in patients with coronary artery disease: Comparison with exercise electrocardiography. Circulation 1979; 60: [2] Berger HJ, Reduto LA, Johnstone DE, Borkowski H. Global and regional left ventricular response to bicycle exercise in coronary artery disease. Assessment by quantitative radionuclide angiocardiography. Am J Med 1979; 66: [3] Rerych SK, Scholz PM, Newman GE, Sabiston DC Jr, Jones RH. Cardiac function at rest and during exercise in normals and in patients with coronary heart disease. Ann Surg 1978; 187: [4] Slutsky R, Karliner J, Ricci D. et al. Response of left ventricular volume to exercise in man assessed by radionuclide equilibrium angiography. Circulation 1979; 60: [5] Iskandrian AS, Hakki A.-H. Left ventricular function in patients with coronary heart disease in the presence or absence of angina pectons during exercise radionuclide ventriculography. Am J Cardiol 1984; 53: [6] Roubin GS, Shen WF, Kelly DT, Harris PJ. The QRS scoring system for estimating myocardial infarct size: Clinical, angiographic and prognostic correlations: J Am Coll Cardiol 1983; 2: 38-^*4. [7] Shen WF, Roubin GS, Hirasawa K. et al. Noninvasive assessment of acute effect of nifedipine on rest and exercise haemodynamics and cardiac function in aortic regurgitation. J Am Coll Cardiol 1984; 4: [8] Tan AT, Sadick N, Kelly DT, Harris PJ, Freedman SB, Bautovich G. Verapamil in stable effort angina: Effects on left ventricular function evaluated with exercise radionuclide ventriculography. Am J Cardiol 1980; 49: [9] Shen WF, Roubin GS, Choong CYP. et al. Evaluation of relationship between myocardial contractile state and left ventricular function in patients with aortic regurgitation. Circulation 1985; 71: [10] Gill JL. Design and analysis of experiments in animal and medical sciences. Iowa: Iowa State University, 1982; 72, vol 3. [11] Weiss JL, Weisfelt ML, Mason SJ, Garrison JB, Livengood SV, Forruin NJ. Evidence of Frank- Starling effect in man during severe semiupright exercise. Circulation 1979; 59: [12] Theroux P, Waters DD, Latour J.-G. Clinical manifestations and pathophysiology of myocardial ischaemia with special reference to coronary artery spasm and the calcium blockers. Prog Cardiovasc Dis 1982; 25: [13] Linden RJ, Mary DASG. Limitations and reliability of exercise electrocardiography tests in coronary heart disease. Cardiovasc Res 1982; 16: [14] Andersen K, Vik-Mo H. Increased left ventricular emptying at maximal exercise after reduction in afterload. Circulation 1984; 69: [15] Lichtlen PR, Engel HJ, Wolf R, Pretschner P. Regional myocardial blood flow in patients with coronary artery disease after nifedipine. In: Lichtlen PR, Kiruma E, Taira N, eds. New experimental and clinical results. International Adalat Panel Discussion. Amsterdam: Excerpta Medica, 1979: [16] Zacca NM, Verani MS, Chahine RA, Miller RR. Effect of nifedipine on exercise-induced left ventricular dysfunction and myocardial hypoperfusion in stable angina. Am J Cardiol 1982; 50: