Author + information
- Received November 8, 1995
- Revision received May 2, 1996
- Accepted May 7, 1996
- Published online October 1, 1996.
- MARCUS F STODDARD*
- ↵*Address for correspondence: Dr. Marcus F. Stoddard, Department of Medicine, Cardiology Division, University of Louisville, 550 South Jackson Street, Louisville, Kentucky 40202.
Objectives. This study sought to determine whether calcium antagonist, compared with nitroglycerin, administration attenuates left ventricular dysfunction after exercise-induced ischemia in humans.
Background. Exercise-induced ischemia impairs left ventricular systolic function and diastolic filling after exercise. The mechanism of this phenomenon is unknown but may relate to intracellular calcium overload.
Methods. Echocardiography was performed in 131 patients before and 30 min, 2 h and 4 h after exercise stress test. Ischemia was defined as a reversible thallium stress defect. No medication, sublingual nitroglycerin or nifedipine was randomly given to each patient at peak exercise.
Results. Isovolumetric relaxation time was significantly prolonged from rest (100 ± 19 ms [mean ± SD]) to 30 min (118 ± 20 ms, p < 0.0005), 2 h (117 ± 18 ms, p < 0.0005) and 4 h (110 ± 22 ms, p < 0.05) after exercise in 21 patients with exercise-induced ischemia who received no medication (ischemia-none group). Isovolumetric relaxation time similarly increased after exercise in 23 patients who received nitroglycerin and had exercise-induced ischemia (ischemia-NTG group) but was unchanged in 20 patients with exercise-induced ischemia who received nifedipine (ischemia-nifedipine group). Peak early filling velocity decreased in the ischemia-none and ischemia-NTG groups from rest to 30 min and 2 h after exercise, but peak early filling velocity was unchanged in the ischemia-nifedipine group. Ejection fraction decreased from rest to 30 min after exercise in the ischemia-none group (59 ± 12% vs. 51 ± 13%, p < 0.025) and ischemia-NTG group (59 ± 14% vs. 49 ± 14%, p < 0.005) but was unchanged in the ischemia-nifedipine group (50 ± 19% vs. 64 ± 18%, p = NS). A new regional left ventricular wall motion abnormality occurred more frequently 30 min after exercise in the ischemia-none group (11 [52%] of 21) and ischemia-NTG group (9 [39%] of 23) compared with the ischemia-nifedipine group (2 [10%] of 20, both p < 0.05). No change occurred in left ventricular systolic function and diastolic filling after exercise in the control groups.
Conclusions. Exercise-induced ischemia impairs systolic function and diastolic filling after exercise. Sublingual nifedipine but not nitroglycerin attenuates this process and suggests that altered calcium homeostasis may play a role in left ventricular dysfunction that occurs after exercise-induced ischemia.
Reversible left ventricular dysfunction that occurs after an acute myocardial ischemic event may be an important determinant of cardiac function in patients with coronary artery disease [1–6]. Clinical echocardiographic studies investigating the effect of exercise-induced myocardial ischemia on left ventricular performance have previously shown left ventricular systolic dysfunction [7–9]and, more recently, impaired diastolic filling after exercise . It is conceivable that exercise-induced left ventricular dysfunction significantly contributes to morbidity in patients with coronary artery disease. The mechanism of how exercise-induced ischemia impairs systolic function and diastolic filling after exercise remains unclear. Clarification of this mechanism will be critical in designing clinical strategies to prevent this process. Intracellular calcium concentration plays a critical role in regulation of myocardial contraction and relaxation. Thus, many experimental studies [11–17]have focused on the potential role of altered intracellular calcium homeostasis on postischemic myocardial dysfunction. Canine models have shown that administration of calcium antagonist after ischemia and during reperfusion may attenuate postischemic systolic dysfunction but have no beneficial influence on diastolic function . To our knowledge, the role of intracellular calcium homeostasis, potentially altered by exercise-induced myocardial ischemia, on systolic and diastolic function after exercise has not been studied in humans.
The present study therefore sought to determine the effects of administration of the calcium antagonist nifedipine on postexercise systolic dysfunction and impaired diastolic filling provoked by exercise-induced ischemia in patients with coronary artery disease. Nifedipine, a 1,4-dihydropyridine, was chosen because it selectively interacts at a set of discrete sites on a major protein of the L class of voltage-gated calcium channels [18, 19]. Nitroglycerin was compared with nifedipine because it is a commonly prescribed medication for exercise-induced ischemia and has no direct influence on myocardial function.
Study patients. One-hundred fifty-six patients were enrolled, and 25 were excluded. Thus, 131 patients (129 men, 2 women; mean [±SD] age 56 ± 11 years, range 26 to 76) undergoing stress testing for evaluation of chest pain constituted the study cohort. Inclusion criteria included age ≥18 years, sinus rhythm and absence of chest pain within 24 h of enrollment. Exclusion criteria included valvular heart disease (n = 10), technically inadequate thallium tomography (n = 4) or echocardiography (n = 18) or a discrepancy between coronary angiography and thallium scintigraphy (n = 12). Several patients met more than one exclusion criteria. Written informed consent was obtained from all patients. The study protocol was approved by our institutional review board.
Study protocol. All studies were performed after a 12-h fast. Systemic blood pressure and echocardiography were performed with subjects in a partial left lateral decubitus position immediately before and 30 min, 2 h and 4 h after exercise stress testing. Systemic blood pressure measured during echocardiography was determined in triplicate using an automated blood pressure machine (Critikon, Dinamap model 1846 SX/P) and averaged. Patients underwent a symptom-limited Bruce protocol treadmill exercise test. One minute before ending exercise, 3.0 mCi of thallium-201 chloride was injected intravenously. Subjects were randomly selected to receive either no medication, 10 mg of sublingual nifedipine (Procardia) or 0.4 mg of sublingual nitroglycerin dinitrate (Nitrolingual Spray) at peak stress, immediately before ending exercise. Nifedipine capsules were punctured, and the medication in a liquid form was administered beneath the tongue. Tomographic imaging was begun 5 min after exercise and repeated at 3 h. Exercise after stress testing was prohibited for the duration of the study. Cardiac catheterization was performed within 3 months of exercise testing in 100 patients.
Nuclear imaging. Nuclear images were acquired by a gamma camera (Starcam 400 AC, General Electric or 3700 Digitrac, Siemens) rotating over a 180° arc. Thirty-two projections were acquired and stored on magnetic disk. Planar images were assessed for patient motion before tomographic reconstruction. A filtered back-projection algorithm was used to reconstruct transaxial tomograms into short-axis and horizontal and vertical long-axis planes [20, 21]. A bull's-eye image displaying counts/pixel over the myocardium was generated with studies performed using the Starcam gamma camera [21, 22]. The extent of diminished thallium-201 activity was compared with an appropriate reference cohort. A severity map was used to illustrate how many standard deviations below the normal range each myocardial region fell. A defect was considered present if visualized in at least two adjacent tomographic slices and in more than one projection. A reversible defect was interpreted as myocardial ischemia. Tomographic images and bull's-eye scans were interpreted by a nuclear cardiologist (S.G.W.) blinded to echocardiographic and angiographic findings and randomization.
Echocardiographic studies. With use of a phased-array echocardiographic machine (Sonos 1500, Hewlett-Packard) and a 2.5-MHz transducer, echocardiographic studies were recorded on videotape. Comprehensive two-dimensional images of the left ventricle were performed from the apical and parasternal windows. Pulsed Doppler of mitral inflow was done on the immediate ventricular side of the mitral annulus from an apical four-chamber view [23, 24]. Simultaneous left ventricular outflow and inflow velocities were acquired from an intermediate position between the outflow tract and mitral valve from an apical five-chamber view . Color flow and spectral Doppler echocardiography were performed from appropriate parasternal and apical views to exclude valvular heart disease. Doppler echocardiography was recorded at a sweep speed of 100 mm/s.
Echocardiographic analysis. All echocardiographic recordings were analyzed with a microcomputer system (GTI, Freeland Medical, Inc.). Doppler curves were digitized along the leading edge. Mitral Doppler diastolic filling indexes included previously reported variables [23, 24]. Isovolumetric relaxation time was measured from the end of left ventricular outflow to the beginning of inflow. All indexes were the average of three to five cardiac cycles.
From apical four- and two-chamber views, the left ventricular endocardial surfaces were digitized using end-diastolic and end-systolic frames. End-diastolic and end-systolic volumes were calculated using a biplane Simpson's method , and the ejection fraction was derived. Quantitative analysis of regional wall motion was assessed from the apical four- and two-chamber views using a centerline method that corrected for ventricular rotation . Three determinations of echocardiographic measurements were averaged. Comprehensive two-dimensional echocardiographic views were qualitatively assessed for regional wall motion. Echocardiographic studies were analyzed by an echocardiographer (M.F.S.) blinded to clinical data, exercise stress test results, angiographic findings and randomization.
Coronary angiography. Selective contrast coronary angiography was performed from multiple orthogonal views using the Seldinger technique. By design, all subjects with reperfusion thallium defects had angiographic confirmation of significant coronary artery disease (i.e., lumen diameter stenosis of a major epicardial vessel or its branches ≥70% or of the left main coronary artery ≥50%).
Statistical analysis. Results are expressed as mean value ± SD or proportion of a group. Analysis of variance (Scheffé F test) was used to assess differences of repeated measures or multiple group comparisons. Chi-square analysis was performed to assess differences between proportions; p < 0.05 was considered statistically significant.
Postexercise diastolic filling (Table 1Table 2). Patients were classified into six groups on the basis of the presence (ischemia) or absence (control) of ischemia on thallium tomography and whether no medication (none), sublingual nifedipine (nifedipine) or nitroglycerin (NTG) was received at peak exercise. At 30 min to 4 hours after exercise, a significant impairment in diastolic filling and prolongation of isovolumetric relaxation time occurred in the ischemia-none (n = 21) and ischemia-NTG (n = 23) groups (Table 1). In the ischemia-none group, isovolumetric relaxation time increased from 100 ± 19 ms to 118 ± 20 ms (p < 0.0005) at 30 min, 117 ± 18 ms (p < 0.0005) at 2 h and 110 ± 22 ms (p < 0.05) at 4 h after exercise. A similar prolongation of isovolumetric relaxation time occurred in the ischemia-NTG group at 30 min to 4 h after exercise. Impairment in diastolic filling occurred in the ischemia-none and ischemia-NTG groups after exercise, as evidenced by significant decreases in peak early filling velocity, mean deceleration rate and peak early/peak atrial filling velocity ratio and increases in percent atrial contribution to filling (Fig. 1Fig. 2). No change occurred after exercise in isovolumetric relaxation time or indexes of diastolic filling in the ischemia-nifedipine group (n = 20). Systolic and diastolic blood pressures slightly decreased at 30 min after exercise in the ischemia-nifedipine group. Heart rate slightly increased at 30 min and at 2 h after exercise in the ischemia-nifedipine group. Indexes of diastolic filling, isovolumetric relaxation time, systolic and diastolic blood pressure and heart rate before exercise did not differ between the ischemia-none, ischemia-nifedipine and ischemia-NTG groups.
Isovolumetric relaxation time and diastolic filling were not altered after exercise in groups without exercise-induced ischemia who received no medication (control-none), nifedipine (control-nifedipine) or nitroglycerin (control-NTG) (Table 2). Heart rate and systolic and diastolic blood pressures were altered 30 min and 2 h after exercise in the control-nifedipine group (n = 24) but unchanged in the control-none (n = 24) or control-NTG (n = 19) groups. Indexes of diastolic filling, isovolumetric relaxation time, systolic and diastolic blood pressure and heart rate before exercise did not differ among the control groups.
Postexercise global systolic function (Table 3Table 4). Left ventricular ejection fraction significantly decreased 30 min after exercise-induced ischemia in the ischemia-none (59 ± 12% vs. 51 ± 13%, p < 0.025) and ischemia-NTG groups (59 ± 14% vs. 49 ± 14%, p < 0.005) because of an increase in end-systolic volume. Ejection fraction and volumes were unchanged after exercise in the ischemia-nifedipine group (Table 3). Left ventricular ejection fraction and end-diastolic and end-systolic volumes were unchanged after exercise in control subjects without exercise-induced ischemia who received no medication, nifedipine or nitroglycerin (Table 4). Left ventricular ejection fraction and end-diastolic and end-systolic volumes before exercise did not differ among the control groups.
Regional systolic function.Qualitative assessment (Table 5). In the ischemia-none group, a new dyskinetic or akinetic regional wall motion abnormality was evident in 11 (52%) of 21 patients at 30 min, 5 (24%) of 21 at 2 h and 2 (10%) of 21 at 4 h after exercise-induced ischemia. Similarly, in the ischemia-NTG group, a new regional wall motion abnormality was evident in 9 (39%) of 23 patients at 30 min, 5 (22%) of 23 at 2 h and 3 (23%) of 23 at 4 h after exercise (Fig. 3). However, in the ischemia-nifedipine group, a new regional wall motion abnormality was present in 2 (10%) of 20 patients 30 min after exercise and resolved 2 and 4 h after exercise. The frequency of a new regional wall motion abnormality after exercise was significantly greater in the ischemia-none and ischemia-NTG groups compared with the ischemia-nifedipine group 30 min (both p < 0.05) and 2 h (both p < 0.05) after exercise. The left ventricular region of myocardial dysfunction was predominantly the inferior wall in the ischemia-none and ischemia-nifedipine groups. The anterior and inferior walls were equally involved in the ischemia-NTG group. The site of myocardial dysfunction at 30 min after exercise was contiguous with a rest regional akinetic or dyskinetic myocardial segment noted before exercise in 5 of 11 patients in the ischemia-none group, 1 of 2 patients in the ischemia-nifedipine group and 5 of 9 patients in the ischemia-NTG group. The region of myocardial dysfunction 30 min after exercise was concordant with the distribution of ischemia by thallium tomography in 9 of 11 patients in the ischemia-none group, 2 of 2 patients in the ischemia-nifedipine group and in 8 of 9 patients in the ischemia-NTG group. In one patient in the ischemia-none group and two in the ischemia-NTG group, regional myocardial dysfunction persisted 4 h after exercise despite complete resolution of myocardial ischemia by thallium tomography. No new wall motion abnormalities were present after exercise in the control-none, control-nifedipine or control-NTG groups.
Quantitative assessment. Quantitative assessment of regional wall motion was performed from the four- and two-chamber views using a centerline method. In general, quantitative analysis agreed with qualitative assessment of wall motion. In the ischemia-none group a reduced inward endocardial excursion was present 30 min after exercise, as evidenced by chord 55 (1.28 ± 0.49 vs. 0.91 ± 0.40 cm, p < 0.02), chord 65 (1.08 ± 0.53 vs. 0.71 ± 0.42 cm, p < 0.01), chord 75 (0.87 ± 0.48 vs. 0.64 ± 0.31 cm, p = 0.06) and chord 85 (0.76 ± 0.37 vs. 0.55 ± 0.31 cm, p = 0.09) from an apical four-chamber view, which represents the apical and mid to distal lateral walls, and chord 25 (0.60 ± 0.35 vs. 0.36 ± 0.39 cm, p < 0.05) and chord 35 (0.68 ± 0.39 vs. 0.39 ± 0.37 cm, p < 0.05) from an apical two-chamber view, which represents the mid-inferior wall. In the ischemia-NTG group, a reduced inward excursion was present 30 min after exercise at chord 15 (0.71 ± 0.38 vs. 0.41 ± 0.42 cm, p < 0.05), chord 25 (0.81 ± 0.36 vs. 0.41 ± 0.42 cm, p < 0.02), chord 35 (0.79 ± 0.35 vs. 0.48 ± 0.51 cm, p < 0.025) and chord 45 (1.00 ± 0.51 vs. 0.87 ± 0.47 cm, p = 0.10) from an apical two-chamber view, which represents the mid to distal inferior wall, and chord 75 (0.95 ± 0.35 vs. 0.70 ± 0.31 cm, p < 0.02) from an apical four-chamber view which represents the mid to distal lateral wall (Fig. 4). Quantitative analysis demonstrated no changes after exercise in endocardial excursion in the ischemia-nifedipine group. No statistically significant changes occurred in inward excursion, as assessed by the centerline method in the control-none, control-nifedipine or control-NTG groups.
Extent and severity of ischemia. In the ischemia-none, ischemia-nifedipine and ischemia-NTG groups, respectively, exercise duration (429 ± 173 vs. 415 ± 172 vs. 499 ± 143 s), heart rate (145 ± 17 vs. 139 ± 19 vs. 143 ± 20 beats/min) and systolic blood pressure (178 ± 27 vs. 195 ± 33 vs. 194 ± 27 mm Hg) at peak exercise and rate pressure product (25,668 ± 5,451 vs. 27,337 ± 7,145 vs. 27,783 ± 5,795 mm Hg × beats/min) did not differ (p = NS). The extent and severity of thallium reperfusion defects were determined in 14 patients in the ischemia-none group, 16 in the ischemia-nifedipine group and 14 in the ischemia-NTG group. The extent of reperfusion defects was measured in pixels, and severity was measured in standard deviations below an appropriate reference population. In the ischemia-none, ischemia-nifedipine and ischemia-NTG subgroups, respectively, the extent (79 ± 8 vs. 77 ± 18 vs. 74 ± 24 pixels) and severity (53 ± 83 vs. 62 ± 62 vs. 87 ± 100 SD) of reperfusion defects did not differ (p = NS).
Coronary angiography demonstrated single-, double- or triple-vessel or left main coronary artery disease, respectively, in five, eight, seven and one patient in the ischemia-none group; four, six, eight and two patients in the ischemia-nifedipine group; and five, nine, eight and one patient in the ischemia-NTG group. Coronary angiography showed no significant coronary artery stenosis in 10 patients in the control-none, 12 in the control-nifedipine and 14 in the control-NTG groups.
In the present study, exercise-induced ischemia was shown to prolong isovolumetric relaxation time and to impair left ventricular diastolic filling for 4 h after exercise in humans. In addition, exercise-induced ischemia reduced global left ventricular systolic function 30 min after exercise and provoked regional wall motion abnormalities for 4 h after exercise in selected patients. Importantly, the present study demonstrates that sublingual nifedipine but not nitroglycerin, given during exercise-induced ischemia and immediately before ending exercise, attenuates abnormalities of isovolumetric relaxation time, diastolic filling and global systolic function after exercise. Similarly, nifedipine decreases the frequency and duration of postexercise regional wall motion abnormalities after exercise-induced ischemia. To our knowledge, this is the first study demonstrating that exercise-induced ischemia may impair isovolumetric relaxation, diastolic filling and regional systolic function for 4 h after exercise and that nifedipine attenuates this process. The mechanism of nifedipine's effects remains undetermined.
Comparison with previous studies.Systolic function. Four previous echocardiographic studies [7–10]and three previous radionuclide studies [28–30]have shown seemingly divergent results for the duration of left ventricular systolic dysfunction after exercise-induced ischemia in humans. Robertson et al. were the first to report wall motion abnormalities 30 min after exercise-induced ischemia in 6 (38%) of 16 subjects with coronary artery disease. Kloner et al. noted regional left ventricular wall motion abnormalities in 18 (95%) of 19 patients at 15 min and 19 (90%) of 21 patients at 30 min after exercise-induced ischemia. Scognamiglio et al. found a decline in left ventricular ejection fraction 30 min after exercise-induced ischemia compared with that at rest in 22 (84%) of 26 patients. Similar to these previous echocardiographic studies, we previously showed a new regional left ventricular wall motion abnormality in 9 (17%) of 52 patients and a reduction in left ventricular ejection fraction 2 h after exercise-induced ischemia. In these previous studies [7–10], reversibility of wall motion abnormalities was not shown. However, in the present study the reversibility of regional wall motion abnormalities after exercise-induced ischemia was shown in the majority of subjects. In addition, selected patients had persistent regional wall motion abnormalities 4 h after exercise-induced ischemia despite complete resolution of stress-induced thallium perfusion defects. Therefore, the results of the present study, compared with those of previous studies [7–10], are more supportive for the presence of myocardial “stunning” provoked by exercise-induced ischemia in humans. Although myocardial stunning after exercise-induced ischemia has been well established in experimental canine models [31–33], a definitive demonstration of this phenomenon due to exercise-induced ischemia in humans awaits documentation of normal myocardial perfusion in the dysfunctional segment by quantitative techniques. Several radionuclide angiographic studies [28–30]have failed to demonstrate a protracted delay in recovery of global or regional left ventricular systolic function after exercise-induced ischemia and are at odds with the results of previous [7–10]and the present echocardiographic study. It is possible that the variance in these results relates to differences in the radionuclide and echocardiographic techniques for assessment of left ventricular systolic function.
Diastolic filling. In a previous study , we demonstrated that exercise-induced ischemia was associated with impaired diastolic filling 2 h after exercise in humans. In the present study, similar impairment of left ventricular diastolic filling as well as prolongation of isovolumetric relaxation time were shown 30 min to 4 h after exercise-induced ischemia. In the present study, impairment in relaxation may explain prolongation of the isovolumetric relaxation time and left ventricular filling abnormalities seen in patients with exercise-induced ischemia after exercise. Carroll et al. demonstrated that exercise-induced ischemia increases early filling pressures and impairs left ventricular relaxation during ischemia. It is possible that ischemia-induced impairment of relaxation persists into the postexercise phase. Also, myocardial perfusion after exercise-induced ischemia may have an independent adverse affect on relaxation.
Mechanism of ventricular dysfunction after exercise-induced ischemia. The mechanism of left ventricular systolic dysfunction and impaired diastolic filling after exercise-induced ischemia is unknown. Experimental studies [11, 13–16, 35, 36]implicate a significant role for transient intracellular calcium overload during ischemia and reperfusion in the postischemic ventricular dysfunction process. The results of the present study, demonstrating attenuation of postexercise systolic dysfunction and impaired diastolic filling by a calcium antagonist, are consistent with the postulate of calcium-mediated contractile and relaxation dysfunction after exercise-induced ischemia. Intracellular cytosolic calcium concentration increases during ischemia and remains elevated for several minutes during reperfusion . The mechanism of the increase in intracellular calcium concentration during ischemia and early reperfusion remains unknown. Some data suggest that calcium transport of the sarcoplasmic reticulum is impaired in this process, thereby decreasing removal of calcium from the cytosol. It has been further postulated that impaired Na+/Ca2+ exchange, known to occur during ischemia and reperfusion, may account for excessive intracellular calcium concentrations.
A characteristic feature of calcium overload is asynchronous oscillations of intracellular calcium concentrations leading to inhomogeneity of intracellular contractile activation and reduced overall contractile force. It is conceivable that increased intracellular calcium concentrations and impairment of mechanisms that remove calcium from the cytoplasm would impair uncoupling of actin-myosin filaments and delay and prolong myocardial relaxation. It is possible that nifedipine attenuates systolic dysfunction and impaired diastolic filling after exercise-induced ischemia by decreasing calcium overload.
It is possible that the effect of nifedipine may be unrelated to its antagonism of voltage-gated calcium channels. Improved coronary perfusion by nifedipine-mediated coronary vasodilation after exercise may have accounted for a lack of deterioration in global systolic function and diastolic filling. It is possible that exercise-induced ischemia leads to transmural maldistribution of coronary blood flow or vasoconstriction in the ischemic zone after exercise. However, nitroglycerin, which also augments coronary flow, did not attenuate left ventricular dysfunction in the present study. This finding may be partly explained by the significantly shorter duration of action of sublingual nitroglycerin compared with that of nifedipine and may not be entirely explained by a lack of calcium antagonist properties of nitroglycerin. Nifedipine may have altered left ventricular afterload and preload and thereby improved systolic function and diastolic filling after exercise in subjects with exercise-induced ischemia. However, in the present study the effects of nifedipine on systolic function and diastolic filling were noted 2 and 4 h after exercise-induced ischemia, despite a lack of decrease in systolic blood pressure or left ventricular size. Also, no influence of nifedipine on systolic function and diastolic filling was seen in the control group. An increase in sympathetic drive, induced by nifedipine, could have enhanced inotropic and lusitropic stimulation and potentially attenuated systolic dysfunction and impaired diastolic filling after exercise. A potential explanation for the apparent attenuation of impaired diastolic filling after exercise-induced ischemia is enhancement of left ventricular diastolic myocardial properties remote from the site of myocardial dysfunction. However, noninvasive methods to assess regional diastolic function are not readily available to test this hypothesis.
Limitations of the study. Although nifedipine was given at peak exercise, we cannot exclude the possibility that the severity and magnitude of exercise-induced ischemia was decreased by its administration. However, no such beneficial influence of nitroglycerin was seen despite its shorter onset of action compared with that of nifedipine. In addition, peak heart rate, systolic blood pressure and rate-pressure product did not differ among the ischemia groups and the extent and severity of exercise-induced ischemia as assessed by quantitative thallium tomography did not differ among a select group of patients with ischemia. A small proportion of the control groups may have included subjects with false negative thallium tomographic scan results. Performing coronary angiography was not feasible in all control patients. It is unclear whether nifedipine's effects are dependent on the timing of its administration relative to the point at which exercise-induced ischemia resolves. Future studies addressing this issue will be of interest. However, the transition from ischemia to reperfusion is less precise in the setting of exercise-induced ischemia compared with coronary occlusion models and complicates the precise investigation of this issue. Although Doppler indexes of diastolic filling are influenced by diastolic function , extrapolating the status of relaxation or compliance from these variables must be done with caution because of the independent effects of loading conditions .
Conclusions. Exercise-induced ischemia impairs systolic function and diastolic filling and prolongs isvolumetric relaxation time from 30 min to 4 h after exercise in humans. This process is attenuated by sublingual nifedipine, but not nitroglycerin, given after provocation of ischemia and before ending exercise. These data suggest that altered calcium homeostasis may play a role after exercise in ventricular dysfunction provoked by exercise-induced ischemia. Future studies are needed that address the potential importance of the timing of nifedipine administration relative to the point at which exercise-induced ischemia resolves. It remains to be determined whether treatment of ambulatory ischemia with sublingual nifedipine, versus nitroglycerin, will have a positive impact on morbidity and mortality from coronary artery disease.
We appreciate the secretarial assistance of Erica Camp in the preparation of the manuscript.
↵1 This study was supported by a grant from the American Heart Association, Kentucky Affiliate, Louisville, Kentucky.
- Received November 8, 1995.
- Revision received May 2, 1996.
- Accepted May 7, 1996.
- THE AMERICAN COLLEGE OF CARDIOLOGY
- ↵Weiner JM, Apstein CS, Author JH, Pirzada FA, Hood WB. Persistence of myocardial injury following brief periods of coronary occlusion. Cardiovasc Res 1976;10:678–86.
- Heyndrickx GR, Baig J, Nellens P, Leusen I, Fishbein MC, Vatner SF. Depression of regional blood flow and wall thickening after brief coronary occlusions. Am J Physiol 1978;234:H653–9.
- Nixon JV, Brown CN, Smitherman TC. Identification of transient and persistent segmental wall motion abnormalities in patients with unstable angina by two-dimensional echocardiography. Circulation 1982;65:1497–503.
- Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemie ventricular dysfunction. Circulation 1982;66:1146–9.
- Becker LC, Levine JH, DiPaula AF, Guarnieri T, Aversano T. Reversal of dysfunction in postischemic stunned myocardium by epinephrine and post-extrasystolic potentiation. J Am Coll Cardiol 1986;7:580–9.
- Jeroudi MO, Cheirif J, Habib G, Bolli R. Prolonged wall motion abnormalities after chest pain at rest in patients with unstable angina: a possible manifestation of myocardial stunning. Am Heart J 1994;127:1241–50.
- ↵Robertson WS, Feigenbaum H, Armstrong WF, Dillon JC, O'Donnell J, McHenry PW. Exercise-echocardiography: a clinically practical addition in the evaluation of coronary artery disease. J Am Coll Cardiol 1983;2:1085–91.
- ↵Kloner RA, Allen J, Cox TA, Zheng Y, Ruiz CE. Stunned left ventricular myocardium after exercise treadmill testing in coronary artery disease. Am J Cardiol 1991;68:329–34.
- ↵Scognamiglio R, Ponchia A, Fasoli G, Miraglia G, Dalla-Volta S. Exercise-induced left ventricular dysfunction in coronary heart disease: a model for studying the stunned myocardium in man. Eur Heart J 1991;12:16–9.
- ↵Stoddard MF, Johnstone J, Dillon S, Kupersmith J. The effect of exercise-induced myocardial ischemia on postischemic left ventricular diastolic filling. Clin Cardiol 1992;15:265–73.
- ↵Nayler WG, Ferrari R, Williams A. Protective effect of pretreatment with verapamil, nifedipine and propranolol on mitochondrial function in the ischemic and reperfused myocardium. Am J Cardiol 1980;46:242–8.
- Kusuoka H, Koretsune Y, Chacko VP, Weisfeldt ML, Marban E. Excitation-contraction coupling in postischemic myocardium. Does failure of activator Ca2+ transients underlie stunning? Circ Res 1990;66:1268–76.
- Fitzpatrick DB, Karmazyn M. Comparative effects of calcium channel blocking agents and varying extracellular calcium concentration on hypoxia/reoxygenation and ischemia/reperfusion-induced cardiac injury. J Pharmacol Exp Ther 1983;228:761–7.
- Eckert R, Utz J, Trautwein W, Mentzer RM. Involvement of intracellular Ca2+ release mechanism in adenosine-induced cardiac Ca2+ current inhibition. Surgery 1993;114:334–42.
- ↵Przyklenk K, Kloner RA. Effect of verapamil on postischemic “stunned” myocardium: importance of the timing of treatment. J Am Coll Cardiol 1988;11:614–23.
- ↵Applegate RJ, Walsh RA, O'Rourke RA. Effects of nifedipine on diastolic function during brief periods of flow-limiting ischemia in the conscious dog. Circulation 1987;6:1409–21.
- ↵Sanguinetti MC, Kass RS. Voltage-dependent block of calcium channel current in calf cardiac purkinje fibers by dihydropyridine calcium channel antagonist. Circ Res 1984;55:336–48.
- Kobubun S, Prod'hom B, Becker C. Studies on Ca2+ channels in intact cardiac cells: voltage-dependent effects cooperative interactions of diphydropyrine thyroid enantiomers. Mol Pharmacol 1987;30:571–84.
- ↵Iskandrian NS, Heo J, Askense A, Segal BL, Helfant RH. Thallium imaging with single photon emission computed tomography. Am Heart J 1987;114:852–65.
- ↵Garcia EV, Van Tran K, Maddahi J, et al. Quantification of rotational thallium-201 myocardial tomography. J Nucl Med 1985;26:117–26.
- Eisener RL, Tamas MG, Cloninger K, et al. Normal SPECT thallium-201 bull's eyes display: gender differences. J Nucl Med 1988;29:2901–9.
- ↵Stoddard MF, Pearson AC, Kerns MJ, Ratcliff J, Mrosek DG, Labovitz AJ. Left ventricular diastolic function: comparison of pulsed Doppler echocardiographic and hemodynamic indexes in subjects with and without coronary artery disease. J Am Coll Cardiol 1989;13:327–36.
- ↵Stoddard MF, Pearson AC, Kerns MJ, Ratcliff J, Mrosek DG, Labovitz AJ. Influence of alteration in preload on the pattern of left ventricular diastolic filling as assessed by Doppler echocardiography in humans. Circulation 1989;79:1226–36.
- ↵Stoddard MF, Seeger J, Liddell NE, Hadley TJ, Sullivan DM, Kupersmith J. Prolongation of isovolumetric relaxation time as assessed by Doppler echocardiography predicts doxorubicin-induced systolic dysfunction in humans. J Am Coll Cardiol 1992;20:62–9.
- ↵Schiller NB, Shah PM, Crawford M, et al. Recommendation for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358–67.
- ↵Assmann PE, Slager CJ, van der Borden SG, Tijssen JGP, Oomen JA, Roelandt JR. Comparison of models for quantitative left ventricular wall motion analysis from two-dimensional echocardiograms during acute myocardial infarction. Am J Cardiol 1993;71:1262–9.
- ↵Schneider RM, Weintraub WS, Klein LW, Seelaus PA, Agarwal JB, Helfant RH. Rate of left ventricular functional recovery by radionuclide angiography after exercise in coronary artery disease. Am J Cardiol 1986;57:927–32.
- Dymond DS, Foster C, Grenier RP, Carpenter J, Schmidt DH. Peak exercise and immediate postexercise imaging for the detection of left ventricular functional abnormalities in coronary artery disease. Am J Cardiol 1984;53:1532–7.
- Marzullo P, Parodi O, Sambuceti G, et al. Does the myocardium become “stunned” after episodes of angina at rest, angina on effort, and coronary angioplasty? Am J Cardiol 1993;71:1045–51.
- ↵Thaulow E, Guth BD, Heusch G, et al. Characteristics of regional myocardial stunning after exercise in dogs with chronic coronary stenosis. Am J Physiol 1989;257:H113–9.
- Homans DC, Laxson DD, Sublett E, Lindstrom P, Bache RJ. Cumulative deterioration of myocardial function after repeated episodes of exercise-induced ischemia. Am J Physiol 1989;256:H1462–71.
- Homans DC, Laxson DD, Sublett E, Pavek T, Crampton M. Effect of exercise intensity and duration on regional function during and after exercise-induced ischemia. Circulation 1991;83:2029–37.
- ↵Carroll JD, Hess OM, Hirzel HO, Krayenbuehl HP. Exercise-induced ischemia: the influence of altered relaxation on early diastolic pressures. Circulation 1983;67:521–8.
- Kitakaze M, Weisman HF, Marban E. Contractile dysfunction and ATP depletion after transient calcium overload in perfused ferret hearts. Circulation 1988;77:685–95.
- ↵Marban E, Kitakaze M, Koretsune Y, Yue DT, Chacko VP, Pike MM. Quantification of [Ca2+]i in perfused hearts. Critical evaluation of the 5F-BAPTA and nuclear magnetic resonance method as applied to the study of ischemia and reperfusion. Circ Res 1990;66:1255–67.
- ↵Krause SM, Jacobus WE, Becker LC. Alterations in cardiac sarcoplasmic reticulum calcium transport in the postischemic “stunned” myocardium. Circ Res 1989;65:526–30.