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© 1999 International Anesthesia Research Society
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Abstract |
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It has been speculated but never proven that tachycardia-induced ischemia per se may lead to myocardial infarction. In 17 anesthetized dogs, the proximal left anterior descending (LAD) artery was cannulated and perfused via bypass from the left subclavian artery. Distal LAD pressure was reduced by a screw clamp to cause
20% decrease in wall thickening during pacing tachycardia but no decrease in resting heart rate (approximately 90 bpm). Dogs were randomly assigned to three groups: 1) control (n = 6) maintained at resting heart rate (approximately 90 bpm) and mean coronary pressure of 49 ± 5 mm Hg for 4 h; 2) 4-h ischemia (n = 6), paced at 150 bpm and mean coronary pressure maintained at 59 ± 6 mm Hg for 4 h; and 3) 1-h ischemia (n = 5), paced at 150 bpm and mean coronary pressure of 54 ± 8 mm Hg for 1 h. Myocardial blood flow and infarct area were measured by radiolabeled microspheres and triphenyl-tetrazolium chloride staining, respectively. Despite the higher coronary pressure in the 4-h ischemia group (P = 0.02), patchy subendocardial necrosis occurred in all these dogs and in two of the 1-h ischemia dogs, and one control dog had minimal papillary muscle necrosis. Infarct area was largest in the 4-h ischemic group (15.5% ± 9.1%) compared with control and 1-h ischemia groups (0.09% ± 0.2% and 1.6% ± 2.1%, respectively) (P < 0.002). Relative (risk/nonrisk areas) subendocardial flow was lower at the end of ischemia in the 4- and 1-h ischemia groups compared with the control group (0.3 ± 0.1 and 0.4 ± 0.1 vs 0.9 ± 0.2; P = 0.008 and 0.01, respectively). Prolonged tachycardia-induced ischemia, in the face of fixed coronary stenosis causing no ischemia at the resting heart rate, leads to patchy subendocardial necrosis, despite anticoagulation and antiplatelet treatment. Implications: Prolonged tachycardia-induced ischemia, in the face of fixed coronary stenosis causing no ischemia at the resting heart rate, leads to subendocardial infarction in dogs. These findings suggest a possible mechanism for postoperative myocardial infarction.
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Introduction |
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The pathogenesis of perioperative myocardial infarction is unknown (1). Several important factors distinguish perioperative from nonoperative myocardial infarction: perioperative myocardial infarctions are mostly silent, frequently preceded by prolonged ischemia, denoted almost exclusively by ST-segment depression rather than elevation, and most are non–Q-wave infarctions (2,3). Moreover, whereas coronary thrombosis is the initiating event in Q-wave infarction and treatments directed at reopening the occluded vessel reduce cardiac morbidity and mortality (4), the pathogenesis of non–Q-wave infarction is unclear. Early coronary angiography fails to demonstrate coronary occlusion in most non–Q-wave myocardial infarctions (5). Thrombus in the infarct-related vessel is infrequently found (6), and thrombolytic therapy is of no benefit in non–Q-wave myocardial infarction (7).
Tachycardia is a common cause of myocardial ischemia in the postoperative period. Whether prolonged tachycardia or demand-ischemia, without coronary occlusion, leads to myocardial infarction remains an unanswered question. Patchy subendocardial fibrosis in patients with diffuse coronary artery disease without a history of myocardial infarction has long been recognized, yet its mechanism is disputed. The notion that prolonged or recurrent silent ischemia may cause myocardial necrosis has been suggested but never validated either clinically or experimentally (8,9) and has never gained acceptance among clinicians. To the contrary, numerous clinical and experimental studies have shown the existence of myocardial hibernation, i.e., myocardial functional downregulation as an adaptation to prolonged periods of limited coronary blood flow (10).
The effects of short-term tachycardia-induced ischemia on myocardial perfusion-contraction matching in both humans and animals with limited coronary blood flow have been expansively studied (11,12). Tachycardia also increases infarct size caused by acute coronary occlusion in dogs (13) but not in pigs (14). One study reported normal recovery of regional systolic myocardial function in dogs with severe coronary stenosis after 30 min of rapid artrial pacing (15). However, no previous study has tested the effects of prolonged (>30 min) tachycardia-induced ischemia (16).
The goal of the present study was to test whether prolonged moderate (a 66% increase in heart rate) tachycardia-induced ischemia leads to myocardial infarction.
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Methods |
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With the approval of the institutional committee of animal care and use control, 17 mongrel dogs (25–30 kg) were anesthetized with sodium thiopental (25 mg/kg). After tracheal intubation, normocapnia and anesthesia were maintained with an anesthesia machine using 50% oxygen (in air) and up to 1% halothane. Stable hemodynamic conditions and a slow baseline heart rate were facilitated by the continuous IV infusions of fentanyl (10 µg · kg-1 · h-1) and succinylcholine (5 µg · kg-1 · h-1). Arterial oxygen saturation and end-tidal CO2 were monitored and kept within normal limits. A fluid-filled catheter was advanced to the descending aorta via the left femoral artery and connected to a pressure transducer zeroed at the level of the heart. A separate arterial catheter was placed in the contralateral femoral artery for withdrawal of blood samples. Thoracotomy was performed in the left fifth intercostal space, and the pericardium was incised, exposing the heart and great vessels. A miniature solid-state pressure transducer was introduced into the left ventricle through a left atrial sleeve. A catheter was placed in the left atrium for the injection of radiolabeled microspheres, and a pair of atrial electrodes enabled pacing of the heart.
The left anterior descending (LAD) artery was dissected free proximal to its main diagonal branch. Miniature piezoelectric crystals were placed in the anterior (risk area) and posterior (control area) left ventricular walls in the region of LAD and left circumflex (LCX) coronary arteries, respectively, for measurement of myocardial wall thickness. The risk area (LAD artery) crystals were placed in the center of intended ischemia zone, between the LAD artery and its main diagonal branch. One crystal from each pair was advanced tangentially to the endocardium. The other was placed on the epicardium and aligned so that the distance between the two crystals was minimized, and the greatest signal amplitude and shortest transit time were obtained on the oscilloscope. Wall thickness was measured using a pulse transit sonomicrometer. The left subclavian artery was dissected and cannulated with a plastic tube (5-mm internal diameter). After the IV administration of heparin (10,000 IU), the LAD artery was ligated, cannulated using a metal cannula (2-mm internal diameter, with a side arm for coronary pressure measurement), and perfused via the tube inserted in the subclavian artery. Aspirin (200 mg IV) was infused slowly over the next 1 h, and heparin (5,000 IU IV) was reinjected every hour for anticoagulation. LAD artery flow was continuously monitored via an in-line electromagnetic flowmeter. Perfusion pressure was continuously recorded with a fluid-filled transducer connected via a side arm at the tip of the cannula to the LAD coronary artery. A delicate screw occluder on the plastic tube was used to control LAD coronary flow and pressure. Data were recorded on an eight-channel recorder and sampled (at 200 Hz) to a personal computer with a 12-bit analog-to-digital converter.
Regional myocardial blood flow was determined by injecting radionuclide-labeled microspheres (153Gd, 46Sc, 103Ru, and 113Sn) using the reference withdrawal method. Approximately 2 x 106 microspheres of 15 µm diameter were injected into the left atrium for each blood flow measurement, and a reference blood sample was withdrawn from the aortic catheter in the femoral artery at a rate of 7.75 mL/min (17).
Myocardial thickening was calculated as follows (18): absolute thickening = end-systolic - end-diastolic thickness; percent thickening = absolute thickening/end-diastolic thickness x 100. End-systole was at 20 ms before peak negative left ventricular dP/dt and end-diastole just before the upstroke of left ventricular dP/dt.
Ten minutes after coronary cannulation and at a heart rate of approximately 90 bpm radiolabeled microspheres were injected into the left atrium for baseline myocardial blood flow measurement. Dogs were randomly assigned to three groups. In the control group (n = 6), baseline hemodynamic data were recorded at heart rates of 90 (normal sinus rhythm [NSR]) and 120 bpm (atrial pacing). Coronary stenosis was gradually created using a delicate screw occluder on the bypass tube until a 20% reduction in LAD area systolic thickening was achieved at a heart rate of 120 bpm, yet with no observable change in systolic thickening at 90 bpm. This degree of coronary stenosis occurred at mean coronary pressure of 49 ± 5 mm Hg. Radiolabeled microspheres were injected for myocardial blood flow measurement at heart rates of both 90 and 120 bpm, after which the same coronary stenosis and a heart rate of approximately 90 bpm were maintained for the next 4 h. In the 4-h ischemia group (n = 6), baseline hemodynamic data were recorded at heart rates of 90 (NSR) and 150 (atrial pacing) bpm. Coronary stenosis was gradually produced using the screw occluder until a 20% reduction in LAD area systolic wall thickening was observed at a heart rate of 150 bpm, with no change in systolic thickening at 90 bpm. This degree of stenosis occurred at mean coronary pressure of 59 ± 6 mm Hg. Radiolabeled microspheres were injected at heart rates of both 90 and 150 bpm, and the same coronary stenosis was maintained for an additional 4 h with atrial pacing of 150 bpm. In the 1-h ischemia group (n = 5), LAD coronary pressure was lowered to a level intermediate between the previous two groups (i.e., 54 ± 8 mm Hg). This group was treated the same as the 4-h ischemia group, except that ischemia at the paced heart rate of 150 bpm was maintained for only 1 h. At the end of the 1- to 4-h study period, a fourth bolus of radiolabeled microspheres was injected in all dogs. Distal coronary pressure was deliberately maintained lower in the control group, causing ischemia only at a heart rate of 120 bpm, compared with that in the 4-h ischemia group designed to cause ischemia only at 150 bpm. The reason was that the critical coronary pressure (at which myocardial function steeply declines) differs among dogs even at the same heart rate, with a standard deviation of 5–6 mm Hg, because of variations among dogs in coronary collateral flow, the site of coronary stenosis, and the amount of myocardium at risk. Maintaining the same coronary pressure in all dogs would have necessitated at least 10 times more dogs in each group just to ensure (with 
error of 0.05 and ß of 80%) that critical coronary pressure was the same in all groups.
At the end of the experiment, all dogs were killed and the area of LAD artery cannulation was examined. No coronary thrombosis was found at the cannulation site or elsewhere in the bypass tube. Hearts were excised and sectioned from base to apex into five 1- to 1.5-cm rings in a plane parallel to the atrioventricular groove. Rings were immersed in 1.0% triphenyl tetrazolium chloride (TTC) for 20 min at 37°C to identify infarcted tissue (19) and photographed. The rings were cut into 16 radial sections, and each section was further cut into epi-, mid-, and endocardial pieces. All pieces were weighed and counted using a 
-counter, and regional myocardial flow was calculated after appropriate correction for background counts. Infarct area was calculated by planimetry of the photographs by an examiner blinded to the grouping of the dogs. Infarcted mass was expressed both as a percentage of total left ventricular mass and as a percentage of area at risk. The area at risk was defined as the sum weight of all sections in which the endo/epicardial flow ratio was <50% of normal LCX area during stenosis and pacing (i.e., beginning of ischemia period).
Analysis of variance was used to compare means of variables among the groups. Intergroup differences in variables measured over time were analyzed by using analysis of variance for repeated measures and Duncan's post hoc test. A paired t-test was used to identify trends in time variables. The effect of variables on infarct area was tested by linear regression analysis. Data are presented as mean ± SD, and P < 0.05 determined statistical significance.
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Results |
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Baseline hemodynamic conditions were similar among the groups, and there were no significant changes in aortic, left ventricular end-diastolic, and coronary perfusion pressures during the 1- to 4-h study periods (Fig. 1). Heart rate was lower in the control group (88 ± 4 bpm) than in the other two groups (150 bpm) during the study periods. Coronary arterial pressure distal to the stenosis was lower, by intent, in the control group than in the 4-h ischemia group (49 ± 5 vs 59 ± 6 mm Hg; P = 0.02) but was not statistically different from the 1-h ischemia group (54 ± 8 mm Hg).
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LAD artery blood flow supplied through the bypass tube declined with the creation of stenosis but did not change significantly after atrial pacing and during the 1- to 4-h ischemia period. Blood flows were not statistically different among the groups either at baseline or after stenosis and during the ischemia period (Fig. 2). In four of the dogs (two controls, one of the 1-h ischemia and one of the 4-h ischemia dogs), blood flow measurement drifted during the experiment, yielding false mean flow data. Flow measurements of these dogs after the drift were excluded from the collective data, although their phasic blood flow recordings were used to indicate the patency of the artery and continuation of flow in it.
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Systolic wall thickening at the LAD artery territory declined within the first 15 min of tachycardia-induced ischemia in both the 1- and 4-h ischemia groups and remained significantly lower than that in the control group (P = 0.01) (Fig. 2). There was no significant change in LCX area systolic thickening during the study period in any of the groups.
Myocardial blood flow at the different stages of the experiment are displayed in Table 1. The calculated risk area was comparable in all groups: 23% ± 5%, 25% ± 4%, and 21% ± 4% of total left ventricular mass in the control, 4-h, and 1-h ischemia groups, respectively.
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Patchy, subendocardial myocardial infarction occurred in all 4-h ischemia dogs, in two (40%) of the 1-h ischemia dogs, and in the tip of the papillary muscle of one (16.6%) control dog (Table 2). Infarct size was significantly larger in the 4-h ischemia dogs than in either the 1-h ischemia or control animals (P = 0.002 and 0.005, respectively), ranging from 4% to 27% of calculated risk area.
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Relative, but not absolute, risk area endocardial blood flow was lower at the end of the study in both 4- and 1-h ischemia groups, compared with the control group (Table 1, Fig. 3). Infarct size was related to duration of tachycardia-induced ischemia (P = 0.005) and to relative endocardial flow at the end of the experiment, as measured by risk/nonrisk or by endo/epicardial flow ratio (P = 0.02 and 0.04, respectively). Absolute risk area endocardial blood flow at the end of the experiment had a borderline association with infarct size (P = 0.05).
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Discussion |
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Our data show that an increase of 66% in heart rate in dogs with fixed coronary stenosis, causing no ischemia at resting heart rate, produced severe loss of myocardial function within 15 min and a patchy subendocardial infarction in up to 27% of estimated risk area within 1–4 h. Subendocardial necrosis occurred in the 1- and 4-h ischemia groups, despite a higher coronary perfusion pressure than that in the control group. The extent of necrosis correlated with the duration of ischemia and was inversely related to subendocardial blood flow at the end of the ischemia period.
Myocardial blood flow, measured at four stages of the experiment, provides substantial insight into the mechanism of evolution of tachycardia-induced subendocardial infarction. Coronary clamping and cannulation was associated with an increase in myocardial blood flow above normal (relative risk/nonrisk flow > 1) in all myocardial layers (Table 1), probably because of a residual reactive hyperemia or some impairment in coronary autoregulation. Coronary stenosis caused LAD artery blood flow to decrease by 61% ± 12% (Fig. 2), with no impairment in regional wall thickening at baseline heart rate and a close to normal risk area myocardial blood flow (relative risk/nonrisk area myocardial blood flow \F 1) (Table 1). This normal myocardial blood flow, despite a significant decrease in LAD coronary flow, is explainable by the dogs' excellent coronary collateral circulation, which was particularly evident at slow heart rates (20). In pigs with sparse collateral circulation, both myocardial function and flow decline with much smaller decrements in coronary blood (21). At the beginning of pacing tachycardia with coronary stenosis, there was an increase in absolute, but not relative, epicardial blood flow and a decrease in relative, but not absolute, endocardial blood flow in the risk area in all groups. These changes reflect the combined effect of an increase in myocardial blood flow in areas with unrestricted coronary flow, caused by the tachycardia, and the inability of risk area subendocardial blood flow to increase due to the flow-limiting coronary stenosis. At the end of ischemia, there was a significant decrease in absolute as well as relative subendocardial flow in both the 1- and 4-h ischemia groups. Relative subendocardial blood flow at the end of ischemia in the 1- and 4-h ischemia groups was significantly lower than that in the control group (Table 1). Such a decrease in blood flow over time during ischemia has been previously described and attributed to the progressive coronary microvascular vasoconstriction that occurs with prolonged ischemia (22).
Patchy subendocardial fibrosis in patients with coronary artery disease without overt myocardial infarction has been recognized, yet its mechanism has never been clarified. Geft et al. (23) showed that repeated brief episodes of coronary occlusion may cause subendocardial necrosis in dogs. Others suggested that repeated episodes of demand-ischemia may lead to progressive subendocardial necrosis (8,9), although such a mechanism has never been validated clinically or experimentally (16). Our study provides the first experimental evidence that prolonged tachycardia-induced ischemia per se leads to progressive subendocardial necrosis.
The absolute risk area subendocardial blood flow at the end of 4 h of ischemia was 0.34 ± 0.1 mL · min-1 · g-1. In a previous study, a reduction of subendocardial blood flow to 0.36 ± 0.07 mL · min-1 · g-1 for 4 h in conscious dogs at resting heart rate resulted in almost complete functional recovery with minimal necrosis in the posterior papillary muscle 1 wk after reperfusion (24). Acute coronary occlusion causing myocardial infarction is typically associated with subendocardial blood flow reduction to <0.2 mL · min-1 · g-1 (25), whereas in experimental myocardial hibernation, subendocardial blood flow is most often >0.6 mL · min-1 · g-1 (10). Thus, subendocardial blood flow at the end of 1–4 h of ischemia in our study was higher compared with that found after coronary occlusion but lower than that in most experimental studies of myocardial hibernation.
Only three recent studies have challenged the limits of myocardial hibernation. One showed that a 41% reduction in coronary blood flow by fixed coronary stenosis in conscious pigs leads to subendocardial necrosis after 24 h of ischemia and 2 days of reperfusion (21). Two other studies examined the effects of increasing myocardial oxygen demand to the already hibernating myocardium. Ten minutes of rapid atrial pacing in swine with hibernating myocardium resulted in myocardial lactate accumulation and rapid hydrolysis of phosphocreatine (26), and intracoronary dobutamine infusion for a period of 85 min in pigs led to myocardial necrosis after 2 additional hours of reperfusion (27). Our study extends those previous observations by showing that prolonged tachycardia-induced ischemia may lead to subendocardial necrosis even in a myocardium that is normal and nonhibernating at a resting heart rate.
A strong line of evidence suggests that demand-ischemia and myocardial infarction are not entirely independent phenomena: circadian variations in heart rate and acute myocardial infarction are correlated (28). Increased heart rate is an independent predictor of both short-term and long-term survival (29), and ß-adrenergic blockers reduce mortality and reinfarction after myocardial infarction (30). Physical exertion triggers myocardial infarction within 24 h in sedentary patients (31), and postoperative myocardial infarction is often preceded by prolonged perioperative ischemia (2). Our study offers a possible pathogenic mechanism to the association between tachycardia-induced ischemia and myocardial injury.
Limitations of the experimental model include the use of general anesthesia, the open chest, and cannulation of the coronary artery, which impair coronary flow autoregulation, myocardial function, and myocardial sensitivity to ischemia. Although fentanyl-based anesthesia, as used in our experiments, has the least effect on coronary vasoreactivity and myocardial metabolism (32), coronary autoregulation was nevertheless affected by the cannulation in our dogs, as indicated by the higher than normal myocardial blood flow at baseline (risk/nonrisk area flow ratios >1) (Table 1). Another limitation was that the critical coronary pressure, below which myocardial thickening rapidly declines, is higher in anesthetized (approximately 70 mm Hg) than in conscious dogs (<40 mm Hg) (11). Thus, the autoregulatory and compensatory mechanisms that protect against subendocardial ischemia may be diminished. Coronary perfusion pressure was maintained, by design, significantly lower in the control group than in the 4-h ischemia group. This was possible because the critical coronary pressure is heart rate-dependent and is lower at slower heart rates. Otherwise, it would have been necessary to study many more dogs in each group just to prove with sufficient statistical power that there was no significant difference in critical coronary pressure among the groups. Finally, the myocardial risk area was defined as the area with endo/epicardial flow ratio of <50% during stenosis and pacing. We preferred this method over the myocardial staining method by injection of intracoronary dye at the end of the experiment, so as to avoid any possible interference of the dye with later TTC staining and impairment of accurate measurement of myocardial necrosis. This approach, however, could have introduced an error in our estimation of the actual risk area.
In summary, tachycardia-induced ischemia in the face of fixed coronary stenosis leads to patchy subendocardial necrosis within 1–4 h despite demonstrable continuous blood flow in the related artery and no coronary thrombosis. The cellular mechanisms determining myocardial hibernation versus necrosis under these circumstances of prolonged tachycardia-induced ischemia merit further investigation.
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