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*Department of Anesthesiology and Critical Care Medicine, Hebrew University-Hadassah Hospital, Jerusalem, Israel; and
Department of Medicine, Division of Cardiology, Johns Hopkins Hospital, Baltimore, Maryland
Address correspondence and reprint requests to Giora Landesberg, MD, DSc, Department of Anesthesiology and C. C. M., Hebrew University-Hadassah Hospital, Ein-Kerem, Jerusalem, Israel 91120. Address e-mail to gio{at}cc.huji.ac.il
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Abstract |
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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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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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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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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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Discussion |
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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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This article has been cited by other articles:
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  H.-J. Priebe Triggers of perioperative myocardial ischaemia and infarction Br. J. Anaesth., July 1, 2004; 93(1): 9 - 20. [Abstract] [Full Text] [PDF]
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 G. Landesberg, M. Mosseri, D. Zahger, Y. Wolf, M. Perouansky, H. Anner, B. Drenger, Y. Hasin, Y. Berlatzky, and C. Weissman Myocardial infarction after vascular surgery: the role of prolonged, stress-induced, ST depression-type ischemia J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1839 - 1845. [Abstract] [Full Text] [PDF]
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