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© 1999 International Anesthesia Research Society
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Abstract |
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Atrial natriuretic peptide (ANP) exerts a dilatory effect on coronary arteries in humans. We investigated the effects of ANP on pacing-induced myocardial ischemia during enflurane anesthesia in patients with coronary artery disease (CAD). In 20 patients with CAD, myocardial ischemia was induced by atrial pacing before and after an iv infusion of ANP (50 mg · kg-1 · min-1, n = 10) or placebo (n = 10). We studied the effects of ANP or placebo on pacing-induced changes in central hemodynamics, myocardial blood flow and regional myocardial indices of lactate uptake (RMLU), and oxygen consumption (RMVO2) and extraction (RMO2E). ST-segment depression was less pronounced during pacing with ANP compared with control pacing (-0.09 ± 0.01 vs -0.24 ± 0.02 mV; P < 0.001). RMLU decreased to -11.1 µmol/min during control pacing compared with -0.7 µmol/min during pacing with ANP (P < 0.01). ANP did not affect pacing-induced changes in RMVO2, RMO2E, or the rate pressure product. Placebo did not affect pacing-induced changes in ST-segment depression or RMLU. In conclusion, ANP attenuates ischemic ST-segment depression and lactate release during pacing-induced myocardial ischemia in patients with CAD. The antiischemic effect of ANP was not accompanied by any improvement in the regional myocardial oxygen supply/demand relationship.
Implications: We evaluated the effects of IV atrial natriuretic peptide (50 ng · kg-1 · min-1) on pacing-induced myocardial ischemia during general anesthesia in patients with coronary artery disease. In contrast to placebo, atrial natriuretic peptide attenuated ST-segment depression and myocardial lactate production and improved left ventricular function during pacing-induced ischemia.
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Introduction |
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Atrial natriuretic peptide (human ANP 99-126) is an endogenous diuretic and natriuretic hormone released from the cardiac atria in response to atrial stretch and plays an important role in the regulation of body fluid homeostasis (1,2). ANP is also a potent vasodilatory substance and induces systemic vasodilation both in normal subjects and in patients with heart failure or hypertension (3,4).
A number of studies have focused on the effects of ANP on the intact coronary vasculature in humans. Rapoport et al. (5) demonstrated that ANP causes an endothelium-dependent dilation of human coronary arteries. Herrmann et al. (6) studied the effects of an IV infusion of ANP on coronary and central hemodynamics in patients with heart failure. No changes in coronary blood flow or myocardial oxygen extraction were seen, which indicates that ANP did not exert a direct effect on the coronary vascular resistance vessels. Rosenthal et al. (7) studied the coronary hemodynamic effects of intracoronary infusion of ANP in patients with coronary artery disease (CAD) and concluded that ANP exerts its vasodilatory effect mainly on large epicardial coronary arteries, rather than on coronary resistance vessels. Chu et al. (8) showed that left ventricular bolus injections of ANP caused a sustained dilation of proximal coronary arteries in patients with CAD. This increase in the epicardial coronary artery diameter was also confirmed by Herrmann et al. (9) and Egashira et al. (10) after intracoronary and IV infusions of ANP in normal subjects.
In a dose-response study, we demonstrated that ANP at an infusion rate of 50 ng · kg-1 · min-1 improved myocardial lactate metabolism after coronary artery bypass surgery (11). In the present study, we tested the hypothesis that an identical dose of ANP exerts antiischemic effects during general anesthesia in patients with CAD. We assessed the effects of ANP on pacing-induced myocardial ischemia by analyzing the changes in the ST segment, myocardial lactate production, and central hemodynamic variables.
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Methods |
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The study protocol was approved by the Human Ethics Committee of the University of Göteborg. Twenty-five patients (5 women and 20 men) with a mean (range) age of 70 (53–77) yr, scheduled for coronary artery bypass grafting surgery were included after giving their informed consent. The patients were randomized to receive either ANP or placebo during the experimental procedure. All patients had a history of stable angina pectoris with two or three vessel coronary artery disease, including the left anterior descending artery, and an ejection fraction >0.5. ST-segment depression (
0.1 mV) was seen in leads V2–V6 in all patients during a preoperative standardized exercise stress test. All patients received their ß-adrenergic receptor blocking drugs on the morning of surgery. No patient received other antianginal medication within 12 hours before the study. The two groups were comparable with respect to age, gender, coronary anatomy, number of previous myocardial infarctions, left ventricular ejection fraction, and cardiac medication. The experimental procedure was performed after the induction of anesthesia but before surgery. Premedication consisted of flunitrazepam (1 mg PO), morphine (0.1 mg/kg IM), and scopolamine (0.4 mg IM). Anesthesia was induced with thiopental (2–5 mg/kg IV) and fentanyl (2–3 µg/kg IV), followed by pancuronium (0.1 mg/kg IV). The patients were ventilated to normocapnia with a mixture of oxygen and air (fraction of inspired oxygen 0.4), and anesthesia was maintained throughout the experimental procedure with enflurane at an inspiratory concentration of 1%. The experimental procedure prolonged general anesthesia by approximately 2–3 h.
Before the study, femoral and pulmonary artery catheters were inserted for continuous monitoring of systemic and pulmonary arterial pressures and for blood sampling. A pacing coronary sinus catheter with four thermistors was inserted via the right internal jugular vein, using the Seldinger technique, under fluoroscopic guidance and continuous pressure monitoring, and placed with its distal mixing thermistor in the great cardiac vein (GCV). The appropriate position of the coronary sinus catheter was confirmed by the injection of 5 mL of contrast medium and by rapid central venous injection of cold saline during continuous flow recording. Blood was sampled from the GCV, and the GCV flow (GCVF) and the coronary sinus flow (CSF) were determined in all patients.
Systolic (SAP), diastolic, and mean (MAP) arterial pressures were measured throughout the study, together with mean pulmonary arterial and central venous pressure. Pulmonary capillary wedge pressure (PCWP) was measured intermittently during the experimental procedure. The ST segment was monitored by a 12-lead electrocardiogram (ECG) sampled every 30 s using a computer-assisted system (Mac 15; Marquette Electronics Inc., Milwaukee, WI). The ST-segment trend of all leads was recorded continuously. The criterion for significant ST-segment depression was horizontal or downward-sloping depression of >0.1 mV 0.06 s after the J point in more than two leads. Blood samples for lactate and O2 content measurements were drawn simultaneously from the GCV and the femoral artery. Blood oxygen saturation was determined by using a photometric method (OSM 2 Hemoximeter; Radiometer, Copenhagen, Denmark), and lactate concentration was determined by using an enzymatic method (YSI 2300 STAT PLUS; YSI Inc., Yellow Springs, OH). Blood withdrawn from the GCV represents left anterior descending artery perfusion, as this area is drained by the GCV. Cardiac output (CO) was determined in triplicate using the thermodilution technique. GCVF and total coronary sinus flow (CSF) were determined by using the retrograde thermodilution technique originally described by Ganz et al. (12) and modified by Pepine et al. (13). Room-temperature isotonic sodium chloride solution was used as an indicator and was infused at a rate of 40 mL/min over approximately 20 s for each measurement. Changes in thermistor resistance due to temperature changes were measured by using a Wheatstone bridge.
Cardiac index (CI), stroke volume index (SVI), systemic (SVRI) and pulmonary vascular resistance indices, and regional myocardial oxygen consumption (RMVO2) and extraction (RMO2E) were calculated using standard formula. Regional myocardial lactate extraction (RMLE) and uptake (RMLU) were calculated using the following formulae: RMLE (%) = (arterial concentration of lactate - GCV concentration of lactate)/arterial concentration of lactate x 100; RMLU (µmol/min) = (arterial concentration of lactate - GCV concentration of lactate) x GCVF.
Blood samples for the analysis of immunoreactive ANP (IrANP) in plasma were obtained from the femoral artery before and 15 min after the start of the ANP infusion. Blood samples were collected in prechilled glass tubes containing Na2-EDTA. Each sample was immediately centrifuged at 4°C and stored at -70°C until analysis. Radioimmunoassay was performed after extraction to measure plasma levels of IrANP (Shiono RIA assay kit; Shionogi Co., Ltd., Osaka, Japan), as previously described by Yoshibayashi et al. (14).
Figure 1 summarizes the design of the study. Approximately 40 min after the induction of anesthesia, baseline measurements of central and coronary hemodynamics, blood samples, and ECG recordings were obtained at a pacing frequency of 50–60 bpm, i.e., 3–5 bpm faster than the patient's spontaneous heart rate (I). The pacing rate was then increased by 10 beats every other minute, until the ST segment of at least two leads became depressed by more than 0.1 mV (control pacing; A). Measurements and blood sampling were then repeated (II), and the heart rate was decreased to the baseline pacing level. After a recovery period of 50–70 min, the patients were randomized to receive ANP or placebo. New baseline measurements (III) were performed, followed by the start of ANP or placebo infusion. ANP was infused at a rate of 50 ng · kg-1 · min-1. Fifteen minutes after the start of the ANP or placebo infusion, baseline measurements were performed (IV), followed by the same pacing procedure as described above (ANP/placebo pacing; B). Measurements and blood sampling were performed (V) at an identical pacing rate in the same way as during control pacing. In eight ANP patients, the pacing rate was further increased by approximately 10 bpm during the ANP infusion (ANP pacing + 10 bpm;C), followed by final measurements of hemodynamics and blood sampling (VI). If the patient developed signs of left ventricular failure during pacing, i.e., a decrease in MAP <65 mm Hg and/or an increase in PCWP to >20 mm Hg or third-degree heart block, pacing was stopped. Evaluation of the various variables obtained during the experimental procedure was performed in a blinded fashion.
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All results are given as mean ± SEM. The effects of ANP or placebo on hemodynamics during pacing and on the ECG and metabolic signs of pacing-induced myocardial ischemia were analyzed using a hierarchic one-way analysis of variance for repeated measurements with pacing procedure as the lower level and control versus ANP/placebo as the higher level. The differential effect of control pacing compared with pacing with ANP or placebo was evaluated using the analysis of variance interaction (15) (A vs B and A vs C) (Figure 1). The effects of ANP on baseline hemodynamics and metabolic variables (III vs IV) were tested using a paired Student's t-test. A P value <0.05 was considered to be statistically significant.
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Results |
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Three patients in the ANP group and two in the placebo group were excluded because they developed nonischemic third-degree heart block during control pacing (A). Data on systemic and pulmonary hemodynamics during atrial pacing without and with ANP (n = 10) infusion are shown in Table 1. Data on coronary hemodynamics and myocardial metabolism during atrial pacing with and without ANP are shown in Table 2 and Figure 2. The effects of placebo (n = 10) on pacing-induced myocardial ischemia are shown in Figure 3.
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ANP induced a 15% decrease in MAP and a 30% decrease in SVRI. This was accompanied by a 20% increase in CI and SVI. ANP caused no changes in cardiac filling pressures, heart rate, or pulmonary arterial pressures. Because of the decrease in SAP, ANP significantly reduced the rate pressure product (RPP). Global (CSF) and regional (GCVF) myocardial blood flow were not affected by ANP. Furthermore, ANP caused no changes in RMVO2 or RMO2E and no changes in RMLU or RMLE.
During control pacing (A), the ST segment was depressed by more than 0.1 mV, and myocardial lactate production was seen in all patients (Figure 2). During control pacing, the mean ST-segment depression was -0.24 ± 0.02 mV. During ANP pacing (B), the ST-segment depression was attenuated (-0.09 ± 0.01 mV; P < 0.001) compared with control pacing. In the subgroup of eight patients in which the paced heart rate was further increased by approximately 10 bpm during the ANP infusion, the ST-segment depression was -0.11 ± 0.01 mV (P < 0.01 compared with control pacing).
During control pacing, PCWP increased, which was not seen during ANP pacing (P < 0.05). No other changes in systemic and pulmonary hemodynamic variable during ANP pacing were seen compared with control pacing. The pronounced decrease in RMLU and RMLE seen during control pacing was attenuated during ANP pacing (P < 0.001) (Figure 2 and Table 2). No other changes in myocardial circulatory and metabolic variables during ANP pacing were found compared with control pacing. In the subgroup of eight patients in which the pacing rate was further increased by approximately 10 bpm during ANP infusion, RMLU and RMLE were attenuated compared with control pacing (P < 0.01 and P < 0.001, respectively).
ST-segment depression was -0.24 ± 0.02 and -0.25 ± 0.02 mV during control pacing and placebo pacing, respectively (no significant difference). RMLE was 10.1% ± 3.0% at baseline and -7.6% ± 2.9% during control pacing. RMLE returned to 7.5% ± 3.1% (new baseline) and was -9.8% ± 2.6% during placebo pacing (no significant difference) (Figure 3). RMLU was 6.6 ± 1.6 µmol/min at baseline and -8.8 ± 3.9 µmol/min during control pacing. Similarly, RMLU was 4.8 ± 1.5 µmol/min after return to baseline and -8.9 ± 3.5 µmol/min during placebo pacing (no significant difference). PCWP was 11 ± 1 and 13 ± 1 mmHg during control pacing and placebo pacing, respectively. The other systemic and pulmonary hemodynamic variables during the control pacing and placebo pacing were not significantly different.
The baseline values of IrANP before the ANP infusion was 41 ± 7 pg/mL. Fifteen minutes after the start of the ANP infusion, the IrANP had increased to 1532 ± 116 pg/mL.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, we evaluated the possible antiischemic effects of ANP during general anesthesia in patients with CAD. The main findings were that ANP infusion at a rate of 50 ng · kg-1 · min-1 significantly attenuated pacing-induced ST-segment depression, regional myocardial lactate production, and PCWP increase. Our data are consistent with those of a previous study by Lai et al. (16), which demonstrated that an ANP infusion (100 ng · kg-1 · min-1) attenuated exercise-induced ischemic ST-segment depression in 12 patients with CAD. In seven of these patients, they were also able to show that the extent and severity of myocardial perfusion defects assessed by 201TI-SPECT were decreased by the ANP infusion. However, the authors did not measure central hemodynamics, myocardial blood flow or metabolism, or any functional correlates to the antiischemic effect of ANP during stress-induced myocardial ischemia.
Under baseline conditions, without pacing, ANP caused systemic vasodilation as previously described by several authors (6,17). Previous investigators have shown that ANP decreases cardiac filling pressures in humans (6,18), a finding that we could not confirm in the present study. The combination of a decrease in SVRI and maintained cardiac filling pressures may explain why CO and stroke volume significantly increased in the present study. We previously described the same hemodynamic response to ANP infusion, at an identical infusion rate, in a study in which ANP was used as a vasodilator soon after coronary artery bypass surgery (17). In the present study, the increase in PCWP seen during control pacing was attenuated during ANP pacing, which could be explained by the antiischemic effect of ANP, with a consequent improvement in left ventricular function or by systemic vasodilation. Ukai et al. (18) studied the effect of IV ANP on exercise-induced acute left ventricular dysfunction in patients with CAD. They found that ANP at an infusion rate of 50 ng · kg-1 · min-1 displaced the left ventricular function curve to the left during exercise. This finding was attributed mainly to a preload reduction and, to some extent, to the decrease in afterload. These authors did not present data on the possible antiischemic effects of ANP during exercise.
What are the mechanisms behind the antiischemic effects of ANP during cardiac pacing? Both RPP and RMVO2 were lower during ANP pacing compared with control pacing, which could be explained by the somewhat lower arterial blood pressure during ANP pacing. We therefore increased the pacing frequency in eight patients by approximately 10 bpm to further increase RPP and RMVO2 to or above the levels seen during control pacing. Despite this increase in RPP and RMVO2, the ST-segment depression and the myocardial lactate production were still significantly lower compared with control pacing. It is therefore unlikely that the antiischemic effect of ANP during cardiac pacing can be explained by a reduction in myocardial oxygen demand.
Myocardial blood flow was maintained during the ANP infusion under baseline conditions, without pacing, despite the decrease in coronary perfusion pressure, which is probably explained by a coronary autoregulatory response to the decrease in coronary perfusion pressure, rather than by a direct effect of ANP on coronary vascular resistance vessels. If ANP had induced a direct dilatory effect on coronary resistance vessels, one would have expected a decrease in RMVO2E, which was not seen in the present study. The same myocardial circulatory and metabolic response to ANP observed in the present study was also described by Herrman et al. (6). The infusion of ANP did not change the intercoronary distribution of flow, as reflected by the GCVF/CSF ratio. One possible explanation for the antiischemic effects of ANP could therefore be a favorable transmural redistribution of blood flow, which cannot be detected by using the retrograde coronary sinus thermodilution technique. A study by Chu et al. (19) in conscious dogs demonstrated that ANP favorably redistributes blood flow to the subendocardium and reduces subendocardial ischemia after transient coronary occlusion in the presence of a flow-limiting coronary stenosis.
The beneficial antiischemic effects of ANP seen during the second pacing procedure may not have been caused by ANP, but rather by ischemic preconditioning. However, several studies have shown that pacing-induced ischemic preconditioning does not occur if the duration of the recovery period between the two pacing procedures is >20 min (20–22). In the present study, the recovery period between the two pacing procedures was 50–70 min in each patient. Finally, in the present study, pacing with placebo had no effect on ECG or metabolic indices of myocardial ischemia compared with control pacing (Figure 3), which indicates that the attenuation of myocardial ischemia seen during ANP pacing was caused by ANP itself, not by ischemic preconditioning.
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Acknowledgments |
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This study was supported by grants from the Swedish Medical Research Council (8682 and 8642), the Gothenburg Medical Association, the Sahlgrenska Hospital Foundation, and the Gothenburg Medical Faculty (LUA).
The assistance of the staff of the Departments of Cardiothoracic Anesthesia and Cardiothoracic Surgery and the technical assistance of Maud Petterson and Marita Ahlqvist are gratefully acknowledged.
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Footnotes |
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This study was presented in part at the 23rd Congress of the Scandinavian Society of Anaesthesiologists, Reykjavik, Iceland, June 1995.
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References |
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