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Ann Thorac Surg 1998;65:1353-1359
© 1998 The Society of Thoracic Surgeons

Retrograde Infusion of Lidocaine or L-Arginine Before Reperfusion Reduces Myocardial Infarct Size

^a Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

Accepted for publication January 5, 1998.

Address reprint requests to Dr Gay, Division of Cardiothoracic Surgery, Washington University School of Medicine, One Barnes Hospital Plaza, 3108 Queeny Tower, St. Louis, MO 63110

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Retrograde perfusion preserves ischemic myocardium when initiated shortly after coronary artery occlusion. However, benefits diminish as the delay increases. In this study, we used this technique to deliver agents known to reduce the injury associated with the reperfusion of ischemic myocardium. We proposed that the local delivery of lidocaine or L-arginine before reperfusion would reduce the damage caused during reperfusion, even after a delay between onset of ischemia and intervention designed to approximate clinical reality.

Methods. In a porcine model of myocardial ischemia, the left anterior descending coronary artery was snared immediately distal to its second diagonal branch. After 1 hour of occlusion, 34 animals were randomized into six groups: no intervention (control) (n = 6); administration of normal saline solution into the great cardiac vein (Retro-NS) (n = 6); administration of lidocaine either intravenously (IV-LID) (n = 6) or retrograde (Retro-LID) (n = 6); and administration of L-arginine either intravenously (IV-L-ARG) (n = 5) or retrograde (Retro-L-ARG) (n = 5). After 90 minutes of ischemia, the snare was released, and the myocardium was reperfused for 3 hours. Two-dimensional echocardiograms were made prior to occlusion and 60, 150, 210, and 270 minutes after occlusion. The infarct size and the area at risk were determined by lissamine green and triphenyltetrazolium chloride staining with computer planimetric quantification. Regional wall motion was assessed by a wall motion score: normal = 1; mild hypokinesia = 2.0; severe hypokinesia = 2.5; and akinesia = 3.

Results. The area of the left ventricle at risk for infarction was similar in all groups and represented 25.4% (5.2% [standard deviation]) of the left ventricular mass (p = 0.63). The percent area of infarction in the area at risk after 3 hours of reperfusion was 76.7% (7.1% for the control group, 73.9% (5.7%) for the Retro-NS group, 72.1% (8.7%) for the IV-LID group, 54.5% (10.2%) for the Retro-LID group, 58.8% (4.0%) for the IV-L-ARG group, and 54.3% (4.0%) for the Retro-L-ARG group p < 0.005, Retro-LID and Retro-L-ARG versus Control, Retro-NS, and IV-LID; p < 0.03, IV-L-ARG versus control and Retro-NS). No significant difference in wall motion scores between groups was detected by echocardiography (p = 0.578).

Conclusions. Retrograde delivery of lidocaine or L-arginine before reperfusion reduces infarct size without acutely affecting wall motion after 90 minutes of ischemia and 3 hours of reperfusion. Lidocaine must be present before reperfusion to have an effect, whereas L-arginine is beneficial if it is delivered at the time of reperfusion.

	Introduction

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In cardiac surgery, retrograde myocardial perfusion is a well-established adjuvant to antegrade cardioplegia [1]. This technique enables a surgeon to deliver cardioplegia into tissue distal to an occluded coronary artery. The first use of the cardiac venous system to access ischemic myocardium can be traced to Claude Beck and precedes conventional coronary artery bypass surgery [2]. Although the conversion of the coronary sinus to an artery proved to be a suboptimal long-term solution for the treatment of myocardial ischemia, it did initiate investigation into the use of the coronary venous system as an avenue to the coronary microcirculation.

Subsequently, a substantial number of investigators have demonstrated the utility of retrograde venous perfusion during myocardial ischemia. In experimental models of coronary artery occlusion, immediate retrograde administration of both venous blood [13] and arterial blood [4] has decreased myocardial infarct size by either coronary sinus occlusion or perfusion synchronized with diastole. Recently, a simplified retroperfusion technique has resulted in a reduction in infarct size by delivering venous blood 60 minutes after arterial occlusion [5]. However, other investigators [6] have shown that myocardial preservation is minimal when therapy is delayed 1 hour after occlusion and is lost entirely after 2 hours of ischemia.

Ischemic damage represents only one component of myocardial injury after acute arterial occlusion. Additional injury often occurs after the myocardial circulation is restored [7]. This reperfusion injury may be due in part to neutrophil (PMN) oxygen radical production and migration into tissue initiated by PMN adhesion to the vascular endothelium [8]. A number of strategies have been shown to reduce reperfusion injury by the inhibition of the PMN–endothelial adhesion. Some, such as anti–intercellular adhesion molecule antibodies, which target endothelial adhesion molecules [9] and neutrophil depletion [10], currently have a limited application for clinical practice. Other substances, such as lidocaine hydrochloride and nitric oxide (NO), are already used safely in clinical practice for other applications.

Although its exact mechanism of action is unclear, lidocaine has been shown to inhibit neutrophil adherence in vitro [11] and in vivo [12]. Lidocaine also reduces infarct size [13] and protects the myocardium during ischemia [14]. L-Arginine is the amino acid substrate for the enzyme NO synthase in the production of NO. During reperfusion, NO release is decreased, and endothelium-dependent relaxation is impaired [7]. Intravenous administration of L-arginine during reperfusion has attenuated neutrophil accumulation, preserved endothelial function, and reduced infarction in ischemic tissue [15].

In this study, we attempted to limit the damage caused by reperfusion by administering lidocaine or L-arginine retrograde to the ischemic myocardium before antegrade reperfusion. Retrograde delivery during coronary artery occlusion allows a higher local concentration of drug in the tissue [16]. In addition, it provides the opportunity to deliver agents to the site of injury before reperfusion. Because we believe that 1 hour represents a reasonable interval between the onset of symptoms and clinical intervention, we performed no therapeutic interventions until 1 hour after occlusion in this study. We hypothesized that retrograde administration of these agents before reperfusion would protect the myocardium against some of the deleterious effects of reperfusion even after a clinically relevant delay.

	Material and methods

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General preparation
All animals received humane treatment in accordance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 86-23, revised 1985).

Fifty-five adult pigs (mean weight, 32 kg) were premedicated with ketamine hydrochloride (15 mg/kg), xylazine hydrochloride (2.2 mg/kg), atropine sulfate (0.05 mg/kg), and acepromazine maleate (0.2 mg/kg), and endotracheal intubation was performed. Ventilation with 98% oxygen and 2% halothane was accomplished with an Ohio positive-pressure ventilator. After an adequate plane of anesthesia was established, a neck dissection was performed. Catheters were placed into the tip of the right atrium through the internal jugular vein and into the thoracic aorta through the right carotid artery. This allowed fluid administration and continuous blood-pressure monitoring, respectively. Next, a median sternotomy was performed, and the pericardium was incised. The azygos and hemizygos veins were dissected and ligated.

The left anterior descending coronary artery (LAD) was carefully dissected from the epicardium immediately distal to its second diagonal branch, and a 2-0 silk ligature was passed beneath it. Two-dimensional epicardial echocardiography was performed using a short-axis projection. The blood pressure was recorded, and the LAD was occluded with a vascular snare.

To verify that the simplified retroperfusion technique [5] provided delivery to the venous endothelium, 5 animals were used for a preliminary study. In these animals, the coronary sinus was immediately cannulated through a right atrial pursestring suture with a catheter (fashioned from standard intravenous tubing) positioned at the orifice of the great cardiac vein. The catheter was connected to an Omni-Flow 4000 infusion pump, and 100 mL of triphenyltetrazolium chloride (Sigma Chemical, St. Louis, MO) was infused at a rate of 7 mL/min. After 30 minutes of incubation, the hearts were sectioned and examined.

Experimental protocol
After the preliminary study, 50 animals were assigned to the experimental protocol. After LAD ligation, 28 degenerated into ventricular fibrillation during the first 30 minutes of ischemia; 12 were successfully cardioverted with 20 J of direct current, but 16 were refractory to cardioversion and were excluded from the study.

After 1 hour of ischemia, the remaining 34 animals all received heparin sodium (300 IU/kg), and echocardiography was performed. The animals were then randomized into one of six groups (Fig 1). At this time, the animals that were to receive retrograde fluid administration underwent cannulation of the coronary sinus through a right atrial pursestring suture (Fig 2). The catheter (fashioned from standard intravenous tubing) was deaired, positioned at the level of the great cardiac vein, and connected to an Omni-Flow 4000 infusion pump and a pressure transducer. The six groups were as follows:

Control: Six animals received no further intervention during the 90 minutes of coronary artery occlusion.

Retrograde normal saline solution (Retro-NS): Six animals received infusion of 210 mL of normal saline solution at room temperature over 30 minutes at 7 mL/min into the great cardiac vein.

Intravenous lidocaine (IV-LID): Six animals received a right atrial bolus of lidocaine (2 mg/kg) in 210 mL of saline solution at room temperature over 30 minutes at 7 mL/min, which was followed by a continuous infusion of 0.04 mg · kg^-1 · min^-1 of lidocaine in 90 mL of normal saline solution at a rate of 30 mL/h.

Retrograde lidocaine (Retro-LID): Six animals received an infusion of lidocaine (2 mg/kg) in 210 mL of room-temperature normal saline solution into the great cardiac vein over 30 minutes at 7 mL/min, which was followed by a continuous right atrial infusion of 0.04 mg · kg^-1 · min^-1 of lidocaine in 90 mL of normal saline solution at a rate of 30 mL/h.

Intravenous L-arginine (IV-L-ARG): Five animals received a 30 mg/kg bolus of L-arginine into the right atrium followed by a continuous infusion of 10 mg · kg^-1 · min^-1 in 210 mL of room-temperature normal saline solution at a rate of 7 mL/min over 30 minutes.

Retrograde L-arginine (Retro-L-ARG): Five animals received a 30 mg/kg bolus of L-arginine followed by a continuous infusion of 10 mg · kg^-1 · min^-1 in 210 mL of room-temperature normal saline solution at a rate of 7 mL/min into the great cardiac vein over 30 minutes.

View larger version (26K): [in this window] [in a new window]   Fig 1. Experimental protocol at each time point (T). (D2 = second diagonal branch; IV-L-ARG = intravenous L-arginine; IV-LID = intravenous lidocaine; LAD = left anterior descending coronary artery; Retro-L-ARG = retrograde L-arginine; Retro-LID = retrograde lidocaine; Retro-NS = retrograde normal saline solution; TTC = triphenyltetrazolium chloride.)

View larger version (23K): [in this window] [in a new window]   Fig 2. The occlusion site (A) is immediately distal to the second diagonal branch of the left anterior descending coronary artery. The infusion catheter (B) is placed through the coronary sinus, and the tip is positioned at the orifice of the great cardiac vein.

Measurements and data analysis
Electrocardiographic leads were used to monitor heart rate during ischemia and reperfusion. Blood pressure was monitored by a Hewlett-Packard 1290A transducer (Andover, MA).

Two-dimensional echocardiographic recordings were obtained with a hand-held 7.5 MHz ultrasound transducer (Hewlett-Packard Sonos 100 ultrasound) applied to the epicardium. An echocardiographic short-axis image was obtained at the level of the papillary muscles. In the short axis projection, the left ventricular wall can be divided into six equal segments. The three segments supplied by the LAD (anterior-septal, anterior wall, and anterior-lateral) corresponded to the area at risk. For each of these three segments, the wall motion was graded qualitatively by a double-blinded, experienced echocardiographer (K.M.H.) using a numeric score: 1 = normal; 2 = mild hypokinesia; 2.5 = severe hypokinesia; and 3 = akinesia. The score for the three areas was averaged to provide a single score for each animal during each time interval.

The area at risk and the area of necrosis were determined by histochemical staining as previously described [17]. After the incubation period, the left ventricle was systematically divided into 5- to 10-mm cross-sectional slices, and each slice was weighed. The slices were photographed using 35-mm slide film. After the images had been developed, they were scanned into digital images and blindly analyzed with software designed by our laboratory. With reperfusion of the ischemic myocardium, there is a washout from the nonviable cells of dehydrogenases necessary to reduce nitro blue tetrazolium, and these areas remain pale [18]. This stain fails to work in tissue exposed to formalin, thus allowing a clear demarcation of both the areas at risk and the areas of infarction. These areas are determined for each slice, and each area is adjusted for the weight of the slice to calculate the mass of the left ventricle at risk and the mass of the infarct in the area at risk.

Statistical methods
Data are presented as the mean with the standard deviation in parentheses. Statistical evaluation between groups was performed by an analysis of variance and a Tukey a posteriori test of significance, or a repeated-measures analysis of variance. Differences were considered significant at a p value of less than 0.05.

	Results

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Preliminary experiment
In the 5 animals that received retrograde infusion of triphenyltetrazolium chloride, the epicardium distal to the occlusion site demonstrated staining in the occluded region. On sectioning, the endothelium of the entire great cardiac vein also was stained, indicating that the infused stain reached the venous system of the ischemic myocardium.

Lidocaine and -arginine experiment
The mean blood pressure was similar in all groups (p = 0.61). However, there was a significant decline in mean blood pressure in all groups over time (p < 0.001) (Table 1). The area of left ventricle at risk for infarction measured as a percentage of left ventricular mass was also similar in all groups (p = 0.631) and represented 25.4% (5.2%) of the left ventricular mass (Fig 3). The area of necrosis after 3 hours’ reperfusion, presented as a percentage of the area of the left ventricle at risk for infarction, was significantly lower in the Retro-LID and Retro-L-ARG groups compared with the control, Retro-NS, and IV-LID groups (p < 0.005), with a reduction of 25% to 30% (Fig 4). The area of necrosis was significantly lower in the IV-L-ARG group compared with the control and Retro-NS groups (p < 0.03), with a reduction of 20% to 23%. When the IV-L-ARG group was compared with the IV-LID group, although there was an 18% reduction in infarction size, this did not reach significance (p = 0.055). There was no significant difference between the 12 animals who underwent cardioversion during the ischemic interval and the animals within the same treatment groups.

View larger version (19K): [in this window] [in a new window]   Fig 3. Comparison of left ventricular (LV) area at risk (presented as a percentage of LV mass) between treatment groups. All groups were similar (p = 0.631). The error bar represents one standard deviation. See Figure 1 for group definitions.

View larger version (14K): [in this window] [in a new window]   Fig 4. Comparison of area of necrosis (presented as percentage of left ventricular mass) between experimental groups. The error bar represents one standard deviation. The broken line represents 75% necrosis in the area at risk, the mean of the control, Retro-NS, and IV-LID groups. (diamond = p < 0.005 versus control, Retro-NS, and IV-LID groups; asterisk = p < 0.03 versus control and Retro-NS only; see Fig 1 for group definitions.)

View larger version (18K): [in this window] [in a new window]   Fig 5. Comparison of mean coronary sinus (C.S.) pressure (millimeters of mercury) at baseline and during retrograde infusion between treatment groups and all groups receiving retrograde perfusion. The error bar represents one standard deviation. There was no significant difference between groups (p = 0.620), but there was a difference before and during infusion in all groups (p < 0.001). See Figure 1 for group definitions.

	Comment

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The results of this study suggest that both lidocaine and L-arginine reduce myocardial infarct size by 25% to 30% after a 90-minute ischemic insult without acutely affecting regional ventricular wall motion.

At clinically therapeutic levels, lidocaine can reduce reperfusion damage only if it is delivered to the ischemic myocardium before reperfusion or at local tissue concentrations that cannot be safely achieved intravenously. Intravenous lidocaine had no effect on infarct size, a finding suggesting that the primary site of its action is the local endothelium rather than the circulating PMNs. Lidocaine is known to inhibit both fast-sodium and slow-calcium channels [19]. An increase in free cytosolic calcium in endothelial cells is an important signaling event in leukocyte-endothelial adhesion [20]. In addition, in activated endothelial cells, free cytosolic calcium increase has a regulatory function on vascular permeability [21] and on PMN adhesion and migration [22]. Lidocaine may be effective in endothelial cells by inhibiting signals of activation, but the exact mechanism of its action remains unclear.

Both intravenous and retrograde L-arginine administration reduce myocardial damage after reperfusion. Because there was no significant difference between the IV-L-ARG and Retro-L-ARG groups, the data suggest that the benefits of L-arginine occur primarily at the time of reperfusion or at concentrations that can be achieved intravenously without deleterious effects. Endothelial dysfunction associated with reperfusion injury is characterized by a markedly decreased release of NO in response to endothelium-dependent vasodilators [15]. In the vascular system, the biosynthesis of NO by endothelial cells produces relaxation of vessels, inhibition of platelet aggregation [23], and attenuation of neutrophil adherence [24]. During reperfusion, NO supplementation by direct donors and precursors (L-arginine) preserves endothelial function and decreases myocardial injury [15]. Although the exact cardioprotective mechanisms of L-arginine are not known with certainty, it seems unlikely that the primary mechanism is coronary vasodilation [15].

The echocardiographic data show that the ischemic injury caused a severe depression of regional wall motion, which worsened on reperfusion. None of the tested interventions resulted in an improvement in regional wall motion. This finding is consistent with previous work [5] and suggests that despite significant differences in histochemical viability, these agents do not attenuate regional postischemic left ventricular dysfunction during the acute reperfusion period. However, the techniques used to evaluate function may have been insufficiently sensitive to demonstrate a difference. Alternatively, the reperfusion interval may have been too short to demonstrate a benefit.

The strength of this study lies in the model’s simulation of a clinical event. A porcine model was selected because of the similarities between the coronary circulation of the pig and that of humans [25]. Because the pig can tolerate only a moderate ischemic insult without significant hemodynamic deterioration, the LAD was ligated distal to its second diagonal branch, resulting in an ischemic area of 25.4% (5.2%) of the left ventricular mass. This area was similar in all experimental groups.

A delay to intervention corresponding to the earliest treatment time in a clinical setting of coronary artery occlusion was chosen to provide clinical relevance. In addition, no agents other than the ones mentioned were administered. In contrast, most models of coronary occlusion administer lidocaine and heparin to all animals prior to coronary artery occlusion [3–6, 13, 14]. In addition, in most prior studies, the retrograde catheters were placed before the coronary artery was occluded [3–6]. Catheter placement alone may elevate coronary sinus pressures and exert a beneficial effect during myocardial ischemia. Further, the results in the lidocaine groups may explain some of the benefit shown by previous studies that delivered retrograde blood containing lidocaine to ischemic myocardium prior to reperfusion.

The main limitation of this study is the lack of direct evidence that local delivery of lidocaine and L-arginine was achieved. However, our success at achieving local delivery is supported by two indirect findings. First, the preliminary studies clearly showed that this technique was effective at delivering triphenyltetrazolium chloride to the venous endothelium. Second, the serum lidocaine levels after the bolus administration were significantly lower in the group with retrograde delivery compared with the group with right atrial delivery. Three hours after reperfusion, the lidocaine levels in both groups were similar. This suggests that the lidocaine delivered retrograde accumulated in the myocardium during ischemia. Because we believe that direct tissue biopsy of the ischemic area would have compromised the evaluation of infarct size, we chose to accept the indirect findings.

From these results, we conclude that the retrograde administration of agents that reduce reperfusion injury before reestablishment of antegrade flow has a beneficial effect on myocardial tissue even after major ischemic insults. We believe that this may have direct clinical application in situations of acute coronary artery occlusion. Retrograde administration of lidocaine or L-arginine before revascularization through coronary artery bypass grafting, angioplasty, or thrombolysis may attenuate the damage caused by reperfusion. Further investigation is warranted.

	Acknowledgments

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This work was supported in part by grant 5T32HL07776 from the National Institutes of Health and by a grant from the AMA-ERF.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Richard Lee Takashi Nitta Ralph A. Schmid William A. Gay, Jr Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, R. Articles by Gay, W. A. Search for Related Content PubMed PubMed Citation Articles by Lee, R. Articles by Gay, W. A., Jr