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Ann Thorac Surg 1998;66:487-492
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Beneficial effects of angiotensin-converting enzyme inhibitors during acute revascularization

^a Department of Cardiothoracic Surgery, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA
^b Section of Cardiology, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA

Accepted for publication March 28, 1998.

Address reprint requests to Dr Lazar, Department of Cardiothoracic Surgery, Boston Medical Center, B402, 88 E Newton St, Boston, MA 02118

Presented at the Eighty-third Annual Clinical Congress of the American College of Surgeons, Chicago, Illinois, Oct 12–17, 1997.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. This experimental study was undertaken to determine whether using angiotensin-converting enzyme inhibitors during surgical revascularization of acutely ischemic myocardium would improve wall motion and limit infarct size.

Methods. Twenty pigs underwent 90 minutes of occlusion of the second and third diagonal arteries followed by 45 minutes of cardioplegic arrest and 180 minutes of reperfusion. In 10 animals, the angiotensin-converting enzyme inhibitor enalaprilat (0.05 mg/kg) was infused intravenously during coronary occlusion; 10 other animals received no angiotensin-converting enzyme inhibitors. Ischemic damage was assessed by the number of cardioversions required for ventricular tachycardia or fibrillation; wall motion scores using echocardiography (4 = normal to -1 = dyskinesia); and infarct size using histochemical staining. Epicardial coronary artery vasomotor function was assessed using standard organ chamber methodology.

Results. Enalaprilat-treated hearts had the least amount of ventricular irritability (0.84 ± 0.24 versus 2.77 ± 0.22 cardioversions; p < 0.01), the best recovery of wall motion score (3.20 ± 0.15 versus 1.52 ± 0.07; p < 0.0001), and the lowest infarct size (22.6% ± 1.4% versus 37.7% ± 3.0%; p < 0.001). Endothelium-independent relaxation was preserved in all hearts; however, endothelium-dependent relaxation was impaired in both groups.

Conclusions. Angiotensin-converting enzyme inhibitors reduce myocardial damage during surgical revascularization of acutely ischemic myocardium.

	Introduction

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Clinical studies have shown that treatment with angiotensin-converting enzyme (ACE) inhibitors after an acute myocardial infarction improves ventricular function and prolongs survival [1–4]. Angiotensin-converting enzyme inhibitors have also been shown to decrease infarct size in animal models after periods of ischemia and reperfusion [5–7]. In isolated heart preparations involving cardioplegic arrest, ACE inhibitors were also found to improve ventricular function after periods of global ischemia [8, 9].

The mechanism for the beneficial effects of ACE inhibitors during periods of acute ischemia and reperfusion are still unknown. Several lines of evidence suggest that ACE inhibitors have favorable effects on endothelial vasomotor function [10, 11]. This effect may be mediated in part through the reduced metabolism of bradykinin by ACE or through decreased production of vasoconstrictor substances by the endothelium [10]. There is growing evidence to suggest that angiotensin II contributes to vascular oxidative stress by producing superoxide anions in vascular smooth muscle cells by reduced nicotinamide-adenine dinucleotide phosphate (NADPH) and nicotinamide-adenine dinucleotide oxidase [12]. This may lead to impaired vasomotor function of the coronary epicardial and microvascular endothelium, which contributes to tissue ischemia and infarction during the surgical revascularization of acutely ischemic myocardium.

Despite these beneficial properties of ACE inhibitors, their role during the surgical revascularization of acutely ischemic myocardium is still unknown. We therefore undertook this experimental study to investigate the acute effects of an intravenously active ACE inhibitor, enalaprilat, on vascular and myocardial preservation in a porcine model of ischemia–reperfusion simulating conditions of urgent coronary artery bypass grafting.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Randomization
Twenty-four pigs were entered into the study. Animals were excluded because of hypotension after induction of anesthesia (1), pneumonia (2), and pericarditis (1). An enalaprilat-containing or non–enalaprilat-containing saline solution was prepared in the pharmacy and delivered to the laboratory in unlabeled infusion bags. The investigators were blinded as to the content of each infusion.

Preparation
Twenty adult pigs (35 to 37 kg) were premedicated with intramuscular ketamine (15 mg/kg) and acepromazine (0.5 mg/kg), anesthetized with -chloralose (75 mg/kg), and placed on positive-pressure endotracheal ventilation. After a median sternotomy, catheters were placed into the right femoral artery and vein for monitoring systemic pressure and administering fluids. The azygos vein was ligated to prevent retrograde flow from the coronary sinus during the administration of retrograde cardioplegia. After systemic heparinization (3 mg/kg), the second and third diagonal branches just distal to the takeoff of the left anterior descending coronary artery were occluded with snares for 90 minutes. Intravenous lidocaine was used to treat ventricular arrhythmias. Electrical cardioversion was used to treat sustained ventricular tachycardia or ventricular fibrillation. After the 90-minute period of coronary occlusion, animals were placed on total cardiopulmonary bypass with a no. 20 cannula in the left femoral artery and a no. 36 venous catheter in the right atrium. A catheter was inserted into the left atrium to infuse volume so that left ventricular end-diastolic pressure (LVEDP) and volume could be varied. During cardiopulmonary bypass, mean arterial pressure (MAP) ranged from 65 to 75 mm Hg, and pump flow was kept at 80 mL · kg^-1 · min^-1. The hematocrit averaged 27% ± 2% and pH was maintained at 7.43 ± 0.05.

After institution of cardiopulmonary bypass, all hearts underwent 45 minutes of cardioplegic arrest with multidose antegrade and retrograde cold blood cardioplegia (K⁺ = 25 mEq/L; hematocrit = 20%; pH = 7.6; temperature = 4°C) supplemented with topical hypothermia. An initial arresting dose (10 mL/kg) was followed by additional doses (5 mL/kg) every 20 minutes. Half of each dose was given antegrade through a catheter inserted into the ascending aorta and the other half through a catheter positioned into the coronary sinus through a pursestring suture in the right atrium. After the period of cardioplegic arrest, the cross-clamp was removed, the coronary snares were released, and all hearts were reperfused for 180 minutes on cardiopulmonary bypass at 37°C.

Experimental groups
During the 90-minute period of coronary occlusion, the animals were divided into two groups.

Enalaprilat group
In 10 animals, the ACE inhibitor enalaprilat (0.05 mg/kg) was intravenously infused for 30 minutes during the period of coronary occlusion. The infusion was started 5 minutes after the coronary vessels were snared.

Nonenalaprilat group
In 10 animals, no enalaprilat was given. Instead, these animals received a saline infusion for 30 minutes during the period of coronary occlusion.

Measurements and data analysis
Electrocardiographic leads were placed to measure heart rate and to monitor electrical activity during arrest. Left ventricular end-diastolic pressure was recorded with a piezoelectric Mikro-Tip catheter pressure transducer (Millar Instruments, Inc., Houston, TX) inserted through a stab wound in the left ventricular apex. Systemic body temperature was measured with a rectal temperature probe (Yellow Springs Instrument Co, Yellow Springs, CO).

Wall motion was analyzed qualitatively by a numerical score (4 = normal, 3 = mild hypokinesis, 2 = moderate hypokinesis, 1 = severe hypokinesis, 0 = akinesis, and -1 = dyskinesis) from two-dimensional echocardiograms using a technique described previously [13]. Wall motion scoring was made in a blinded fashion by an experienced echocardiographer and the scores were averaged for the periods of coronary occlusion and reperfusion for each experiment and, in turn, for the enalaprilat and nonenalaprilat groups.

The areas of risk and necrosis were determined by histochemical staining techniques using triphenyltetrazolium chloride as previously described [13]. Areas of risk and infarct were measured using planimetry to determine the area of risk compared with the total left ventricular mass and the percent area of infarct in that area of risk.

Epicardial vascular relaxation was assessed using standard organ chamber methodology. A segment of the second or third diagonal vessel in the area at risk and a segment of a circumflex coronary artery in a nonobstructed territory were dissected, cut into rings, and suspended in organ chambers with oxygenated Krebs buffer at 37°C. Ring tension was determined using a force displacement transducer (Grass Instruments, Inc, West Warwick, RI) attached to each tensiometer apparatus and recorded on MacLab recording software. The rings were allowed to equilibrate at a passive tension of 4 to 6 g for 60 minutes and then contracted with 1 µmol/L prostaglandin (PG) F₂ and allowed to stabilize. Once a stable contraction was obtained, coronary vasomotor function was assessed by generating dose–response curves to cumulative concentrations of nitroglycerin (10^-9 to 10^-5 mol/L), an endothelial-independent coronary vasodilator, and the calcium ionophore A23187, an endothelial-dependent coronary vasodilator. Relaxation in response to each concentration of the agonist was calculated as the percent reduction in isometric tension from the tension produced by 1 µmol/L PGF₂. Values were calculated for each experiment and mean values were computed for the enalaprilat and nonenalaprilat groups.

All values represent the mean ± standard error. Dose–response curves of endothelial function; echo-derived wall motion scores during ischemia and reperfusion; and heart rate, MAP, and LVEDP during the period of coronary ischemia were compared by analysis of variance for repeated measures. Dose–response curves of endothelial function, the number of cardioversions required for ventricular fibrillation or tachycardia, echo-derived wall motion scores, heart rate, MAP, LVEDP, and the area of necrosis to area of risk ratio between treatment groups were compared by two-way analysis of variance. Differences were considered significant at a probability less than 0.05. All animals received humane care in compliance 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" prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication 86-23, revised 1985).

	Results

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Heart rate, mean arterial pressure, and left ventricular end-diastolic pressure
The effects of enalaprilat on heart rate, MAP, and LVEDP during the period of coronary occlusion are summarized in Table 1. Both groups had similar heart rates before coronary occlusion (121 ± 4 beats/min enalaprilat versus 128 ± 3 beats/min no enalaprilat; not significant [NS]). Heart rate in each group decreased significantly during the period of coronary occlusion; however, there was no difference between the groups after 90 minutes (107 ± 4 beats/min enalaprilat versus 103 ± 4 beats/min no enalaprilat; NS). Mean arterial pressure was also similar between both groups before coronary occlusion (85 ± 3 mm Hg enalaprilat versus 85 ± 2 mm Hg no enalaprilat; NS). Although each group showed a small but significant decrease in MAP after 90 minutes of coronary occlusion, there was no difference in MAP between the two groups (76 ± 3 mm Hg enalaprilat versus 75 ± 3 mm Hg no enalaprilat; NS). Both groups also showed a small but statistically significant increase in LVEDP from preischemic values (6.4 ± 0.8 versus 9.2 ± 0.5 mm Hg enalaprilat; p < 0.01; 5.8 ± 0.5 versus 10.2 ± 0.6 mm Hg no enalaprilat; p < 0.02). However, there was no difference in LVEDP between the two groups after 90 minutes of occlusion (9.2 ± 0.5 mm Hg enalaprilat versus 10.2 ± 0.6 mm Hg no enalaprilat; NS).

The area of myocardium at risk for an infarct was similar in both groups (20.1% ± 1.9% enalaprilat versus 20.2% ± 3.0% no enalaprilat; NS). The area of necrosis to area of risk ratio was 37.7% ± 3.0% for the non–enalaprilat-treated hearts. Hearts treated with enalaprilat had only a 22.6% ± 1.4% area of necrosis to area of risk ratio, significantly less (p < 0.002) than the non-enalaprilat animals.

Coronary vasomotor function
Vasodilator responses to endothelium-independent and -dependent relaxation in vessels from the ischemic diagonal and unobstructed circumflex territory are shown in Figures 1 and 2. Endothelium-independent relaxation to nitroglycerin (10^-9 to 10^-5 mol/L) is summarized in Figure 1. Nitroglycerin induced comparable concentration-dependent relaxation in circumflex coronary artery segments in both enalaprilat- and non–enalaprilat-treated hearts. Although the concentration–response curves were shifted to the right in rings from the diagonal arteries compared with rings from the unobstructed circumflex territory, there was no difference in the nitroglycerin response curves between the enalaprilat and non-enalaprilat groups.

View larger version (23K): [in this window] [in a new window]   Fig 1. Endothelial-independent relaxation to nitroglycerin. Endothelium-independent relaxation was well preserved in the circumflex vessels (left panel) in both the enalaprilat and nonenalaprilat groups. Although slightly impaired relative to the circumflex vessels, there was no difference in endothelium-independent relaxation between the enalaprilat and nonenalaprilat groups in vessels from the ischemic diagonal territory (right panel).

View larger version (21K): [in this window] [in a new window]   Fig 2. Endothelial-dependent relaxation to calcium ionophore A23 187. Endothelium-dependent relaxation was slightly impaired in the circumflex vessels from both the enalaprilat and non-enalaprilat hearts (left panel). Enalaprilat failed to prevent the significant impairment in endothelial-dependent relaxation seen in vessels from the ischemic diagonal territory in the non–enalaprilat-treated hearts (right panel).

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Our results are similar to those of previous experimental studies in isolated and intact animal models that have shown that ACE inhibitors limit infarct size after periods of myocardial ischemia [5–10]. Our study also supports the work of other investigators who have demonstrated that endothelial-dependent and -independent vasodilation is only mildly impaired in nonobstructed coronary vessels after less than 1 hour of cardioplegic arrest [16]. Endothelium-independent vasodilation was slightly impaired in vessels from the ischemic diagonal territory compared with those from the unobstructed circumflex artery. However, there was significant impairment in endothelial-dependent relaxation in the ischemic diagonal vessels. Enalaprilat failed to prevent this significant decrease in vasomotor function (Fig 2).

Our results differ from those of Piana and coworkers [10], who demonstrated preserved endothelium-dependent relaxation in ischemic animals using enalaprilat. In that study, pigs underwent 30 minutes of left anterior descending coronary artery occlusion followed by 60 minutes of reperfusion. Five minutes before reperfusion, intravenous infusions of either captopril or enalaprilat were given. Both captopril and enalaprilat restored endothelium-dependent relaxation to the calcium ionophore A23187. Similar to our data, these beneficial effects occurred without any significant alterations in systemic hemodynamics during the infusion of the ACE inhibitors.

There are several explanations for the beneficial effects of ACE inhibitors on endothelial-independent vasomotor function observed by Piana and colleagues [10]. Their period of coronary occlusion was much less, 30 versus 90 minutes. Ninety minutes of coronary occlusion in the pig may have resulted in irreversible endothelial damage. Our study included a period of cardioplegic arrest, which is also known to impair vasomotor function [16]. Piana and coworkers gave their ACE inhibitors immediately before reperfusion, as opposed to our study, in which the coronary occlusions remained in place throughout the 45 minutes of cardioplegic arrest. Most importantly, Piana and associates studied changes in blood-perfused microvascular endothelium; our vasomotor studies involved epicardial vessels instrumented in nonperfused organ chambers. Previous studies have shown that ACE inhibitors may fail to elicit endothelium-dependent relaxation in porcine coronary artery rings incubated in organ chambers in the absence of flow [17]. However, if these same nonflow preparations are studied after being exposed to bradykinin, endothelial-dependent relaxation occurs [18]. This suggests that shear stress may induce the release of bradykinins, which potentiate the vasodilatory effects of ACE inhibitors. Indeed, Piana and coworkers noted increased bradykinin responses to the microvasculature after treatment with captopril and enalaprilat. Hence, although ACE inhibitors do not appear to prevent dysfunction of endothelium-dependent vasomotor function in the isolated, nonperfused epicardial coronary artery, they may still have beneficial effects in perfused in vivo midmyocardial and subendocardial vessels.

Although our study shows that ACE inhibitors limit ischemic injury during acute surgical revascularization, the mechanism for their beneficial effects is still unknown. Angiotensin-converting enzyme inhibitors were thought to work by reducing systemic arterial pressure, thereby decreasing afterload. However, our studies, as well as the results of others, indicate that the anti-ischemic effects of ACE inhibitors occur in doses that have no effect on systemic hemodynamics [10, 14, 15]. There may be several other mechanisms for the anti-ischemic effects of these drugs. Angiotensin-converting enzyme inhibitors decrease the synthesis of angiotensin II, which has been implicated in the production of superoxide anion in vascular smooth muscle cells by NADPH and reduced nicotinamide-adenine dinucleotide (NADH) oxidases [12]. Angiotensin II-induced hypertension in rats was associated with a large increase in vascular production of superoxide radicals, which was associated with impaired endothelium-dependent relaxation to the calcium ionophore A23187 [19]. In a similar model, Rajagopalan and associates [20] were able to reverse this impairment in endothelial-dependent relaxation by treating the vessels with liposome-encapsulated superoxide dismutase. When losartan, an angiotensin II receptor antagonist was administered concomitantly with angiotensin II, vascular superoxide production and endothelial-dependent relaxation were normalized. These studies suggest that ACE inhibitors act to block the upregulation of oxidases in the vascular wall that leads to increased levels of superoxide radicals, which inactivate nitric oxide.

Another possible mechanism for the antiischemic effects of ACE inhibitors is derived from their ability to attenuate the degradation of endogenous bradykinin by inhibition of kininase II, an enzyme that is identical to ACE [21]. Activation of endothelial B₂ kinin receptors leads to the formation of the potent vasodilators nitric oxide and prostacyclin, which may further protect the ischemic myocardium by activating signal transduction pathways that generate secondary messengers such as cyclic guanosine monophosphate and cyclic adenosine monophosphate [22]. In a rabbit model of 30 minutes of coronary ischemia followed by 120 minutes of reperfusion, myocardial infarct size was reduced by 49% by infusing the ACE inhibitor ramiprilat before coronary occlusion [6]. Pretreatment with either icatibant (HOE 140), a potent B₂ kinin receptor antagonist, or the nitric oxide synthase inhibitor N^G-nitro-L-arginine methyl ester before ramiprilat abolished this protective effect. Hartman [6] also demonstrated that ramiprilat protected cultured cardiomyocytes exposed to ischemia, suggesting that the beneficial effects of ACE inhibitors occur at the local tissue level.

Our study supports previous investigations that indicate that ACE inhibitors are most effective in reducing myocardial dysfunction when given early during ischemia [5–7, 14]. It was initially postulated that only sulfhydryl-containing ACE inhibitors would be most effective in reversing ischemic damage because they might scavenge free radicals more effectively [23]. However, several studies, including our own, have shown that a sulfhydryl-containing ACE inhibitor is not necessary to demonstrate an anti-ischemic effect and that several different types of ACE inhibitors have been equally effective in decreasing ischemic injury [5–8, 10, 14].

In conclusion, our experimental study has shown that ACE inhibition with enalaprilat significantly decreases ventricular irritability, improves regional wall motion, and limits infarct size during surgical revascularization of acutely ischemic myocardium. These beneficial effects appear to be unrelated to changes in afterload or the preservation of endothelial-dependent epicardial arterial relaxation. Future studies are planned to better delineate the role of bradykinin, nitric oxide, and prostacyclin in enhancing the actions of ACE inhibitors on cardiopulmonary bypass and to determine whether the addition of ACE inhibitors to cardioplegic solutions and reperfusates will limit myocardial injury.

	Acknowledgments

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The secretarial support of Mrs. Ellie LaBombard in preparing the manuscript is greatly appreciated. We also appreciate the work of Diane Lancaster, PhD, who performed all the statistical analyses, and Sheilah Bernard, MD, who performed the echo analysis.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments 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): Harold L. Lazar Yusheng Bao Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lazar, H. L. Articles by Keaney, J. F. Search for Related Content PubMed PubMed Citation Articles by Lazar, H. L. Articles by Keaney, J. F., Jr