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Right arrow Myocardial protection

Ann Thorac Surg 2004;78:628-633
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Brief pressure overload of the left ventricle preconditions rabbit myocardium against infarction

Cheng-Hsiung Huang, MD, PhDa*, Jih-Shiuan Wang, MDa, Shu-Chiung Chiang, MHSb, Yi-You Wang, BSa, Shiau-Ting Lai, MDa, Zen-Chung Weng, MDa

a Division of Cardiovascular Surgery, Department of Surgery, Information Service Center, National Yang-Ming University School of Medicine and Taipei Veterans General Hospital, Taipei, Taiwan
b Biostatistics Task Force, Information Service Center, National Yang-Ming University School of Medicine and Taipei Veterans General Hospital, Taipei, Taiwan

Accepted for publication January 22, 2004.

* Address reprint requests to Dr Huang, Division of Cardiovascular Surgery, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Rd, Taipei, Taiwan 11217
e-mail: chhuang{at}vghtpe.gov.tw


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Several nonischemic stimuli have been shown to precondition myocardium. We investigated cardioprotective effects and underlying mechanisms of brief pressure overload of the left ventricle in this study.

METHODS: Brief pressure overload of the left ventricle was achieved by two 10-minute partial snaring of the ascending aorta so that systolic left ventricular pressure was raised 50% above the baseline value. Ischemic preconditioning was elicited by two 10-minute coronary artery occlusions. Ten minutes after different pretreatments, myocardial infarction was induced by a 60-minute coronary artery occlusion followed by 3-hour reperfusion. Area at risk and myocardial infarct was determined by blue dye injection and triphenyl tetrazolium chloride staining.

RESULTS: The myocardial infarct size, expressed as percentage of area at risk, was significantly reduced in the pressure overload group (15.9% ± 2.9%, p < 0.001, n = 9) as well as in the ischemic preconditioning group (14.9% ± 1.9%, p < 0.001, n = 9) versus the control group (30.0% ± 6.9%, n = 10). Pretreatment with a blocker of stretch-activated ion channels (gadolinium, 40 µmol/kg, intravenous) abolished the protection induced by pressure overload and ischemic preconditioning. Gadolinium itself did not alter the extent of infarct. There was no significant difference in hemodynamics, area at risk, and mortality among all groups of animals.

CONCLUSIONS: Brief pressure overload of the left ventricle by partial snaring of the ascending aorta preconditioned rabbit myocardium against infarction. The underlying mechanism might be related to activation of stretch-activated ion channels.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Ischemic preconditioning achieved by brief coronary artery occlusion before a sustained ischemic period reduced myocardial infarct (MI). When Murry and colleagues [1] first reported on ischemic preconditioning, it was elicited by brief ischemia in canine hearts. However, several nonischemic stimuli can precondition myocardium, including rapid cardiac pacing [2, 3], heat stress [4], and pharmacological administration [5, 6]. In spite of many extensive studies, the exact mechanisms of ischemic preconditioning are not fully understood. Besides activation of adenosine receptors [7, 8], adenosine triphosphate–sensitive potassium channels [6, 9], and protein kinase C [10, 11], myocardial stretch might also be related to preconditioning [12, 13]. Przyklenk and associates [12] reported brief occlusion of the left circumflex coronary artery could protect myocardium in the remote left anterior descending coronary artery. The myocardium in the left anterior descending coronary artery had not rendered ischemic but had been stretched during the preconditioning period. Ovize and coworkers [13] stretched canine myocardium by infusing 500 mL of normal saline solution into the left atrium and significantly reduced MI. The protective effect was blocked by gadolinium (Gd3+), a potent inhibitor of stretch-activated ion channels.

Prolonged partial snaring or banding of the ascending aorta is a common method to induce pressure overload and left ventricular hypertrophy in animal experiments [14, 15]. In off-pump coronary artery bypass grafting surgery, cardiac surgeons cause brief stenosis when applying a partial clamp on the ascending aorta to perform anastomoses with saphenous vein grafts. Partial stenosis might cause obstruction and stretch of the left ventricle. In the current study, we induce pressure overload of the left ventricle by partial snaring of the ascending aorta. The purpose is to investigate whether brief pressure overload of the left ventricle can precondition rabbit myocardium against infarction and whether the underlying mechanism is related to activation of stretch-activated ion channels.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
This study was approved by the Animal Experiment Committee of the National Yang-Ming University, and animals used in this study were cared for humanely in accordance with the "Guide for the Care and Use of Laboratory Animals" (National Institutes of Health publication 85-23, revised 1985).

Animal preparation
The techniques of animal preparation have been described in a previous report [16]. New Zealand white rabbits (body weight, 2.8 ± 0.5 kg) were anesthetized by pentobarbiturate (30 mg/kg, intravenous), and anesthesia was maintained by infusion at 5 mg · kg–1 · h–1. Body temperature was maintained at 37°C with a heating pad. After tracheotomy, animals were intubated and ventilated with a ventilator (Harvard Apparatus, Natick, MA). Femoral artery was cannulated for arterial pressure monitoring. Arterial pressure was measured using a Statham P23 pressure transducer coupled to a pressure processor amplifier (Gould Instruments, Cleveland, OH). Electrocardiography leads were placed on limbs. A median sternotomy was performed, and the heart was exposed. A 2-0 silk suture was passed around the proximal part of left anterior descending coronary artery. The ends of the silk suture were threaded through a small vinyl tube to form a snare. Meticulous dissection of the ascending aorta was performed. A ribbon tape was passed around the ascending aorta. A microtipped manometer (Millar, Houston, TX) was inserted into the left ventricle to measure left ventricular pressure. The first derivative of left ventricular pressure (dP/dt) was obtained by electronic differentiation using a differentiator (Gould Instruments). Arterial pressure, heart rate, electrocardiography, left ventricular pressure, and dP/dt were recorded on a pressurized ink-chart recorder (Gould Instruments) and on a personal computer with waveform data analysis software (AcqKnowledge; Biopac System, Goleta, CA).

Experimental protocol
After hemodynamics were stable for 30 minutes, rabbits were randomly allocated to six groups. Figure 1 showed the experimental protocol. Group 1 received no intervention (control group). Group 2 received brief pressure overload of the left ventricle by partial snaring of the ribbon tape around the ascending aorta to increase systolic left ventricular pressure 50% above the baseline value for 10 minutes. Two episodes of pressure overload were done (left ventricle pressure overload group). Group 3 received ischemic preconditioning by two episodes of 10-minute coronary artery occlusion (ischemic preconditioning group). Group 4, 10 minutes before pressure overload as in group 2, received intravenous infusion of gadolinium (III) chloride hexahydrate 99.999% (Gd3+, 40 µmol/kg; Aldrich, Milwaukee, WI), a blocker of stretch-activated ion channels (Gd3+-left ventricle pressure overload group). Group 5 received infusion of Gd3+ 10 minutes before ischemic preconditioning as in group 3 (Gd3+-ischemic preconditioning group). Group 6 received infusion of Gd3+ (Gd3+-control group). The infusion was continued for 10 minutes. Ten minutes after the above treatments, a 60-minute coronary artery occlusion was performed by pulling the snare around the left anterior descending coronary artery, which was then fixed by clamping the vinyl tube with a mosquito clamp. The performance of successful occlusion was verified by observing the development of ST-segment elevation and changes in the QRS complex on electrocardiography, and cyanotic change of myocardium in the occluded area. After the 60-minute coronary artery occlusion, the snare was released for reperfusion for 3 hours. No antiarrhythmic agents were given at any time. Arterial pressure, heart rate, electrocardiography, left ventricular pressure, and dP/dt were recorded simultaneously at baseline (before treatment) and during the treatment period, sustained 60-minute coronary artery occlusion, and 3-hour reperfusion.



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  		Fig 1. The experimental protocol. All rabbits underwent 60-minute coronary artery occlusion (CAO) and 3-hour reperfusion (CAR) after different treatments. In the treatment period, group 1 received no intervention, whereas group 2 received two 10-minute left ventricular pressure overload (LVPO) by partial snaring of the ascending aorta, and group 3 received ischemic preconditioning by two 10-minute coronary artery occlusions. Gadolinium (Gd3+), a blocker of stretch-activated ion channels, was intravenously administered in the remaining three groups. Then, group 4 received left ventricular pressure overload, group 5 received ischemic preconditioning, and group 6 received no intervention.

 
Determination of area at risk and myocardial infarct size
At the end of experiments, 2000 U of heparin were administered. The heart was rapidly excised and placed on a perfusion apparatus. The methods for blue dye perfusion were similar to those previously reported [5]. Briefly, the coronary artery was ligated at the site of previous occlusion. The ascending aorta was cannulated (distal to the sinus of Valsalva) and retrogradely perfused with 1% Evans blue dye. After perfusion was completed, the atria and right ventricular free wall were removed. The left ventricle plus septum was then cut into six to seven transverse slices, which were incubated at 37°C in 1% triphenyl tetrazolium chloride solution in phosphate buffer (pH = 7.4) for 20 minutes to visualize MI (area unstained by triphenyl tetrazolium chloride). The slices were weighed and fixed in a 10% formalin solution. The basal surfaces were photographed. Images were traced with a digitizer to calculate both the area at risk (AAR), identified by the blue dye exclusion, and the MI area. The AAR and MI area of each slice were calculated from planimetry, and the values for each slice were summed for the entire left ventricle plus septum. The AAR was reported as the percentage of left ventricle plus septum, with MI size as percentage of AAR.

Exclusion criteria
Rabbits with AAR less than 10% of left ventricular weight and rabbits that exhibited ST-segment shift on electrocardiography during the pressure overload period were excluded.

Statistics and data analysis
All values were expressed as mean value ± standard deviation. Hemodynamic variables were analyzed by a two-way analysis of variance with repeated measurement. The difference of AAR and MI size among groups was analyzed with the Kruskal-Wallis test. The multiple comparisons were made by the Wilcoxon rank sum test with Bonferroni method. The analysis of covariance was performed to evaluate the group difference of MI (expressed as percentage of the left ventricular weight) with AAR (expressed as percentage of the left ventricular weight) as covariate. Differences were considered significant at p less than 0.05.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Mortality and exclusions
There were 69 rabbits entering this study. Eight rabbits exhibited ventricular fibrillation and died (Table 1). Another 5 rabbits died of heart failure, which was defined as a progressive decrease of arterial pressure to a systolic value less than 50 mm Hg with global left ventricular dilatation and poor contraction. One rabbit had electrocardiography changes during the pressure overload period. One rabbit in group 2 suffered from bleeding of sternum and hypotension. They were excluded.


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  		Table 1. Mortality and Exclusions

 
Characteristics of brief pressure overload
During partial snaring of the ascending aorta, systolic left ventricular pressure increased significantly from 101 ± 15 mm Hg to 155 ± 25 mm Hg in group 2 and from 103 ± 16 mm Hg to 152 ± 16 mm Hg in group 4, whereas systolic arterial pressure decreased significantly from 101 ± 15 mm Hg to 75 ± 12 mm Hg in group 2 and from 103 ± 16 mm Hg to 75 ± 9 mm Hg in group 4. Systolic left ventricular pressure was increased 50% above the baseline, causing obvious pressure overload of the left ventricle. The left ventricular dP/dt and heart rate increased during the pressure overload period; however, the increases were not significant. After brief pressure overload, heart rate, arterial pressure, left ventricular pressure, and dP/dt returned to baseline level.

Hemodynamic changes during experiments
The baseline heart rate, arterial pressure, left ventricular pressure, and dP/dt of the six groups were not significantly different. The treatments before 60-minute coronary artery occlusion did not cause any significant hemodynamic changes. There was no significant change in heart rate, arterial pressure, left ventricular pressure, and dP/dt throughout the experiment (Table 2). The hemodynamic variables among the six groups were not significantly different during experiments.


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  		Table 2. Changes of First Derivative of Left Ventricular Pressure During Experiments

 
Area at risk and myocardial infarct size analysis
The AAR, expressed as percentage of left ventricular weight, of the six groups averaged 46.5% ± 5.6% (group 1), 42.4% ± 4.9% (group 2), 44.7% ± 4.2% (group 3), 43.7% ± 5.5% (group 4), 41.7% ± 4.7% (group 5), and 44.7% ± 6.7% (group 6). The AAR was not significantly different. The MI size, expressed as a percentage of AAR, was 30.0% ± 6.9% in the control group. Brief pressure overload in group 2 significantly reduced MI to 15.9% ± 2.9% (p < 0.001 versus control group; Fig 2 and Table 3). Ischemic preconditioning in group 3 also significantly decreased MI (14.9% ± 1.9%, p < 0.001 versus control group). However, administration of Gd3+ before pressure overload (group 4) and ischemic preconditioning (group 5) abolished their protective effects (MI size of 29.9% ± 4.7% and 27.6% ± 3.4%, respectively, not significant versus control group). Administration of Gd3+ alone (group 6) did not alter the extent of MI (26.8% ± 4.0%, not significant).



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  		Fig 2. The myocardial infarct (MI) size, expressed as percentage of area at risk (AAR). *p < 0.001 versus groups 1, 4, 5, and 6.

 

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  		Table 3. Myocardial Infarct Size, Expressed as Ratio of Myocardial Infarct to Area at Risk

 
Although AAR was not significantly different among the six groups, AAR is the major determinant of MI size. We performed analysis of covariance with extent of MI (expressed as percentage of left ventricular weight) as the dependent variable and AAR (expressed as percentage of left ventricular weight) as covariate to further evaluate the effect of AAR on MI size. Figure 3
Fig 3. Myocardial infarct (MI) size was plotted as a function of area at risk (AAR). Both MI and AAR were expressed as percentage of the left ventricular (LV) weight. "
", regression line of group 1 ("MI = 3.09 + 0.23AAR", p = 0.28, r2 = 0.14). "
", regression line of group 2 ("MI = –2.76 + 0.22AAR", p = 0.05, r2 = 0.46). "
", regression line of group 3 ("MI = 3.66 + 0.07AAR", p = 0.32, r2 = 0.14). "
" regression line of group 4 ("MI = –8.57 + 0.50AAR", p = 0.01, r2 = 0.64). "
", regression line of group 5 ("MI = –1.38 + 0.31AAR", p = 0.02, r2 = 0.54). "
", regression line of group 6 ("MI = 8.45 + 0.08AAR", p = 0.35, r2 = 0.15). The slopes of regression equations of six groups were not significantly different.

shows that data points for group 2 (left ventricle pressure overload group) and group 3 (ischemic preconditioning group) fell below the regression line of group 1 (control group). Administration of Gd3+ did not significantly change the MI size (group 6), but abolished the protection of pressure overload (group 4) and ischemic preconditioning (group 5). Analysis of covariance showed regression lines of groups 1, 4, 5, and 6 were not significantly different. However, the regression lines of groups 2 and 3 differed significantly from that of group 1 (p < 0.001). This result indicated, for any value of AAR, groups 2 and 3 developed significantly smaller MI size than group 1.


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
In the current study, we demonstrated two episodes of brief pressure overload of the left ventricle by partial snaring of the ascending aorta significantly reduced MI in rabbits (15.9% ± 2.9% versus 30.0% ± 6.9% in control group; p < 0.001; Table 3). This is the first report demonstrating the preconditioning effect of brief pressure overload of the left ventricle. The protective effect was comparable to that of ischemic preconditioning (14.9% ± 1.9%, not significant). There were no significant hemodynamic changes during the 60-minute coronary artery occlusion. The reduction of MI could not be ascribed to hemodynamic changes. Although the exact mechanism is not known, the protection was abolished by administration of Gd3+, an inhibitor of stretch-activated ion channels. Therefore, the protective effect might be related to activation of stretch-activated ion channels.

There are many regimens to induce preconditioning. Murry and associates [1] reported ischemic preconditioning by four episodes of 5-minute coronary artery occlusion. A transient ischemic insult of only 1 to 2 minutes was found insufficient to induce protection, and an episode of at least 3 minutes was required [17, 18]. Although a short single ischemic episode was reported to be as effective as multiple episodes in dogs [19], three-cycle ischemic preconditioning was found to reduce more MI than one cycle in rabbits [20]. The left ventricular pressure was raised 40% above the baseline in chronic left ventricular hypertrophy studies [21, 22]. In this acute experiment, we increased left ventricular pressure 50% above the baseline value. Two episodes of 10-minute pressure overload were used. It requires further study to determine whether a shorter duration of pressure overload, a lesser increase of systolic left ventricular pressure, or a single episode would induce the same MI reduction.

Demonstration of increase in segment length of myocardium will definitely confirm stretch during pressure overload. Although we did not provide evidence of increase in segment length of the left ventricle, the protection of pressure overload was abolished by an inhibitor of stretch-activated ion channels. Besides, systolic left ventricular pressure was raised 50% above the baseline. The increase of left ventricular pressure was obvious. The left ventricular dP/dt and heart rate increased during pressure overload. Rapid cardiac pacing was reported to precondition the myocardium [2, 3]. However, the increase of heart rate in our study was not significant. Prolonged banding of the ascending aorta induced ventricular hypertrophy and coronary circulation abnormalities [14, 15]. Brief pressure overload might also cause changes of myocardial blood flow and affect the response of the myocardium to ischemia. We did not investigate the effects of brief pressure overload on myocardial blood flow in this study.

Gadolinium is a potent inhibitor of stretch-activated ion channels [23]. Ovize and coworkers [13] and Gysembergh and colleagues [24] reported Gd3+ prevented MI limitation by rapid infusion of normal saline solution in dogs and rabbits. Piriou and associates [25] also demonstrated Gd3+ prevented preconditioning induced by isoflurane. Although Gd3+ partially reversed protection of ischemic preconditioning in dogs [13], the effect of ischemic preconditioning was completed blocked by Gd3+ in rabbits [24]. Administration of Gd3+ did not significantly modify heart rate, arterial pressure, and myocardial blood flow [13]. In the present study, we also found administration of Gd3+ did not significantly change the hemodynamic variables, but prevented MI reduction induced by pressure overload and ischemic preconditioning.

The results of ischemic preconditioning in cardiac surgery are conflicting. Yellon and colleagues [26] first reported preconditioning of human myocardium in coronary artery bypass grafting surgery. Under cardiopulmonary bypass, they induced global ischemia of human hearts with two 3-minute aortic cross-clamping intervals interspersed with 2 minutes of reperfusion. A slowing rate of the adenosine triphosphate depletion was found in preconditioned hearts. Although Kaukoranta and coworkers [27] reported ischemic preconditioning did not offer any additional benefits over normothermic retrograde blood cardioplegia, most studies showed brief cross-clamping of the aorta protected human hearts in cardiac surgery [28–30]. However, Vaage and Valen [30] indicated ischemic preconditioning with repeated clamping of the aorta would never get widespread use, for fear of possible embolism from the ascending aorta and unprotected ischemia. In this study, we induced preconditioning by partial snaring of the ascending aorta. No ischemia was elicited, and partial snaring, instead of cross-clamping, was used. Fewer chances of embolism are expected. However, the clinical effects were not investigated in this study and need further evaluation.

There were several limitations in this study. The effects of pressure overload and administration of Gd3+ on myocardial blood flow were not investigated. We verified the performance of successful coronary artery occlusion by observing the development of ST-segment elevation and changes in the QRS complex on electrocardiography and the cyanotic change of the myocardium in the occluded area. No myocardial blood flow data were provided. However, rabbits have a minimal collateral coronary circulation [31]. Besides, the rabbit model was widely used in experiments on myocardial ischemia and preconditioning [7, 10, 24, 32]. The current study was conducted on anesthetized, open-chest rabbits. The acute effects of anesthesia and surgery should be taken into account when interpreting the results [32, 33]. Although triphenyl tetrazolium chloride technique was commonly used in MI experiments, the infarct size might have been underestimated [34].

In conclusion, we demonstrated brief pressure overload of the left ventricle by partial snaring of the ascending aorta preconditioned myocardium and reduced MI in rabbits. The protective effect was comparable to that of ischemic preconditioning. Although the exact mechanism is not known, the reduction of MI was abolished by administration of Gd3+, an inhibitor of stretch-activated ion channels. Therefore, preconditioning by brief pressure overload might be related to activation of stretch-activated ion channels. Pressure overload of the left ventricle provides a new nonischemic maneuver to induce myocardial protection in animal experiments. Further studies are required to determine its role in clinical patient treatment.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by grants from National Scientific Council, Taiwan (NSC 89–2314-B-075–133), and Taipei Veterans General Hospital (V88–219).


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
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