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Ann Thorac Surg 1996;61:925-929
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Is the Preconditioning Response Conserved in Senescent Myocardium?

Division of Cardiothoracic Surgery, Department of Surgery, Deaconess Hospital, Harvard Medical School, Boston, Massachusetts

Accepted for publication November 28, 1995.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Senescent myocardium differs from adult myocardium at both functional and cellular levels. To adjudicate the efficacy of ischemic preconditioning as an alternative or adjuvant myoprotective strategy a reproducible, age-independent, intact laboratory model is necessary.

Methods. Adult (0.5 to 1.0 years) and senescent (5.7 to 8.0 years) sheep underwent 60 minutes of normothermic regional ischemia with 150 minutes of reperfusion. Group II (adult-ischemic preconditioning) and group IV (aged-ischemic preconditioning) underwent preconditioning with three 5-minute episodes of normothermic regional ischemia. Group I (adult-control) and group III (aged-control) were not preconditioned.

Results. Risk size and infarct size weights were delineated by monastryl blue pigment infusion and buffered tetrazolium solution. Ischemic preconditioning was evidenced by an infarct size reduction of 54% for adult sheep and 47% for senescent sheep (p < 0.01 versus age-matched controls; p = not significant for adult versus senescent).

Conclusions. The data suggest that the cellular pathways involved with the preconditioning response are well preserved in senescent myocardium and support the utility of the ovine heart model to investigate the clinical relevance of ischemic preconditioning for the increasingly aged population presently undergoing cardiac operations.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Short periods of ischemia separated by intermittent reperfusion render myocardium tolerant to subsequent prolonged ischemic episodes and induce a marked reduction of resultant infarct size [1]. This myoprotective response has been demonstrated in a wide variety of species, including dogs [1, 2], rabbits [3], and rats [4], and has been proposed to exist in humans [5]. The preconditioning phenomenon suggests that transient stresses (ischemia, hypoxia [6], heat shock [7], ₁-adrenergic stimulation [8]) can induce intrinsic changes within myocardium to enhance resistance to subsequent ischemia-reperfusion injury, including a reduction in associated infarct size after prolonged ischemia and a decreased incidence of arrhythmias. The precise mechanism by which preconditioning protects the heart, however, remains unknown [9]. Present theories include stimulation of one or more types of myocyte receptors: adenosine A₁ receptors [3], muscarinic receptors [10], or alpha sympathomimetic receptors [8]. Such receptor stimulation results in translocation of protein kinase C to the cellular membrane, working through an inhibitory G protein mechanism [11]. Subsequent phosphorylation of the adenosine triphosphate–dependent potassium channel may be responsible for triggering the actual preconditioning response [12].

Aging has been demonstrated to affect myocardium at both histologic and functional levels. Senescent myocardium has decreased adrenergic responsiveness [13], an altered coronary microcirculation [14], impaired calcium transport [15, 16], and impaired excitation-contraction coupling [17]. At a cellular level senescent myocytes demonstrate increased DNA nicking [18], increased V3 to V1 myosin isozyme ratio [17], and a loss of proteins along the inner mitochondrial membrane [19]. Investigations in this laboratory have demonstrated that senescent hearts are more vulnerable to global ischemia [20] and protected cardioplegic arrest [21]. It is necessary to address the presence of the ischemic preconditioning response in an in vivo large animal model of senescent myocardium before incorporating ischemic preconditioning into present clinical methods of myoprotection that have enabled cardiac operations to be performed on an increasingly aged population [22].

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
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 National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Surgical Preparation
Twelve adult (0.5 to 1.0 years) and 12 senescent (5.7 to 8.0 years) Dorsett or Suffolk sheep of either sex were sedated with ketamine (20 mg/kg intramuscularly) and anesthetized with pentobarbital (25 mg/kg intravenously). Adulthood was defined as the age of sexual maturity [20]. A tracheostomy was performed and ventilation begun with a volume-cycled ventilator (Harvard Apparatus, Natick, MA). The right external jugular vein and common carotid artery were cannulated for intravenous access and arterial pressure monitoring (Millar Instruments, Houston, TX). A partial sternectomy with bilateral anterior rib resection was performed. The second or third diagonal branch of the left anterior descending artery was atraumatically isolated and snared to define a regional area measuring between 5 and 10% of the mass of the left ventricle (LV). Heparin (250 USP/kg) was administered to prevent thrombosis. Attention was paid to the stabilization of arterial blood gases, acid-base status, temperature, hemoglobin level, and electrolytes throughout the protocol (pH of 7.35 to 7.45; oxygen tension > 100 mm Hg; temperature of 37°C; hemoglobin level > 5.0 mg/dL; K⁺ level < 5.0 mEq/L).

Experimental Protocol
Animals were divided into four groups of 6 animals. Group I (adult-control) and group III (aged-control) animals served as nonpreconditioned controls. They received 60 minutes of normothermic regional ischemia followed by 150 minutes of reperfusion. Group II (adult-ischemic preconditioning) and group IV (aged-ischemic preconditioning) animals were preconditioned with three 5-minute episodes of normothermic regional ischemia before 60 minutes of sustained normothermic regional ischemia. Lidocaine (2 mg/kg intravenous bolus) was administered for antiarrhythmia prophylaxis before the initiation of 60 minutes of normothermic regional ischemia and at the time of subsequent reperfusion.

Data Acquisition
At the conclusion of the protocol the previously occluded diagonal branch of the left anterior descending artery was ligated and monastryl blue pigment was instilled into the aortic root to delineate the nonstaining perfusion bed (``risk area''). After administration of hyperkalemic cardioplegia, hearts were excised and trimmed of right ventricular free walls, atria, chordae tendineae, and valvular tissue. All hearts were confirmed to be free of gross atherosclerotic disease. The remaining LVs were transversely sliced into 1-cm-thick sections and weighed. Dye-free ``risk areas'' on each slice were sharply demarcated from blue stained nonischemic areas and traced onto acetate sheets. All slices were next incubated in phosphate-buffered 3,5,5-triphenyltetrazolium chloride at 38°C for 40 minutes. Viable tissue, stained red, was distinguished from pale necrotic myocardium. Both sides of each slice were again traced to determine ``infarct areas.'' Left ventricular areas, ``risk areas'' and ``infarct areas'' were measured using a planimeter with the aid of a digitizing graphic tablet. Risk size and infarct size were calculated with the following formulas: risk size = slice weight x (risk area_{[side 1]} + risk area_{[side 2]})/(LV area_{[side 1]} + LV area_{[side 2]}); infarct size = slice weight x (infarct area_{[side 1]} + infarct area_{[side 2]})/(LV area_{[side 1]} + LV area_{[side 2]}).

Statistical Analysis
Data are expressed as mean (standard deviation). For between-groups comparison of hemodynamic variables, as well as body mass, LV mass indexed to body mass, area at risk, and infarct size indexed to LV mass, a one-factor analysis of variance was used. When the analysis of variance test was significant, pairwise comparisons were made using Tukey's post hoc analysis. Differences were considered significant when p was less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Group characteristics and hemodynamic data are summarized in Table 1. Body weight and LV weight of the senescent sheep were greater than those of the adult animals. However, LV sizes normalized to body weight were not different. Heart rate and systolic blood pressure were similar in all groups. No animal experienced sustained ventricular arrythmias during the protocol in the presence of prophylactic lidocaine administered before the 60-minute period of regional ischemia and again immediately before reperfusion.

View larger version (15K): [in this window] [in a new window]   Fig 1. . Mass of infarcted myocardium (infarct size) relative to the mass of myocardium at risk (risk area). Columns are group means and bars are standard deviations. Ischemic preconditioning (IPC) significantly reduced infarct percentage when compared with age-matched controls by analysis of variance/Tukey's test. There were no differences in infarct percentage between groups that underwent the same protocol, despite an age difference, indicating that IPC is preserved in aged ovine myocardium.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Sheep were selected to elucidate the isolated effects of aging on the ischemic preconditioning response because the ovine heart is known to be free of a range of cardiac diseases, including hypertrophy, dilatation, fibrosis, parasites, cardiac storage diseases, and atherosclerotic plaques [20]. Senescent hearts demonstrated increased LV mass occurring with advanced age. However, this increase was equal and proportional to increased body weight, thereby confirming the absence of isolated hypertrophy.

Although the precise mechanism of ischemic preconditioning is still under investigation, several theories have been discounted in the past 8 years. Ischemic preconditioning is a basic well-preserved phenomenon that does not appear to be due to recruitment of collateral flow, stunning, acute protein synthesis, inhibition of mitochondrial adenosine triphosphate, or protection by antioxidants [9]. The precise mechanism of preconditioning appears to be species dependent and can involve a variety of cellular receptors. One popular explanation is the adenosine hypothesis. Adenosine, which is released during ischemia-reperfusion injury, stimulates adenosine A₁ receptors, which couple to inhibitory G proteins [11]. Through second-messenger pathways protein kinase C is translocated from the cytosol to the myocyte membrane. This results in the subsequent phosphorylation of an unidentified protein that in turn may mediate actual preconditioning. The adenosine triphosphate–dependent potassium channel, which becomes activated during ischemic preconditioning, may be this responsible mediating protein. Acting through both shortened action potential duration and decreased calcium ion influx, an energy-sparing loss of contractile function and preservation of cellular adenosine triphosphate may result [12].

In a similar theory -adrenergic stimulation (₁-receptor mediated) may trigger preconditioning working through a similar inhibitory G protein mechanism [8]. Because myocardial ischemia has been shown to induce the release of both endogenous catecholamines and adenosine, it may be that both ₁-adrenergic receptor and adenosine A₁ receptor activation together contribute to ischemic preconditioning in some species. Interestingly, senescent rat hearts have been shown to release higher levels of interstitial adenosine during adrenergic stimulation when compared with mature animals [13]. Such data support a role for adenosine in the myocardial preconditioning response that is preserved with senescence. Although this study does not elucidate the exact mechanism of preconditioning in sheep, previous work from this laboratory has shown that the preconditioning response associated with total cardiopulmonary bypass can be eliminated by either adenosine or -receptor blockade in this species [23].

Aging has many complex effects on myocardium. Frolkis and associates [15] described an age-dependent alteration in calcium handling during low-flow ischemia. Senescent hearts demonstrate greater increases in sarcolemmal calcium influx and greater decrements in sarcoplasmic reticulum calcium uptake during ischemia. An elevated intracellular calcium level suggests that the senescent myocyte has a limited ability to function under ischemic conditions. These observations were confirmed by Misare and colleagues [20], using an ovine model similar to the present study, when global normothermic ischemia was demonstrated to be less tolerated by senescent animals. Caldarone and co-workers [21] extended this work to illustrate that senescent hearts are more functionally impaired by protected ischemia. The present study illustrates that despite the biochemical changes characteristic of senescent myocardium, which usually cause intolerance to even short periods of ischemia, the myoprotective preconditioning response exists during prolonged ischemia.

The altered coronary microcirculation present in senescent myocardium could have influenced the presence or magnitude of the preconditioning-associated infarct size reduction measured in the present study. An age-dependent decrease in maximal coronary artery blood flow and a decrement in the endocardial to epicardial blood flow ratio has been proposed to indicate ischemic vulnerability in senescent hearts [14]. An age-related arteriolar decrease in the ratio of lumen diameter to wall thickness in senescent hearts further suggests decreased coronary blood flow reserve [24]. Such age-related microcirculatory changes could interfere with an ischemic preconditioning response that appears to involve local vasculature release of triggering mediators. Despite an altered myocardial microcirculation no such effect of senescence on preconditioning was demonstrated.

In the present study only the infarct size reduction associated with ischemic preconditioning was measured. Because no animals experienced sustained arrhythmias with the use of prophylactic lidocaine, no potential reduction in arrhythmia incidence could be evaluated. Regional mechanical function in the ischemic bed proved difficult to quantitate in this preparation given the complex relationship between myocardial preconditioning and myocardial stunning induced by 60 minutes of normothermic regional ischemia. Analysis of mechanical function in selected pilot animals using regional sonomicrometric crystals placed in the ischemic bed failed to distinguish the potential myoprotective benefit of increased myocyte survival due to preconditioning from the associated deleterious effects of regional myocardial stunning. Prior data indicate that a reperfusion period of more than 24 hours would be necessary for full recovery of regional mechanical function after stunning [25].

Infarct size in this study was determined by staining with triphenyltetrazolium chloride stain. Determination of the extent of early infarction by this method has generally been found to be an accurate measure of ultimate infarct size at 2 to 48 hours of reperfusion in swine when compared with subsequent histologic analysis in animals not receiving further treatment [26]. Tetrazolium staining has been demonstrated to reveal equivalent infarct size values when compared with histologic determination in dogs [27] and rabbits [28] after 2 to 3 hours of reperfusion. Downey and associates [3, 4, 11] have routinely used tetrazolium staining after 2- to 3-hour periods of reperfusion following sustained ischemia to extensively investigate the preconditioning phenomenon. In pilot animals there were no differences in infarct size, as measured by tetrazolium staining, after variable periods of reperfusion extending from 2 to 4 hours.

Ischemic preconditioning has been recognized as one of the most powerful and reproducible methods of preventing myocyte necrosis known to date. A wide variety of ``stresses'' have been shown to stimulate the preconditioning response in laboratory animals. Since its discovery several years ago the potential clinical applications of this mechanism have received much attention in the literature. The preservation of this phenomenon in senescent myocardium, despite altered biochemical and morphologic properties, supports the potential clinical use of preconditioning as an adjuvant methodology that safely stimulates and potentially prolongs the myoprotective preconditioning response for the increasingly aged population undergoing modern cardiac operations.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Supported by National Institutes of Health grants R29-HL48751 and HL29077.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Krukenkamp, Division of Cardiothoracic Surgery, New England Deaconess Hospital, 110 Francis St, Suite 2-C, Boston, MA 02215.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract 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): Paul G. Burns Irvin B. Krukenkamp Christopher A. Caldarone Sidney Levitsky Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Burns, P. G. Articles by Levitsky, S. Search for Related Content PubMed PubMed Citation Articles by Burns, P. G. Articles by Levitsky, S.