Animal Models of Myocardial and Vascular Injury

Journal of Surgical Research 162, 239–249 (2010)doi:10.1016/j.jss.2009.06.021

RESEARCH REVIEW

Animal Models of Myocardial and Vascular Injury

Aaron M. Abarbanell, M.D.,† Jeremy L. Herrmann, M.D.,† Brent R. Weil, M.D.,† Yue Wang, Ph.D.,†Jiangning Tan, M.D., Ph.D.,† Steven P. Moberly, B. S.,† Jeremy W. Fiege,†

and Daniel R. Meldrum, M.D.*,†,‡,§,1

*Clarian Cardiovascular Surgery, Methodist Hospital; †Department of Surgery; ‡Department of Cellular and Integrative Physiology;and §Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana

Over the past century, numerous animal modelshave been developed in an attempt to understandmyocardial and vascular injury. However, the success-ful translation of results observed in animals to humantherapy remains low. To understand this problem, wepresent several animal models of cardiac and vascularinjury that are of particular relevance to the cardiac orvascular surgeon. We also explore the potentialclinical implications and limitations of each modelwith respect to the human disease state. Our resultsunderscore the concept that animal research requiresan in-depth understanding of the model, animal physi-ology, and the potential confounding factors. Futureoutcome analyses with standardized animal modelsmay improve translation of animal research from thebench to the bedside. � 2010 Elsevier Inc. All rights reserved.

Key Words: ischemia/reperfusion; myocardial infarc-tion; heart failure; atherosclerosis; endothelial damage;animal models; comparative physiology.

INTRODUCTION

Coronary artery disease and peripheral vasculardisease are leading causes of morbidity and mortality[1–4]. As with all potential therapies, the efficacy ofnew treatments needs to be proven in clinical trialsprior to widespread use. However, human studiesinvolving interventions for acute injury (e.g., myocar-dial infarction [MI], aneurysm rupture, thromboembo-lus) are hampered by the inability to assess efficacyuntil an event occurs. Potentially, animal modelsthat replicate myocardial and peripheral vasculardisease/injury can lead to the development of novel

1 To whom correspondence and reprint requests should beaddressed at Indiana University School of Medicine, 2017 Van NuysMedical Science Building, 635 Barnhill Drive, Indianapolis,IN 46202. E-mail: [email protected].

239

treatment strategies. However, the costs of animalresearch, especially new model development, are sig-nificant from both a monetary and animal mortalityperspective [5, 6]. This has led some investigators toadvocate that animal models are inappropriatelyused for research.

Several systematic reviews have been conducted in anattempt to define the exact role of animal models as plat-forms for future human therapy [7, 8]. One review of 76animal studies found that only 37% (28) of the studieswere replicated in humans, while 45% remaineduntested in humans [9]. In addition, only eight of the 28studies were eventually approved for human use. Fur-ther supporting this low statistic was a recent reportfroma National Heart,Lungand BloodInstitute workinggroup specifically investigating the failure to translatetherapies for myocardial ischemia/reperfusion injury(I/R) from the bench to the clinical world. The workinggroup concluded that inappropriately chosen animalmodels, as well as a lack of reproducibility, standardizedmodels, and blinding of the investigators hindered thesuccess of translational research [3].

To understand the difficulties inherent in animalmodels of myocardial and vascular injury, this review(1) describes several current models of myocardialinjury, heart failure, and vascular injury; (2) presentsselected new research findings based on these models;and (3) details the challenges inherent in the modelsand the limitations across species.

MYOCARDIAL ISCHEMIA/INFARCT MODELS

The incidence of MI is estimated at 770,000 Ameri-cans/year with an additional 430,000/year havinga recurrent MI [1]. Given this high incidence, signifi-cant emphasis has been placed on the use of animalmodels to understand the pathophysiology of acute MI

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JOURNAL OF SURGICAL RESEARCH: VOL. 162, NO. 2, AUGUST 2010240

and I/R (Table 1). The Langendorff, the isolatedworking heart, and the left anterior descendingcoronary artery (LAD) occlusion models are threepredominant models of myocardial ischemia/infarction.

Langendorff (Isolated Heart Perfusion System)

The Langendorff is an ex vivo model used to studycardiac physiology, acute global or regional I/R, andthe efficacy of drug or cell therapy on the heart [10].While large mammalian hearts can be studied withthe Langendorff, small animals are predominantlyused due to low cost and the ease of small animal care.Rodents in particular have short breeding cycles. Inaddition, the availability of genetically modified micefacilitates the investigation of myocardial cytokinesand signaling despite the technical challenges of usingthe small mouse heart on the Langendorff.

Elias Cyon developed the precursor model for isolatedheart perfusion using an explanted frog heart in 1866[11, 12]. Oscar Langendorff modified Cyon’s design tostudy mammalian hearts in 1895 [13]. Langendorffused a retrograde aortic cannula to supply whole bloodto the aorta under constant pressure. This retrogradeflow closed the aortic valve, sending the blood into thecoronary arteries and, subsequently, into the coronarysinus and right atrium. Right atrial coronary effluentwas measured as well as the muscular shortening ofthe heart via a pulley system connected to the apex ofthe heart [11, 12]. However, the model did not measureventricular stroke work (the product of the ejectedvolume and the pressure required to move the fluid)as the left ventricle (LV) had no preload and did noteject volume.

The modern Langendorff only retains the retrogradeperfusion of the aorta. A physiologic solution describedby Krebs and Hensleit (KH solution) replaces the blood.The KH solution is delivered at either constantpressure or constant flow [12]. To evaluate the function

TABL

Select Models of Cardi

Myocardial injury models Injury or conditionIsolated heart (Langendorff) Acute global or reIsolated working heart (Neely) Acute global or reLAD occlusion I/R, MI (acute or c

Heart failure modelsIschemia HF associated witPressure overload Left ventricular hVolume overload Dilated cardiomyo

Vascular injury modelsAAA Aneurysm formatHind limb ischemia Acute and chronicBalloon angioplasty/wire Endothelial injuryCarotid artery ligation Neointimal lesionPerivascular injury Neointimal lesion

of the heart, the left atrial appendage is excised, anda balloon attached to a pressure transducer is placedthrough the left atrium into the LV [14]. The balloonis inflated to maintain a constant pressure. Contractionof the LV against the inflated balloon generatesa continuous pressure reading that is converted intomeasurements of heart rate, LV developed pressure(LVDP), end diastolic pressure (EDP), the rate ofcontraction (þdP/dt), and the rate of relaxation (�dP/dt). Using the above parameters, the Langendorffgenerates reproducible data regarding ex vivo heartfunction.

One of the Langendorff’s strengths is the ability toassess the impact of acute regional or global I/R injuryon the heart. Regional I/R injury can be induced viatransient ligation of the LAD [15] or via a dual lumencatheter that selectively provides perfusion to one ofthe coronary ostia [16]. Regional ischemia is arrhyth-mogenic and is often used to study the effects of drugson arrhythmias. However, global I/R is of particularinterest to the cardiac surgeon as it reproduces the ef-fects of I/R on the heart when the heart is arrestedand restarted for cardiac surgery. To induce globalischemia on the Langendorff, the coronary perfusionis stopped, and the heart is immersed in a warm waterbath to induce injury for a set time prior to reperfusion.There are four key differences between this model of I/Rand the human heart undergoing arrest for cardiacsurgery. First, cold cardioplegia is given to arrest theheart in humans. Secondly, the animal prior to cardiec-tomy receives intraperitoneal heparin and not intrave-nous heparin. Thirdly, warm ischemia induces injury inthe Langendorff versus cold ischemia in the human.Finally, the isolated heart on the Langendorff is freeof any systemic factors (e.g., autonomic signaling,whole blood).

Despite the differences between the animal model ofI/R and human I/R, the Langendorff continues toprovide new insights into myocardial I/R at the

E 1

ac and Vascular Injury

s studied with the model Selected referencesgional I/R, normal physiology 10, 11, 14, 15gional I/R, LV work 20, 21hronic injury) 13, 25, 26

h ischemic injury 30, 31ypertrophy 31, 35, 36pathy 39–41, 42

ion and rupture 60–61, 67limb ischemia 54, 55, plaque formation 65, 67, 68

s 71, 76, 77s 78, 81

ABARBANELL ET AL.: MYOCARDIAL AND VASCULAR INJURY MODELS 241

molecular and genomic level. Recent representativestudies include (1) the importance of the Toll-like recep-tor 4 to myocardial dysfunction after I/R [17]; (2) theessential role of ferritin in ischemic preconditioning ofthe heart [18]; (3) the interaction between the reperfu-sion injury salvage kinase and Janus kinase-signaltransducers and activators of transcription pathwaysin post-conditioning of the heart [19]; and (4) the roleof embryonic stem cells in myocardial recovery afterI/R [20]. These developments would not have beenpossible without the use of animal hearts on theLangendorff. This knowledge may be the foundationof novel strategies that improve myocardial recoveryin patients after acute I/R.

FIG. 1. Isolated working heart model. Neely’s modification of theisolated heart perfusion model (Langendorff), which allows measure-ment of LV work. Unlike the contemporary Langendorff, perfusate issupplied by the left atrial cannula instead of the aortic cannula. Theaortic cannula in the Neely model is attached to a pressure chamberwhich the LV ejects against. The change in pressure created by theLV contracting can then be converted into work. (Reprinted withpermission from Neely et al. Am. J Physiol 1967 [21] as reproducedin Zimmer News Physiol Sci 1998 [11]).

The Isolated Working Heart Model

Neely and colleagues modified the Langendorff toovercome its inability to quantify left ventricularwork [21] and developed the isolated working heartmodel (Fig. 1). In this model, the KH solution is deliv-ered into the left atrium via a cannula attached toa peristaltic pump. The LV ejects this volume againsta constant pressure head created by a hydrostaticcolumn connected to the aorta. By providing volumefor the LV to eject, the work of the LV can be can calcu-lated as mentioned previously.

Others have taken Neely’s modification one stepfurther with a four chamber working model where allfour chambers of the heart are filled and eject [22].This last modification has even been applied to humanhearts that were deemed unsuitable for transplanta-tion after explantation [23]. However, the majority ofexperiments using the isolated working heart involvesmall animals due to short breeding cycles and cost.The working heart model offers the advantage of study-ing cardiac function under variable loading conditions[24]. Recently, this model was combined with trans-genic mice and microarray data to elucidate the roleof vascular endothelial growth factor (VEGF) receptor2 in myocardial protection after I/R [25]. While theisolated working heart is technically difficult, suchresults will likely ensure the place of this model in im-proving our understanding of myocardial injury in anex vivo setting.

LAD Occlusion Models

Unlike the Langendorff and the working heartmodel, which study the heart outside the systemicinfluences from the body [12, 24], the LAD occlusionmodel provides insight into the systemic influences onthe heart after myocardial I/R or MI. Occlusion of theLAD is generally performed through a left thoracotomy.After exposing the LAD, a suture or occlusion device is

used to either temporarily occlude or permanentlyligate the LAD or a branch of the LAD [14].

Transient LAD occlusion can also be achieved via‘‘closed chest’’ methods (Fig. 2) [26]. One closed chestmodel still involves a thoracotomy to implant an occlu-sive device, however, I/R injury is not induced untilseveral days post-operatively, when the acute inflam-matory response from surgery has resolved [26, 27].A second closed chest model utilizes catheter-basedocclusion without thoracotomy [6].

Using the LAD occlusion model, in vivo myocardialfunction as well as infarct size can be measured follow-ing injury. Two-dimensional echo and MRI are themainstays of assessing in vivo heart function. To quan-tify infarct size, triphenyltetrazolium chloride (TTC)can be infused into the LAD distal to the occlusion priorto explanation of the heart. TTC will stain the viable

FIG. 2. ‘‘Closed chest’’ model of myocardial ischemia/reperfusion.Nossuli and colleagues developed a murine model of I/R thatsurgically implants a suture snare around the LAD (A). This snareis exteriorized and the chest is closed (B). After sufficient time haselapsed to allow the inflammation of the surgery to resolve, the snareis tightened to induce myocardial ischemia (C). (Reprinted withpermission from Nossuli et al. Am J Physiol 2000 [26]).


heart tissue delineating the at-risk and infarct regions.Explanted myocardial tissue can also be analyzed forprotein expression and gene translation.

While any species can be used with the LAD occlusionmodel, small animals, such as mice, are technicallydifficult [5, 14]. Nevertheless, the short breeding cycleof the mouse, and the ability to design transgenicanimals, make the use of mice more compelling [28].Two recent examples include (1) Vidavalur andcolleagues, who using the murine LAD occlusion modeldemonstrated the potential of Sildenafil (a phosphodi-esterase inhibitor) to increase transcription of myocar-dial protective genes 24 hours after LAD occlusion [29],and (2) Aleshin and associates, who correlated the recep-tor for advanced glycation end-products (RAGE) withmyocardial damage following I/R in mice [30]. Althoughmany new pathways such as these are still to be corrob-orated in humans, these new developments based on

animal models have the potential to identify proteinsassociated with myocardial I/R. Potentially, blockadeof injurious proteins or exogenous delivery of beneficialproteins may attenuate the effects of an acute MI.

HEART FAILURE MODELS

Heart failure (HF) is a common occurrence followingMI or I/R. While HF is often considered a medicaldisease, there are aspects of the disease that requiresurgical intervention. Models of HF can be inducedvia ischemia, genetic modification, volume or pressureoverload, sustained tachycardia, or toxic drugs [31, 32].Similar to models mentioned previously, measurementof myocardial function can be performed in vivo with 2-D echo or MRI while ex vivo function can be measuredwith the Langendorff or the working heart model.Three models of heart failure of particular interest tothe surgeon are the ischemia induced HF model, thepressure overload HF (aortic banding) model, and thevolume overload HF (shunt) model.

Ischemia Induced Models of HF

Ligation of the LAD or a branch of the LAD has beenused to induce regional injury and subsequent heartfailure in multiple animal models [32]. While the proce-dures used are the same as the LAD occlusion modelsfor acute MI, a significant amount of time is requiredfor the animals to develop HF. In addition, not allanimals will progress to HF during the time frame ofthe experiment. Nonetheless, these models haveincreased our understanding of cellular and molecularevents related to ischemia-induced HF. For instance,Murray et al. examined the role of mitochondrialdysfunction in decreased efficiency of chronicallyinfarcted rat heart [33].

Clinically, ischemic models of HF have been used tostudy heart failure associated conditions, such as ische-mia related mitral regurgitation (MR). To characterizethe role of MR with respect to ischemic HF, Beeri et al.induced apical MI in sheep via LAD ligation, and useda LV to left atrial shunt to overload the left side of theheart resulting in MR [34]. This model was used todispute the clinical hypothesis that a mitral valvulo-plasty for MR after an ischemia event did not influenceremodeling of the heart [35].

Aortic Banding (Pressure Overload) Models of HF

Aortic banding models create a pressure overloadphysiology such as that which may be found in aorticstenosis, systemic hypertension, and coarctation ofthe aorta (Fig. 3) [32, 36–38]. Continued pressure over-load causes the LV to hypertrophy and eventually leads

FIG. 3. Latex casts of aortic banding model. Hu and associatesdeveloped a minimally invasive transverse aortic banding model inmice. Latex casts of the mouse heart and aorta clearly denote thestenotic area of the aorta (arrow) created by a suture ligature (leftheart) as compared to the sham (right heart). (Reprinted withpermission from Hu et al. Am. J Physiol 2003 [36]).

TABLE 2


to HF. The aorta may be banded in several locations toproduce these results. In adult guinea pigs, banding ofthe descending thoracic aorta has led to HF [37]. Band-ing of the ascending aorta in rats has also been used toinduce LV hypertrophy (LVH) and HF [39]. Recently,Stansfield et al. described a minimally invasive murinemodel of transverse aortic banding that may yield clin-ical insights [40]. They banded the transverse arch ofthe aorta with a suture slip knot placed between theinnominate and left carotid arteries. The operationwas performed through a small incision at the supra-sternal notch, which allowed subsequent removal ofthe band up to 4 wk later through the same incision.This technique creates a reversible model of LVH,which may lead to an understanding of the molecularsignaling associated with LVH.

Benefits and Challenges of Animal Modelsfor Myocardial and Vascular Injury Research

BenefitsAbility to study injury in the acute settingPlatform for drug or cell therapiesAvailability of transgenic or knock-out/in animalsAbility to study individual protein expression and function

ChallengesPhysiologic and anatomical differences between different animalspeciesInjury or lesion does not completely replicate the human state andcomorbid conditionsFew studies in animals have been translated to human therapyLack of model standardizationCost of animal husbandry, model development, and transgenic orknock-out/ in animalsPublic perception of animal research

Volume Overload Models of HF

Arteriovenous shunts are used to create volume over-load leading to dilated cardiomyopathy and subsequentHF. Carotid artery to jugular vein shunts have beensuccessfully performed in large animal models, suchas dogs and goats [41–43]. However, these models oftenrequire doxorubicin administration to develop HF.Others have used femoral artery to femoral vein fistu-las in rodents, and demonstrated HF without the needfor doxorubicin [44]. The reported mortality, however,in all these prior studies exceeds 25%. While the priorstudies were performed to avoid a laparotomy, the

creation of an aortocaval shunt may be a viable alterna-tive. Garcia et al. reported successful aortocaval shunt-ing in rodents with 10 of 11 rats alive at postoperativeweek 4 [45]. It should be noted that this study didnot perform any hemodynamic monitoring but wasintended to improve on the high mortality of prior stud-ies of rodent aortocaval induced HF. In support ofaortocaval fistula induced HF for research, a recentstudy using this model correlated the inhibitory effectsof angiotensin converting enzyme inhibitors on matrixmetalloprotease activity to better postoperative cardiacfunction in rats [46]. The authors did not comment onmortality, but their groups appeared to be intact at8 wk post-fistula creation. Taken together, the mortal-ity of arteriovenous shunts may be high, however, theshunt model appears to be a viable method of studyingvolume overload induced HF.

SPECIES LIMITATIONS OF MYOCARDIAL INJURY ANDHEART FAILURE MODELS

While the models previously described continue toimprove our understanding of myocardial injury, inter-species differences limit the reproducibility of infarctsize and the induction of HF across animal models(Table 2). Two noteworthy differences are the presenceof collateral circulation and variable inflammatoryreactions. Dogs and guinea pigs have a well-developedcollateral circulation compared with other animals,such as rat, pig, and baboon [47, 48]. The effect of collat-eral circulation is most apparent in the guinea pig,where I/R or MI cannot be induced due to extensivecollaterals [10, 48]. Interspecies variation is alsoevident by the fact that rats tolerate a significantlygreater infarct area (>46%) than dogs, that developfatal arrhythmias with infarcts of 30% or more [49].With respect to the variable species inflammatory


responses to myocardial injury, Dewald et al. studiedthe differences between dogs and mice after closedchest I/R injury [27]. Compared with dogs, mice hada more rapid inflammatory course, less capillarydensity in the infarct region, and very transient macro-phage infiltration. These differences in the coronarycirculation and the inflammatory process likely contrib-ute to extreme variability of published results.

The history of the LAD occlusion model developmentfurther underscores the challenges of interspeciesreproducibility in animal models. In the 1950s, dogswere predominantly used to study human coronaryartery occlusion because the canine coronary circula-tion was thought to closely approximate the human.However, the canine occlusion model was plagued byhighly variable infarct sizes and a mortality exceeding50% [5]. Other models, such as the porcine model,which more closely approximated the human coronarycirculation, were equally difficult in generating consis-tent ischemic injury due to arrhythmias. As recently as2005, despite the use of angiography in a closed chestmodel, Krombach et al. induced MI in only 34 of 44swine with a high intraoperative rate of ventricularfibrillation [6]. Given the numerous challenges of largeanimal models, many investigators have focused on thedevelopment of small animal models, which haveshorter breeding cycles, require less animal husbandry[5, 50], and permit the use of transgenic or knock-outanimals.

In an attempt to avoid some challenges of the LADligation model, others have developed a spontaneousmodel of MI. Shiomi et al. bred hyperlipidemic rabbitsthat have a greater than 90% incidence of spontaneousMI associated with complex intracoronary plaques [51].However, this model requires almost 11 mo before spon-taneous MIs develop. In addition, while these rabbitsdevelop complex plaques similar to humans, theseplaques do not rupture like human plaques.

Given all the preceding data, it is no surprise that ata molecular level interspecies variation also exists.Known differences include intracellular calcium han-dling, myocardial force-frequency relationships, andthe a and b myosin chain composition of the myocar-dium [31]. These data, and the concepts they entail,must be considered when attempting to apply animalexperimental observations of myocardial injury andHF to humans.

VASCULAR INJURY MODELS

Vascular injury is associated with hyperlipidemia,hypertension, infectious microorganisms, and smoking.Injury to the arterial intima results in the formationof atherosclerotic plaques and smooth muscle cell

activation associated with neointimal hyperplasia[52, 53]. This injurious cascade leads to the develop-ment abdominal aortic aneurysms (AAA), limb ische-mia, in-stent stenosis, and restenosis of vessels afterangioplasty. As a result, animal models have beenused in an attempt to improve our understanding ofthe inflammatory and immune responses involvedwith vascular injury [54, 55]. Subsequently, clinicaltherapies, such as drug eluting stents [56, 57] and endo-vascular repair of AAAs [58, 59] have been developed orundergone clinical trials as a result of animal models.Five groups of models exemplify current approachesto study vascular injury—AAA, hind limb ischemia,balloon angioplasty/wire induced injury, carotid arteryligation, and perivascular injury models.

Abdominal Aortic Aneurysm Models

AAA models predominantly involve mice, rats, ordogs [60, 61]. Numerous methods have been used toinduce aneurysms in animals. In broadest terms, theycan be classified as genetic or metabolic manipulation;direct chemical treatment or surgical alteration of theaorta; or elastase infusion. Initial animal models ofaneurysms in the 1950s and 1960s involved systematicmetabolic changes by dietary manipulation, directchemical toxicity to the aorta, or surgical alteration ofthe aorta. One group noted that rats fed a diet of 50%sweet peas developed skeletal deformities and aorticaneurysms [62]. Another group injected nitrogenmustard into the aortic adventitia of dogs to createaneurysms [63]. Surgical excision of the adventitiaand chemical treatment of the aorta was also attempted[64]. However, the size of the aneurysms could not bereliably reproduced in these models. More recently,the use of genetically altered mice appears to bea more viable option. For instance, mice lacking tissueinhibitors of matrix metalloproteinases (TIMP) wereused to study the role of matrix metalloproteinases(MMPs) in AAA formation [65]. Others have used trans-genic mice overexpressing renin and angiotensin lead-ing to hypertension and aneurysm formation [66].One of the more often cited models of AAAs involveselastase. Elastase is a pancreatic enzyme that degradesthe elastin in the aorta, leading to subsequent aneu-rysm formation. This model has been used to furtherexplore the role of MMPs, hypertension, and variousdrugs on AAA formation [67].

While this review covers a select subset of AAAmodels, other genetic modifications and chemicalagents have been used to induce AAAs. These arecovered more extensively elsewhere [60, 61, 68]. Modelsof AAA are certainly still evolving, but the insightsgained from the current models have been significantto date.


Hind Limb Ischemia Model

The hind limb ischemia model is a model of periph-eral arterial disease initially developed in rabbits andmice [69]. This model creates unilateral hind limbischemia with the contralateral limb serving as a con-trol (Fig. 4) [70]. Severe limb ischemia may be inducedby proximal ligation of the femoral artery and its sidebranches. To mimic chronic ischemia, distal ligation ofthe femoral artery may be performed while leavingthe arterial side branches intact. This latter methodproduces a model of mild chronic ischemia at rest andreduced blood flow reserve with exercise [71]. Thesetwo models have helped researchers identify molecularand gene transcription processes of ischemia, with theaim of developing future therapies [72–75]. Addition-ally, the hind limb model has elucidated aspects ofangiogenesis following ischemia [69, 76]. The hindlimb model can also be used to study I/R by use ofa temporary tourniquet.

Balloon Angioplasty and Wire Induced Injury Models

The balloon angioplasty model simulates the effectson the endothelium of percutaneous angioplasty. Stud-ies document that repeated endothelial injury viaballoon angioplasty causes similar lesions to that of hu-man atherosclerosis [77–80]. The balloon angioplastymodel is suggested to be superior to other vascularinjury models, which study smooth muscle prolifera-tion. This model is also used to investigate the inflam-matory and bone marrow responses to vascular injury[55, 81, 82].

The wire injury model is similar to the balloon angio-plasty model, and is mostly used in mice. This techniqueinvolves exposing the carotid artery and passing a flexi-ble wire into the common carotid artery to completelydenude the endothelium [83–85]. This technique canalso be used in the femoral artery [86]. The wire injurymodel is criticized for its inability to produce consistentinjury. In addition, endothelial injury only producesa small proliferative response, which usually does notexceed two to three cell layers [83].

FIG. 4. Hind limb ischemia model. Scanning laser Doppler perfusiofemoral artery. Immediately after ligation of the femoral artery, signifi(Reprinted with permission from Chalothorn et al. Am J Physiol 2005 [7

Carotid Artery Ligation Model

The carotid artery ligation model was developed byKumar and Lindner in the mouse [87]. The rationalefor this model is that alterations in blood flow areknown to increase intimal lesion formation in vasculargrafts and balloon injured vessels [88–90]. In thismodel, the common carotid artery is ligated near thebifurcation. Two to 4 wk following ligation, neointimallesions form. While this model is relatively simple toperform, abrupt total occlusion of the carotid arterydoes not replicate a physiological situation [84]. None-theless, investigators have used this model to clarifythe role of lipid lowering agents, such as statins, inmodulating the inflammatory cascade [91]. Severalexcellent review articles detail the potential uses forthis method, which are beyond the scope of this review[92, 93].

Perivascular Electrical Injury and Occlusion Models

Perivascular electric stimulation can be used toinjure the endothelium [94]. This model destroys themedial smooth muscle cells, denudes the endotheliumof the associated arterial segment, and transientlyinduces platelet-rich mural thrombosis. However, thistechnique is seldom used due to the extensive damageto the vessel. Alternatively, perivascular collars havebeen used to reduce blood flow and promote neointimalformation in the carotid artery. A hollow silastic band isplaced around the carotid artery, which induces macro-phage infiltration into the subendothelium, smoothmuscle cell proliferation, and deposition of extracellu-lar lipid. The collar is thought to cause obstruction ofthe adventitial vasa vasorum [95]. A similar modeldescribed in mice uses the femoral artery [96]. Unlikethe other vascular injury models described, the endo-thelial cells are not directly manipulated or removed.This permits the study of individual endothelial factors,such as endothelium-derived nitric oxide [52]. Theperivascular collar model is easy to reproduce andeasily quantified.

n images of a mouse hind limb before and after ligation of the rightcant collateral flow is seen as compared to the left control hind limb.0]). (Color version of figure is available online.)


SPECIES LIMITATIONS OF VASCULAR ANIMAL MODELS

Similar to the myocardial injury models, animalmodels of vascular disease/injury can be difficult toreproduce across species primarily due to differencesin atherosclerosis formation. Ignatowski and Anitsch-kow are credited with the discovery of the first animalmodel of atherosclerosis in 1908 and 1912, respectively[97, 98]. Their research was among the first to demon-strate that cholesterol induced atherosclerotic lesionsdiffer among species. For instance, while rabbits fedcholesterol-enriched diets form lesions similar tohuman atherosclerotic plaques, rabbits requireextremely high plasma cholesterol levels to developatherosclerotic plaques. In addition, rabbit plaquesform in the aortic arch and thoracic aorta, whereasthe abdominal aorta is the more likely site in humans[85]. Later research demonstrated that certain strainsof mice (e.g., Balb and common wild type) do not developspontaneous atherosclerosis secondary to high intake ofcholesterol [87, 90]. This has been attributed to highlevels of anti-atherosclerotic high-density lipoprotein(HDL), low levels of low-density lipoprotein (LDL),and very low-density lipoprotein (VLDL). Nonetheless,the ability to create transgenic or knock-out mice hasbeen useful in developing atherosclerotic models[99–101]. Some of the more commonly used mousemodels are the apolipoprotein E deficient (Apo E–/–),LDL receptor deficient (LDLr–/–), or Apo E3 Leiden(E3L) mice. Knockout of the ApoE or LDLr gene leadto severe hypercholesterolemia and spontaneous ather-oma formation [101]. The E3L mouse expressesa mutated form of the human ApoE3 gene, which cre-ates a hyperlipidemic phenotype. However, there aremany differences between these genetically alteredmice and humans. In mice, the disease course prog-resses rapidly, which leads to shorter induction time,unlike the more indolent course in the human. Addi-tionally, mice do not present with end-stage ischemiclesions, such as occlusive coronary artery disease orlimb ischemia [90]. Additional species differences areevident in wild type rats, which in general do notdevelop atheromas as they lack plasma cholesterylester transfer protein, unlike humans, and thus HDLis the major carrier of plasma cholesterol [98]. Hyper-lipidemia and atherosclerosis can be induced in ratswith a high cholesterol/high fat diet containing cholicacid and thiouracil. Thiouracil induces hypothyroidism,which leads to decreased LDL receptor activity andhypercholesterolemia. There are also strains of ratswith heritable hyperlipidemia and associated athero-genesis [102, 103]. Other animals have also been usedto model atherosclerosis, such as quail and chickens.Certain strains of quail can develop advanced athero-sclerotic lesions and myocardial infarction. The short

induction time of 2 wk makes chickens an attractiveatherosclerotic animal model. However, atheroscleroticlesions in chickens are not the complex plaques seen inhumans, and rarely result in complications such asmyocardial infarction [97, 104–107].

With respect to angioplasty induced injury, the por-cine model produces similar responses to humans afterangioplasty [108]. However in order to produce plaquerich in lipids, the pigs must be maintained on a highfat/cholesterol diet [109]. There are naturally occurringpigs with defective mutations in cholesterol metabo-lism. However, atherosclerosis develops in these pigsafter 7 mo of age, which leads to significant animalhusbandry costs [110].

Despite the inherent challenges of vascular injurymodels, recent research using these models has pointedto novel potential treatments of atherosclerosis andvascular injury with nitric oxide [111, 112] and genemediated therapies [113–115].

CONCLUSIONS

Animal models can provide novel mechanisticinsights into myocardial and vascular disease. Themodels described point to potential clinical therapies.However, the translation rate from the bench to thebedside remains low, likely due to differences in physi-ology and molecular pathways. A clinical understand-ing of the disease process of interest combined within-depth knowledge of the model and animal to beused may increase the predictive value of the animalmodels. Whether or not the institution of an animalmodel screening research consortium or randomizedcontrol trials, as some have proposed, will lead to thesuccessful translation of animal research is unclear inthe literature. Further outcomes analysis with stan-dardized animal models would be needed to draw thatconclusion. At the very minimum, careful scrutinyand stringent self-oversight are required to fulfill theethical, financial, and social responsibilities requiredof animal research.

ACKNOWLEDGMENTS

This work was supported in part by NIH R01GM070628 (DRM),NIH R01HL085595 (DRM), NIH 1F32HL092718 (AMA), and NIH1F32HL092719 (JLH).

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Animal Models of Myocardial and Vascular Injury

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