A nModels of Heart FailureRecent Developmentsand PerspectivesMinoru Hongo, Tsutomu Ryoke, and John Ross Jr.

Heart failure is a complex syndrome characterized by inability of theheart to supply sufficient cardiac output to meet the metabolic needs ofthe body. Over the past few decades, a number of animal models ofheart failure have been developed to study questions that cannot bereadily studied in the clinical setting. Because the syndrome of heartfailure in humans has many underlying causes, Tangingfrom primarymyocardial disease (often of unknown etiology) to myoca~dialfailureconsequent to ventricular ovedoad with seconda~ cardiac hypert~ophy(as in hypertension, valvular heart disease, or myocat-dialinfarction),no single animal model can successfully mimic the pathophysiology ofthese clinical settings. Regardless of the original cardiac abnormality,howeve~ the end-stage heart failure syndrome gene~ally presents apicture of cardiac dilation and circulatory congestion associated withmaladaptiveneurohumoral responses affecting the heartandperipheralcirculation, which pi-ovideprime targets for new treatment strategies.An idealanimal model of heartfailure should mimic the clinical settingas closely as possible, be accessible and reproducible, relatively stableunder chronic conditions, and sufficiently economical to permit exper-iments in a large number of animals. In this review, we discuss theadvantages and disadvantages of naturally occum”ng models of heartfailure and models in which hea~tfailure is induced in normal animals,focusing in particular on models that are useful for exploring diseasemechanisms and interventions to prevent or treatheartfailure. Much isbeing learned from large animals such as the dog and pig, althoughsmall animal models (rat and hamster) have many favorable featw-es,and as genetic methods and miniaturized physiologic techniques ma-ture, the mouse is beginning to provide gene-based models of cardiacfailure aimed at better understanding of molecular mechanisms.(TrendsCardiovascMed 1997;7:161-167). @ 1997, Elsevier Science Inc.

Cardiac failure is a pathophysiologiccondition in which the heart is unable tosupply sufficient blood flow to meet themetabolic demands of the body. It is de-

Minoru Hongo, TsutomuRyoke, and JohnRoss Jr. are at the Divisionof Cardiology,Departmentof Medicine,Universityof Cali-fornia San Diego, School of Medicine, LaJolla,CA92093-0613,USA.

fined as congestive heart failure whenassociated with evidence of fluid accu-mulation in the lungs (left heart failure)or the peripheral tissues (right heart fail-ure). Accompanying changes in the au-tonomic nervous system, the renin-an-giotensin system, and aldosteronesecretion usually lead to vasoconstric-tion and retention of salt and wate~ Thefailing myocardium exhibits many sub-

cellular abnormalities, including alteredintracellular Ca2+ handling, alterationsin contractile proteins, myocyte hyper-trophy, and a decrease in the numberand functional sensitivity of myocardial&adrenergic receptors. Chronic conges-tive heart failure is one of the leadingcauses of death in industrialized coun-tries.

Many animal models of heart failurehave been developed [reviewed byBishop (1982), Smith and Nuttall (1985),Gross (1994), ELsnerand Riegger (1995),Gwathmey (1995)]. An ideal animalmodel of heart failure should mimic hu-man disease and be easy to reproduce,chronically stable, suitable for measure-ments of cardiac size and function, andsufficiently economical to allow thera-peutic trials. No single model can com-pletely fulfill these criteria, althougheach model may be useful for addressinga specific mechanism, and it should berecognized that important differencesexist in pathophysiologic, cellular, andmolecular derangements among animalmodels and among species, which maylimit extrapolation to the clinical setting.There are two general types of animalmodels: those occurring naturally andthose experimentally induced in normalanimals (Table 1), several of which re-semble, at least in part, heart failure inhumans. The most common forms ofchronic heart failure observed clinicallyare idiopathic dilated cardiomyopathy(DCM), which recent studies indicate ishereditary in approximately 257. of pa-tients (McMinn and Ross 1995), heartfailure due to coronary artery diseasewith myocardial infarction, and heartfailure consequent to long-standing me-chanical cardiac overload, such as hy-pertension and valvular heart disease.This review directs attention to the ad-vantages, limitations, and applicationsof the most widely used animal modelsthat are relevant to human diseases andto the potential role of genetically al-tered mice for exploring the primary andsecondary molecular determinants ofmyocardial failure.

. NaturallyOccurringModelsof Heart Failure

The Cardiomyopathic Hamster

Cardiomyopathic strains of the Syriangolden hamster exhibit an autosomal re-

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Table 1. Animal models of heart failure

Techniques Species

NaturallyoccurringmodelsDilated cardiomyopathySalt-sensitive hypertension

Experimentallyinduced modelsMyocardial ischemia

Coronary ligationCoronary embolismElectrical shock

Chronic rapid cardiac pacingVentricular pacingSupraventricular pacing

Pressure overloadAortic bandingPulmonary artery banding

Volume overloadArteriovenous shuntMitral regurgitationAortic regurgitation

Toxic cardiomyopathyDoxorubicinAlcohol

Genetically altered animalsDilated cardiomyopathy

Hamster, dog, turkeyRat

Rat, dog, pig, rabbitDog, pigDog

Dog, pig, rabbitDog, rabbit

Rat, guinea pigMouse, rat, cat, dog, pig

Rat, dogDogRabbit

Rat, rabbit, dog, pigRat, turkey

Mouse

Boldtypeindicatesmostfrequentlyusedmodels.

cessive mode of inheritance (Bajusz1969) and have been used as a model forcardiac hypertrophy and congestiveheart failure because of their resem-blance to DCM in humans, Althoughmolecular mechanisms are unknown,cardiomyopathic hamsters at the latestage (7–10 months) reveal severe biven-tricular dilation and dysfunction associ-ated with congestive heart failure (pleu-ral effusion, ascites, edema, congestedlungs, and liver). The cardiomyopathichamster is being used increasingly as amodel because of the predictable diseaseprogression and relatively uniform fea-tures of the failing heart, the low costscompared with large animal models,and the ease with which large numbersof animals can be studied for testingtherapies. The cardiac disease in cardi-omyopathic hamster proceeds progres-sively in four histologic and clinicalphases (focal myolysis, hypertrophy,marked dilatation, and failure) duringthe life of the animal, varying to somedegree among the strains (Jasmin andProschek 1982). Microvascular spasmwithin the myocardium, which can re-spond to Ca2+-channel blockade, hasbeen described by some as a potentialpathogenetic mechanism (Factor andSonnenblick 1985); Ca2+ deposits in the

myocardium and myofibrillar loss havealso been described (Perennec et al.1987). The BIO 14.6 and CHF146 strainsexhibit a somewhat greater degree ofmyocardial hypertrophy and have a lifeexpectancy somewhat longer than theBIO 53.58, UM-X7.1, MS200, CHF147,and T02 strains (Hunter et al. 1984),although in the late phase there is leftventricular (LV) chamber dilation, wallthinning, and markedly impaired func-tion by transthoracic echocardiographyin both general groups, resembling thefindings of DCM in human subjects.

The hemodynamic profile in con-scious cardiomyopathic hamsters of theT02 strain, for example, is characterizedby low cardiac output, elevated IN end-diastolic pressure and total peripheralresistance, and r-educed renal bloodflow, mimicking the hemodynamic fea-tures of human heart failure (Panchaland Trippodo 1993). Markedly delayedW relaxation rate was also shown inthese hamsters in an isolated workingheart preparation, suggesting a decreasein the volume or number of sarcoplas-mic reticulum (SR) Ca2+ transport sites(Whitmer et al. 1988). Calcium seques-tration is impaired in the late stage,manifested by slow decay of intracellu-lar Ca2+transients,prolongation of con-

traction, and the activation of the Na+/Ca2’ exchanger (Hatem et al. 1994),features resembling those of failing hu-man hearts. Among the other abnormali-ties described are overexpression of c-myc proto-oncogene in the early stage ofUM-X7.1 (Deguchi et al. 1988), de-creased Ca2+ sensitivity of troponin andtropomyosin at the late stage inBI053.58 (Malhotra 1990), and alter-ations of G-protein mRNA in the latestage of BI014.6 (Katoh et al. 1990). Theprofile of elevations in the plasma atrialand brain natriuretic peptide (ANP,BNP) concentrations in BIO 53.58closely resembles that in patients withcongestive heart failure and in acutemyocardial infarction, but differs fromthat in rat models of myocardial infarc-tion (Tamura et al. 1994). Finally, treat-ment of the cardiomyopathic hamsterwith angiotensin-converting enzyme(ACE) inhibition has been shown to im-prove LV contractile performance, coro-nary flow, and prognosis (Haleen et al.1991), as well as LV energy reserves(Nascimben et al. 1995), indicating theusefulness of this model for testing druginterventions.

Cardiomyopathy in Other Species

Development of idiopathic DCM hasbeen described in dogs at the age of 1-2years, with Doberman pinschers andboxers having a particularly high inci-dence of DCM. The disease is character-ized by biventricular chamber dilatationwith dilatation of the annulus of theatrioventricular valves, leading to mitraland tricuspid regurgitation, atrial en-largement, and clinical and laboratoryfeatures resembling those in humanDCM (Smucker et al. 1990). IdiopathicDCM exhibiting depressed LV ejectionfunction and blood pressure occurs inturkey poults, developing in approxi-mately 20V0by 14 days of age (Gruver etal. 1993).

Lack of genetic information concern-ing all of the above species will limittheir applicability for studies of molecu-lar mechanisms of disease.

● Induction of Heart FailureinNormal ExperimentalAnimals

Myocardial Ischemia and Infarction

Coronary artery disease is the most com-mon etiology of cardiac failure in the

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United States, accounting for over 50Y0of patients presenting with congestiveheart failure. Coronary artery ligationand microembolization have been usedto produce myocardial infarction in thedog, but there are important differencesin the patterns of infarction between thehuman and the dog owing to the exten-sive collateral circulation and limitednature of subendocardial infarctions inthe latter, usually without significantheart failure (Richard et al. 1995). Theintracoronary microembolization modelin the dog appears to exhibit some sim-ilarity to heart failure caused by is-chemic cardiomyopathy in humans(Sabbah et al. 1991). Although suchmodels are expensive, the dog has beenused to study the effects of ACE inhibi-tion on LV remodeling (Jugdutt et al.1995), the incidence of ventricular ar-rhythmias and adrenergic activation(Sabbah et al. 1992), and the density andaffinity of myocardial fi-adrenergic re-ceptors (Gengo et al. 1992). Transmyo-cardial direct current shock in dogs,which results in scarring with reducedLVejection fraction and elevated plasmanorepinephrine levels, has been used toexamine the efficacy of drug interven-tions on ventricular remodeling (Mc-Donald et al. 1994).

MyocardialInfarction in the Rat

Chronic myocardial infarction inducedby left coronary artery ligation in rats isa well-established and widely usedmodel of chronic heart failure, whichresembles that seen in humans late aftera single large transmural myocardial in-farction. The rat myocardial infarctionmodel results in LV remodeling, charac-terized by a series of pathological, struc-tural, and geometric alterations accom-panied by myocardial hypertrophyprogressive chamber dilation, and latefailurw of surviving myocardium, withovert congestive heart failure developingin rats with large infarctions encompass-ing 40% to 50% of the LV (Pfeffer et al.1979, Anversa et al. 1992). The renin-angiotensin system appears to play animportant role in the postinfarction re-modeling process in the rat (Lindpaint-ner and Ganten 1991), and treatmentwith an ACE inhibitor attenuates ven-tricular remodeling, improves cardiacfunction (J.M. Pfeffer et al. 1985), andprolongs survival (M.A. Pfeffer et al.1985, Wollert et al. 1994). Use of an an-

giotensin II type l-receptor antagonistalso has favorable effects on remodeling(Schieffer et al. 1994).

Recent studies in the rat myocardialinfarction model indicate that therapywith insulin-like growth factor-1 (IGF-1)has favorable effects on cardiac perfor-mance and induces hypertrophy earlyafter infarction (Duerr et al. 1995), andin the same model with heart failure lateafter infarction, growth hormone, aloneor in combination with IGF-1, has ben-eficial effects on systemic vascular resis-tance and LV contractility (Yang et al.1995, Duerr et al. 1996).

The rat infarction model is relativelysimple to produce, is inexpensive,and hasrelevance to at least one form of clinicalheart failure.It also has some limitations,including effects of thoracotomy, consid-erable variability in the extent of infarc-tion between animals, and differencesfi-omthe failinghuman heartwith respectto the composition of myosin heavychainisofonns (Gay et al. 1988).

Chronic Rapid CardiacPacing

Recently, sustained rapid electrical pac-ing of the ventricle or atrium has beenused extensivelyas a model of heart fail-ure in the dog (Armstrong et al. 1986,Wilson et al. 1987, Spinale et al. 1990,Komamura et al. 1992); ventricular pac-ing has been used in pigs (Roth et al.1993), and ventricular and atrial pacinghas been used in the rabbit (Freemanand Colston 1992, Masaki et al. 1993,Ryu et al. 1997). This approach providesa reproducible model in which chroniccongestive heart failure can be reliablyinduced within several weeks of sus-tained rapid pacing and is characterizedby biventricular chamber dilatation anddysfunction, impairment of LV myocar-dial contractility, neurohumoral activa-tion with peripheral vasoconstriction,and abnormal reflex control (Evans et al.1995). Also, in the dog with mild to mod-erate hemodynamic derangements andno signs of heart failure, increasedplasma atrial natriuretic factor and cat-echolamines were found, without activa-tion of the renin-angiotensin system(Redfield et al. 1993), resembling find-ings in humans with mild DCM.Changes in the &adrenergic system withsevere tachycardia-induced cardiomy-opathy in the dog have included de-creased ~-adrenergic receptor density,reduced sarcolemmal content of the

stimulator-ycomponent of the G protein(Gs), increased content of the inhibitorycomponent of the G protein (Gi), anddiminished activity of adenylate cyclase,associated with a blunted myocyte con-tractile response to ~-agonist and for-skolin and increased Gi mRNA content(Spinale et al. 1994). Findings werepartly similar in rapid ventricular pac-ing-induced heart failure in the pig: Gsprotein content and function in the LVwere reduced, but Gi protein was alsoreduced (Roth et al. 1993). Also, in pigswith pacing-induced heart failure, thenormal action of &adrenergic receptorstimulation to cause amplification of theforce-frequency effect (Ross et al. 1995)was found to be lost (Eising et al. 1994).

The limitations of the rapid pacingmodel include an uncertain pathogene-sis, which is different from that of heartfailure in humans, and lack of long-termstabiIity because the heart failure is re-versible when pacing is stopped, a fea-ture that may limit applicability for test-ing some forms of therapy. Also,ventricular pacing can produce regionalwall motion and blood flow distributionabnormalities, and there is evidence forrelative myocardial ischemia duringpacing (Helmer et al. 1996). Neverthe-less, this model has been very valuablefor studying neurohumoral mechanismsand peripheral circulator alterations inheart failure, as well as for a few studieson drug efficacy (Evans et al. 1995, Spi-nale et al. 1995).

pressure Overload

Ascending aortic constriction in rats hasbeen reported to cause compensatedconcentric LV hypertrophy at 6 to 8weeks, followed by the onset of LV fail-ure (Feldman et al. 1993). Chronic ACEinhibition in this model decreased theextent of LVhypertrophy, attenuated car-diac dysfunction and LV dilatation, andcaused improved survival (Weinberg etal. 1994, Litwin et al. 1995). Also, theDahl salt-sensitive rat, which developssystemic hypertension after receiving ahigh-salt diet, was shown to exhibit com-pensato~ LV hypertrophy, which wasusually followed by LV chamber dilationand congestive heart failure as assessedby echocardiography (Inoko et al. 1994).These models may mimic the heart fail-ure that occurs late in the course of in-adequately treated hypertension in hu-mans, and the salt-sensitive rat model

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could allow study of the transition fromcompensated hypertrophy to congestiveheart failure without the use of surgicalbanding.

In the adult guinea pig, aortic bandingresulted in diminished LV contractilityin some animals, and impaired LVrelax-ation was associated with decreased ex-pression of phospholamban and SRCa2+-ATPaseproteins (K&s et al. 1995).A model of right ventricular pressureoverload caused by pulmonary arterybanding in the cat (Tsutsui et al. 1994)showed persistent association of exces-sive cytoskeletal microtubules associ-ated with myocyte contractile dysfunc-tion. Pulmonary artery banding of themouse has been shown to cause rightventricular failure when the banding issevere, which was associated with cie-creased expression of phospholambanmRNA (Rockman et al. 1994).

Volume Overload

The most common technique for accom-plishing volume overload has been cre-ation of a surgical arteno-venous shuntin dogs (McCullagh et al. 1972) or rats(Porter et al. 1983, Liu et al. 1991) inwhich compensated eccentric LV hyper-trophy initially occurs, followed by LVdysfunction, with heart failure in someanimals. Although the progression toheart failure is variable, such modelshave been useful for investigation of dis-turbances in fluid balance, electrolytes,and hormones commonly seen in heartfailure.

Chronic experimental mitral regurgi-tation has been produced in dogs andcan result in late LV dysfunction andheart failure; treatment with ~-adrener-gic receptor blockade resulted in im-proved LV function and was accompa-nied by improvement in the function ofisolated cardiomyocytes (Tsutsui et al.1994).

Chronic severe aortic regurgitationhas been created in rabbits by aorticvalve perforation with a catheter. Ini-tially compensatory eccentric LV hyper-trophy was observed, frequently fol-lowed by heart failure with systolicdysfunction (Magid et al. 1994). This se-quence, characterized by serial M-modeand Doppler echocardiography, appearsto provide a model resembling that oc-curring in humans with this lesion, al-though with a markedly compressedtime course.

Toxic Cardiomyopathy

Certain animal models may be useful forunderstanding specific cardiomyopa-thies that can be observed in the clinicalsetting. Chronic administration of doxo-rubicin, an antineoplastic agent, cancause cardiotoxicity in humans, andwhen administered intravenously forseveral weeks to swine, biventricularheart failure develops associated withmyocyte vacuolization and marked lossof myofibrils (Herman and Ferrans1983). Alcohol-induced cardiomyopathy,produced by infusion of 5Y0ethanol, ischaracterized by ventricular chamberdilatation and cardiac hypertrophy, ac-companied by alterations in myocardialultrastmcture and myocardial phospho-Iipid and fatty acid composition (Norenet a]. 1983),

c GeneticallyAltered Mice

Methods for introducing defined muta-tions into the germ line, or to producetargeted disruption of a specific gene,along with the development of miniatur-ized technologies to assess quantita-tively in vivo the physiologic cardiacphenotype in mice using cardiac cath-eterization (Rockman et al. 1993, Gott-shall et al. 1997) and transthoracicechocardiography to define LV function(Hoit et al. 1995) and ventricular cham-ber size and wall thickness as well asfunction (Tanaka et al. 1996) now pro-vide the potential for identifying pri-mary and secondary molecular determin-ants of a disease (Chien 1993, Field1993). Several genetic murine modelsthat have some relevance to the heartfailure state have been reported, and re-cently genetic models of heart failure inthe mouse have been described.

Phospholamban is a phosphoproteinthat regulates Ca2+-ATPase activity incardiac SR. Phospholamban-deficientmice generated by targeted disruption ofthe phospholamban gene exhibit en-hanced basal myocardial contractility,without any further increase with &ago-nist stimulation, reflecting a baseline in-crease in the affinity of the SR Ca2+pump for Ca2+(Luo et al. 1994). Insightsinto the potential role of this gene inheart failure may be provided by ani-mals overexpressing or underexpressingthis gene, or by eventual crossbreedingexperiments between the phospholam-

ban-deficient mutant and mice withheart failure.

In failing myocardium, the &adrener-gic system is known to exhibit decreasedresponsiveness at the receptor and pos-treceptor levels, and upregulation of theactivity and mRNA level of fl-adrenergicreceptor kinase (PARK) has been de-scribed (Ungerer et al. 1993). Transgenicmice overexpressing either ~ARKl oranother G-protein–coupled receptor ki-nase (GRK5) have shown reductions inLV contractility in vivo and reduced re-sponsiveness to isoproterenol, alongwith depressed myocardial adenylyl cy-clase activity and functional uncouplingof the ~-adrenergic receptors (Koch etal. 1995, Rockman et al. 1995). In con-trast, mice overexpressing a BARK in-hibitor exhibited enhanced basal myo-cardial contractility in vivo (Koch et al.1995). Such transgenic animal modelsproducing alterations in myocardialcontractility have potential for providinginsights into mechanisms of adrenergiccontrol in heart failure and potential av-enues for therapy.

Genetic Models of CardiacHypertrophy in the Mouse

Hypertrophic cardiomyopathy (HCM)has been shown in family studies oftento involve mutations of the ~-myosinheavy chain (MHC) gene and typically ischaracterized by asymmetrical LV hy-pertrophy, myofiber disarray, diastolicLV dysfunction, maintained systolicfunction, and an increased incidence ofsudden death (Fananapazir and Epstein1994). A murine model of this disorderresembling one of the human HCM gen-otypes (a missense mutation ofArg403+Gln in the a cardiac MHC gene)has been reported (Geisterfer-Lowranceet al. 1996), which exhibits similar his-tologic features, along with LV hypertro-phy, left atrial enlargement, and im-paired LV relaxation. Although cardiacoutput of the isolated heart was reducedin this model, no evidence was providedof depressed LVmyocardial contractilityor heart failure. Another murine modelof LV hypertrophy with many pheno-typic features of HCM resulting fromoverexpression of the H-ras gene tar-geted to the ventricles with the MLC2Vpromoter has been described (Hunter etal. 1995), including myofiber disarray,

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MLP25,38.2 g

14200msec +

I 2.0mm

Figure1. TransthoracicM-modeechocardiographictracingsusinga 9 MHztransducerof theshort axis of the left ventricle (LV)in awild-typemouse (left panel) and a mouse homozygousfor gene-targeted disruption of the muscle LIM protein (MLP) (right panel). The arrowsindicate the endocardium of the LV chamber at end-diastole [anterior (upper) and posterior(lower) LV walls]. Note the dilated LV chamber in the cardiomyopathic mouse, with reducedsvstolic excursion and thinniruzof the LVwalls.Modifiedfrom Arberet al. 1997and repro-duced by permission from Arb;r et al. 1997.

asymmetrical LV hypertrophy, and im-paired LVrelaxation, but again, LVmyo-cardial contractility was not depressednor was heart failure evident (Gottshallet al. 1997).

Genetic Models of DilatedCardiomyopathy in the Mouse

A murine model of DCM associated withheart failure has been described recently(Arber et al. 1997). It was produced bygene-targeted disruption of the muscleLIM protein (MLP), an essential regula-tor of myogenesis expressed at high lev-els in the adult heart (Arber et al. 1994).In studies in mice homozygous for theMLP knockout, marked disruption ofmyofibrillar organization was observedin cardiac myocytes, and there was hy-pertrophy of atria and ventricles, withincreased wet-lung weight consistentwith LV failure (Arber et al. 1997). Tran-sthoracic echocardiography in mice sur-viving to adulthood (10–12 weeks)showed a dilated, thin-walled LV cham-ber, with markedly diminished LV wallshortening (Figure 1). Using in vivocatheter-tip micromanometry, there alsowas depressed LVmyocardial contractil-ity evidenced by reduced maximum LVdP/dt with elevated LV end-diastolicpressure and impaired relaxation (pro-longed LV time constant of LV pressure

fall, tau). The LVdP/dt response to &adr-energic stimulation also was severely re-duced. LV myocardial atrial natriureticfactor mRNA expression was markedlyupregulated, and a skeletal actin wasmoderately increased compared withwild-type littermates, whereas no differ-

2+ ATpase or phosphola-ences in SR Camban mRNA levels were detected (Arberet al. 1997). This genetic model of heartfailure in the mouse shows a number ofmorphologic, echocardiographic, hemo-dynamic, and molecular features resem-bling those of idiopathic DCM associ-ated with LV failure in humans.

Anothermodel of DCM recentlywas re-ported in transgenicmice associated withoverexpressionof the cardiac stimulatorG-protein (G~a), which leads to chroni-cally enhancedresponsivenessto &adren-ergic stimulation. Echocardiographicstudies in older mice (age 15 months)showed the latedevelopment of LVcham-ber enlargement with reduced LV waifshortening and increased incidence of ar-rhythmias, although hemodynamic orother evidence of LV failure was not pro-vided (Iwase et al. 1997). Thus, in thismodel, long-term overactivityof &adren-ergic stimulation appeared to contributeto the development of a DCM.

The availability of genetic mousemodels of DCM will provide a number of

advantages over larger animal models,including ready maintenance of echo-cardiographically selected strains withsevere disease and the ability to cross-breed with other phenotypes (for exam-ple, genes that could rescue selected ab-normalities). Also, the availability of anextensive genome map of the mousealong with many molecular probesshould permit isolation of genes that arecausative or secondary to the heart fail-ure phenotype using subtraction clon-ing. Finally,such genetic murine modelsshould allow assessment of potentialtherapies at various stages of the diseasein a rapid and relatively cost-effectivemanner.

● Acknowledgments

This review was supported by an en-dowed chair awarded by the AmericanHeart Association, California Affiliate,San Diego County Division (J.R.), theRichard D. Winter Fund, and by the HL53773 awarded by the National HeartLung and Blood Institute. The MLP car-diomyopathic mouse was developed in acollaboration between the laboratoriesof P. Caroni and K. Chien. The authorsthank Cheryl Bugsch for expert manu-script preparation.

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