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Right arrow Congestive Heart Failure

Ann Thorac Surg 2005;79:1445-1453
© 2005 The Society of Thoracic Surgeons

Review

Animal Models of Heart Failure: What Is New?

Eric Monnet, DVM, PhDa,*, Juan Carlos Chachques, MD, PhDb

a Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado, USA
b Cardiovascular Surgery, Pompidou Hospital, University of Paris, Paris, France

* Address reprint requests to Dr Monnet, Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA
eric.monnet{at}colostate.edu


   Abstract
Top
 Abstract
Introduction
 Volume Overload
 Pressure Overload
 Rapid Pacing Model of...
 Drug-Induced Models of Heart...
 Models of Ischemia
 Naturally Occurring Dilated...
 Genetically Modified Models
 Heart Failure Model Induced...
 Conclusions
 References
 
Heart failure is the major cause of mortality in Western countries. Medical treatment of heart failure is associated with 50% survival at 5 years. Experimental models are required to better understand the progression of the disease and elaborate new therapy. Heart transplantation, left ventricular assist devices, artificial hearts, and cardiac bioassist techniques require animal models for testing and optimizing before they are implemented on human patients. The perfect model of heart failure that reproduces every aspect of the natural disease does not exist. Acute and chronic heart failure models have been developed to reproduce different aspect of the pathology.


   Introduction
Top
 Abstract
 Introduction
Volume Overload
 Pressure Overload
 Rapid Pacing Model of...
 Drug-Induced Models of Heart...
 Models of Ischemia
 Naturally Occurring Dilated...
 Genetically Modified Models
 Heart Failure Model Induced...
 Conclusions
 References
 
Heart failure is the major cause of mortality and morbidity in Western countries. Despite significant improvements in the medical therapy of congestive heart failure, the mortality rate is in excess of 50% after 5 years [1, 2]. Surgical treatment, including heart transplantation, cardiac bioassist techniques, and left ventricular assist devices, is used to interrupt the progression toward death.

Congestive heart failure is characterized by alteration of hemodynamic parameters (preload and cardiac output). Complex reflex changes in the sympathetic nervous system, the cardiac endocrine system, and the renin-angiotensin system (which contributes to vasoconstriction and retention of salt and water) are then triggered by the reduction of cardiac function [3–6]. Chronic congestive heart failure is also associated with subcellular abnormalities that are associated with stimulus to hypertrophy insufficient to maintain adequate cardiac output [3, 7, 8]. Apoptosis, activation of tumor necrosis factor alpha, and nitric oxide have been shown to be involved in the progression of heart failure [5, 7, 9].

Research associated with heart failure has focused on identification, quantification, and characterization of the injured tissue, evaluation of different therapeutic modalities, and understanding the mechanism of heart failure [2, 4, 6]. A requirement of all studies on heart failure is an adequate and appropriate model of heart failure. The ideal model should be able to reproduce each of the aspects of the progression of naturally occurring congestive heart failure. However, none of the models available is able to entirely reproduce congestive heart failure. Some models reproduce neuroendocrine changes whereas others better reproduce the remodeling that occurs during chronic heart failure. Acute models are not going to reproduce the neuroendocrine dysfunction, whereas a chronic model might. Therefore, the correct model should be used to evaluate specific aspects of the treatment of heart failure. Each model has inherent limitations including a lack of stability, a lack of predicability of damage, and a lack of adjustability.

Our personal experience in the research and development of surgical procedures for the treatment of heart failure provides support for the analysis and evaluation of different heart failure models. In addition, a literature search including more than 20 years (1980–2003) was conducted on Medline with the following keywords: heart failure, model, and animal. The literature selected was based on the description of the model, the potential utilization of the models, and value of the models for testing new surgical interventions for the treatment of congestive heart failure.

The purpose of this review was to assess different models of heart failure and their respective contribution to the development of different surgical interventions for heart failure treatment. We considered animal models of heart failure that simulate one or several of the more common etiologies of heart failure, namely, myocardial ischemia, dilated cardiomyopathy, hypertension, and valvular abnormalities. Surgical interventions for the treatment of heart failure mostly target systolic function. However, because diastolic dysfunction and postischemic ventricular remodeling are becoming more prominent in the progression of heart disease we also present models of heart failure that reproduce some diastolic dysfunction.

Heart failure has been induced in different species with volume overload, pressure overload, fast pacing, myocardial infarction, or with cardiotoxic drugs. Models of genetically induced cardiomyopathy are also available in small animals.


   Volume Overload
Top
 Abstract
 Introduction
 Volume Overload
Pressure Overload
 Rapid Pacing Model of...
 Drug-Induced Models of Heart...
 Models of Ischemia
 Naturally Occurring Dilated...
 Genetically Modified Models
 Heart Failure Model Induced...
 Conclusions
 References
 
Acute Volume Overload
Acute volume overload with isotonic fluids or colloids has been used to reproduce the hemodynamic situation of congestion observed in chronic heart failure [10, 11]. It can be used alone or, commonly, in conjunction with another model of heart failure. Volume overload will aggravate the hemodynamic changes induced by the model of heart failure. Volume overload has been used to evaluate myocardial reserve. This model has been used mostly in combination with another model to exacerbate modifications of hemodynamic parameters. This technique is effective for evaluating diastolic dysfunction after induction of heart failure.

Chronic Volume Overload
Chronic volume overload induced left- and right-sided heart failure with severe ventricular dilation. Surgical techniques used to induce volume overload are the creation of an arteriovenous fistula (carotid artery to jugular vein), and induction of mitral valve regurgitation [12–15].

Creation of an arteriovenous fistula between the carotid artery and the jugular vein resulted in a 50% increase of the left ventricular end-diastolic volume without increasing end-diastolic pressure [13]. In another study, surgical creation of an arteriovenous fistula was described in goats in combination with doxorubicin injection to induce a biventricular heart failure [15]. Stable ventricular hypocontractility with left ventricular dilation was observed. A higher dose of doxorubicin was associated with more pronounced left ventricular dysfunction and was associated with clinical symptoms of heart failure.

Mitral regurgitation has been induced in dogs with a transvenous approach, resulting in significant mitral regurgitation and dilation of the left ventricle. Under general anesthesia, an introducer sheath is placed into the left ventricle through the carotid artery. Flexible rat-tooth forceps inserted through the sheath are used to cut chordae. Chordae were cut until the pulmonary capillary wedge pressure increased by 20 mm Hg, cardiac output dropped by 50%, and arterial pressure decreased [12]. In 6 months, mitral regurgitation increased left ventricular end-diastolic volume by 75% and doubled left ventricular stroke volume. Left ventricular mass increased while right ventricular free wall mass was relatively unchanged. Chronic mitral regurgitation produced asymmetric left ventricular dilatation with regional variation in geometry. The septum increased its contribution to the left ventricular stroke volume [12]. Mitral regurgitation is associated with myocyte lengthening and reduction of myocytes contractility. This model has the advantage of being minimally invasive; however, it induces anatomic changes in the mitral valve. This model has been used mostly to test medical treatment of heart failure.

Canine models of mitral regurgitation have been used to elucidate numerous abnormalities at the cellular level associated with the development of left ventricular dysfunction. Models of mitral valve regurgitation do not represent the complete spectrum of heart failure. Mitral valve regurgitation has been recognized as an important measurement for the progression of heart failure; however, these models do not have alterations in the myocardial structure observed in congestive heart failure due to ischemia, or hypertrophy. Chronic models of volume overload have been used to evaluate the effect of cardiomyoplasty and cardiac binding of the development of ventricular dilation.


   Pressure Overload
Top
 Abstract
 Introduction
 Volume Overload
 Pressure Overload
Rapid Pacing Model of...
 Drug-Induced Models of Heart...
 Models of Ischemia
 Naturally Occurring Dilated...
 Genetically Modified Models
 Heart Failure Model Induced...
 Conclusions
 References
 
Models involving an abnormal pressure load have been most useful in the study of the pathogenesis of hypertrophy, subcellular failure, and vascular changes. Hypertension is associated with an increase risk for the development of heart failure. Induction of hypertension and ventricular hypertrophy should be considered when the evaluation of new treatment of heart failure is tested in an animal model.

Aortic Banding
Supravalvular aortic stenosis with narrowing of the aorta above the valve induces a pattern of ventricular strain similar to that of aortic stenosis [16]. Producing this model involves dissecting the ascending aorta free from the pulmonary artery and placing a Dacron (C.R. Bard, Covington, GA) patch 1.5 to 2.0 cm wide and 6 to 7 cm long to encircle it. The diameter of the aorta is reduced by 50%. Aortic and left ventricular pressure are then rechecked to confirm that a 50- to 60-mm Hg systolic pressure gradient has been created.

This model produces marked left ventricular hypertrophy, but does not reproduce neurohormonal activation or left ventricular systolic dysfunction. Alteration of left ventricular stiffness and reduction of relaxation make models of hypertension interesting for the evaluation of diastolic dysfunction. It is well established that diastolic dysfunction is an important factor in the development of left ventricular failure [17]. Models of left ventricular hypertrophy may not be of primary importance for the cardiac surgeons who want to evaluate a surgical intervention for the treatment of heart failure. However, such a model might be combined with another model of heart failure to further reproduce the progression of the disease in a human patient with congestive heart failure.

Monocrotaline
Monocrotaline has been used in dogs and rats to induce pulmonary hypertension and right-sided hypertrophy [18, 19]. Monocrotaline is a pyrrolizidine alkaloid found in the plant species Crotalaria spectabilis. Administration of monocrotaline causes a pulmonary vascular syndrome characterized by proliferative pulmonary vasculitis, pulmonary hypertension, and cor pulmonale [20]. Monocrotaline undergoes hepatic transformation from the action of the cytochrome P450 monooxygenase system in the liver to form the monocrotaline pyrrole, which then circulates to the lung parenchyma. The initial injury leads to increased capillary permeability, moderate interstitial edema, fibrosis, macrophage accumulation, modification of pneumocytes II, and alveolar edema [20]. The initial injuries result in endothelial degeneration or hyperplasia, hypertrophy of medial smooth muscle, and adventitial edema. These changes result in augmentation of pulmonary vascular resistance and pressure overload of the right ventricle. In dogs the monocrotaline pyrrole needs to be administered, probably because the adult dog liver does not possess the enzymatic components necessary to process the monocrotaline to its active metabolite, monocrotaline pyrrole [21].

This model has been used to evaluate neointimal proliferation during pulmonary hypertrophy and its modulation, ventricular hypertrophy, regulation of gene expression, neuroendocrine modulation, and hemodynamic variations with pulmonary hypertension [19]. This model has been used in dogs to evaluate cardiopulmonary transplantation with chronic pulmonary hypertension [18].

Systemic Hypertension in Rats
The systemic hypertensive rat is a well-established model of genetic hypertension. The cardiac function fails at 20 months, and more than 50% of the animals have clinical signs of heart failure [22, 23]. Left geometry and function are altered on echocardiography. Heart failure is characterized by neurohumoral changes and apoptosis. The systemic hypertensive rat is a good model to reproduce hypertension-induced heart failure in humans and to study the transition from hypertrophy to failure [22, 23]. An advantage of this model is that it does not require surgery and pharmacologic intervention for induction. Another strain of rats with diabetes develops systemic hypertension and heart failure at an earlier age [24].


   Rapid Pacing Model of Heart Failure
Top
 Abstract
 Introduction
 Volume Overload
 Pressure Overload
 Rapid Pacing Model of...
Drug-Induced Models of Heart...
 Models of Ischemia
 Naturally Occurring Dilated...
 Genetically Modified Models
 Heart Failure Model Induced...
 Conclusions
 References
 
Fast pacing of the heart has been used to produce a progressive, reliable model of heart failure in different animal species [25]. Dogs, pigs, sheep, and rabbits have been used for this model [26–28].

Right ventricular pacing has been accomplished in dogs with transvenous lead implantation [26]. The right ventricle was paced at a rate varying from 180 to 240 bpm, which produced congestive heart failure in 3 to 4 weeks [27, 29]. With the right atrium paced at 400 bpm, the left and right ventricles dilated without hypertrophy [30]. This model is characterized by augmentation of cardiac volume with fluid retention, elevation of catecholamines, atrial natriuretic peptide, renin angiotensin, aldosterone, endothelin-1, and tumor necrosis factor alpha. Chronic tachycardia also induced abnormalities in calcium handling and disruption of the extracellular matrix by activation of matrix myocardial metalloproteases, gelatinase, and other cytokines. Extracellular matrix remodeling is accompanied by decreased and delayed systolic left ventricular torsional deformation and loss of early diastolic recoil. Fast pacing for 1 week induces a reduction in the number of myocytes. Apoptosis has been reported as one of the causes of myocyte loss during fast pacing. After cessation of the stimulation, systolic and diastolic function of the heart recovered in 2 to 3 weeks. Diastolic dysfunction persisted longer than systolic dysfunction after interruption of fast pacing. Recovery of the cardiac function is associated with hypertrophy of the wall of the ventricles with persistence of the dilation.

A chronic model of heart failure has been induced with fast pacing by altering the pacing protocol. Different protocols have been implemented to induce chronic congestive heart failure. Takagaki and associates [31] induced heart failure in dogs with rapid pacing at 230 bpm for 4 weeks and then 190 bpm for another 4 weeks. Measurements of pressure volume loops, hemodynamic parameters, echocardiography, left ventricular mass and wall stress, pathologic examinations, and plasma atrial natriuretic peptide and catecholamine levels all confirmed severe, persistent congestive heart failure [31]. Most of the systolic and diastolic measurements were abnormal and stable at 8 weeks. However, tau, min dp/dt, left ventricular end-diastolic pressure (LVEDP), and wall stress decreased significantly after 4 weeks of fast pacing but were still not back to baseline [31]. Patel and colleagues [32] also induced a chronic model of heart failure by pacing dogs for 10 weeks.

Fast pacing the heart has been used to produce a reliable model of progressive heart failure in different animal species [25]. This model is particularly well suited for the evaluation of congestive heart failure because it does not require major surgical trauma such as thoracotomy and pericardiectomy, which may interfere with the interpretation of physiologic data. This model has been used to evaluate the progression of heart failure. It progresses over several weeks, which allows sequential observation. It triggers left ventricular dilation and pump failure similar to those observed in patients with dilated cardiomyopathy. The neurohormonal activation induced closely parallels that observed in humans with congestive heart failure. However, myocardial ischemia and hypertrophy, which are a common component of the development of congestive heart failure, are not present in this model. The severity of the congestive heart failure is a function of the stimulus. The severe dilation of both ventricles has been associated with dilation of mitral valve annulus and regurgitation of the valve, which is a major factor for the progression of heart failure [28].

Fast-pacing models have been used to evaluate defects at the cellular and extracellular levels and to evaluate new pharmacologic strategies. Fast-pacing models have also been used to evaluate different surgical interventions to alter remodeling during heart failure or to evaluate the recovery phase after different interventions [33–36]. Chronic models without recovery of cardiac function are more appropriate for the evaluation of different therapeutic modalities than the model with recovery of the cardiac function.


   Drug-Induced Models of Heart Failure
Top
 Abstract
 Introduction
 Volume Overload
 Pressure Overload
 Rapid Pacing Model of...
 Drug-Induced Models of Heart...
Models of Ischemia
 Naturally Occurring Dilated...
 Genetically Modified Models
 Heart Failure Model Induced...
 Conclusions
 References
 
Doxorubicin
Doxorubicin is well known for its cardiac toxicity during chemotherapy for cancer. The cardiotoxicity is due to free radical formation and lipid peroxidation, which results in changes in lysosomes, sarcolemmas, mitochondria, and sarcoplasmic reticulum [37]. These changes induce calcium overload, activation of hydrolytic enzyme, and reduction in energy production [38]. Reduction of cardiac function was a result of the loss of structural integrity.

Because doxorubicin cardiotoxicity is dose dependent [39], it has been used to predictably induce heart failure in different animal species—dog, sheep, and goats [14, 15, 39–41]. Doxorubicin has been delivered with intravenous and intracoronary injections [40, 41]. Intracoronary injection allows delivery of doxorubicin at a smaller dose to induce heart failure without systemic toxicity [40, 42]. Intracoronary injection can be performed after surgical placement of a catheter in a diagonal branch of a coronary artery [43] or after percutaneous coronary artery catheterization [42].

Heart failure induced by doxorubicin has been characterized by bilateral enlargement, thinning of the ventricular wall, and reduction of the ejection fraction during echocardiography [40, 43]. An arteriovenous fistula has been used to induce biventricular heart failure with injection of doxorubicin [13–15]. After doxorubicin injection, the ejection fraction measured on echocardiography decreased from 0.54 to 0.35 while the cardiac output decreased from 5.6 to 3.9 L/min in 2 weeks. Left ventricular end-diastolic and -systolic diameter indices have been shown to increase by 10% and 30%, respectively [40]. The association of an arteriovenous shunt and doxorubicin administration has different advantages. The injected dose of doxorubicin can be reduced, avoiding animal toxic effects that can be related to animal mortality. Also, toxicity to the environment is reduced.

Heart failure induced by doxorubicin has been used to evaluate different treatment modalities for heart failure. However, this model has several limitations. First, the degree of left ventricular dysfunction is variable. Second, this model is associated with a high incidence of arrhythmia that contributes to the mortality rate. Third, doxorubicin has undesirable bone marrow and gastrointestinal toxicities. Although intracoronary injection eliminates this problem, multiple intracoronary injections are required as with the microembolization technique, thus increasing the cost of the model. Doxorubicin-induced heart failure is irreversible and progressive. Cellular transplantation, dynamic cardiomyoplasty, and adynamic cardiomyoplasty have been evaluated for the treatment of heart failure [14, 41, 44].

Propranolol
Propranolol is a beta-blocker that has a profound and prolonged negative inotropic effect. Intravenous injection at a dosage of 2 to 3 mg/kg will induce a significant reduction of mean arterial pressure, cardiac output, left ventricular max dp/dt, and Emax [45–48]. Left ventricular systolic dysfunction was characterized by a diminished resting ejection fraction of 0.45 and a depressed +dP/dtmax of 1537 mm Hg/s [45]. Left ventricular max dp/dt was reduced from 1762 to 745 mm Hg/s in another experiment [49]. Propranolol injection has been used to evaluate cardiomyoplasty, aortomyoplasty, and skeletal muscle [46, 47, 50, 51].

Intravenous propranolol injection provides an acute, stable, and predictable model of heart failure. This model does not provide ventricular dilation, which might be a limitation for the testing of cardiac bioassist techniques.

Saponin
Another acute model of heart failure has been created with intracoronary injection of saponin in dogs. Injections of saponin were followed by volume loading and continuous intravenous infusion of methoxamine. After the treatment, aortic blood flow and left ventricular dP/dt markedly decreased, whereas LVEDP, right atrial pressure, and systemic vascular resistance increased [52].

Imipramine
Imipramine is a tricyclic antidepressant agent with a detrimental effect on cardiac function. Imipramine blocks the sodium channels and {alpha}-adrenergic receptors, interferes with calcium handling, and has an anticholinergic effect [53]. The value of intravenous imipramine in creating a reversible model of short-term heart failure was evaluated in anesthetized dogs. After a 30-minute imipramine intravenous infusion, positive left ventricular dP/dtmax decreased from 1368 to 909 mm Hg/s, LVEDP increased, and left ventricular pressure decreased from 106 to 87 mm Hg [53]. Cessation of imipramine administration resulted in partial restoration of cardiac function within 60 minutes. This deterioration and subsequent recovery was also demonstrated with echocardiographic measurements. Repeated infusions of imipramine in 3 anesthetized dogs with a 2-week interval showed the reproducibility of the hemodynamic effects and partial recovery of ventricular function [53]. During imipramine injection, skeletal muscle function does not seem to be affected [53]. Widening of the QRS complexes occurred with prolonged injection, but no arrhythmias were reported [53].

This model can be used to produce short-term reversible heart failure in anesthetized animals to test the efficacy of supportive interventions such as dynamic cardiomyoplasty, intraaortic balloon pumping, and mechanical cardiac assist devices [53].


   Models of Ischemia
Top
 Abstract
 Introduction
 Volume Overload
 Pressure Overload
 Rapid Pacing Model of...
 Drug-Induced Models of Heart...
 Models of Ischemia
Naturally Occurring Dilated...
 Genetically Modified Models
 Heart Failure Model Induced...
 Conclusions
 References
 
Myocardial ischemia or infarction is a common risk factor for the development of congestive heart failure in humans. Myocardial ischemia is associated with left ventricular remodeling including changes in geometry, structure, and function. Persistence of the remodeling, although initially adaptive, ultimately precipitates the progression of heart failure. The mechanism responsible for this deleterious transition from adaptive remodeling to dysfunction is not fully understood and is more likely under the influence of the neurohormonal axis, loading conditions of the remaining myocardium, and alteration of the extracellular matrix [2–5].

In an effort to more closely reproduce the progression of heart failure in humans with coronary disease, models of myocardial ischemia have been developed with different techniques.

Techniques Used to Induce Ischemia or Infarction
MICROEMBOLIZATION
Coronary microembolization has been used extensively and it leads to a reduced ejection fraction, an increased LVEDP, and elevated plasma norepinephrine levels [54–56]. The chronic changes of this model support the argument that multiple embolizations will exhaust the compensatory mechanisms of the myocardium, leading to left ventricular dysfunction and compromised coronary flow reserve. However, this model only reproduces a global ischemia and not a localized infarction with development of an aneurysm.

Myocardial ischemia is induced by serial injections of 90-micron diameters of polystyrene microspheres in the left coronary artery. The injections are usually performed with a Judkins catheter introduced through the femoral artery [55]. Approximately 20,000 microspheres are delivered per injection and three injections are performed at 15-minute intervals. The injections are repeated every week until the desired effect is achieved. Usually four to 14 injections are required to obtain a chronic model of heart failure. Routinely the injections are discontinued when the ejection fraction reaches 0.35 [57, 58].

Myocardial ischemia induced by microembolization is an irreversible model of heart failure. Huang and associates [55] showed that their model in sheep was stable for 6 months. The mortality rate of this model has been reported to be between 30% and 50% [55].

CORONARY ARTERY LIGATION
Ligation of diagonal or marginal branches of the left anterior descending coronary artery has been used to induce myocardial ischemia and postinfarction disturbance in different animal species [59–64]. Ligation of the first and second diagonal branches of the left anterior descending artery in sheep induced a 24% infarction of the left ventricle [59]. Left ventricular end-diastolic pressure increased from 1.7 to 8.2 mm Hg and cardiac output decreased from 2.98 to 2.44 L/min within 8 weeks [59]. Left ventricular dp/dt was also significantly reduced. This model is robust and mimics a subset of patients in whom postinfarction dilated cardiomyopathy developed after a single, moderate-sized infarct. The noninfarcted myocardium maintained normal blood flow while the blood flow in the infarcted myocardium was 22% of normal.

This model, without confounding variables (collateral circulation, arteriosclerosis, several infarcts), provides an opportunity to understand the progression of a normally perfused and contractile myocardium to hypocontractile after transmural infarction. This model might reproduce a remodeled myocardium which is a fully perfused, hypocontractile myocardium next to an infarct [65].

Ligation of the distal part of the left anterior descending and the second diagonal branches of the circumflex coronary artery and ligation of the posterior descending artery in sheep have induced aneurysmal dilation of the left ventricular wall within 4 hours of ligation [62]. The aneurysm progressed over the next 2 months with thinning of the left ventricular wall [62]. Ligation of the second and third oblique branches from the circumflex coronary artery induced a 21% infarction in the posterior wall and the papillary muscle [61]. Mitral valve regurgitation developed within 8 weeks. Ligation of the second and third marginal branches of the circumflex artery and the posterior descending artery induced a 40% infarction of the posterior wall with infarction of the papillary muscle [61]. Severe mitral regurgitation developed within 1 hour of ligation [61]. This model reproduces the acute and chronic changes of the clinical disease without damage to the mitral valve apparatus.

AMEROID CONSTRICTORS
Ameroid constrictors have been used to induce a progressive occlusion of coronary arteries in different species [66–68]. Ameroid constrictors are made of hygroscopic casein in a stainless ring. The casein swells after absorption of water from the surrounding tissue. Also, fibrous tissue develops around the ameroid constrictor. Placement of ameroid constrictors requires a thoracotomy and dissection of a coronary artery. Multiple ameroid constrictors can be placed around multiple coronary arteries [66, 69]. Coronary arteries are occluded in 3 to 6 weeks with different degrees of collateral circulation [70]. In dogs, left ventricular dysfunction develops within 65 days of implantation of ameroid constrictors with different degrees of congestive heart failure. The development of left ventricular dysfunction and congestive heart failure is more likely a function of the ability of the animal to develop collateral circulation [70]. Dogs have been known to possess preexisting extensive collateral circulation whereas pigs, like humans, do not have an extensive network of collaterals [67, 69, 70]. Delayed occlusion induces a collaterally dependent ischemic bed that can support normal cardiac function in pigs.

COILING/GELFOAM
After surgical exposure of a carotid artery, coils have been placed into the left anterior descending artery of pigs. Gelfoam sponges have been placed within the coil to completely obstruct the coronary artery [71]. The coil and the sponges have also been placed at the origin of the second diagonal artery. This technique eliminates the need for a thoracotomy for the placement of a suture around a diagonal branch. Surgical placement of a suture may induce inflammation and development of collateral circulation. Percutaneous transcatheter occlusion of coronary arteries have been facilitated by the development of platinum coils, compatible with magnetic fields (Tornado Embolization Coils, Cook Group Inc, Bloomington, IN).

CRYONECROSIS
Myocardial infarction has been induced in rats and rabbits with cryosurgery. After an intercostal thoracotomy, a 0.18 x 1.2-cm2 liquid nitrogen probe was applied for 20 seconds 15 times on the left ventricular free wall [72]. However, cryoinjury may not always induce a transmural lesion, in which case the animal heals without fibrosis and development of an aneurysm.

Differences Between Animal Species Used
Development of collateral circulation after induction of myocardial ischemia is the limiting factor of models of ischemia. Collateral circulation can contribute to the healing of the infarcted tissue.

Canine models of myocardial ischemia are more difficult to control because extensive collateral circulation can develop in dogs after ligation of the diagonal branch. Extensive collateral can reperfuse and salvage ischemic tissue. To palliate this problem, repeated embolization of microspheres for more than 10 weeks has been used to decrease the ejection fraction to less than 0.35. However, renin levels remain normal and the animals achieve a stable degree of left ventricular dysfunction, which makes this model less attractive in dogs. Nevertheless, this model has been used to evaluate different surgical interventions to treat heart failure [56, 73]. The major advantage of this model is that varying degrees of left ventricular dysfunction can be regulated by the number of embolic events. However, malignant dysrhythmias can contribute to mortality rates in excess of 30%.

Porcine and ovine hearts have a coronary anatomy similar to the anatomy of the human heart. They seem to develop much less collateral circulation than dogs after induction of coronary occlusion, which makes them more attractive for the reproduction of left ventricular dysfunction and congestive heart failure [74]. Pigs are more prone to malignant arrhythmias induced by ischemia, which increases the mortality rate and complicates the protocols.

Because myocardial infarction is the most common cause of heart failure, models of myocardial ischemia have been commonly used to evaluate remodeling of the cellular and the extracellular matrix after myocardial infarction. They have been useful for the evaluation of treatment strategies for postmyocardial infarction congestive heart failure. Each of these models requires either a surgical intervention to place a ligature or a device around a coronary artery or cardiac catheterization to perform coronary embolization. The unique ability to create different patterns and degrees of myocardial injury with or without mitral valve regurgitation in sheep holds particular relevance for the development of different therapies for postmyocardial infarction congestive heart failure.


   Naturally Occurring Dilated Cardiomyopathy
Top
 Abstract
 Introduction
 Volume Overload
 Pressure Overload
 Rapid Pacing Model of...
 Drug-Induced Models of Heart...
 Models of Ischemia
 Naturally Occurring Dilated...
Genetically Modified Models
 Heart Failure Model Induced...
 Conclusions
 References
 
Large-Breed Dogs
Large-breed dogs develop idiopathic dilated cardiomyopathy around the age of 5 to 7 years [75, 76]. At the time of presentation, dogs are in atrial fibrillation or have ventricular arrhythmias. Severe left ventricular or biventricular dilation with thinning of the ventricular wall are present, resulting in augmentation of left ventricular wall stress and neurohormonal activation, the hallmark of dilated cardiomyopathy in humans. Progression of the disease leads to congestive heart failure in 4 to 6 months after onset of the first clinical signs, even with medical treatment [75, 77].

Idiopathic dilated cardiomyopathy in large-breed dogs is similar to the human form of the disease [78]. Also, because the 50% survival of dogs showing signs of congestive heart failure is only 2 to 4 months, this model has the potential to be valuable for demonstrating the effect of new therapeutic strategies on survival [79–81]. This model is underused, probably because most large-breed dogs are pets, potentially limiting the extent of the investigation. However, echocardiography, cardiac catheterization, and evaluation of the neurohormonal axis can be performed on a routine basis in dogs.

Syrian Hamsters
BIO 14.6 and the CHF 147 hamsters develop a cardiomyopathy with moderate compensatory hypertrophy that finally leads to dilated cardiomyopathy. This model has been used to study the pathophysiology and treatment of congestive heart failure [82–84]. Invasive monitoring has been performed to measure LVEDP, dp/dt, tau, and cardiac output in the hamster after femoral cutdown [83]. Cardiac myolysis develops in BIO 14.6 hamsters at 30 to 40 days, cardiac hypertrophy at 150 days, and dilated cardiomyopathy at 250 days. Finally, they develop congestive heart failure at 1 year of age. Heart failure occurs in BIO 53.58 hamsters at 17 weeks of age without them developing cardiac hypertrophy before dilation. The ventricular wall thinning is apparent by 10 weeks [84].


   Genetically Modified Models
Top
 Abstract
 Introduction
 Volume Overload
 Pressure Overload
 Rapid Pacing Model of...
 Drug-Induced Models of Heart...
 Models of Ischemia
 Naturally Occurring Dilated...
 Genetically Modified Models
Heart Failure Model Induced...
 Conclusions
 References
 
To reproduce different aspects of dilated cardiomyopathy, genetically engineered hamsters and mice have been developed with ß-myosin heavy chain mutation, dystrophin and MyoD-gene (specific skeletal muscle transcription factor) deficiencies, FKBP-12 deficiency (binding protein involved in regulation of ryanodine receptor), G{alpha}q overexpression, Gs{alpha} overexpression, mutation in the desmin gene, null mutation of the cardiac {alpha}-actin gene, deficiency in dystrophin and utrophin, mutation of the sarcoglycan gene, knockout of the muscle LIM protein gene, and mitochondrial mutation [82, 85]. Mutation in the force-generating contractile apparatus (myosin heavy chain mutations) leads to hypertrophic cardiomyopathy, whereas mutation in the cytoskeleton is more prone to induce dilated cardiomyopathy. Engineered mouse lacking dystrophin and utrophin develops severe muscular dystrophies and cardiomyopathy, similar to humans with dystrophin deficiency [82, 85]. Mouse with muscle LIM protein knockout has many phenotypic features of the human dilated cardiomyopathy. The muscle LIM protein is localized at the Z-line with vinculin. This model is predictable and useful to study treatment of heart failure. Desmin-deficiency models have been able to reproduce heart failure with heart showing severe loss of architecture, degeneration, and calcification. G{alpha}q overexpression can lead to cardiomyopathy with marked myocardial apoptosis. These mice are interesting to understand the importance of apoptosis in the development of heart failure and the utilization of antiapoptosis agents. Gs{alpha} overexpression results in hyperfunction and fibrosis of the myocardium as for dilated cardiomyopathy due to long-term overexpression of ß1 adrenergic receptors. Mutations in mitochondria cause deficient oxidative phosphorylation and dilated cardiomyopathy with atrioventricular block.


   Heart Failure Model Induced by Animal Toxins
Top
 Abstract
 Introduction
 Volume Overload
 Pressure Overload
 Rapid Pacing Model of...
 Drug-Induced Models of Heart...
 Models of Ischemia
 Naturally Occurring Dilated...
 Genetically Modified Models
 Heart Failure Model Induced...
Conclusions
 References
 
Several animal toxins have direct and indirect cardiac toxicity [86]. Snake venoms are made of polypeptides, which include enzymes and toxins. Hyaluronidase is present in most snake venoms, which facilitates distribution of the other components of the venom. Toxins present in snake venoms have been reported as presynaptic or postsynaptic neurotoxins (bungarotoxin), myotoxins inducing edema and muscle necrosis (notexin, dendrotoxin), and cardiotoxins blocking potassium or calcium channels (crotamines) [86, 87]. Other toxins induced hemorrhagic symptoms because of the thrombinlike effect and the direct effect on vascular endothelium.

Intramyocardial injection of 3 mg of snake venoms from Naja mossambica has been used to induce myocardial injury in sheep after a left thoracotomy [88]. One injection resulted in significant augmentation of troponin I at 3 and 24 hours after the injection. The ejection fraction in the sheep was 0.47 3 weeks after injection. Myocardial injury resulted in a 2 cm3 transmural scar with adipose fibrous tissue. Under echocardiography with color kinesis, limited contraction of the scar tissue was observed [88]. This model has been used to evaluate cellular cardiomyoplasty in sheep with a 100% survival rate [88]. Injections have been carried out through a thoracotomy; injection may be possible under thoracoscopy.


   Conclusions
Top
 Abstract
 Introduction
 Volume Overload
 Pressure Overload
 Rapid Pacing Model of...
 Drug-Induced Models of Heart...
 Models of Ischemia
 Naturally Occurring Dilated...
 Genetically Modified Models
 Heart Failure Model Induced...
 Conclusions
References
 
A wide variety of animal models of heart failure are available for understanding heart failure and evaluating new treatment modalities. Animal models have been instrumental in elucidating cellular and extracellular mechanisms causing left ventricular remodeling and dysfunction. When heart failure models are induced in small animals, it is important to consider the short biological periods for pathological development and functional evaluation. None of the models reproduces completely the progression of the natural disease. Each model has its own limitations and interest. Therefore, the researcher should choose the models that will best reproduce the aspect of heart failure under investigation. Development of heart failure is often associated with diabetes, obesity, and hypertension in humans, disorders that are unusual in animal models. Combinations of different techniques (ie, myocardial ischemia plus fast pacing) could produce a model that more closely resembles congestive heart failure in patients. To our knowledge, this approach has not been used.

Combinations of different causes of heart failure might provide a new avenue for the understanding of congestive heart failure and the development of therapeutic strategies. Because diastolic dysfunction is getting recognized a risk factor for the development of congestive heart failure it would be of paramount value to combine models of diastolic dysfunction with models of myocardial ischemia for example.


   References
Top
 Abstract
 Introduction
 Volume Overload
 Pressure Overload
 Rapid Pacing Model of...
 Drug-Induced Models of Heart...
 Models of Ischemia
 Naturally Occurring Dilated...
 Genetically Modified Models
 Heart Failure Model Induced...
 Conclusions
 References
 

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