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- – > Mestrado – Dissertation – Tabelas, Figuras e Gráficos – Tables, Figures and Graphics – ´´My´´ Dissertation @ #Innovation #energy #life #health #Countries #Time #Researches #Reference #Graphics #Ages #Age #Mice #People #Person #Mouse #Genetics #PersonalizedMedicine #Diagnosis #Prognosis #Treatment #Disease #UnknownDiseases #Future #VeryEfficientDrugs #VeryEfficientVaccines #VeryEfficientTherapeuticalSubstances #Tests #Laboratories #Investments #Details #HumanLongevity #DNA #Cell #Memory #Physiology #Nanomedicine #Nanotechnology #Biochemistry #NewMedicalDevices #GeneticEngineering #Internet #History #Science #World
The influence of physical activity in the progression of experimental lung cancer in mice
- PMID: 22683274
- DOI: 10.1016/j.prp.2012.04.006
GRUPO_AF1 – GROUP AFA1 – Aerobic Physical Activity – Atividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO AFAN 1 – GROUP AFAN1 – Anaerobic Physical Activity – Atividade Física Anaeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO_AF2 – GROUP AFA2 – Aerobic Physical Activity – Atividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO AFAN 2 – GROUP AFAN 2 – Anaerobic Physical Activity – Atividade Física Anaeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
Slides – mestrado – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
DMBA CARCINOGEN IN EXPERIMENTAL MODELS
Avaliação da influência da atividade física aeróbia e anaeróbia na progressão do câncer de pulmão experimental – Summary – Resumo – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
Lung cancer is one of the most incident neoplasms in the world, representing the main cause of mortality for cancer. Many epidemiologic studies have suggested that physical activity may reduce the risk of lung cancer, other works evaluate the effectiveness of the use of the physical activity in the suppression, remission and reduction of the recurrence of tumors. The aim of this study was to evaluate the effects of aerobic and anaerobic physical activity in the development and the progression of lung cancer. Lung tumors were induced with a dose of 3mg of urethane/kg, in 67 male Balb – C type mice, divided in three groups: group 1_24 mice treated with urethane and without physical activity; group 2_25 mice with urethane and subjected to aerobic swimming free exercise; group 3_18 mice with urethane, subjected to anaerobic swimming exercise with gradual loading 5-20% of body weight. All the animals were sacrificed after 20 weeks, and lung lesions were analyzed. The median number of lesions (nodules and hyperplasia) was 3.0 for group 1, 2.0 for group 2 and 1.5-3 (p=0.052). When comparing only the presence or absence of lesion, there was a decrease in the number of lesions in group 3 as compared with group 1 (p=0.03) but not in relation to group 2. There were no metastases or other changes in other organs. The anaerobic physical activity, but not aerobic, diminishes the incidence of experimental lung tumors.
Copyright © 2012 Elsevier GmbH. All rights reserved.
Investors may soon get a chance to buy Apple at lower levels: Strategist
WATCH NOWVIDEO03:13Apple is doing better than expected in China, says investing expert
Apple is looking sweeter and sweeter.
The stock climbed by more than 2% on Monday, putting its year-to-date gains at nearly 42%, after J.P. Morgan analysts raised their price target on Apple for what they expect to be stronger-than-anticipated sales of the company’s newest iPhone. As of Monday’s close, the firm’s $265 price target implied 18% upside for Apple shares.
But the tech stock could face some near-term pain before J.P. Morgan’s story plays out, warns Matt Maley, chief market strategist at Miller Tabak.
“It’s made a higher low and a higher high, so that’s very positive,” Maley said Monday on CNBC’s “Trading Nation,” citing the weekly chart of Apple’s stock.
“However, you look at the intermediate-term chart … and [the relative strength index is] getting quite extended,” Maley said, referencing a widely followed momentum indicator. “If [the stock] rallies a little bit more, it’s going to get … [to] an overbought condition that has led to significant sell-offs in the past.”
That could put Apple in a tough spot as the stock nears its all-time high of $233.47, Maley said.
“When you have that kind of extreme coming at a time when a stock is testing its all-time high, you run the risk of a double top,” he warned. “Basically, what I’m saying is … if you’re a short-term trader, you could play it on the short side, [with] its all-time high as the stop. And if you like it and you believe in J.P. Morgan’s call, I think you’ll get a chance to buy it at lower levels so it can work off that overbought condition.”
Boris Schlossberg, managing director of FX strategy at BK Asset Management, was in J.P. Morgan’s camp.
“The brand may be tired, innovation may be com[ing] to a standstill, but Apple’s grip on the consumer remains very, very strong,” he said in the same “Trading Nation” interview. “Ultimately, I kind of agree with J.P. Morgan that the [iPhone] 11 is kind of underestimated at this point.”
Schlossberg predicted some tail winds from marginal buyers, who he said would switch to the iPhone 11 “if for nothing else than just simply the fact that the battery power in the [iPhone] 8 is so horrible.” Apple’s newest iPhone software includes a feature meant to preserve battery life.
“The other interesting thing, by the way, is that 5G actually hasn’t really come on board as fast as I think people thought, so that sort of plays to Apple’s strength at this point in terms of the replacement cycle,” Schlossberg said.
That largely echoes J.P. Morgan’s call. The firm expects 5G, the next generation of wireless network technology, to begin to meaningfully drive iPhone sales in 2020 and 2021.
“It’s basically a clean, safe bet [on] a product and there’s just nothing else out there that’s just going to blow it away, and for that reason alone, I think the upgrade cycle still favors the Apple story,” Schlossberg said. “Therefore, it still favors, I think, going to fresh highs. So, I do like the J.P. Morgan call. I think it’s kind of underestimated in this marketplace and is probably much more of a buy than it is a sell at this point.”
- One FANG stock could rally another 40% before it gets overvalued, trader says
- US pulling investment from China would be an ‘unmitigated disaster,’ says Yale’s Stephen Roach
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- These two market moves would cause bank stocks to ‘skyrocket,’ trader says
- This could be the market rally’s missing element, top strategist says
Brokerages losing advantages as IPOs slip, funding markets clog and commissions evaporateMichael SantoliOne FANG stock could rally another 40% before it gets overvalued, trader saysKeris LahiffUS pulling investment from China would be an ‘unmitigated disaster,’ says Yale’s Stephen RoachLizzy GurdusREAD MORE
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- Valvular Lesions That Cause HF
- Dilated Cardiomyopathy
- Hypertensive Heart Disease
- Restrictive Cardiomyopathy
- Methodological Recommendations
Animal Models of Heart Failure
A Scientific Statement From the American Heart AssociationSteven R. Houser, Kenneth B. Margulies, Anne M. Murphy, Francis G. Spinale, Gary S. Francis, Sumanth D. Prabhu, Howard A. Rockman, David A. Kass, … Show all Authors and on behalf of the American Heart Association Council on Basic Cardiovascular Sciences, Council on Clinical Cardiology, and Council on Functional Genomics and Translational BiologyOriginally published17 May 2012https://doi.org/10.1161/RES.0b013e3182582523Circulation Research. 2012;111:131–150
Heart failure (HF) is a leading cause of morbidity and mortality in the United States. Despite a number of important therapeutic advances for the treatment of symptomatic HF,1 the prevalence, mortality, and cost associated with HF continue to grow in the United States and other developed countries. Given the aging of our population and the prevalence of diseases such as diabetes mellitus and hypertension that predispose patients to this syndrome, it is possible that HF prevalence will increase in the next decade. Current treatments primarily slow the progression of this syndrome, and there is a need to develop novel preventative and reparative therapies. Development of these novel HF therapies requires testing of the putative therapeutic strategies in appropriate HF animal models.
The purposes of this scientific statement are to define the distinctive clinical features of the major causes of HF in humans and to recommend those distinctive pathological features of HF in humans that should be present in an animal model being used to identify fundamental causes of HF or to test preventative or reparative therapies that could reduce HF morbidity and mortality.
HF is a clinical syndrome with primary symptoms including dyspnea, fatigue, exercise intolerance, and retention of fluid in the lungs and peripheral tissues. The causes of HF are myriad, but the common fundamental defect is a decreased ability of the heart to provide sufficient cardiac output to support the normal functions of the tissues because of impaired filling and/or ejection of blood.
HF is a significant health burden in both the developed world and in emerging nations. In the United States, over a half million new diagnoses of HF occur each year, and the prevalence is 5.8 million individuals >20 years of age.1 HF has a substantial societal burden, with yearly costs in the United States estimated to be 39.2 billion.1 The increasing prevalence of HF is due in part to the aging of the population, but prevalence of HF is also increasing because better treatment and increased survival of ischemic cardiac disease earlier in life result in survivors at risk for HF in the longer term. HF is recognized as a progressive syndrome, and in 2005 the joint American College of Cardiology/American Heart Association guidelines proposed a new classification of HF based on the recognition of 2 stages preceding symptomatic HF (Figure 1) and symptomatic (stage C) and refractory (stage D) symptomatic HF, as well.3,4 This scheme is a conceptual framework not meant to displace the well-established New York Heart Association classification scheme that defines progressive clinical symptoms and signs of HF. The American College of Cardiology/American Heart Association schema and New York Heart Association classifications should be used by HF investigators to inform assessment and classification of animal models.
Although the current standard of care for HF improves outcomes, the syndrome continues to progress and there is a need for novel therapies that can prevent, further slow the progression, and/or reverse the structural and functional defects of the failing heart. Research to identify novel targets for HF therapy usually requires preclinical testing in appropriate HF animal models. Although numerous animal models are available for use, there are inadequate standards for what clinical features should be present in these models, and the presence or absence of the HF phenotype is often not documented.
The intention of this statement is to define critical features of HF and propose a set of parameters that investigators should measure to ensure that they have an animal model with the clinical features known to be present in HF patients. The statement discusses the critical features that are present in patients with HF induced by specific causes and discusses animal models that mimic these clinical scenarios. The statement seeks to identify standard features of HF in the whole animal (increased activity of the sympathetic nervous system is an example), within the heart (increased filling pressures is an example), and at the cellular level (expression of fetal genes is an example). The statement will review approaches for producing HF animal models with critical clinical features of valve diseases, (pressure and volume overload), hypertension, myocardial ischemia, and other diseases or genetic abnormalities that cause dilated cardiomyopathies, and restrictive cardiomyopathies. The hope is that HF therapeutic targets identified and tested in animal models with critical features of HF in humans will have a higher likelihood of translating to HF patients.
It is understood that HF in humans is a complex clinical syndrome that can be caused by a variety of diseases. In the clinical realm, chronic hypertension and ischemic heart disease are major contributing factors.1,3 In addition, many forms of acquired, structural, and genetically determined disorders can underlie the clinical presentation. In some cases, animal models may mimic the human condition closely. In others, an acute intervention such as coronary obstruction may mimic only a single discrete time point of an otherwise chronic disease that develops over a lifetime. In addition, animal models are often developed on a defined genetic background that does not reflect the diversity of human populations, which can result in a variety of phenotypes from the same monogenic disorder. Despite these limitations, properly assessed animal models have much to offer to the advancement of clinical care. Investigation of molecular pathways in early or late stages of HF can identify novel targets for therapeutic intervention or biomarkers for disease progression. Studies in large-animal models usually provide important preclinical proof of concept for novel therapies before US Food and Drug Administration-approved clinical trials. Helping investigators develop well-characterized HF animal models with characteristics that reproduce key features of HF in humans should aid in the development of novel HF therapies.
The sections below describe 4 clinical conditions that can result in HF: valvular lesions, dilated cardiomyopathies, hypertensive heart disease, and restrictive cardiomyopathies. Each section will describe the critical features of the clinical phenotype and will recommend those features of the clinical situation that should be present in an animal model that seeks to replicate the human condition. The authors recognize that the complexities of the human diseases that lead to HF are difficult to mimic in most animal models.
Valvular Lesions That Cause HF
Description of Overall Clinical Entity
The canonical symptoms of HF, which include shortness of breath, peripheral and pulmonary edema, and low exercise tolerance, can arise from structural defects in the aortic and/or mitral valve. The valvular lesions that necessitate medical and surgical interventions include those which are due to stenosis (abnormally high resistance to ejection and failure to fully open) or regurgitation (a failure of complete coaptation of the leaflets and adequate closure). For the purposes of illustration and focus, a prototypical lesion such as aortic stenosis (which causes a significant left ventricular (LV) pressure overload) and that of mitral regurgitation (which causes a significant LV volume overload) will be discussed with respect to the pathophysiology and natural history of events that ultimately lead to HF. Although each of these lesions can result in elevated LV diastolic/atrial pressures causing fluid retention and fatigue, the underlying pathophysiology of aortic stenosis (AS) and mitral regurgitation (MR) are quite distinct.
Causes and Associated Features of AS
Common causes of AS include atherosclerotic disease with or without calcification, calcification independent of atherosclerosis, and aortic valve malformations (ie, bicuspid aortic valve). All result in increased stiffness of the aortic valve and reduce orifice area. The increased resistance to LV ejection with AS causes increased LV afterload. The physical obstruction to LV ejection requires increased pressure to be developed to propel blood across the reduced aortic orifice. Under normal conditions, the resistance to ejection offered by the open aortic value is very small, and there is no perceptible pressure gradient across the valve during ejection. AS causes a higher than normal resistance to ejection, and increased LV pressure is required throughout the ejection phase to eject the normal stroke volume. As a consequence, a difference between the LV and aortic pressures occur during the ejection phase, which is defined as the LV-aortic pressure gradient. The magnitude, duration, and progression of this pressure gradient are the determinants that stimulate the myocardial response.5,6 Specifically with AS, significantly increased LV systolic wall stress occurs and thereby evokes myocardial growth, LV hypertrophy (LVH). In AS, LVH is characterized as concentric hypertrophy whereby wall thickness is increased while LV volumes remain the same or decrease. At the cellular level, myocytes undergo hypertrophy by adding sarcomeres in parallel to achieve an increase in width. In addition, fibroblasts proliferate within the myocardium and in concert with localized activation of a number of bioactive molecules, resulting in increased extracellular matrix deposition. Structural hallmarks of prolonged AS are significantly increased collagen accumulation between individual hypertrophied myocytes and myocyte fascicles.7,8
In the most common forms of AS, there is an initial “compensatory” phase in which indices of LV pump function such as ejection fraction are within normal limits. However, this phase is associated with increased myocyte cross-sectional area and progressive accumulation of myocardial extracellular proteins and fibrosis. Thus, LV active relaxation, which depends on myocyte Ca2+ resequestration, and passive relaxation, which depends on myocardial stiffness, become abnormal. In particular, enhanced synthesis and deposition of myocardial matrix is directly associated with increased LV myocardial stiffness, which causes disturbed filling characteristics during diastole. Clinical studies of patients with AS and significant LVH suggest that a fundamental structural milestone in the transition from this compensated state to HF symptoms is myocardial fibrosis with diastolic dysfunction.7–9 The progressive impairment in LV diastolic function with AS results in elevated LV diastolic and left atrial pressures, atrial enlargement, increased pulmonary venous pressures, and subsequently the manifestation of HF symptoms. In patients with AS, the development of systolic dysfunction such as a fall in LV ejection fraction, and diastolic dysfunction, as well, is an extremely poor prognostic sign and represents a “decompensated” condition. Although the relief of AS can be achieved through aortic valve replacement and results in significant regression of LVH, abnormalities in myocardial extracellular matrix content persist for months to years.9 Thus, in clinical AS there is a compensated phase with LVH and relatively normal LV systolic function. Later in time, with increases in myocardial fibrosis, there is diastolic dysfunction and, eventually, decompensation with pump failure and a poor prognosis.
Critical Features of an Animal Model of AS in Humans
A critical and poorly reversible feature of progressive LVH and subsequent HF is myocardial fibrosis with diastolic dysfunction. As such, critical features of an animal model that would replicate human AS would include the following:
- A slowly evolving LV-aortic pressure gradient (Figure 2),
- Initial development of LVH with increased myocyte cross-sectional area, myocardial fibrosis, and normal ejection fraction,
- Progression of myocardial fibrosis and diastolic dysfunction resulting in increased filling pressures that lead to left atrial enlargement and eventually reduced systolic function with the development of HF symptoms.
Large-Animal Models of AS
Large animal models with progressive aortic constriction within the supravalvular position have been described in cats, dogs, sheep, and pigs. These animal models replicate many of the critical features of human AS,10–13 including progressive increases in the LV-aortic pressure gradients and a compensatory LV remodeling response, significant LVH with myocyte hypertrophy, and abnormalities in the myocardial matrix with evidence of diastolic HF.7 For example, progressive constriction of a surgically placed aortic band in dogs over a 2-month period allowed for a nearly 2-fold increase in LV mass and a resultant LV-aortic pressure gradient of >150 mm Hg (Figure 2).7 Overall, this progressive increase in LV load does not cause an acute compromise in LV ejection fraction or hemodynamic instability. In the sheep model of progressive AS, changes in myocardial collagen matrix synthetic and degradation pathways have been identified, which resulted in collagen accumulation and diastolic dysfunction as quantified by increased LV myocardial stiffness.13 These large-animal models of progressive AS replicate many critical structural and functional aspects of the clinical phenotype of AS and the eventual development of HF. These models systems should be useful to identify appropriate timing of surgical interventions and to explore novel therapies to promote full recovery of the heart after surgical correction of AS.
Small-Animal Models of AS
The most common model of AS in small animals is transverse aortic constriction (TAC) in the mouse. This technique causes a fixed aortic constriction and an abrupt increase in LV afterload, and can cause such severe constriction that there is acute hemodynamic instability with reduction in ejection fraction (EF) and early postoperative mortality.14–16 The relative degree of mortality and immediate decline in LVEF can be attenuated to some degree by reducing the severity of the TAC. The inciting stimulus for LVH produced by acute, severe pressure overload is likely to be different than in animal models with slow progressive pressure overload and in patients with AS. Therefore, activation of growth regulatory pathways and contractile and Ca2+ regulatory proteins and extracellular remodeling, as well, may have less relevance to humans with AS. In addition, the myocardial fibrosis and diastolic dysfunction that develop in these models could represent a primary defect in LV systolic dysfunction or could be secondary to the acute cardiac decompensation that is often present in this model. The utility of mouse models is the ability to test the roles of specific molecules in TAC-induced cardiac dysfunction in genetically modified mice. The weaknesses of these models include the fact that they do not have some of the key features of the disease in humans, including the inability to easily induce slow progressive pressure overload. Therefore, an integrated approach that identifies and tests putative AS HF targets in mouse models and then validates these targets in an appropriate large-animal model could provide a solid platform to develop new AS therapies.
Causes and Critical Features of MR
The mitral valve apparatus contains the mitral leaflets, mitral annulus, chordae tendineae, and papillary muscles. Cardiovascular diseases that affect one or all of these structures can result in significant mitral valve incompetence (allowing the retrograde flow of blood from the ventricle to the atria during systole [MR]). MR is the most common valvular disorder and can arise from mitral valve prolapse, papillary muscle dysfunction secondary to ischemic heart disease, endocarditis, and rheumatic disease. LV dilation from ischemic or cardiomyopathic disease can also cause MR. The LV loading abnormality with MR is diastolic volume overload. During LV systole, which includes the isovolumetric contraction and the ejection phases, as well, the pressure developed within the LV first causes retrograde ejection of blood into the left atrium through the incompetent mitral valve. Thus, there are 2 pathways for LV ejection: a low-impedance path through the mitral valve and into the left atrium and a higher-impedance path through the aortic valve.17 As a consequence, abnormally high LV emptying occurs during systole and results in low LV end-systolic volumes. The total LV stroke volume is therefore divided between the regurgitant volume (into the atria) and volume ejected through the aorta (the forward stroke volume). A common calculation in MR is the regurgitant fraction, which is the ratio of the regurgitant volume and total stroke volume expressed as a percentage. The severity of MR is often quantified by the regurgitant fraction, and this parameter is used as an index for the likelihood for progressive LV myocardial remodeling, dysfunction, and eventual HF. During the compensated (pre-HF) phase of MR, adequate forward stroke volume into the aorta is maintained by augmenting LV end-diastolic volume and total stroke volume. A unique hemodynamic feature of compensated MR is that LVEF is supranormal because of the low-impedance ejection pathway, and this makes the assessment of LV muscle contractility difficult. In chronic and severe MR, LV dilation continues, with progressive enlargement of the left atrium and increased pulmonary venous pressures with signs and symptoms of HF. If this disease progresses without correction, then LV myocardial contractile dysfunction occurs with a rapid decline in hemodynamic status and HF.17
The fundamental mechanical driving force for changes in LV geometry and structure with MR is a chronic and often a progressively increasing volume overload. LV end-diastolic volumes are significantly increased, which results in increased end-diastolic and systolic wall stress with a unique pattern of eccentric LVH. The myocyte remodeling with MR is the addition of sarcomeres in series to achieve an increase in myocyte length with no significant increase in cross-sectional area. In addition, with significant MR and subsequent LV dilation, a distinctive loss of the collagen fibrils surrounding individual myocytes occurs. This cellular and extracellular remodeling produces a highly compliant LV.
Critical Features of the Animal Model
Critical features to consider in animal models that would replicate the pathophysiological features of MR would include the following:
- LV volume overload with significant increases in end-diastolic volume and LV and LA dilation,
- A supernormal EF with ejection divided between retrograde flow into the atria and antegrade flow through the aortic valve,
- Eccentric LVH with myocyte lengthening and a disruption/loss of myocardial matrix.
Large-Animal Models of MR
The clinical phenotype of chronic MR can be induced by severing the chordae tendineae, which induces significant MR.17–19 The canine model of MR causes LV dilation and an eccentric LVH pattern, which is accompanied by myocyte lengthening.18,19 Unlike the LVH that occurs in large-animal models of AS, chronic MR in dogs causes severe LV contractile dysfunction at both the chamber and myocyte level. In this chronic MR model, significant myocardial matrix accumulation does not occur, but, instead, histological assessment reveals collagen matrix disruption, again, significantly different than that of LV pressure overload. This chronic MR model has been successfully used to examine the contributory effects of the β-adrenergic and the angiotensin II receptor pathways in the progression of HF in this large-animal model of MR.19,20 These large-animal models of MR replicate some critical features of this form of HF.
LV Volume Overload in Smaller Animals
MR induction in rodents has not been accomplished to date. However, the induction of LV volume overload either through the creation of aortic insufficiency or an aortocaval fistula has been described.21–26 A retrograde catheter technique has been used in rabbits to induce damage to the aortic valve with significant aortic regurgitation and thereby LV volume overload. In this model of LV volume overload, LV dilation and eccentric LVH occurs over a period of weeks to months with accompanying increased LV filling pressures and the manifestations of HF.21,22
LV volume overload can also be induced by creation of a small bridge between the abdominal aorta and inferior vena cava, thereby inducing a functional aortocaval fistula.21–26 Detailed LV morphometric studies have been performed in the rat model of aortocaval fistula and have provided some of the early insight into the level of LV myocardial and myocyte remodeling that occurs with chronic volume overload.23,24 This rat model of LV volume overload has been successfully used to examine the effects of pharmacological interruption of signaling and proteolytic pathways that likely contribute to LV remodeling and failure secondary to a volume overload.25,26 Although this aortocaval fistula model is not caused by valvular defects, this type of LV volume overload replicates many critical features of MR-induced LV remodeling and failure.
Animal models that replicate phenotypic features of AS (pressure overload, concentric hypertrophy, increased myocyte width with no major change in length) and MR (volume overload, eccentric hypertrophy and increased myocyte length with no major increase in myocyte width) in humans are available and provide a valuable resource for identification of novel therapeutic targets and testing novel approaches to improve cardiac structure and function. Critical features of AS animal models are an adaptive phase of concentric LVH with minimal or no chamber dilation. This compensated phase should be followed by fibrosis, diastolic dysfunction, and eventually decompensated systolic failure. Achieving all of these features in a progressive manner in models of AS can be difficult, especially in rodent models. Therefore, putative targets identified in rodent TAC models should be validated in AS animal models with slow progressive pressure overload.
Acute MR animal models should produce rapid and robust changes in LV volumes and geometry, with progressive myocyte lengthening, and a loss of myocardial matrix support. These critical phenotypic geometric and structural hallmarks can be found in large-animal models of MR and in smaller animal models of volume overload.
Critical unresolved issues in patients with valve disease are how to enhance cardiac repair after correction of the valve defects. Animal models that replicate human phenotypes that are amenable to correction of the inciting defects (unbanding of the aorta, repair of the mitral or aortic valve, and fistula correction) would be useful to define better strategies to enhance beneficial cardiac remodeling after repairing those defects that produce pressure and volume overload.
Description of the Clinical Entity
Dilated cardiomyopathy (DCM) is characterized by ventricular dilatation, systolic dysfunction (reduced ventricular EF), abnormalities of diastolic filling, and either normal or reduced wall thickness (ie, pathological ventricular remodeling; eccentric hypertrophy). Both diastolic and systolic wall stress are increased in proportion to the HF syndrome. There is biventricular and biatrial enlargement, elevation of left- and right-sided filling pressures, and an increase in organ and chamber weight with myocyte hypertrophy.27,28 Along with myocardial changes, DCM is also characterized by annular dilatation of the mitral and tricuspid valves, apical displacement of the papillary muscles, and lengthening of the mitral leaflets, and atrioventricular valve regurgitation.29,30 Ventricular remodeling is triggered by index insults (below) and is perpetuated over the long term by factors that include augmented diastolic and systolic wall stress, and the activation of neurohormonal systems not only help to maintain cardiac output, but also to impart deleterious effects in the heart.31–33 The syndrome of HF occurs when the dysfunctional heart cannot maintain adequate output to the peripheral tissues or can do so only at elevated filling pressures.3,34 This results in the classical signs and symptoms of HF that reflect low cardiac output and pulmonary and/or systemic congestion and include fatigue, effort intolerance, exertional dyspnea, fluid retention, and reduced tissue perfusion.32,35
Causes and Associated Features
The DCM phenotype results from a broad variety of primary and secondary etiologies. Primary conditions solely affect the heart muscle (idiopathic DCM) and are linked to heterogeneous genetic mutations in cytoskeletal, sarcolemmal, sarcomeric, and nuclear envelope proteins.36 Secondary causes are extensive, with the most frequently encountered clinical conditions being coronary artery disease and antecedent myocardial infarction (ischemic cardiomyopathy) and long-standing hypertension.3,37 Other causes include myocarditis (especially viral), Chagas disease, chemotherapeutic drugs (eg, anthracyclines), sustained and inappropriate tachycardia, autoimmune disorders (eg, systemic lupus erythematosus), endocrine disorders (eg, hypothyroidism, diabetes mellitus), excessive alcohol consumption, nutritional deficiencies, neuromuscular disorders, and peripartum cardiomyopathy.36 Despite the diverse array of underlying causes, there are striking similarities in the associated structural, functional, biochemical, and molecular phenotypes31,32,35 related to the long-term cardiotoxic effects of augmented mechanical load (increased wall stress) and neurohormonal activation.3
Neurohormonal systems activated in HF include the adrenergic and renin-angiotensin-aldosterone systems, endothelin, vasopressin, and inflammatory mediators.3,31–33,35,38,39 Although these systems impart some compensatory effects, their activation over the long term are felt to impart detrimental biological effects that promote adverse remodeling. There is also the elaboration of antihypertrophic factors such as natriuretic peptides, including atrial natriuretic factor and B-type natriuretic peptide, in response to atrial and ventricular stretch.40,41 Molecular hallmarks of DCM include activation of the fetal/hypertrophic gene program,33,42,43 local and systemic inflammation,44–46 and oxidative stress.47–49 Common molecular changes include upregulation of atrial natriuretic factor and downregulation of sarcoplasmic reticulum calcium ATPase, α-myosin heavy chain, and β1-adrenergic receptors.33
The histopathologic hallmarks of DCM are myocyte hypertrophy (increases in myocyte length and width), interstitial and replacement fibrosis, and alterations of the extracellular matrix, progressive cardiomyocyte death (from apoptosis, necrosis, and autophagy), and relative capillary rarefaction.32,33,38,50–55 Alterations in ventricular performance result from deranged systolic and diastolic function at rest and diminished contractile reserve on stress, and from persistent and progressive increases in systolic wall stress, as well. DCM hearts exhibit depressed isovolumic (eg, peak dP/dt), ejection phase (eg, EF), and pressure-volume plane indexes (eg, end-systolic elastance), and slower relaxation rates (eg, tau).56–59 There is blunted contractile augmentation with catecholamine stimulation and during exercise (β-adrenergic hyporesponsiveness),60–64 depression of the stretch-induced force response,57,58,65 and blunting of force-frequency responses.66–68 At the myocyte level, mechanical dysfunction is a manifestation of altered Ca2+ uptake, storage, and release,69,70 altered β-adrenergic receptor (β-AR) function (reduced β-AR density and β-AR uncoupling)62,63 and activation of CaMKII signaling cascades.71
Critical Features of the Animal Model
DCM animal models should reproducibly exhibit the chamber level structural phenotype in humans: spherical LV dilatation, eccentric hypertrophy with relative wall thinning (reduced mass-to-volume ratio), depressed LV systolic and diastolic performance, and reduced functional reserve with provocation (eg, exercise or tachycardia). If appropriate equipment is available, LV size should be evaluated with planimetry to measure 2-dimensional chamber area or volume at end-systole and end-diastole. Linear measures of end-diastolic and end-systolic diameter can produce spurious results with regional injury models and should be used cautiously. To index hypertrophy, LV wall thickness should be measured at end-diastole, and relative wall thickness should be included to normalize for chamber size. LV systolic function by echocardiography is best assessed by LVEF or fractional area change, although single-dimension fractional shortening is also reasonable with global injury models. The imaging data should be supported by gravimetric data to show chamber hypertrophy and/or elevation of filling pressure (eg, wet lung weight), and ideally by mechanical data demonstrating depressed contractility and lusitropy and elevated filling pressure.
There are shortcomings to all HF animal models that limit their relevance to disease in humans. For example, the manifestations of clinical HF (reduced blood flow and elevated cardiac filling pressure) are often temporally removed from the onset of pathological remodeling.35 This is also the case in most DCM animal models. Therefore, it is possible to have significant remodeling in an animal model without severe clinical signs (eg, asymptomatic LV dysfunction).3,32,34 Studies in animals at these early stages would be more accurately classified as an examination of pathological remodeling during early HF. In addition, although the DCM phenotype shares multiple similarities regardless of the inciting etiology, there are differences specific to the underlying etiology that should be considered. For example, tachycardia-induced cardiomyopathy in large animals is reversible to some extent on reversal of the tachycardia.72,73 Moreover, myocyte hypertrophy and fibrosis do not feature prominently in this form of cardiomyopathy despite changes in hemodynamics, neurohormonal activation, and chamber structure and function that replicate clinical DCM.73–75
Animal Models Currently Used for the DCM Phenotype
Rodent DCM Models
Rodent models are available for studies of DCM. They are relatively inexpensive (compared with large-animal models), and manipulation of mouse genetics allows gain or loss of function of specific genes in specific cell types at specific times. These features allow for experimental designs that evaluate specific molecular mechanisms in greater animal numbers with more substantial statistical power. However, there are critical structural, functional, and molecular differences between small and large mammalian hearts,81 such that promising therapeutic approaches generally require preclinical testing in larger-animal models before human translation.
Ischemic Injury/Myocardial Infarction
DCM can be induced in rodents by surgical interruption of coronary arteries to produce myocardial infarction via either permanent coronary ligation39,82–88 or reperfused infarction (ischemia/reperfusion).89–92 After an infarction, the DCM phenotype progressively develops. It is essential to recognize that, in these models, the degree of long-term LV remodeling and chamber dilatation is directly proportional to the initial infarct size.93 Therefore, it is necessary to demonstrate equivalence of infarct size between groups when comparing subsequent remodeling responses in different groups of animals. Cryo injury94 is often used as an alternative technique to interrupt coronary blood flow because it can give a more reliable area of injury.
Transgenic Overexpression and Knockout Models
Animals with constitutive and inducible transgenic overexpression and gene knockout models that exhibit a DCM phenotype are available for study.80,95 The penetrance and magnitude of the DCM phenotype, and whether the phenotype is brought out spontaneously during aging or only under conditions of stress varies according to the specific genetic modulation. These models can be useful to identify important causes of DCM or its progression and to identify putative targets for therapy, as well.
A DCM phenotype has been induced with doxorubicin96–98 or isoproterenol.99–101 These approaches can produce a dose-dependent dilated phenotype and HF over time after sufficient myocardial injury and cell death. These models are characterized by myocyte apoptosis and oxidant stress.80 Toxic models of cardiomyopathy are highly specific forms of injury and also can be useful in assessing cardiac responses to stress.102
Hypertensive, pressure overload, and volume overload rodent models of DCM are also available, and these are discussed in other portions of this statement. The spontaneous hypertensive rat103 also develops HF, and this model can be useful for defining causes and putative new therapies.
Large-Animal DCM Models
Preclinical validation of novel therapeutic approaches usually requires large-animal models because they more closely approximate human cardiac structure and physiology.76,77 Furthermore, testing of device therapies are not easily performed in small-animal models. In addition, structural, hemodynamic, and physiological assessments can often be made with much less invasive approaches in large animals. DCM can be induced in large animals by myocardial infarction, coronary microembolization, pacing-induced tachycardia, and toxic injury.76,77 These models can be used to define hemodynamic, mechanical, neurohormonal, cellular, and molecular changes during HF and to evaluate the potential efficacy of novel therapeutics.
Coronary Ligation/Regional Myocardial Infarction
DCM infarction studies (both reperfused and nonreperfused) have used dogs,104 pigs,105–108 and sheep109–112 to evaluate the pathophysiological mechanisms of postinfarction remodeling and DCM development and progression, and the response to therapies. Posterior infarction models (eg, ligation of the posterior descending artery and distal branches of the circumflex artery) have been used to study the role of ischemic MR in postinfarction remodeling.110,111 Importantly, dogs have a well-developed collateral circulation in comparison with pigs,113,114 which can result in higher variability in infarct size and subsequent remodeling, making the use of canine myocardial infarction models problematic. Porcine and ovine models are characterized by predictable infarction sizes and closely mimic ischemic cardiomyopathy in humans.105,110
Serial left coronary artery microembolization with polystyrene microspheres has been used to induce dilated ischemic cardiomyopathy in dogs115–117 and sheep.118–120 Acutely microembolized myocardium exhibits contractile dysfunction with a profound perfusion-contraction mismatch, and localized inflammatory responses and TNF expression, as well.121 Repeated microembolization over a period of 10 weeks induces microinfarcts and progressive LV dilatation and contractile dysfunction (LVEF <35%) resembling human ischemic cardiomyopathy, with neurohormonal activation, natriuretic peptide elaboration, myocyte hypertrophy, MMP upregulation and interstitial fibrosis, and reduced β-AR responsiveness. This model has provided insights into the effects of pharmacological and device-based therapies for HF.
Chronic tachycardia-mediated DCM is a recognized clinical condition.72,73 In dogs,122–126 pigs,74,75,127 and sheep,128–130 rapid pacing of either the atrium or the ventricle for at least 3 to 4 weeks produces a progressive, reliable, and reproducible model of DCM and chronic HF, that is at least partially reversible over time on discontinuation of pacing. This disease model closely replicates the mechanical, structural, neurohormonal, and myocyte functional alterations of DCM in humans and has been used to test pharmacological and gene-based therapies. The predictability and reproducibility of the model, and its parallels to the hemodynamic and mechanical phenotype of DCM in humans, render this an attractive model. Limitations include the absence of myocyte hypertrophy and fibrosis at the tissue level73–75 and the reversible nature of this myopathy.
Serial administration of intracoronary and intravenous doxorubicin induces toxic DCM in dogs,131–133 sheep,134,135 and, more recently, in cows.136 As in rodents, doxorubicin cardiotoxicity is dose dependent and characterized by myocyte injury, myocyte and endothelial cell loss and apoptosis, microvascular insufficiency, and oxidative stress. Use of this DCM model in sheep and cows can provide an experimental platform for evaluating the effects of mechanical circulatory support devices. Limitations of this model include variability of response to doxorubicin and the degree of LV dysfunction, animal mortality caused by arrhythmias, and the potential for systemic, gastrointestinal, and bone marrow side effects.
Fly and Fish Models
This statement focuses on mammalian models of HF. The readers should be aware that fly137 and fish138 models are available. These animal models are particularly well suited for studies exploring the role(s) of specific genes in the development, progression, or prevention of HF. These models are also useful for studies of cardiac regeneration.139 The ease with which genes can be modified in these animals is their major strength. The limitations of these models are that they are far removed from the complexity of the adult mammalian heart.
DCM animal models should exhibit the structural and mechanical alterations of DCM in humans and also share many of neurohormonal, cellular, and molecular features that were detailed above. The central features of the model should include ventricular dilatation and relative wall thinning with eccentric hypertrophy, depressed contractility and lusitropy, and diminished contractile/lusitropic reserve with stress, all leading to the systemic manifestations of HF (reduced output/flow and elevated filling pressure). Phenotypic assessment should typically include morphological assessment via echocardiography (and/or cardiac magnetic resonance imaging [MRI] if available) and gravitometry. Most studies should use invasive in vivo measurement of cardiac pressures and mechanics to critically evaluate cardiac function, especially if the study seeks to evaluate therapeutics that are thought to improve systemic HF. Isolated myocyte, muscle, or perfused heart preparations can also be used when animals are euthanized to define myocyte contraction status. Most studies should also include histopathologic, biochemical, cellular, and molecular studies to document a human DCM phenotype and the bases of any beneficial effect of a tested therapeutic.
The most common underlying causes for acquired DCM in humans are ischemic heart disease and hypertension. Therefore, defining critical causes of DCM in large-animal models of ischemic and load-dependent DCM are of great relevance. In addition, testing pharmacological, gene-based, cell-based, and device therapeutics in well-characterized large-animal models is felt to be critical to the development of novel therapies for patients experiencing DCM. Primary (idiopathic) DCM is often the result of genetic mutations, many of which are undiscovered. Mechanism discovery for genetically based DCM is ideally performed in transgenic and knockout mice, and initial evaluation of novel molecular mediators or targets in DCM is best facilitated by the generation of genetically modulated mouse models for the molecule of interest. The expression levels and function of the specific target should also be determined in acquired DCM models or human hearts to help establish disease relevance.
Hypertensive Heart Disease
Description of the Clinical Entity
Hypertensive heart disease (HHD) is a major public health problem that contributes importantly to cardiovascular morbidity and mortality.140 This is particularly the case in the black population, where LVH is 2- to 3-fold more common than in the general population.141 The overarching concept in this field is that, with persistent hypertension, or pressure overload, there is a transition from compensated hypertrophy to HF.140 There are substantial data, both in animal and human studies, that support this concept.142 The operative principle is that HHD is initially characterized by concentric hypertrophy, typically with a normal EF and normal or decreased end diastolic volume (similar to AS, as described earlier). With progression of the syndrome, there is often an increase in LV end-diastolic and end-systolic volume and decreased EF (Figure 3). This is an ominous sign and is usually associated with signs and symptoms of systolic HF.142 It is also clear that increases in LV chamber stiffness and/or impaired active relaxation associated with pathological myocyte hypertrophy and matrix remodeling can impair LV filling, raise LV filling pressure, and induce the syndrome of HF without a major decrease in LVEF.
There are still many unknowns regarding how HHD patients transition from a phase of compensated hypertrophy to HF. Large, longitudinal cohort studies in humans with HHD who have undergone sequential imaging are needed if we are to be better informed regarding the relative likelihood of a transition to HF with low EF versus HF with preserved EF among patients with hypertension. It is also possible that elevated blood pressure in humans leads to a dilated HF phenotype without a phase of concentric LVH.143 The lack of critical information in humans makes it difficult to know the critical features of an appropriate HHD animal model.
Among HHD patients with concentric LVH, some manifest reduced regional systolic function,144,145 because midwall fractional shortening can be impaired even with preserved EF. An important unanswered question is whether LVH with regional systolic abnormalities is a critical prelude to the development of overt systolic failure. Long-term follow-up with sequential imaging studies would be necessary to firmly establish this concept in humans so that appropriate animal models could be developed.
Causes and Associated Features of HHD
The patient with HHD typically is older, commonly black, more likely to be female, and more often manifests obesity and type 2 diabetes mellitus. Coronary disease is common in such patients, and there is a 6-fold increase in the prevalence of myocardial infarction. Among hypertensive patients who develop HHD, treatment has frequently been inadequate. Some element of renal insufficiency is not uncommon because of hypertensive nephrosclerosis, and this risk is greater with concomitant diabetes and/or atherosclerosis. Thus, HHD in humans is a complex multifactorial process that often leads to HF, with all of its classical signs and symptoms. Echocardiography can be used to assess the LV morphology and mass, LVEF, the presence or absence of regional contractile abnormalities, and the presence, pattern, and degree of diastolic dysfunction.146,147
Other imaging techniques used to assess the phenotype of HHD in patients include MRI, which is especially useful to demonstrate patchy replacement fibrosis along with most of the findings identified via echocardiography. Cardiac catheterization with angiography is sometimes performed to assess coronary vasculature.
Circulating biomarkers increased in HHD include B-type natriuretic peptide, N-terminal pro-B-type natriuretic peptide, and troponin I or troponin T levels. There is general agreement that elevation of these biomarkers is related to the severity of HF and is associated with a poor diagnosis.
Critical Features of an Animal Model of HHD
Because the spectrum of HHD in humans is varied, complex and multifactorial (Table 1), it is clear that a given animal model of HHD-induced HF can only reproduce selected elements of the phenotype. Indeed, the ability to exploit the relative consistency of animal models to increase our understanding of a variable clinical entity is a major justification for animal experimentation. Moreover, because most patients with hypertension and LVH are at risk to develop HF (stage B), animal models that represent that different stages of HHD can be useful for studying disease progression and for testing novel therapeutics that could improve cardiac structure and function.
|High blood pressure (>140/90 mm Hg; may be normal in end stages)|
|Breathlessness at rest or with minimal activity|
|LVH (concentric hypertrophy with cardial myocytes demonstrating an increased diameter) or increased LV mass|
|Impaired active relaxation|
|Impaired passive filling|
|Impaired regional midwall systolic function|
|Impaired EF (late)|
|Dilated LV internal chamber (late)|
|Enlarged left atrium|
|Concomitant coronary artery disease|
|Previous myocardial infarction|
|Myocardial fibrosis (reactive and replacement)|
|Abnormal pressure/volume relationship in the LV with increased LV filling pressure (increased chamber stiffness) relative to LV volume|
|Decreased intramyocardial capillary density|
|Coronary arteriolar thickening|
|Decreased coronary blood flow reserve|
|Increase biomarkers such as NT-proBNP, BNP, and troponin|
|Obesity, type 2 diabetes mellitus insulin resistance|
LVH indicates left ventricular hypertrophy; LV, left ventricular; EF, ejection fraction; BNP, B-type natriuretic peptide; and NT-proBNP, N-terminal pro-B-type natriuretic peptide.
Animal models of HHD should have critical characteristics of the disease in humans, including arterial hypertension, an increase in LV mass, and characteristic changes in LV geometry. Cardiac performance should initially be maintained, but eventually diastolic and/or systolic dysfunction should be present. These changes may either be demonstrated by use of echocardiography, MRI, or catheter-based techniques as used in humans. Large-animal models with LV structural and functional impairment may develop a human-like condition of HF, including cough, exercise intolerance, and ascites. These features are more difficult to faithfully demonstrate in small animals. Peripheral biomarkers may complement the assessment of animal models of HHD by identifying relevant pathophysiological processes and clarifying the stage and/or severity of disease. Changes in the structure and/or function of myocytes, the interstitium, and the vasculature should also be documented (Figure 4). At the myocyte level, pathological hypertrophy is associated with activation of calcineurin, nuclear factor of activated T-cell signaling.148 The reader should be aware that this statement does not address right ventricular hypertrophy and failure that results from hypoxia or pulmonary hypertension.149 These are important clinical problems, and there are animal models of these conditions.
Current Animal Models
Many different animal models that mimic HHD have been used over the years to gain insight into the complex biology of this clinical problem. These studies have shown that the transition from concentric LVH to HF can be demonstrated in animal models, including the in spontaneously hypertensive rat,150 in aortic banding,151 and in mice with genetic alterations of various molecules.148
A dog model of HHD produced by wrapping 1 kidney in silk and subsequently performing contralateral nephrectomy has been used previously.152 Recently, a variant of this model has been used153–156 and is one well-established approach to producing a large-animal model of HHD.
There are still considerable gaps in our understanding of HHD, and many of these are best addressed in small- or large-animal models of HHD. For example, 1 hypothesis is that LVH is compensatory and prevents the development of dilated HF. However, some studies in animal models suggest that prevention of the LVH normally induced by pressure overload does not promote dilated cardiac failure157–159 and may prevent HHD. This is an area that can be studied further in small- and large-animal models of HHD to develop and test novel therapeutic targets. The natural history of HHD in animal models should be defined longitudinally to determine which features of human HHD are present. These studies should define the proportion of HHD animals that develop a reduction in LVEF and proceed from HHD to dilated HF.
Frequently, HHD in humans is associated with concomitant coronary artery disease with myocardial infarction, diabetes mellitus, metabolic syndrome, conduction system–induced ventricular dyssynchrony, or impaired filling of the LV because of reduced chamber distensibility. Animal studies with more complex etiologies of HF could be developed to address these issues and to test novel therapeutics as they are developed.
Description of Clinical Entity
Restrictive cardiomyopathies are predominantly defined by a physiological dynamic in which relatively small or normal increases in ventricular filling volumes are associated with exaggerated increases in diastolic pressures.160 Typically, this restrictive ventricular filling pattern is associated with a normal ventricular EF. Anatomically, the LV and right ventricle chamber sizes are usually normal, and wall thickness is normal or mildly increased. Biatrial dilation is usually present because of chronically increased ventricular diastolic pressures in both ventricles.161 Indeed, massive biatrial enlargement combined with normal or reduced ventricular chamber size is a classic morphological pattern among patients with restrictive cardiomyopathies. Clinical presentations of patients with restrictive cardiomyopathy are characterized by dyspnea resulting from elevated diastolic pressures, prominent signs of fluid retention, and often fatigue and weakness reflective of impaired cardiac output reserve, but no evidence of cardiomegaly on chest radiography.160 This clinical presentation of acquired restrictive cardiomyopathy can be similar to that of constrictive pericarditis, although the underlying origin of the syndrome is very distinct.
Causes and Associated Features
Etiologies of restrictive cardiomyopathy include sarcoidosis, eosinophilic cardiomyopathy, endomyocardial fibrosis, scleroderma, radiation-induced fibrosis, familial restrictive cardiomyopathies, amyloidosis, hemochromatosis, and idiopathic restrictive cardiomyopathy.160 A common feature of many acquired restrictive cardiomyopathy etiologies is a predominant remodeling of the myocardial extracellular matrix via either pathological protein deposition or an aggressive fibrotic process resulting from diffuse myocyte cell death. Although potentially present, defects in cardiac myocyte physiology per se have not been described among patients with these acquired restrictive cardiomyopathies. However, for inherited restrictive cardiomyopathies, several recent studies demonstrate that specific sarcomeric protein mutations are associated with defects in myocardial function and increased myofilament calcium sensitivity.162 Mutations involving cardiac troponin I (cTnI),163–167 cardiac troponin T,165–169 desmin,170–174 and α-β-crystallin175 have been most often associated with a restrictive cardiomyopathy phenotype, although alternative mutations of these proteins can also produce a hypertrophic cardiomyopathy phenotype.166,176,177 The histological abnormalities observed in restrictive cardiomyopathies vary with, and are often diagnostic of, the underlying etiology.160,178 For example, demonstration of amyloid or iron deposition within the myocardium is diagnostic of amyloidosis and hemochromatosis, respectively.
The onset of restrictive cardiomyopathy during childhood in the absence of extracardiac abnormalities strongly suggests a primary genetic etiology. However, some familial restrictive cardiomyopathies are not apparent until adulthood.162 Atrial fibrillation is seen with many etiologies of restrictive cardiomyopathy. Ventricular arrhythmias are particularly prevalent among patients with sarcoidosis and some of the mutations associated with familial restrictive cardiomyopathy. Cardiac conduction defects often accompany amyloidosis. Although patients with restrictive cardiomyopathy may present with acute HF after arrhythmias or volume overload, most of the etiologies involved exert their detrimental effects on myocardial performance over the course of many months or years. With the exception of some cases of iron overload cardiomyopathy following iron chelation therapy and the control of some cases of cardiac amyloidosis with stem cell transplantation and/or chemotherapy, the great majority of restrictive cardiomyopathies are progressive and associated with a poor prognosis. Survival is <50% at 5 years after diagnosis.161,164,178–180
Critical Features of an Animal Model of Restrictive Cardiomyopathy
A clinically relevant animal model of restrictive cardiomyopathy must have a documented increase in ventricular chamber stiffness as manifested by an exaggerated increase in LV diastolic pressure in response to a volume challenge. Increased myocardial passive stiffness during in vitro testing should also be documented. Atrial enlargement is another critical feature that should be present to document that increases in ventricular filling pressures have been sustained over time.
Because increased chamber stiffness can be seen in severe cases of hypertrophic or DCM, the absence of marked myocardial hypertrophy (increased voltage on ECG, increased wall thickness without substantial myocyte hypertrophy), and the absence of LV dilation are additional essential distinguishing criteria for animal models of restrictive cardiomyopathy.
For an animal model of restrictive cardiomyopathy to be considered a heart failure model, evidence of progressive impairment of cardiac functional reserve, increased mortality attributable to cardiac causes, and extracardiac features of the HF syndrome such as fluid retention (increased lung weight to body weight, edema, ascites) and neurohormonal activation such as increased natriuretic peptides should be documented. If possible, there should be studies that show that the characteristic restrictive increase in LV chamber stiffness is associated with reduced exercise tolerance or a pathological response (reduced natriuresis and/or pulmonary edema) following a volume challenge. Documenting all of these features of a restrictive cardiomyopathy in an animal model would allow novel mechanistic features under investigation to be related to characteristic phenotypic features of the disease in humans or for therapeutics to be related to these same features.
Restrictive Cardiomyopathy: Current Animal Models
Because diverse etiologies can produce restrictive cardiomyopathies, the potential animal models associated with this phenotype are likewise diverse. As illustrated in Table 3, the majority of the animal models of restrictive cardiomyopathy described to date are rodent models with a relatively few large-animal models reported. It is convenient to segregate these models into those that are related to acquired restrictive cardiomyopathies and those modeling familial cardiomyopathies. In theory, the clinical relevance of an animal model of an acquired restrictive cardiomyopathy is enhanced when it replicates the relationship between an exposure and a tissue abnormality (eg, iron overload/iron deposition or radiation exposure/radiation-induced vascular and myocardial injury) that is observed in clinical settings. On the other hand, the clinical relevance of an animal model of a familial restrictive cardiomyopathy is likely greatest when the mutation produced in a genetically modified mouse strain is identical or analogous to a mutation known to be associated with familial restrictive cardiomyopathy in humans.
|High blood pressure (>140/90 mm Hg)|
|Breathlessness at rest or with minimal activity|
|LVH (concentric hypertrophy with cardiac myocytes demonstrating an increased diameter) or increased LV mass|
|Impaired active relaxation|
|Impaired passive filling|
|Impaired EF (late)|
|Dilated LV internal chamber (late)|
|Enlarged left atrium|
|Myocardial fibrosis (reactive and replacement)|
|Abnormal pressure/volume relationship in the LV with increased LV filling pressure (increased chamber stiffness) relative to LV volume|
|Decreased intramyocardial capillary density|
|Coronary arteriolar thickening|
|Decreased coronary blood flow reserve|
|Increase biomarkers such as NT-proBNP, BNP, or troponin|
HHD indicates hypertensive heart disease; LVH, left ventricular hypertrophy; LV, left ventricular; EF, ejection fraction; BNP, B-type natriuretic peptide; and NT-proBNP, N-terminal pro-B-type natriuretic peptide.
|Rodent models of acquired RCM|
|Rodent models of hereditary RCM|
|Hereditary hemochromatosis||175, 197–199|
|Sarcomeric protein mutations||176, 200, 201|
|Spontaneously occurring RCM in cats||202, 203|
|Amyloidosis in aged vervet monkeys||204|
|Bovine systemic AA amyloidosis||205|
|Amyloidosis in Abyssinian cats||206|
RCM indicates restrictive cardiomyopathy.
In rodent models of acquired restrictive cardiomyopathy, investigators have used simple analogues of clinically detrimental exposures to produce acquired hemochromatosis181–183 and radiation-induced myocardial disease184–186 or immune sensitization and adoptive cell transfer to produce eosinophilic myocarditis.187 Although scleroderma (also known as systemic sclerosis) is an etiology of acquired restrictive cardiomyopathy, numerous studies used the tight skin (Tsk) mouse as a model of scleroderma before188,189,191,192 and after190,193 the recognition that fibrillin-1 overexpression is responsible for the excessive fibrosis associated with this strain. In a like manner, mice overexpressing amyloidogenic proteins, such as transthyretin, have been used to mimic systemic amyloidosis.194 Only a few studies focusing on exogenous iron overload181 and radiation-induced myocardial injury185,186 have demonstrated that the animal model demonstrates critical features of restrictive cardiomyopathies in humans.
Rodent models of familial restrictive cardiomyopathy have generally focused on mimicking the clinical entities of hereditary hemochromatosis or restrictive cardiomyopathies associated with sarcomeric protein mutations. For hereditary hemochromatosis, murine models with homozygous knockout of hemojuvelin (JUV−/−) have produced the most consistent and marked increases in myocardial iron deposition,197,198 whereas studies using HFE gene knockout mice have required administration of a high-iron diet to induce myocardial iron deposition.175,199 These models replicate genotypes observed in humans with familial hemochromatosis, but, as yet, there is little evidence for critical physiological features of restrictive cardiomyopathy leading to HF.
To date, 2 different cTnI mutations have produced mouse models to mimic familial restrictive cardiomyopathy in humans. In 1 model, transgenic mice carrying the R193H mutation (analogous to the R192H mutation associated with restrictive cardiomyopathy in humans), developed atrial dilation with reduced LV chamber size and increased chamber stiffness in the absence of increased wall thickness.200,201 In comparison with nontransgenic littermates, mice with the R193H cTnI mutation demonstrate a reduced resting cardiac output, reduced contractile reserve in response to dobutamine, and a higher mortality by 12 months of age.200 Studies in the cTnI R145W mouse have shown that the same cTnI locus can be associated with either a hypertrophic or a restrictive cardiomyopathy phenotype (in both humans or mice) depending on which base pair is substituted at the locus.176 In this case, isolated cardiac muscles fibers from the mutation associated with the restrictive cardiomyopathy phenotype exhibited increased Ca2+ sensitivity, a 40% increase in peak force and prolonged force, and [Ca2+]i transients that would tend to impair ventricular filling.176 These studies validate that the animal model has the salient features of restrictive cardiomyopathy in humans.
As highlighted in Table 3, the large animal models of restrictive cardiomyopathy consist mainly of naturally occurring states that have been reported by investigators. For the most part, the characterization of these models has been limited to pathological and histological analysis without characterization of myocardial/chamber stiffness. Although models using purposeful exposure of large animals to iron overload or cardiac irradiation could be developed and characterized, we cannot find evidence of such efforts to date.
There are small- and large-animal models for study of the causes and consequences or for the treatment of restrictive cardiomyopathy. Functional demonstration of increased myocardial/chamber stiffness leading to the syndrome of HF caused by a restrictive cardiomyopathy should be a central feature of future studies with these animal models.
HF animal models must be carefully characterized to ensure that they have the critical features that have been described above. The level of characterization will ultimately be determined by the study design and the available equipment and resources. The approaches that have been used routinely to reliably characterize large- and small-animal HF models are outlined below.
Evaluation of Large-Animal Models
Large-animal models continue to be a mainstay for drug, cell, and gene therapy development, and for device development and surgical procedure testing, as well. There has been nearly half a century of technological development for assessing cardiovascular function in large animals. Importantly, essentially anything that can be used in humans can be applied to large-animal models and should be considered. Furthermore, in large-animal models it is possible to obtain data in the conscious rather anesthetized state, so the hemodynamic characterization is more physiological. This also allows measurements to be made over time in the same animal.
The methods that are recommended to assess large-animal cardiovascular function include (1) implantable sensors that can be used chronically in conscious animals, (2) catheters and other sensors that are used acutely under anesthesia or sedation, (3) noninvasive imaging methodologies that may be used in conscious or sedated animals depending on the method. The types of measurements made in any given study will depend on the goals of the analysis, and measurements can be simple or quite complex. Importantly, the principals and approaches are all well established.207
These techniques require a surgical intervention for insertion of instrumentation208 before the induction of the HF stressor. Typically, one combines a series of sonomicrometers implanted into the LV (or right ventricle) to assess dimensions and thereby calculate chamber volume±wall thickness. Micromanometers can be inserted into arterial, venous, and ventricular cavities to measure pressure, ultrasound probes can be used to record central and regional blood flow, fluid-filled catheters can be inserted for calibration, pacing wires can be used to control heart rate, and inferior vena cava cuff occluders can be used to modulate preload volume. With this classic instrumentation, cardiac performance can be assessed by using pressure-volume relations, which facilitates the dissection of primary systolic and diastolic properties of the heart from vascular loading influences. Cardiac power, dP/dt, systemic resistance, aortic input impedance, and essentially any mechanical parameter that can be derived from pressures, volumes, and flows are available. Recording can be made by connecting a single electric plug to a skin-button where all internal sensor wires merge, or by radio telemetry. These approaches allow cardiac structural and functional changes to be measured in conscious animals during the progression of induced disease and after a therapeutic intervention.
Studies can be performed by use of catheters much as one would use catheters in a cardiac catheterization laboratory. Sedation and/or full anesthesia is generally required, and, depending on the location, the catheters must be positioned; some imaging tool, such as fluoroscopy, is needed. The most common methods involve placement of balloon-tipped catheters into the pulmonary artery, often combined with a simple imaging approach, such as contrast ventriculography or echocardiography, and micromanometer catheters placed in arterial or ventricular cavities. These methods provide cardiac output, ventricular systolic and diastolic pressures, chamber end-systolic and end-diastolic volume, and EF, but can also be used to derive more complex mechanical parameters. For example, single-beat estimation methods have been reported to assess end-systolic elastance, a measure of maximal chamber stiffening that is otherwise derived from more complex pressure-volume relations.209 The gold standard catheterization approach for comprehensive analysis of heart and vascular function is again based on pressure-volume relations and arterial/flow relations. Properly calibrated multielectrode conductance (or impedance) catheters developed in the 1980s210 provide pressure-volume signals simultaneously without the need for imaging and post hoc image processing. These techniques are very valuable for critical evaluation of cardiac status in patients and animal models of all sizes.
Noninvasive Imaging Modalities
Nearly all of the imaging methods that can be used in small-animal models are easier to use in larger animals. The exceptions are the molecular imaging methods involving visible or infrared light-emitting reagents that can be visualized in small animals.211 Magnetic resonance methods can be used and provide detailed quantitation of regional function (tagging methods), accurate chamber volumes and structure, functional imaging, flow-encoded imaging, coronary perfusion imaging, and other signals. Essentially all the echocardiography Doppler methods used in clinical medicine can be applied to large-animal models, with the caveat being that finding optimal echocardiography windows can be difficult in some instances because of the more vertical orientation of the heart relative to the thoracic cavity. Imaging can provide measures of remodeling geometry, fractional shortening, and flows, but it is recommended that pressures also be measured, otherwise the characterization of cardiac and vascular function will be incomplete. Combinations of noninvasive imaging approaches with pressure data, either from implanted sensors or transiently introduced catheters, are recommended, because they provide a more complete picture and allow the investigator to calculate more specific metrics of heart and vessel function.
There have been recent advances in noninvasive imaging techniques, and these techniques should be used where appropriate. Advanced MRI techniques and speckle-tracking strain-related imaging (with 3-dimensional reconstruction) with ultrasound echocardiography have been shown to improve early predictions of outcomes in humans.212 These new approaches may more accurately measure ventricular volumes and diastolic function in both small- and large-animal models.213 If MRI is not available, then 3-dimensional transdiaphragmatic echocardiography or 2-dimensional transdiaphragmatic echocardiography should be considered (to alleviate problems with finding useable echocardiography windows).
ECGs should be measured in both small- and large-animal models of HF. ECGs are measured routinely in patients to give insight into rate and rhythm disturbances and blood flow abnormalities. This simple technique should be used routinely at the time of euthanasia in studies of all HF animal models.
In Vivo Cardiac Function
The noninvasive technique of transthoracic echocardiography can be used to evaluate cardiac function in anesthetized or conscious mice.214–219 Transthoracic 2-dimensaional guided M-mode echocardiography can be performed by using a variety of commercially available echocardiograph machines. LV end-diastolic and end-systolic dimensions, heart rate, velocity of circumferential shortening ,and percentage of fractional shortening should be determined. Serial measurements should be performed to evaluate structural and functional progression of HF or to evaluate the efficacy of therapeutics.
In Vivo Measurements of Intrinsic Contractile Function
Since loading conditions can affect isovolumic phase indices of contractility, such as LV dP/dtmax, and ejection phase indices, such as fractional shortening and EF, techniques have been developed to measure contractility by using the end-systolic pressure volume relation in intact mice.157,215,220,221 Established methods most commonly use miniaturized conductance micromanometry.222,223 Cardiac catheterization should be performed by using a small conductance catheter inserted retrograde through the right carotid artery into the LV or through an apical stab. Loading conditions should be varied by either inferior vein occlusion or with transient TAC.218,224 Modification of these methods can be used to measure myocardial stress-strain relations in normal and “diseased” mice in vivo.157,221
In Vivo β-AR Responsiveness
Isovolumic phase indices of contractility (such as LV dP/dtmax) have limited sensitivity when comparing groups of different animals. However, LV dP/dtmax provides useful information on relative changes in contractile behavior when conditions are controlled in the same animal.225 A change in maximal and minimal first derivative of LV pressure (LV dP/dtmax, min) in response to catecholamine stimulation is an excellent and sensitive measure of in vivo β-AR function.226–228 The methodology for cardiac catheterization in the mouse is now considered routine and has been performed in many laboratories around the world. A high-fidelity 1.0F or 1.4F micromanometer catheter is inserted into a carotid artery and advanced into the LV. Following bilateral vagotomy, continuous high-fidelity LV pressure can be recorded at baseline and following bolus doses of a catecholamine such as isoproterenol or dobutamine. Parameters measured are heart rate, aortic pressure, LV systolic and diastolic pressure, and the LV dP/dtmax, min. These approaches should be considered to evaluate basal contractile defects and alteration in contractility reserve.229
|Writing Group Member||Employment||Research Grant||Other Research Support||Speakers’ Bureau/Honoraria||Expert Witness||Ownership Interest||Consultant/Advisory Board||Other|
|Steven R. Houser||Temple University School of Medicine||None||None||None||None||None||None||None|
|Kenneth B. Margulies||University of Pennsylvania||None||None||None||None||None||None||None|
|Gary S. Francis||University of Minnesota||None||None||None||None||None||None||None|
|David A. Kass||Johns Hopkins University School of Medicine||None||None||None||None||None||None||None|
|Walter J. Koch||Thomas Jefferson University||None||None||None||None||None||None||None|
|Jeffrey D. Molkentin||Howard Hughes Medical Institute/Children’s Hospital Medical Center||None||None||None||None||None||None||None|
|Anne M. Murphy||Johns Hopkins University||The Cardiovascular Medical Research and Education Fund*; NIH†||None||None||None||Sold stock of Merck and Pfizer (jointly owned) in Dec 2009*||None||None|
|Sumanth D. Prabhu||The University of Alabama at Birmingham||Abiomed†; NIH/NHLBI/NCRR†; SCR Inc.†; VA†||None||Thoratec Corp*||None||None||SCR, Inc.*||None|
|Howard A. Rockman||Duke University||None||None||None||None||Trevena Inc.*||Trevena Inc.†||None|
|Francis G. Spinale||University of South Carolina School of Medicine||None||None||None||None||None||None||None|
|Mark A. Sussman||San Diego State University||None||None||None||None||Founder and Chief Scientific Officer of CardioCreate Inc.†||None||None|
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
|Reviewer||Employment||Research Grant||Other Research Support||Speakers’ Bureau/ Honoraria||Expert Witness||Ownership Interest||Consultant/ Advisory Board||Other|
|Piero Anversa||Harvard Medical School/Brigham & Women’s Hospital||None||None||None||None||None||None||None|
|Burns Blaxall||University of Rochester||None||None||None||None||None||None||None|
|Robert Gorman||University of Pennsylvania||Johnson and Johnson†||Johnson and Johnson, Medtronic†||None||None||None||Medtronic*||None|
|Åsa B. Gustafsson||University of California, San Diego||NIH/NHLBI†||None||None||None||None||None||None|
|Joshua M. Hare||University of Miami Miller School of Medicine||NHLBI†NHLBI†||None||None||None||None||None||None|
|Raj Kishore||Northwestern University||None||None||None||None||None||None||None|
|Yibin Wang||UCLA||National Institutes of Health†||None||None||None||None||None||None|
This table represents the relationships of reviewer that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire that all reviewers are required to complete and submit. A relationship is considered to be “Significant” if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on March 15, 2012. A copy of the document is available at http://my.americanheart.org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase additional reprints, call 843-216-2533 or e-mail firstname.lastname@example.org.
The American Heart Association requests that this document be cited as follows: Houser SR, Margulies KB, Murphy AM, Spinale FG, Francis GS, Prabhu SD, Rockman HA, Kass DA, Molkentin JD, Sussman MA, Koch WJ; on behalf of the American Heart Association Council on Basic Cardiovascular Sciences, Council on Clinical Cardiology, and Council on Functional Genomics and Translational Biology. Animal models of heart failure: a scientific statement from the American Heart Association. Circ Res. 2012;111:131–150.
Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the “Policies and Development” link.
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- 1.Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Roger VL, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J. Heart disease and stroke statistics–2010 update: a report from the American Heart Association. Circulation. 2010; 121:e46–e215.LinkGoogle Scholar
- 2.Ganau A, Devereux RB, Roman MJ, de Simone G, Pickering TG, Saba PS, Vargiu P, Simongini I, Laragh JH. Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension. J Am Coll Cardiol. 1992; 19:1550–1558.CrossrefMedlineGoogle Scholar
- 3.Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009; 119:e391–e479.LinkGoogle Scholar
- 4.Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). Circulation. 2005; 112:e154–e235.LinkGoogle Scholar
- 5.Ross J, Braunwald E. Aortic stenosis. Circulation. 1968; 38:61–67.LinkGoogle Scholar
- 6.Hess OM, Villari B, Krayenbuehl HP. Diastolic dysfunction in aortic stenosis. Circulation. 1993; 87(suppl IV):IV73–IV76.MedlineGoogle Scholar
- 7.Krayenbuehl HP, Hess OM, Monrad ES, Schneider J, Mall G, Turina M. Left ventricular myocardial structure in aortic valve disease before, intermediate, and late after aortic valve replacement. Circulation. 1989; 79:744–755.CrossrefMedlineGoogle Scholar
- 8.Heymans S, Schroen B, Vermeersch P, Milting H, Gao F, Kassner A, Gillijns H, Herijgers P, Flameng W, Carmeliet P, Van de Werf F, Pinto YM, Janssens S. Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation. 2005; 112:1136–1144.LinkGoogle Scholar
- 9.Monrad ES, Hess OM, Murakami T, Nonogi H, Corin WJ, Krayenbuehl HP. Time course of regression of left ventricular hypertrophy after aortic valve replacement. Circulation. 1988; 77:1345–1355.CrossrefMedlineGoogle Scholar
- 10.Tagawa H, Koide M, Sato H, Zile MR, Carabello BA, Cooper Gt. Cytoskeletal role in the transition from compensated to decompensated hypertrophy during adult canine left ventricular pressure overloading. Circ Res. 1998; 82:751–761.CrossrefMedlineGoogle Scholar
- 11.Weidemann F, Herrmann S, Stork S, Niemann M, Frantz S, Lange V, Beer M, Gattenlohner S, Voelker W, Ertl G, Strotmann JM. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation. 2009; 120:577–584.LinkGoogle Scholar
- 12.Ye Y, Gong G, Ochiai K, Liu J, Zhang J. High-energy phosphate metabolism and creatine kinase in failing hearts: a new porcine model. Circulation. 2001; 103:1570–1576.CrossrefMedlineGoogle Scholar
- 13.Wisenbaugh T, Allen P, Cooper G, Holzgrefe H, Beller G, Carabello B. Contractile function, myosin ATPase activity and isozymes in the hypertrophied pig left ventricle after a chronic progressive pressure overload. Circ Res. 1983; 53:332–341.CrossrefMedlineGoogle Scholar
- 14.Walther T, Schubert A, Falk V, Binner C, Kanev A, Bleiziffer S, Walther C, Doll N, Autschbach R, Mohr FW. Regression of left ventricular hypertrophy after surgical therapy for aortic stenosis is associated with changes in extracellular matrix gene expression. Circulation. 2001; 104(suppl I):I54–I58.CrossrefMedlineGoogle Scholar
- 15.Sakata Y, Hoit BD, Liggett SB, Walsh RA, Dorn GW. Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice. Circulation. 1998; 97:1488–1495.CrossrefMedlineGoogle Scholar
- 16.Teekakirikul P, Eminaga S, Toka O, Alcalai R, Wang L, Wakimoto H, Nayor M, Konno T, Gorham JM, Wolf CM, Kim JB, Schmitt JP, Molkentin JD, Norris RA, Tager AM, Hoffman SR, Markwald RR, Seidman CE, Seidman JG. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β. J Clin Invest. 2010; 120:3520–3529.CrossrefMedlineGoogle Scholar
- 17.Tsutsui H, Spinale FG, Nagatsu M, Schmid PG, Ishihara K, DeFreyte G, Cooper G, Carabello BA. Effects of chronic beta-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation. J Clin Invest. 1994; 93:2639–2648.CrossrefMedlineGoogle Scholar
- 18.Spinale FG, Ishihra K, Zile M, DeFryte G, Crawford FA, Carabello BA. Structural basis for changes in left ventricular function and geometry because of chronic mitral regurgitation and after correction of volume overload. J Thorac Cardiovasc Surg. 1993; 106:1147–1157.MedlineGoogle Scholar
- 19.Perry GJ, Wei CC, Hankes GH, Dillon SR, Rynders P, Mukherjee R, Spinale FG, Dell’Italia LJ. Angiotensin II receptor blockade does not improve left ventricular function and remodeling in subacute mitral regurgitation in the dog. J Am Coll Cardiol. 2002; 39:1374–1379.CrossrefMedlineGoogle Scholar
- 20.Borer JS, Truter S, Herrold EM, Falcone DJ, Pena M, Carter JN, Dumlao TF, Lee JA, Supino PG. Myocardial fibrosis in chronic aortic regurgitation: molecular and cellular responses to volume overload. Circulation. 2002; 105:1837–1842.LinkGoogle Scholar
- 21.Truter SL, Catanzaro DF, Supino PG, Gupta A, Carter J, Herrold EM, Dumlao TF, Borer JS. Differential expression of matrix metalloproteinases and tissue inhibitors and extracellular matrix remodeling in aortic regurgitant hearts. Cardiology. 2009; 113:161–168.CrossrefMedlineGoogle Scholar
- 22.Mickle JP, Menges JT, Day AL, Quisling R, Ballinger W. Experimental aortocaval fistulae in rats. J Microsurg. 1981; 2:283–288.CrossrefMedlineGoogle Scholar
- 23.Gerdes AM, Campbell SE, Hilbelink DR. Structural remodeling of cardiac myocytes in rats with arteriovenous fistulas. Lab Invest. 1988; 59:857–861.MedlineGoogle Scholar
- 24.Su X, Brower G, Janicki JS, Chen YF, Oparil S, Dell’Italia LJ. Differential expression of natriuretic peptides and their receptors in volume overload cardiac hypertrophy in the rat. J Mol Cell Cardiol. 1999; 31:1927–1936.CrossrefMedlineGoogle Scholar
- 25.Chancey AL, Brower GL, Peterson JT, Janicki JS. Effects of matrix metalloproteinase inhibition on ventricular remodeling due to volume overload. Circulation. 2002; 105:1983–1988.LinkGoogle Scholar
- 26.Wei CC, Lucchesi PA, Tallaj J, Bradley WE, Powell PC, Dell’Italia LJ. Cardiac interstitial bradykinin and mast cells modulate pattern of LV remodeling in volume overload in rats. Am J Physiol Heart Circ Physiol. 2003; 285:H784–H792.CrossrefMedlineGoogle Scholar
- 27.Beltrami CA, Finato N, Rocco M, Feruglio GA, Puricelli C, Cigola E, Quaini F, Sonnenblick EH, Olivetti G, Anversa P. Structural basis of end-stage failure in ischemic cardiomyopathy in humans. Circulation. 1994; 89:151–163.CrossrefMedlineGoogle Scholar
- 28.Beltrami CA, Finato N, Rocco M, Feruglio GA, Puricelli C, Cigola E, Sonnenblick EH, Olivetti G, Anversa P. The cellular basis of dilated cardiomyopathy in humans. J Mol Cell Cardiol. 1995; 27:291–305.CrossrefMedlineGoogle Scholar
- 29.Timek TA, Lai DT, Dagum P, Liang D, Daughters GT, Ingels NB, Miller DC. Mitral leaflet remodeling in dilated cardiomyopathy. Circulation. 2006; 114(suppl I):I518–I523.LinkGoogle Scholar
- 30.Schenke-Layland K, Stock UA, Nsair A, Xie J, Angelis E, Fonseca CG, Larbig R, Mahajan A, Shivkumar K, Fishbein MC, MacLellan WR. Cardiomyopathy is associated with structural remodelling of heart valve extracellular matrix. Eur Heart J. 2009; 30:2254–2265.CrossrefMedlineGoogle Scholar
- 31.Prabhu SD. Post-infarction ventricular remodeling: an array of molecular events. J Mol Cell Cardiol. 2005; 38:547–550.CrossrefMedlineGoogle Scholar
- 32.Jessup M, Brozena S. Heart failure. N Engl J Med. 2003; 348:2007–2018.CrossrefMedlineGoogle Scholar
- 33.Eichhorn EJ, Bristow MR. Medical therapy can improve the biological properties of the chronically failing heart. A new era in the treatment of heart failure. Circulation. 1996; 94:2285–2296.CrossrefMedlineGoogle Scholar
- 34.Lindenfeld J, Albert NM, Boehmer JP, Collins SP, Ezekowitz JA, Givertz MM, Katz SD, Klapholz M, Moser DK, Rogers JG, Starling RC, Stevenson WG, Tang WH, Teerlink JR, Walsh MN. HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 2010; 16:e1–e194.CrossrefMedlineGoogle Scholar
- 35.Mann DL, Bristow MR. Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation. 2005; 111:2837–2849.LinkGoogle Scholar
- 36.Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation. 2006; 113:1807–1816.LinkGoogle Scholar
- 37.Wexler RK, Elton T, Pleister A, Feldman D. Cardiomyopathy: an overview. Am Fam Physician. 2009; 79:778–784.MedlineGoogle Scholar
- 38.Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000; 101:2981–2988.CrossrefMedlineGoogle Scholar
- 39.Prabhu SD, Chandrasekar B, Murray DR, Freeman GL. Beta-adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling. Circulation. 2000; 101:2103–2109.CrossrefMedlineGoogle Scholar
- 40.Edwards BS, Zimmerman RS, Schwab TR, Heublein DM, Burnett JC. Atrial stretch, not pressure, is the principal determinant controlling the acute release of atrial natriuretic factor. Circ Res. 1988; 62:191–195.CrossrefMedlineGoogle Scholar
- 41.Hall C. NT-proBNP: the mechanism behind the marker. J Card Fail. 2005; 11(suppl):S81–S83.CrossrefMedlineGoogle Scholar
- 42.Olson EN, Schneider MD. Sizing up the heart: development redux in disease. Genes Dev. 2003; 17:1937–1956.CrossrefMedlineGoogle Scholar
- 43.Swynghedauw B. Molecular mechanisms of myocardial remodeling. Physiol Rev. 1999; 79:215–262.CrossrefMedlineGoogle Scholar
- 44.Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res. 2002; 91:988–998.LinkGoogle Scholar
- 45.Testa M, Yeh M, Lee P, Fanelli R, Loperfido F, Berman JW, LeJemtel TH. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J Am Coll Cardiol. 1996; 28:964–971.CrossrefMedlineGoogle Scholar
- 46.Torre-Amione G, Kapadia S, Lee J, Durand JB, Bies RD, Young JB, Mann DL. Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart. Circulation. 1996; 93:704–711.CrossrefMedlineGoogle Scholar
- 47.Mak S, Lehotay DC, Yazdanpanah M, Azevedo ER, Liu PP, Newton GE. Unsaturated aldehydes including 4-OH-nonenal are elevated in patients with congestive heart failure. J Card Fail. 2000; 6:108–114.CrossrefMedlineGoogle Scholar
- 48.Mallat Z, Philip I, Lebret M, Chatel D, Maclouf J, Tedgui A. Elevated levels of 8-iso-prostaglandin F2alpha in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure. Circulation. 1998; 97:1536–1539.CrossrefMedlineGoogle Scholar
- 49.Rochette L, Tatou E, Vergely C, Maupoil V, Bouchot O, Mossiat C, Jazayeri S, Benkhadra S, Brenot R, Girard C, David M. Regional heterogeneity of decreased myocardial norepinephrine and increased lipid peroxidation levels in patients with end-stage failing heart secondary to dilated or ischemic cardiomyopathy. J Heart Lung Transplant. 2008; 27:767–774.CrossrefMedlineGoogle Scholar
- 50.Foo RS, Mani K, Kitsis RN. Death begets failure in the heart. J Clin Invest. 2005; 115:565–571.CrossrefMedlineGoogle Scholar
- 51.Dorn GW. Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodelling. Cardiovasc Res. 2009; 81:465–473.CrossrefMedlineGoogle Scholar
- 52.Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewski S, Reed JC, Anversa P. Apoptosis in the failing human heart. N Engl J Med. 1997; 336:1131–1141.CrossrefMedlineGoogle Scholar
- 53.Abraham D, Hofbauer R, Schafer R, Blumer R, Paulus P, Miksovsky A, Traxler H, Kocher A, Aharinejad S. Selective downregulation of VEGF-A(165), VEGF-R(1), and decreased capillary density in patients with dilative but not ischemic cardiomyopathy. Circ Res. 2000; 87:644–647.CrossrefMedlineGoogle Scholar
- 54.Karch R, Neumann F, Ullrich R, Neumuller J, Podesser BK, Neumann M, Schreiner W. The spatial pattern of coronary capillaries in patients with dilated, ischemic, or inflammatory cardiomyopathy. Cardiovasc Pathol. 2005; 14:135–144.CrossrefMedlineGoogle Scholar
- 55.Kostin S, Pool L, Elsasser A, Hein S, Drexler HC, Arnon E, Hayakawa Y, Zimmermann R, Bauer E, Klovekorn WP, Schaper J. Myocytes die by multiple mechanisms in failing human hearts. Circ Res. 2003; 92:715–724.LinkGoogle Scholar
- 56.Libby P, Braunwald E. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, PA: Saunders/Elsevier; 2008.Google Scholar
- 57.Fukuta H, Little WC. The cardiac cycle and the physiologic basis of left ventricular contraction, ejection, relaxation, and filling. Heart Fail Clin. 2008; 4:1–11.CrossrefMedlineGoogle Scholar
- 58.Fukuta H, Little WC. Contribution of systolic and diastolic abnormalities to heart failure with a normal and a reduced ejection fraction. Prog Cardiovasc Dis. 2007; 49:229–240.CrossrefMedlineGoogle Scholar
- 59.Pak PH, Kass DA. Assessment of ventricular function in dilated cardiomyopathies. Curr Opin Cardiol. 1995; 10:339–344.CrossrefMedlineGoogle Scholar
- 60.Ogletree-Hughes ML, Stull LB, Sweet WE, Smedira NG, McCarthy PM, Moravec CS. Mechanical unloading restores beta-adrenergic responsiveness and reverses receptor downregulation in the failing human heart. Circulation. 2001; 104:881–886.CrossrefMedlineGoogle Scholar
- 61.Barki-Harrington L, Perrino C, Rockman HA. Network integration of the adrenergic system in cardiac hypertrophy. Cardiovasc Res. 2004; 63:391–402.CrossrefMedlineGoogle Scholar
- 62.White M, Yanowitz F, Gilbert EM, Larrabee P, O’Connell JB, Anderson JL, Renlund D, Mealey P, Abraham WT, Bristow MR. Role of beta-adrenergic receptor downregulation in the peak exercise response in patients with heart failure due to idiopathic dilated cardiomyopathy. Am J Cardiol. 1995; 76:1271–1276.CrossrefMedlineGoogle Scholar
- 63.Port JD, Bristow MR. Altered beta-adrenergic receptor gene regulation and signaling in chronic heart failure. J Mol Cell Cardiol. 2001; 33:887–905.CrossrefMedlineGoogle Scholar
- 64.Mak S, Newton GE. Redox modulation of the inotropic response to dobutamine is impaired in patients with heart failure. Am J Physiol Heart Circ Physiol. 2004; 286:H789–H795.CrossrefMedlineGoogle Scholar
- 65.von Lewinski D, Kockskamper J, Zhu D, Post H, Elgner A, Pieske B. Reduced stretch-induced force response in failing human myocardium caused by impaired Na(+)-contraction coupling. Circ Heart Fail. 2009; 2:47–55.LinkGoogle Scholar
- 66.Pieske B, Kretschmann B, Meyer M, Holubarsch C, Weirich J, Posival H, Minami K, Just H, Hasenfuss G. Alterations in intracellular calcium handling associated with the inverse force-frequency relation in human dilated cardiomyopathy. Circulation. 1995; 92:1169–1178.CrossrefMedlineGoogle Scholar
- 67.Feldman MD, Alderman JD, Aroesty JM, Royal HD, Ferguson JJ, Owen RM, Grossman W, McKay RG. Depression of systolic and diastolic myocardial reserve during atrial pacing tachycardia in patients with dilated cardiomyopathy. J Clin Invest. 1988; 82:1661–1669.CrossrefMedlineGoogle Scholar
- 68.Vollmann D, Luthje L, Schott P, Hasenfuss G, Unterberg-Buchwald C. Biventricular pacing improves the blunted force-frequency relation present during univentricular pacing in patients with heart failure and conduction delay. Circulation. 2006; 113:953–959.LinkGoogle Scholar
- 69.Houser SR, Piacentino V, Weisser J. Abnormalities of calcium cycling in the hypertrophied and failing heart. J Mol Cell Cardiol. 2000; 32:1595–1607.CrossrefMedlineGoogle Scholar
- 70.Bers DM. Altered cardiac myocyte ca regulation in heart failure. Physiology (Bethesda). 2006; 21:380–387.CrossrefMedlineGoogle Scholar
- 71.Anderson ME. CaMKII and a failing strategy for growth in heart. J Clin Invest. 2009; 119:1082–1085.CrossrefMedlineGoogle Scholar
- 72.Dandamudi G, Rampurwala AY, Mahenthiran J, Miller JM, Das MK. Persistent left ventricular dilatation in tachycardia-induced cardiomyopathy patients after appropriate treatment and normalization of ejection fraction. Heart Rhythm. 2008; 5:1111–1114.CrossrefMedlineGoogle Scholar
- 73.Shinbane JS, Wood MA, Jensen DN, Ellenbogen KA, Fitzpatrick AP, Scheinman MM. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J Am Coll Cardiol. 1997; 29:709–715.CrossrefMedlineGoogle Scholar
- 74.McMahon WS, Mukherjee R, Gillette PC, Crawford FA, Spinale FG. Right and left ventricular geometry and myocyte contractile processes with dilated cardiomyopathy: myocyte growth and beta-adrenergic responsiveness. Cardiovasc Res. 1996; 31:314–323.MedlineGoogle Scholar
- 75.Spinale FG, Tomita M, Zellner JL, Cook JC, Crawford FA, Zile MR. Collagen remodeling and changes in LV function during development and recovery from supraventricular tachycardia. Am J Physiol. 1991; 261:H308–H318.MedlineGoogle Scholar
- 76.Dixon JA, Spinale FG. Large animal models of heart failure: a critical link in the translation of basic science to clinical practice. Circ Heart Fail. 2009; 2:262–271.LinkGoogle Scholar
- 77.Monnet E, Chachques JC. Animal models of heart failure: What is new?Ann Thorac Surg. 2005; 79:1445–1453.CrossrefMedlineGoogle Scholar
- 78.Patten RD, Hall-Porter MR. Small animal models of heart failure: development of novel therapies, past and present. Circ Heart Fail. 2009; 2:138–144.LinkGoogle Scholar
- 79.Abarbanell AM, Herrmann JL, Weil BR, Wang Y, Tan J, Moberly SP, Fiege JW, Meldrum DR. Animal models of myocardial and vascular injury. J Surg Res. 2010; 162:239–249.CrossrefMedlineGoogle Scholar
- 80.Wang QD, Bohlooly YM, Sjoquist PO. Murine models for the study of congestive heart failure: implications for understanding molecular mechanisms and for drug discovery. J Pharmacol Toxicol Methods. 2004; 50:163–174.CrossrefMedlineGoogle Scholar
- 81.Piacentino V, Weber CR, Chen X, Weisser-Thomas J, Margulies KB, Bers DM, Houser SR. Cellular basis of abnormal calcium transients of failing human ventricular myocytes. Circ Res. 2003; 92:651–658.LinkGoogle Scholar
- 82.Pfeffer MA, Pfeffer JM, Fishbein MC, Fletcher PJ, Spadaro J, Kloner RA, Braunwald E. Myocardial infarct size and ventricular function in rats. Circ Res. 1979; 44:503–512.CrossrefMedlineGoogle Scholar
- 83.Prabhu SD, Wang G, Luo J, Gu Y, Ping P, Chandrasekar B. Beta-adrenergic receptor blockade modulates Bcl-X(S) expression and reduces apoptosis in failing myocardium. J Mol Cell Cardiol. 2003; 35:483–493.CrossrefMedlineGoogle Scholar
- 84.Patten RD, Aronovitz MJ, Deras-Mejia L, Pandian NG, Hanak GG, Smith JJ, Mendelsohn ME, Konstam MA. Ventricular remodeling in a mouse model of myocardial infarction. Am J Physiol. 1998; 274:H1812–H1820.MedlineGoogle Scholar
- 85.Hamid T, Gu Y, Ortines RV, Bhattacharya C, Wang G, Xuan YT, Prabhu SD. Divergent tumor necrosis factor receptor-related remodeling responses in heart failure: role of nuclear factor-kappaB and inflammatory activation. Circulation. 2009; 119:1386–1397.LinkGoogle Scholar
- 86.Wang G, Hamid T, Keith RJ, Zhou G, Partridge CR, Xiang X, Kingery JR, Lewis RK, Li Q, Rokosh DG, Ford R, Spinale FG, Riggs DW, Srivastava S, Bhatnagar A, Bolli R, Prabhu SD. Cardioprotective and antiapoptotic effects of heme oxygenase-1 in the failing heart. Circulation. 2010; 121:1912–1925.LinkGoogle Scholar
- 87.Zhang R, Khoo MS, Wu Y, Yang Y, Grueter CE, Ni G, Price EE, Thiel W, Guatimosim S, Song LS, Madu EC, Shah AN, Vishnivetskaya TA, Atkinson JB, Gurevich VV, Salama G, Lederer WJ, Colbran RJ, Anderson ME. Calmodulin kinase II inhibition protects against structural heart disease. Nat Med. 2005; 11:409–417.CrossrefMedlineGoogle Scholar
- 88.Dai S, Yuan F, Mu J, Li C, Chen N, Guo S, Kingery J, Prabhu SD, Bolli R, Rokosh G. Chronic AMD3100 antagonism of SDF-1alpha-CXCR4 exacerbates cardiac dysfunction and remodeling after myocardial infarction. J Mol Cell Cardiol. 2010; 49:587–597.CrossrefMedlineGoogle Scholar
- 89.Michael LH, Entman ML, Hartley CJ, Youker KA, Zhu J, Hall SR, Hawkins HK, Berens K, Ballantyne CM. Myocardial ischemia and reperfusion: a murine model. Am J Physiol. 1995; 269:H2147–H2154.MedlineGoogle Scholar
- 90.Tang XL, Rokosh G, Sanganalmath SK, Yuan F, Sato H, Mu J, Dai S, Li C, Chen N, Peng Y, Dawn B, Hunt G, Leri A, Kajstura J, Tiwari S, Shirk G, Anversa P, Bolli R. Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation. 2010; 121:293–305.LinkGoogle Scholar
- 91.Dawn B, Guo Y, Rezazadeh A, Huang Y, Stein AB, Hunt G, Tiwari S, Varma J, Gu Y, Prabhu SD, Kajstura J, Anversa P, Ildstad ST, Bolli R. Postinfarct cytokine therapy regenerates cardiac tissue and improves left ventricular function. Circ Res. 2006; 98:1098–1105.LinkGoogle Scholar
- 92.Liu X, Simpson JA, Brunt KR, Ward CA, Hall SR, Kinobe RT, Barrette V, Tse MY, Pang SC, Pachori AS, Dzau VJ, Ogunyankin KO, Melo LG. Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction. Am J Physiol Heart Circ Physiol. 2007; 293:H48–H59.CrossrefMedlineGoogle Scholar
- 93.Fletcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Left ventricular diastolic pressure-volume relations in rats with healed myocardial infarction. Effects on systolic function. Circ Res. 1981; 49:618–626.CrossrefMedlineGoogle Scholar
- 94.Lefer DJ, Hock CE, Ribeiro LG, Lefer AM. Effects of lisinopril, a new angiotensin converting enzyme inhibitor in a cryo-injury model of chronic left ventricular failure. Methods Find Exp Clin Pharmacol. 1986; 8:357–362.MedlineGoogle Scholar
- 95.Chu G, Haghighi K, Kranias EG. From mouse to man: Understanding heart failure through genetically altered mouse models. J Card Fail. 2002; 8:S432–449.CrossrefMedlineGoogle Scholar
- 96.Weinstein DM, Mihm MJ, Bauer JA. Cardiac peroxynitrite formation and left ventricular dysfunction following doxorubicin treatment in mice. J Pharmacol Exp Ther. 2000; 294:396–401.MedlineGoogle Scholar
- 97.van der Vijgh WJ, van Velzen D, van der Poort JS, Schluper HM, Mross K, Feijen J, Pinedo HM. Morphometric study of myocardial changes during doxorubicin-induced cardiomyopathy in mice. Eur J Cancer Clin Oncol. 1988; 24:1603–1608.CrossrefMedlineGoogle Scholar
- 98.Robert J. Long-term and short-term models for studying anthracycline cardiotoxicity and protectors. Cardiovasc Toxicol. 2007; 7:135–139.CrossrefMedlineGoogle Scholar
- 99.Teerlink JR, Pfeffer JM, Pfeffer MA. Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats. Circ Res. 1994; 75:105–113.CrossrefMedlineGoogle Scholar
- 100.Oudit GY, Crackower MA, Eriksson U, Sarao R, Kozieradzki I, Sasaki T, Irie-Sasaki J, Gidrewicz D, Rybin VO, Wada T, Steinberg SF, Backx PH, Penninger JM. Phosphoinositide 3-kinase gamma-deficient mice are protected from isoproterenol-induced heart failure. Circulation. 2003; 108:2147–2152.LinkGoogle Scholar
- 101.Shan J, Kushnir A, Betzenhauser MJ, Reiken S, Li J, Lehnart SE, Lindegger N, Mongillo M, Mohler PJ, Marks AR. Phosphorylation of the ryanodine receptor mediates the cardiac fight or flight response in mice. J Clin Invest. 2010; 120:4388–4398.CrossrefMedlineGoogle Scholar
- 102.Angert D, Berretta RM, Kubo H, Zhang H, Chen X, Wang W, Ogorek B, Barbe M, Houser SR. Repair of the injured adult heart involves new myocytes potentially derived from resident cardiac stem cells. Circ Res. 2011; 108:1226–1237.LinkGoogle Scholar
- 103.Itter G, Jung W, Juretschke P, Schoelkens BA, Linz W. A model of chronic heart failure in spontaneous hypertensive rats (SHR). Lab Anim. 2004; 38:138–148.CrossrefMedlineGoogle Scholar
- 104.Jugdutt BI, Menon V. Valsartan-induced cardioprotection involves angiotensin II type 2 receptor upregulation in dog and rat models of in vivo reperfused myocardial infarction. J Card Fail. 2004; 10:74–82.CrossrefMedlineGoogle Scholar
- 105.van der Velden J, Merkus D, Klarenbeek BR, James AT, Boontje NM, Dekkers DH, Stienen GJ, Lamers JM, Duncker DJ. Alterations in myofilament function contribute to left ventricular dysfunction in pigs early after myocardial infarction. Circ Res. 2004; 95:e85–e95.LinkGoogle Scholar
- 106.Zeng L, Hu Q, Wang X, Mansoor A, Lee J, Feygin J, Zhang G, Suntharalingam P, Boozer S, Mhashilkar A, Panetta CJ, Swingen C, Deans R, From AH, Bache RJ, Verfaillie CM, Zhang J. Bioenergetic and functional consequences of bone marrow-derived multipotent progenitor cell transplantation in hearts with postinfarction left ventricular remodeling. Circulation. 2007; 115:1866–1875.LinkGoogle Scholar
- 107.Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, Durand DJ, Fitton T, Kuang JQ, Stewart G, Lehrke S, Baumgartner WW, Martin BJ, Heldman AW, Hare JM. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci U S A. 2005; 102:11474–11479.CrossrefMedlineGoogle Scholar
- 108.Lee ST, White AJ, Matsushita S, Malliaras K, Steenbergen C, Zhang Y, Li TS, Terrovitis J, Yee K, Simsir S, Makkar R, Marban E. Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction. J Am Coll Cardiol. 2011; 57:455–465.CrossrefMedlineGoogle Scholar
- 109.Jackson BM, Gorman JH, Moainie SL, Guy TS, Narula N, Narula J, John-Sutton MG, Edmunds LH, Gorman RC. Extension of borderzone myocardium in postinfarction dilated cardiomyopathy. J Am Coll Cardiol. 2002; 40:1160–1167; discussion 1168–1171 .CrossrefMedlineGoogle Scholar
- 110.Gorman JH, Gorman RC, Plappert T, Jackson BM, Hiramatsu Y, St John-Sutton MG, Edmunds LH. Infarct size and location determine development of mitral regurgitation in the sheep model. J Thorac Cardiovasc Surg. 1998; 115:615–622.CrossrefMedlineGoogle Scholar
- 111.Llaneras MR, Nance ML, Streicher JT, Lima JA, Savino JS, Bogen DK, Deac RF, Ratcliffe MB, Edmunds LH. Large animal model of ischemic mitral regurgitation. Ann Thorac Surg. 1994; 57:432–439.CrossrefMedlineGoogle Scholar
- 112.Blom AS, Mukherjee R, Pilla JJ, Lowry AS, Yarbrough WM, Mingoia JT, Hendrick JW, Stroud RE, McLean JE, Affuso J, Gorman RC, Gorman JH, Acker MA, Spinale FG. Cardiac support device modifies left ventricular geometry and myocardial structure after myocardial infarction. Circulation. 2005; 112:1274–1283.LinkGoogle Scholar
- 113.Maxwell MP, Hearse DJ, Yellon DM. Species variation in the coronary collateral circulation during regional myocardial ischaemia: a critical determinant of the rate of evolution and extent of myocardial infarction. Cardiovasc Res. 1987; 21:737–746.CrossrefMedlineGoogle Scholar
- 114.Weaver ME, Pantely GA, Bristow JD, Ladley HD. A quantitative study of the anatomy and distribution of coronary arteries in swine in comparison with other animals and man. Cardiovasc Res. 1986; 20:907–917.CrossrefMedlineGoogle Scholar
- 115.Sabbah HN, Stein PD, Kono T, Gheorghiade M, Levine TB, Jafri S, Hawkins ET, Goldstein S. A canine model of chronic heart failure produced by multiple sequential coronary microembolizations. Am J Physiol. 1991; 260:H1379–H1384.MedlineGoogle Scholar
- 116.Saavedra WF, Tunin RS, Paolocci N, Mishima T, Suzuki G, Emala CW, Chaudhry PA, Anagnostopoulos P, Gupta RC, Sabbah HN, Kass DA. Reverse remodeling and enhanced adrenergic reserve from passive external support in experimental dilated heart failure. J Am Coll Cardiol. 2002; 39:2069–2076.CrossrefMedlineGoogle Scholar
- 117.Morita H, Khanal S, Rastogi S, Suzuki G, Imai M, Todor A, Sharov VG, Goldstein S, O’Neill TP, Sabbah HN. Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. Am J Physiol Heart Circ Physiol. 2006; 290:H2522–H2527.CrossrefMedlineGoogle Scholar
- 118.Huang Y, Hunyor SN, Jiang L, Kawaguchi O, Shirota K, Ikeda Y, Yuasa T, Gallagher G, Zeng B, Zheng X. Remodeling of the chronic severely failing ischemic sheep heart after coronary microembolization: functional, energetic, structural, and cellular responses. Am J Physiol Heart Circ Physiol. 2004; 286:H2141–H2150.CrossrefMedlineGoogle Scholar
- 119.Monreal G, Gerhardt MA, Kambara A, Abrishamchian AR, Bauer JA, Goldstein AH. Selective microembolization of the circumflex coronary artery in an ovine model: dilated, ischemic cardiomyopathy and left ventricular dysfunction. J Card Fail. 2004; 10:174–183.CrossrefMedlineGoogle Scholar
- 120.Huang Y, Kawaguchi O, Zeng B, Carrington RA, Horam CJ, Yuasa T, Abdul-Hussein N, Hunyor SN. A stable ovine congestive heart failure model. A suitable substrate for left ventricular assist device assessment. ASAIO J. 1997; 43:M408–M413.CrossrefMedlineGoogle Scholar
- 121.Heusch G, Kleinbongard P, Bose D, Levkau B, Haude M, Schulz R, Erbel R. Coronary microembolization: from bedside to bench and back to bedside. Circulation. 2009; 120:1822–1836.LinkGoogle Scholar
- 122.O’Rourke B, Kass DA, Tomaselli GF, Kaab S, Tunin R, Marban E. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: Experimental studies. Circ Res. 1999; 84:562–570.CrossrefMedlineGoogle Scholar
- 123.Prabhu SD. Load sensitivity of left ventricular relaxation in normal and failing hearts: evidence of a nonlinear biphasic response. Cardiovasc Res. 1999; 43:354–363.CrossrefMedlineGoogle Scholar
- 124.Prabhu SD, Freeman GL. Effect of tachycardia heart failure on the restitution of left ventricular function in closed-chest dogs. Circulation. 1995; 91:176–185.CrossrefMedlineGoogle Scholar
- 125.Winslow RL, Rice J, Jafri S, Marban E, O’Rourke B. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II: Model studies. Circ Res. 1999; 84:571–586.CrossrefMedlineGoogle Scholar
- 126.Moe GW, Stopps TP, Angus C, Forster C, De Bold AJ, Armstrong PW. Alterations in serum sodium in relation to atrial natriuretic factor and other neuroendocrine variables in experimental pacing-induced heart failure. J Am Coll Cardiol. 1989; 13:173–179.CrossrefMedlineGoogle Scholar
- 127.Tanaka R, Fulbright BM, Mukherjee R, Burchell SA, Crawford FA, Zile MR, Spinale FG. The cellular basis for the blunted response to beta-adrenergic stimulation in supraventricular tachycardia-induced cardiomyopathy. J Mol Cell Cardiol. 1993; 25:1215–1233.CrossrefMedlineGoogle Scholar
- 128.Byrne MJ, Kaye DM, Mathis M, Reuter DG, Alferness CA, Power JM. Percutaneous mitral annular reduction provides continued benefit in an ovine model of dilated cardiomyopathy. Circulation. 2004; 110:3088–3092.LinkGoogle Scholar
- 129.Timek TA, Dagum P, Lai DT, Liang D, Daughters GT, Tibayan F, Ingels NB, Miller DC. Tachycardia-induced cardiomyopathy in the ovine heart: mitral annular dynamic three-dimensional geometry. J Thorac Cardiovasc Surg. 2003; 125:315–324.CrossrefMedlineGoogle Scholar
- 130.Kaye DM, Preovolos A, Marshall T, Byrne M, Hoshijima M, Hajjar R, Mariani JA, Pepe S, Chien KR, Power JM. Percutaneous cardiac recirculation-mediated gene transfer of an inhibitory phospholamban peptide reverses advanced heart failure in large animals. J Am Coll Cardiol. 2007; 50:253–260.CrossrefMedlineGoogle Scholar
- 131.Bristow MR, Sageman WS, Scott RH, Billingham ME, Bowden RE, Kernoff RS, Snidow GH, Daniels JR. Acute and chronic cardiovascular effects of doxorubicin in the dog: the cardiovascular pharmacology of drug-induced histamine release. J Cardiovasc Pharmacol. 1980; 2:487–515.CrossrefMedlineGoogle Scholar
- 132.Toyoda Y, Okada M, Kashem MA. A canine model of dilated cardiomyopathy induced by repetitive intracoronary doxorubicin administration. J Thorac Cardiovasc Surg. 1998; 115:1367–1373.CrossrefMedlineGoogle Scholar
- 133.Monnet E, Orton EC. A canine model of heart failure by intracoronary adriamycin injection: hemodynamic and energetic results. J Card Fail. 1999; 5:255–264.CrossrefMedlineGoogle Scholar
- 134.Borenstein N, Bruneval P, Behr L, Laborde F, Montarras D, Daures JP, Derumeaux G, Pouchelon JL, Chetboul V. An ovine model of chronic heart failure: echocardiographic and tissue Doppler imaging characterization. J Card Surg. 2006; 21:50–56.CrossrefMedlineGoogle Scholar
- 135.Chekanov VS. A stable model of chronic bilateral ventricular insufficiency (dilated cardiomyopathy) induced by arteriovenous anastomosis and doxorubicin administration in sheep. J Thorac Cardiovasc Surg. 1999; 117:198–199.CrossrefMedlineGoogle Scholar
- 136.Bartoli CR, Brittian KR, Giridharan GA, Koenig SC, Hamid T, Prabhu SD. Bovine model of doxorubicin-induced cardiomyopathy. J Biomed Biotechnol. 2011; 2011:758736.CrossrefMedlineGoogle Scholar
- 137.Lin N, Badie N, Yu L, Abraham D, Cheng H, Bursac N, Rockman HA, Wolf MJ. A method to measure myocardial calcium handling in adult drosophila. Circ Res. 2011; 108:1306–1315.LinkGoogle Scholar
- 138.Fiedler J, Jazbutyte V, Kirchmaier BC, Gupta SK, Lorenzen J, Hartmann D, Galuppo P, Kneitz S, Pena JT, Sohn-Lee C, Loyer X, Soutschek J, Brand T, Tuschl T, Heineke J, Martin U, Schulte-Merker S, Ertl G, Engelhardt S, Bauersachs J, Thum T. Microrna-24 regulates vascularity after myocardial infarction. Circulation. 2011; 124:720–730.LinkGoogle Scholar
- 139.Wang J, Panakova D, Kikuchi K, Holdway JE, Gemberling M, Burris JS, Singh SP, Dickson AL, Lin YF, Sabeh MK, Werdich AA, Yelon D, Macrae CA, Poss KD. The regenerative capacity of zebra fish reverses cardiac failure caused by genetic cardiomyocyte depletion. Development. 2011; 138:3421–3430.CrossrefMedlineGoogle Scholar
- 140.Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990; 322:1561–1566.CrossrefMedlineGoogle Scholar
- 141.Drazner MH, Dries DL, Peshock RM, Cooper RS, Klassen C, Kazi F, Willett D, Victor RG. Left ventricular hypertrophy is more prevalent in blacks than whites in the general population: the Dallas Heart Study. Hypertension. 2005; 46:124–129.LinkGoogle Scholar
- 142.Frohlich ED, Apstein C, Chobanian AV, Devereux RB, Dustan HP, Dzau V, Fauad-Tarazi F, Horan MJ, Marcus M, Massie B, Pfeffer MA, Re RN, Roccella EJ, Savage D, Shub C. The heart in hypertension. N Engl J Med. 1992; 327:998–1008.CrossrefMedlineGoogle Scholar
- 143.Drazner MH. The transition from hypertrophy to failure: how certain are we?Circulation. 2005; 112:936–938.LinkGoogle Scholar
- 144.Aurigemma GP, Silver KH, Priest MA, Gaasch WH. Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy. J Am Coll Cardiol. 1995; 26:195–202.CrossrefMedlineGoogle Scholar
- 145.Shimizu G, Hirota Y, Kita Y, Kawamura K, Saito T, Gaasch WH. Left ventricular midwall mechanics in systemic arterial hypertension. Myocardial function is depressed in pressure-overload hypertrophy. Circulation. 1991; 83:1676–1684.CrossrefMedlineGoogle Scholar
- 146.Little WC, Downes TR. Clinical evaluation of left ventricular diastolic performance. Prog Cardiovasc Dis. 1990; 32:273–290.CrossrefMedlineGoogle Scholar
- 147.Cohen GI, Pietrolungo JF, Thomas JD, Klein AL. A practical guide to assessment of ventricular diastolic function using Doppler echocardiography. J Am Coll Cardiol. 1996; 27:1753–1760.CrossrefMedlineGoogle Scholar
- 148.Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998; 93:215–228.CrossrefMedlineGoogle Scholar
- 149.Miller WL, Mahoney DW, Michelena HI, Pislaru SV, Topilsky Y, Enriquez-Sarano M. Contribution of ventricular diastolic dysfunction to pulmonary hypertension complicating chronic systolic heart failure. J Am Coll Cardiol Cardiovasc Imaging. 2011; 4:946–954.CrossrefMedlineGoogle Scholar
- 150.Pfeffer JM, Pfeffer MA, Mirsky I, Braunwald E. Regression of left ventricular hypertrophy and prevention of left ventricular dysfunction by captopril in the spontaneously hypertensive rat. Proc Natl Acad Sci U S A. 1982; 79:3310–3314.CrossrefMedlineGoogle Scholar
- 151.Litwin SE, Katz SE, Weinberg EO, Lorell BH, Aurigemma GP, Douglas PS. Serial echocardiographic-Doppler assessment of left ventricular geometry and function in rats with pressure-overload hypertrophy. Chronic angiotensin-converting enzyme inhibition attenuates the transition to heart failure. Circulation. 1995; 91:2642–2654.CrossrefMedlineGoogle Scholar
- 152.Morioka S, Simon G. Echocardiographic evidence for early left ventricular hypertrophy in dogs with renal hypertension. Am J Cardiol. 1982; 49:1890–1895.CrossrefMedlineGoogle Scholar
- 153.Hart CY, Meyer DM, Tazelaar HD, Grande JP, Burnett JC, Housmans PR, Redfield MM. Load versus humoral activation in the genesis of early hypertensive heart disease. Circulation. 2001; 104:215–220.CrossrefMedlineGoogle Scholar
- 154.Maniu CV, Meyer DM, Redfield MM. Hemodynamic and humoral effects of vasopeptidase inhibition in canine hypertension. Hypertension. 2002; 40:528–534.LinkGoogle Scholar
- 155.Munagala VK, Hart CY, Burnett JC, Meyer DM, Redfield MM. Ventricular structure and function in aged dogs with renal hypertension: a model of experimental diastolic heart failure. Circulation. 2005; 111:1128–1135.LinkGoogle Scholar
- 156.Shapiro BP, Owan TE, Mohammed S, Kruger M, Linke WA, Burnett JC, Redfield MM. Mineralocorticoid signaling in transition to heart failure with normal ejection fraction. Hypertension. 2008; 51:289–295.LinkGoogle Scholar
- 157.Esposito G, Rapacciuolo A, Naga Prasad SV, Takaoka H, Thomas SA, Koch WJ, Rockman HA. Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress. Circulation. 2002; 105:85–92.CrossrefMedlineGoogle Scholar
- 158.Hill JA, Karimi M, Kutschke W, Davisson RL, Zimmerman K, Wang Z, Kerber RE, Weiss RM. Cardiac hypertrophy is not a required compensatory response to short-term pressure overload. Circulation. 2000; 101:2863–2869.CrossrefMedlineGoogle Scholar
- 159.Hill JA, Rothermel B, Yoo KD, Cabuay B, Demetroulis E, Weiss RM, Kutschke W, Bassel-Duby R, Williams RS. Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic function. J Biol Chem. 2002; 277:10251–10255.CrossrefMedlineGoogle Scholar
- 160.Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med. 1997; 336:267–276.CrossrefMedlineGoogle Scholar
- 161.Nihoyannopoulos P, Dawson D. Restrictive cardiomyopathies. Eur J Echocardiogr. 2009; 10:iii23–iii33.CrossrefMedlineGoogle Scholar
- 162.Parvatiyar MS, Pinto JR, Dweck D, Potter JD. Cardiac troponin mutations and restrictive cardiomyopathy. J Biomed Biotechnol. 2010; 2010:350706.CrossrefMedlineGoogle Scholar
- 163.Gambarin FI, Tagliani M, Arbustini E. Pure restrictive cardiomyopathy associated with cardiac troponin i gene mutation: mismatch between the lack of hypertrophy and the presence of disarray. Heart. 2008; 94:1257 .CrossrefMedlineGoogle Scholar
- 164.Kaski JP, Syrris P, Burch M, Tome-Esteban MT, Fenton M, Christiansen M, Andersen PS, Sebire N, Ashworth M, Deanfield JE, McKenna WJ, Elliott PM. Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart. 2008; 94:1478–1484.CrossrefMedlineGoogle Scholar
- 165.Kostareva A, Gudkova A, Sjoberg G, Morner S, Semernin E, Krutikov A, Shlyakhto E, Sejersen T. Deletion in TNNI3 gene is associated with restrictive cardiomyopathy. Int J Cardiol. 2009; 131:410–412.CrossrefMedlineGoogle Scholar
- 166.Mogensen J, Kubo T, Duque M, Uribe W, Shaw A, Murphy R, Gimeno JR, Elliott P, McKenna WJ. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin i mutations. J Clin Invest. 2003; 111:209–216.CrossrefMedlineGoogle Scholar
- 167.Rai TS, Ahmad S, Ahluwalia TS, Ahuja M, Bahl A, Saikia UN, Singh B, Talwar KK, Khullar M. Genetic and clinical profile of Indian patients of idiopathic restrictive cardiomyopathy with and without hypertrophy. Mol Cell Biochem. 2009; 331:187–192.CrossrefMedlineGoogle Scholar
- 168.Huang XP, Du JF. Troponin I, cardiac diastolic dysfunction and restrictive cardiomyopathy. Acta Pharmacol Sin. 2004; 25:1569–1575.MedlineGoogle Scholar
- 169.Yumoto F, Lu QW, Morimoto S, Tanaka H, Kono N, Nagata K, Ojima T, Takahashi-Yanaga F, Miwa Y, Sasaguri T, Nishita K, Tanokura M, Ohtsuki I. Drastic Ca2+ sensitization of myofilament associated with a small structural change in troponin I in inherited restrictive cardiomyopathy. Biochem Biophys Res Commun. 2005; 338:1519–1526.CrossrefMedlineGoogle Scholar
- 170.Arbustini E, Pasotti M, Pilotto A, Pellegrini C, Grasso M, Previtali S, Repetto A, Bellini O, Azan G, Scaffino M, Campana C, Piccolo G, Vigano M, Tavazzi L. Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects. Eur J Heart Fail. 2006; 8:477–483.CrossrefMedlineGoogle Scholar
- 171.Kostareva A, Gudkova A, Sjoberg G, Kiselev I, Moiseeva O, Karelkina E, Goldfarb L, Schlyakhto E, Sejersen T. Desmin mutations in a St. Petersburg cohort of cardiomyopathies. Acta Myol. 2006; 25:109–115.MedlineGoogle Scholar
- 172.Pruszczyk P, Kostera-Pruszczyk A, Shatunov A, Goudeau B, Draminska A, Takeda K, Sambuughin N, Vicart P, Strelkov SV, Goldfarb LG, Kaminska A. Restrictive cardiomyopathy with atrioventricular conduction block resulting from a desmin mutation. Int J Cardiol. 2007; 117:244–253.CrossrefMedlineGoogle Scholar
- 173.Vrabie A, Goldfarb LG, Shatunov A, Nagele A, Fritz P, Kaczmarek I, Goebel HH. The enlarging spectrum of desminopathies: new morphological findings, eastward geographic spread, novel exon 3 desmin mutation. Acta Neuropathol. 2005; 109:411–417.CrossrefMedlineGoogle Scholar
- 174.Zhang J, Kumar A, Stalker HJ, Virdi G, Ferrans VJ, Horiba K, Fricker FJ, Wallace MR. Clinical and molecular studies of a large family with desmin-associated restrictive cardiomyopathy. Clin Genet. 2001; 59:248–256.CrossrefMedlineGoogle Scholar
- 175.Gutierrez L, Quintana C, Patino C, Bueno J, Coppin H, Roth MP, Lazaro FJ. Iron speciation study in Hfe knockout mice tissues: magnetic and ultrastructural characterisation. Biochim Biophys Acta. 2009; 1792:541–547.CrossrefMedlineGoogle Scholar
- 176.Wen Y, Xu Y, Wang Y, Pinto JR, Potter JD, Kerrick WG. Functional effects of a restrictive-cardiomyopathy-linked cardiac troponin i mutation (R145W) in transgenic mice. J Mol Biol. 2009; 392:1158–1167.CrossrefMedlineGoogle Scholar
- 177.Feld S, Caspi A. Familial cardiomyopathy with variable hypertrophic and restrictive features and common HLA haplotype. Isr J Med Sci. 1992; 28:277–280.MedlineGoogle Scholar
- 178.Mogensen J, Arbustini E. Restrictive cardiomyopathy. Curr Opin Cardiol. 2009; 24:214–220.CrossrefMedlineGoogle Scholar
- 179.Zangwill S, Hamilton R. Restrictive cardiomyopathy. Pacing Clin Electrophysiol. 2009; 32(suppl 2):S41–S43 ,.CrossrefMedlineGoogle Scholar
- 180.Falk RH, Dubrey SW. Amyloid heart disease. Prog Cardiovasc Dis. 52:347–361.CrossrefMedlineGoogle Scholar
- 181.Bartfay WJ, Dawood F, Wen WH, Lehotay DC, Hou D, Bartfay E, Luo X, Backx PH, Liu PP. Cardiac function and cytotoxic aldehyde production in a murine model of chronic iron-overload. Cardiovasc Res. 1999; 43:892–900.CrossrefMedlineGoogle Scholar
- 182.Wood JC, Otto-Duessel M, Gonzalez I, Aguilar MI, Shimada H, Nick H, Nelson M, Moats R. Deferasirox and deferiprone remove cardiac iron in the iron-overloaded gerbil. Transl Res. 2006; 148:272–280.CrossrefMedlineGoogle Scholar
- 183.Schwartz KA, Fisher J, Adams ET. Morphologic investigations of the guinea pig model of iron overload. Toxicol Pathol. 1993; 21:311–320.CrossrefMedlineGoogle Scholar
- 184.Boerma M, Hauer-Jensen M. Preclinical research into basic mechanisms of radiation-induced heart disease. Cardiol Res Pract. 2011; 2011:858262 .CrossrefGoogle Scholar
- 185.Boerma M, Roberto KA, Hauer-Jensen M. Prevention and treatment of functional and structural radiation injury in the rat heart by pentoxifylline and alpha-tocopherol. Int J Radiat Oncol Biol Phys. 2008; 72:170–177.CrossrefMedlineGoogle Scholar
- 186.Yarom R, Harper IS, Wynchank S, van Schalkwyk D, Madhoo J, Williams K, Salie R, Genade S, Lochner A. Effect of captopril on changes in rats’ hearts induced by long-term irradiation. Radiat Res. 1993; 133:187–197.CrossrefMedlineGoogle Scholar
- 187.Hirasawa M, Ito Y, Shibata MA, Otsuki Y. Mechanism of inflammation in murine eosinophilic myocarditis produced by adoptive transfer with ovalbumin challenge. Int Arch Allergy Immunol. 2007; 142:28–39.CrossrefMedlineGoogle Scholar
- 188.Bashey RI, Philips N, Insinga F, Jimenez SA. Increased collagen synthesis and increased content of type vi collagen in myocardium of tight skin mice. Cardiovasc Res. 1993; 27:1061–1065.CrossrefMedlineGoogle Scholar
- 189.Gardi C, Martorana PA, Calzoni P, Cavarra E, Marcolongo P, de Santi MM, van Even P, Lungarella G. Cardiac collagen changes during the development of right ventricular hypertrophy in tight-skin mice with emphysema. Exp Mol Pathol. 1994; 60:100–107.CrossrefMedlineGoogle Scholar
- 190.Lemaire R, Farina G, Kissin E, Shipley JM, Bona C, Korn JH, Lafyatis R. Mutant fibrillin 1 from tight skin mice increases extracellular matrix incorporation of microfibril-associated glycoprotein 2 and type I collagen. Arthritis Rheum. 2004; 50:915–926.CrossrefMedlineGoogle Scholar
- 191.Omens JH, Rockman HA, Covell JW. Passive ventricular mechanics in tight-skin mice. Am J Physiol. 1994; 266:H1169–H1176.MedlineGoogle Scholar
- 192.Osborn TG, Bashey RI, Moore TL, Fischer VW. Collagenous abnormalities in the heart of the tight-skin mouse. J Mol Cell Cardiol. 1987; 19:581–587.CrossrefMedlineGoogle Scholar
- 193.Pablos JL, Everett ET, Norris JS. The tight skin mouse: an animal model of systemic sclerosis. Clin Exp Rheumatol. 2004; 22(suppl 33):S81–S85.MedlineGoogle Scholar
- 194.Teng MH, Yin JY, Vidal R, Ghiso J, Kumar A, Rabenou R, Shah A, Jacobson DR, Tagoe C, Gallo G, Buxbaum J. Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin: a possible model for senile systemic amyloidosis. Lab Invest. 2001; 81:385–396.CrossrefMedlineGoogle Scholar
- 195.Benson MD, Kluve-Beckerman B, Zeldenrust SR, Siesky AM, Bodenmiller DM, Showalter AD, Sloop KW. Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve. 2006; 33:609–618.CrossrefMedlineGoogle Scholar
- 196.Buxbaum J, Tagoe C, Gallo G, Reixach N, French D. The pathogenesis of transthyretin tissue deposition: lessons from transgenic mice. Amyloid. 2003; 10(suppl 1):2–6 ,.MedlineGoogle Scholar
- 197.Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. A mouse model of juvenile hemochromatosis. J Clin Invest. 2005; 115:2187–2191.CrossrefMedlineGoogle Scholar
- 198.Nick H, Allegrini PR, Fozard L, Junker U, Rojkjaer L, Salie R, Niederkofler V, O’Reilly T. Deferasirox reduces iron overload in a murine model of juvenile hemochromatosis. Exp Biol Med (Maywood). 2009; 234:492–503.CrossrefMedlineGoogle Scholar
- 199.Turoczi T, Jun L, Cordis G, Morris JE, Maulik N, Stevens RG, Das DK. Hfe mutation and dietary iron content interact to increase ischemia/reperfusion injury of the heart in mice. Circ Res. 2003; 92:1240–1246.LinkGoogle Scholar
- 200.Du J, Liu J, Feng HZ, Hossain MM, Gobara N, Zhang C, Li Y, Jean-Charles PY, Jin JP, Huang XP. Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI. Am J Physiol Heart Circ Physiol. 2008; 294:H2604–H2613.CrossrefMedlineGoogle Scholar
- 201.Du J, Zhang C, Liu J, Sidky C, Huang XP. A point mutation (R192H) in the C-terminus of human cardiac troponin I causes diastolic dysfunction in transgenic mice. Arch Biochem Biophys. 2006; 456:143–150.CrossrefMedlineGoogle Scholar
- 202.Liu SK, Tilley LP. Animal models of primary myocardial diseases. Yale J Biol Med. 1980; 53:191–211.MedlineGoogle Scholar
- 203.Tilley LP, Liu SK, Gilbertson SR, Wagner BM, Lord PF. Primary myocardial disease in the cat. A model for human cardiomyopathy. Am J Pathol. 1977; 86:493–522.MedlineGoogle Scholar
- 204.Nakamura S, Okabayashi S, Ageyama N, Koie H, Sankai T, Ono F, Fujimoto K, Terao K. Transthyretin amyloidosis and two other aging-related amyloidoses in an aged vervet monkey. Vet Pathol. 2008; 45:67–72.CrossrefMedlineGoogle Scholar
- 205.Yamada M, Kotani Y, Nakamura K, Kobayashi Y, Horiuchi N, Doi T, Suzuki S, Sato N, Kanno T, Matsui T. Immunohistochemical distribution of amyloid deposits in 25 cows diagnosed with systemic AA amyloidosis. J Vet Med Sci. 2006; 68:725–729.CrossrefMedlineGoogle Scholar
- 206.DiBartola SP, Tarr MJ, Benson MD. Tissue distribution of amyloid deposits in Abyssinian cats with familial amyloidosis. J Comp Pathol. 1986; 96:387–398.CrossrefMedlineGoogle Scholar
- 207.Yarbrough WM, Spinale FG. Large animal models of congestive heart failure: a critical step in translating basic observations into clinical applications. J Nucl Cardiol. 2003; 10:77–86.CrossrefMedlineGoogle Scholar
- 208.Kinugawa S, Post H, Kaminski PM, Zhang X, Xu X, Huang H, Recchia FA, Ochoa M, Wolin MS, Kaley G, Hintze TH. Coronary microvascular endothelial stunning after acute pressure overload in the conscious dog is caused by oxidant processes: the role of angiotensin II type 1 receptor and NAD(P)H oxidase. Circulation. 2003; 108:2934–2940.LinkGoogle Scholar
- 209.Eichhorn EJ, Bedotto JB, Malloy CR, Hatfield BA, Deitchman D, Brown M, Willard JE, Grayburn PA. Effect of beta-adrenergic blockade on myocardial function and energetics in congestive heart failure. Improvements in hemodynamic, contractile, and diastolic performance with bucindolol. Circulation. 1990; 82:473–483.CrossrefMedlineGoogle Scholar
- 210.Senzaki H, Chen CH, Kass DA. Single-beat estimation of end-systolic pressure-volume relation in humans. A new method with the potential for noninvasive application. Circulation. 1996; 94:2497–2506.CrossrefMedlineGoogle Scholar
- 211.Li Y, Yao Y, Sheng Z, Yang Y, Ma G. Dual-modal tracking of transplanted mesenchymal stem cells after myocardial infarction. Int J Nanomedicine. 2011; 6:815–823.CrossrefMedlineGoogle Scholar
- 212.Shin SH, Hung CL, Uno H, Hassanein AH, Verma A, Bourgoun M, Kober L, Ghali JK, Velazquez EJ, Califf RM, Pfeffer MA, Solomon SD. Mechanical dyssynchrony after myocardial infarction in patients with left ventricular dysfunction, heart failure, or both. Circulation. 2010; 121:1096–1103.LinkGoogle Scholar
- 213.Bauer M, Cheng S, Jain M, Ngoy S, Theodoropoulos C, Trujillo A, Lin FC, Liao R. Echocardiographic speckle-tracking based strain imaging for rapid cardiovascular phenotyping in mice. Circ Res. 2011; 108:908–916.LinkGoogle Scholar
- 214.Curcio A, Noma T, Naga Prasad SV, Wolf MJ, Lemaire A, Perrino C, Mao L, Rockman HA. Competitive displacement of phosphoinositide 3-kinase from beta-adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling. Am J Physiol Heart Circ Physiol. 2006; 291:H1754–H1760.CrossrefMedlineGoogle Scholar
- 215.Esposito G, Santana LF, Dilly K, Cruz JD, Mao L, Lederer WJ, Rockman HA. Cellular and functional defects in a mouse model of heart failure. Am J Physiol Heart Circ Physiol. 2000; 279:H3101–H3112.CrossrefMedlineGoogle Scholar
- 216.Harding VB, Jones LR, Lefkowitz RJ, Koch WJ, Rockman HA. Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci U S A. 2001; 98:5809–5814.CrossrefMedlineGoogle Scholar
- 217.Noma T, Lemaire A, Naga Prasad SV, Barki-Harrington L, Tilley DG, Chen J, Le Corvoisier P, Violin JD, Wei H, Lefkowitz RJ, Rockman HA. Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J Clin Invest. 2007; 117:2445–2458.CrossrefMedlineGoogle Scholar
- 218.Perrino C, Naga Prasad SV, Mao L, Noma T, Yan Z, Kim HS, Smithies O, Rockman HA. Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefaction. J Clin Invest. 2006; 116:1547–1560.CrossrefMedlineGoogle Scholar
- 219.Rockman HA, Chien KR, Choi DJ, Iaccarino G, Hunter JJ, Ross J, Lefkowitz RJ, Koch WJ. Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci U S A. 1998; 95:7000–7005.CrossrefMedlineGoogle Scholar
- 220.Kohout TA, Takaoka H, McDonald PH, Perry SJ, Mao L, Lefkowitz RJ, Rockman HA. Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice. Circulation. 2001; 104:2485–2491.CrossrefMedlineGoogle Scholar
- 221.Takaoka H, Esposito G, Mao L, Suga H, Rockman HA. Heart size-independent analysis of myocardial function in murine pressure overload hypertrophy. Am J Physiol Heart Circ Physiol. 2002; 282:H2190–H2197.CrossrefMedlineGoogle Scholar
- 222.Georgakopoulos D, Christe ME, Giewat M, Seidman CM, Seidman JG, Kass DA. The pathogenesis of familial hypertrophic cardiomyopathy: early and evolving effects from an alpha-cardiac myosin heavy chain missense mutation. Nat Med. 1999; 5:327–330.CrossrefMedlineGoogle Scholar
- 223.Georgakopoulos D, Mitzner WA, Chen CH, Byrne BJ, Millar HD, Hare JM, Kass DA. In vivo murine left ventricular pressure-volume relations by miniaturized conductance micromanometry. Am J Physiol. 1998; 274:H1416–H1422.MedlineGoogle Scholar
- 224.Pacher P, Nagayama T, Mukhopadhyay P, Batkai S, Kass DA. Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats. Nat Protoc. 2008; 3:1422–1434.CrossrefMedlineGoogle Scholar
- 225.Davidson DM, Covell JW, Malloch CI, Ross J. Factors influencing indices of left ventricle contractility in the conscious dog. Cardiovasc Res. 1974; 8:299–312.CrossrefMedlineGoogle Scholar
- 226.Koch WJ, Rockman HA, Samama P, Hamilton RA, Bond RA, Milano CA, Lefkowitz RJ. Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor. Science. 1995; 268:1350–1353.CrossrefMedlineGoogle Scholar
- 227.Milano CA, Allen LF, Rockman HA, Dolber PC, McMinn TR, Chien KR, Johnson TD, Bond RA, Lefkowitz RJ. Enhanced myocardial function in transgenic mice overexpressing the beta 2-adrenergic receptor. Science. 1994; 264:582–586.CrossrefMedlineGoogle Scholar
- 228.Rockman HA, Choi DJ, Rahman NU, Akhter SA, Lefkowitz RJ, Koch WJ. Receptor-specific in vivo desensitization by the g protein-coupled receptor kinase-5 in transgenic mice. Proc Natl Acad Sci U S A. 1996; 93:9954–9959.CrossrefMedlineGoogle Scholar
- 229.Berthiaume JM, Bray MS, McElfresh TA, Chen X, Azam S, Young ME, Hoit BD, Chandler MP. The myocardial contractile response to physiological stress improves with high saturated fat feeding in heart failure. Am J Physiol Heart Circ Physiol. 2010; 299:H410–H421.CrossrefMedlineGoogle Scholar
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From Wikipedia, the free encyclopediaJump to navigationJump to searchFor the anatomy of plants, see Plant anatomy. For other uses, see Anatomy (disambiguation).One of the large, detailed illustrations in Andreas Vesalius‘s De humani corporis fabrica 16th century, marking the rebirth of anatomy
Anatomy (Greek anatomē, “dissection”) is the branch of biology concerned with the study of the structure of organisms and their parts. Anatomy is a branch of natural science which deals with the structural organization of living things. It is an old science, having its beginnings in prehistoric times. Anatomy is inherently tied to developmental biology, embryology, comparative anatomy, evolutionary biology, and phylogeny, as these are the processes by which anatomy is generated over immediate (embryology) and long (evolution) timescales. Anatomy and physiology, which study (respectively) the structure and function of organisms and their parts, make a natural pair of related disciplines, and they are often studied together. Human anatomy is one of the essential basic sciences that are applied in medicine.
The discipline of anatomy is divided into macroscopic and microscopic anatomy. Macroscopic anatomy, or gross anatomy, is the examination of an animal’s body parts using unaided eyesight. Gross anatomy also includes the branch of superficial anatomy. Microscopic anatomy involves the use of optical instruments in the study of the tissues of various structures, known as histology, and also in the study of cells.
The history of anatomy is characterized by a progressive understanding of the functions of the organs and structures of the human body. Methods have also improved dramatically, advancing from the examination of animals by dissection of carcasses and cadavers (corpses) to 20th century medical imaging techniques including X-ray, ultrasound, and magnetic resonance imaging.
- 2Animal tissues
- 3Vertebrate anatomy
- 4Invertebrate anatomy
- 5Other branches of anatomy
- 7See also
- 10External links
A dissected body, lying prone on a table, by Charles Landseer
Derived from the Greek ἀνατομή anatomē “dissection” (from ἀνατέμνω anatémnō “I cut up, cut open” from ἀνά aná “up”, and τέμνω témnō “I cut”), anatomy is the scientific study of the structure of organisms including their systems, organs and tissues. It includes the appearance and position of the various parts, the materials from which they are composed, their locations and their relationships with other parts. Anatomy is quite distinct from physiology and biochemistry, which deal respectively with the functions of those parts and the chemical processes involved. For example, an anatomist is concerned with the shape, size, position, structure, blood supply and innervation of an organ such as the liver; while a physiologist is interested in the production of bile, the role of the liver in nutrition and the regulation of bodily functions.
The discipline of anatomy can be subdivided into a number of branches including gross or macroscopic anatomy and microscopic anatomy. Gross anatomy is the study of structures large enough to be seen with the naked eye, and also includes superficial anatomy or surface anatomy, the study by sight of the external body features. Microscopic anatomy is the study of structures on a microscopic scale, along with histology (the study of tissues), and embryology (the study of an organism in its immature condition).
Anatomy can be studied using both invasive and non-invasive methods with the goal of obtaining information about the structure and organization of organs and systems. Methods used include dissection, in which a body is opened and its organs studied, and endoscopy, in which a video camera-equipped instrument is inserted through a small incision in the body wall and used to explore the internal organs and other structures. Angiography using X-rays or magnetic resonance angiography are methods to visualize blood vessels.
The term “anatomy” is commonly taken to refer to human anatomy. However, substantially the same structures and tissues are found throughout the rest of the animal kingdom and the term also includes the anatomy of other animals. The term zootomy is also sometimes used to specifically refer to non-human animals. The structure and tissues of plants are of a dissimilar nature and they are studied in plant anatomy.
The kingdom Animalia contains multicellular organisms that are heterotrophic and motile (although some have secondarily adopted a sessile lifestyle). Most animals have bodies differentiated into separate tissues and these animals are also known as eumetazoans. They have an internal digestive chamber, with one or two openings; the gametes are produced in multicellular sex organs, and the zygotes include a blastula stage in their embryonic development. Metazoans do not include the sponges, which have undifferentiated cells.
Unlike plant cells, animal cells have neither a cell wall nor chloroplasts. Vacuoles, when present, are more in number and much smaller than those in the plant cell. The body tissues are composed of numerous types of cell, including those found in muscles, nerves and skin. Each typically has a cell membrane formed of phospholipids, cytoplasm and a nucleus. All of the different cells of an animal are derived from the embryonic germ layers. Those simpler invertebrates which are formed from two germ layers of ectoderm and endoderm are called diploblastic and the more developed animals whose structures and organs are formed from three germ layers are called triploblastic. All of a triploblastic animal’s tissues and organs are derived from the three germ layers of the embryo, the ectoderm, mesoderm and endoderm.
Connective tissues are fibrous and made up of cells scattered among inorganic material called the extracellular matrix. Connective tissue gives shape to organs and holds them in place. The main types are loose connective tissue, adipose tissue, fibrous connective tissue, cartilage and bone. The extracellular matrix contains proteins, the chief and most abundant of which is collagen. Collagen plays a major part in organizing and maintaining tissues. The matrix can be modified to form a skeleton to support or protect the body. An exoskeleton is a thickened, rigid cuticle which is stiffened by mineralization, as in crustaceans or by the cross-linking of its proteins as in insects. An endoskeleton is internal and present in all developed animals, as well as in many of those less developed.
Gastric mucosa at low magnification (H&E stain)
Epithelial tissue is composed of closely packed cells, bound to each other by cell adhesion molecules, with little intercellular space. Epithelial cells can be squamous (flat), cuboidal or columnar and rest on a basal lamina, the upper layer of the basement membrane, the lower layer is the reticular lamina lying next to the connective tissue in the extracellular matrix secreted by the epithelial cells. There are many different types of epithelium, modified to suit a particular function. In the respiratory tract there is a type of ciliated epithelial lining; in the small intestine there are microvilli on the epithelial lining and in the large intestine there are intestinal villi. Skin consists of an outer layer of keratinized stratified squamous epithelium that covers the exterior of the vertebrate body. Keratinocytes make up to 95% of the cells in the skin. The epithelial cells on the external surface of the body typically secrete an extracellular matrix in the form of a cuticle. In simple animals this may just be a coat of glycoproteins. In more advanced animals, many glands are formed of epithelial cells.
Muscle cells (myocytes) form the active contractile tissue of the body. Muscle tissue functions to produce force and cause motion, either locomotion or movement within internal organs. Muscle is formed of contractile filaments and is separated into three main types; smooth muscle, skeletal muscle and cardiac muscle. Smooth muscle has no striations when examined microscopically. It contracts slowly but maintains contractibility over a wide range of stretch lengths. It is found in such organs as sea anemone tentacles and the body wall of sea cucumbers. Skeletal muscle contracts rapidly but has a limited range of extension. It is found in the movement of appendages and jaws. Obliquely striated muscle is intermediate between the other two. The filaments are staggered and this is the type of muscle found in earthworms that can extend slowly or make rapid contractions. In higher animals striated muscles occur in bundles attached to bone to provide movement and are often arranged in antagonistic sets. Smooth muscle is found in the walls of the uterus, bladder, intestines, stomach, oesophagus, respiratory airways, and blood vessels. Cardiac muscle is found only in the heart, allowing it to contract and pump blood round the body.
See also: Neuroanatomy
Nervous tissue is composed of many nerve cells known as neurons which transmit information. In some slow-moving radially symmetrical marine animals such as ctenophores and cnidarians (including sea anemones and jellyfish), the nerves form a nerve net, but in most animals they are organized longitudinally into bundles. In simple animals, receptor neurons in the body wall cause a local reaction to a stimulus. In more complex animals, specialized receptor cells such as chemoreceptors and photoreceptors are found in groups and send messages along neural networks to other parts of the organism. Neurons can be connected together in ganglia. In higher animals, specialized receptors are the basis of sense organs and there is a central nervous system (brain and spinal cord) and a peripheral nervous system. The latter consists of sensory nerves that transmit information from sense organs and motor nerves that influence target organs. The peripheral nervous system is divided into the somatic nervous system which conveys sensation and controls voluntary muscle, and the autonomic nervous system which involuntarily controls smooth muscle, certain glands and internal organs, including the stomach.
All vertebrates have a similar basic body plan and at some point in their lives, mostly in the embryonic stage, share the major chordate characteristics; a stiffening rod, the notochord; a dorsal hollow tube of nervous material, the neural tube; pharyngeal arches; and a tail posterior to the anus. The spinal cord is protected by the vertebral column and is above the notochord and the gastrointestinal tract is below it. Nervous tissue is derived from the ectoderm, connective tissues are derived from mesoderm, and gut is derived from the endoderm. At the posterior end is a tail which continues the spinal cord and vertebrae but not the gut. The mouth is found at the anterior end of the animal, and the anus at the base of the tail. The defining characteristic of a vertebrate is the vertebral column, formed in the development of the segmented series of vertebrae. In most vertebrates the notochord becomes the nucleus pulposus of the intervertebral discs. However, a few vertebrates, such as the sturgeon and the coelacanth retain the notochord into adulthood. Jawed vertebrates are typified by paired appendages, fins or legs, which may be secondarily lost. The limbs of vertebrates are considered to be homologous because the same underlying skeletal structure was inherited from their last common ancestor. This is one of the arguments put forward by Charles Darwin to support his theory of evolution.
Main article: Fish anatomyCutaway diagram showing various organs of a fish
The body of a fish is divided into a head, trunk and tail, although the divisions between the three are not always externally visible. The skeleton, which forms the support structure inside the fish, is either made of cartilage, in cartilaginous fish, or bone in bony fish. The main skeletal element is the vertebral column, composed of articulating vertebrae which are lightweight yet strong. The ribs attach to the spine and there are no limbs or limb girdles. The main external features of the fish, the fins, are composed of either bony or soft spines called rays, which with the exception of the caudal fins, have no direct connection with the spine. They are supported by the muscles which compose the main part of the trunk. The heart has two chambers and pumps the blood through the respiratory surfaces of the gills and on round the body in a single circulatory loop. The eyes are adapted for seeing underwater and have only local vision. There is an inner ear but no external or middle ear. Low frequency vibrations are detected by the lateral line system of sense organs that run along the length of the sides of fish, and these respond to nearby movements and to changes in water pressure.
Sharks and rays are basal fish with numerous primitive anatomical features similar to those of ancient fish, including skeletons composed of cartilage. Their bodies tend to be dorso-ventrally flattened, they usually have five pairs of gill slits and a large mouth set on the underside of the head. The dermis is covered with separate dermal placoid scales. They have a cloaca into which the urinary and genital passages open, but not a swim bladder. Cartilaginous fish produce a small number of large, yolky eggs. Some species are ovoviviparous and the young develop internally but others are oviparous and the larvae develop externally in egg cases.
The bony fish lineage shows more derived anatomical traits, often with major evolutionary changes from the features of ancient fish. They have a bony skeleton, are generally laterally flattened, have five pairs of gills protected by an operculum, and a mouth at or near the tip of the snout. The dermis is covered with overlapping scales. Bony fish have a swim bladder which helps them maintain a constant depth in the water column, but not a cloaca. They mostly spawn a large number of small eggs with little yolk which they broadcast into the water column.
Amphibians are a class of animals comprising frogs, salamanders and caecilians. They are tetrapods, but the caecilians and a few species of salamander have either no limbs or their limbs are much reduced in size. Their main bones are hollow and lightweight and are fully ossified and the vertebrae interlock with each other and have articular processes. Their ribs are usually short and may be fused to the vertebrae. Their skulls are mostly broad and short, and are often incompletely ossified. Their skin contains little keratin and lacks scales, but contains many mucous glands and in some species, poison glands. The hearts of amphibians have three chambers, two atria and one ventricle. They have a urinary bladder and nitrogenous waste products are excreted primarily as urea. Amphibians breathe by means of buccal pumping, a pump action in which air is first drawn into the buccopharyngeal region through the nostrils. These are then closed and the air is forced into the lungs by contraction of the throat. They supplement this with gas exchange through the skin which needs to be kept moist.
In frogs the pelvic girdle is robust and the hind legs are much longer and stronger than the forelimbs. The feet have four or five digits and the toes are often webbed for swimming or have suction pads for climbing. Frogs have large eyes and no tail. Salamanders resemble lizards in appearance; their short legs project sideways, the belly is close to or in contact with the ground and they have a long tail. Caecilians superficially resemble earthworms and are limbless. They burrow by means of zones of muscle contractions which move along the body and they swim by undulating their body from side to side.
Reptiles are a class of animals comprising turtles, tuataras, lizards, snakes and crocodiles. They are tetrapods, but the snakes and a few species of lizard either have no limbs or their limbs are much reduced in size. Their bones are better ossified and their skeletons stronger than those of amphibians. The teeth are conical and mostly uniform in size. The surface cells of the epidermis are modified into horny scales which create a waterproof layer. Reptiles are unable to use their skin for respiration as do amphibians and have a more efficient respiratory system drawing air into their lungs by expanding their chest walls. The heart resembles that of the amphibian but there is a septum which more completely separates the oxygenated and deoxygenated bloodstreams. The reproductive system has evolved for internal fertilization, with a copulatory organ present in most species. The eggs are surrounded by amniotic membranes which prevents them from drying out and are laid on land, or develop internally in some species. The bladder is small as nitrogenous waste is excreted as uric acid.
Turtles are notable for their protective shells. They have an inflexible trunk encased in a horny carapace above and a plastron below. These are formed from bony plates embedded in the dermis which are overlain by horny ones and are partially fused with the ribs and spine. The neck is long and flexible and the head and the legs can be drawn back inside the shell. Turtles are vegetarians and the typical reptile teeth have been replaced by sharp, horny plates. In aquatic species, the front legs are modified into flippers.
Tuataras superficially resemble lizards but the lineages diverged in the Triassic period. There is one living species, Sphenodon punctatus. The skull has two openings (fenestrae) on either side and the jaw is rigidly attached to the skull. There is one row of teeth in the lower jaw and this fits between the two rows in the upper jaw when the animal chews. The teeth are merely projections of bony material from the jaw and eventually wear down. The brain and heart are more primitive than those of other reptiles, and the lungs have a single chamber and lack bronchi. The tuatara has a well-developed parietal eye on its forehead.
Lizards have skulls with only one fenestra on each side, the lower bar of bone below the second fenestra having been lost. This results in the jaws being less rigidly attached which allows the mouth to open wider. Lizards are mostly quadrupeds, with the trunk held off the ground by short, sideways-facing legs, but a few species have no limbs and resemble snakes. Lizards have moveable eyelids, eardrums are present and some species have a central parietal eye.
Snakes are closely related to lizards, having branched off from a common ancestral lineage during the Cretaceous period, and they share many of the same features. The skeleton consists of a skull, a hyoid bone, spine and ribs though a few species retain a vestige of the pelvis and rear limbs in the form of pelvic spurs. The bar under the second fenestra has also been lost and the jaws have extreme flexibility allowing the snake to swallow its prey whole. Snakes lack moveable eyelids, the eyes being covered by transparent “spectacle” scales. They do not have eardrums but can detect ground vibrations through the bones of their skull. Their forked tongues are used as organs of taste and smell and some species have sensory pits on their heads enabling them to locate warm-blooded prey.
Crocodilians are large, low-slung aquatic reptiles with long snouts and large numbers of teeth. The head and trunk are dorso-ventrally flattened and the tail is laterally compressed. It undulates from side to side to force the animal through the water when swimming. The tough keratinized scales provide body armour and some are fused to the skull. The nostrils, eyes and ears are elevated above the top of the flat head enabling them to remain above the surface of the water when the animal is floating. Valves seal the nostrils and ears when it is submerged. Unlike other reptiles, crocodilians have hearts with four chambers allowing complete separation of oxygenated and deoxygenated blood.
Birds are tetrapods but though their hind limbs are used for walking or hopping, their front limbs are wings covered with feathers and adapted for flight. Birds are endothermic, have a high metabolic rate, a light skeletal system and powerful muscles. The long bones are thin, hollow and very light. Air sac extensions from the lungs occupy the centre of some bones. The sternum is wide and usually has a keel and the caudal vertebrae are fused. There are no teeth and the narrow jaws are adapted into a horn-covered beak. The eyes are relatively large, particularly in nocturnal species such as owls. They face forwards in predators and sideways in ducks.
The feathers are outgrowths of the epidermis and are found in localized bands from where they fan out over the skin. Large flight feathers are found on the wings and tail, contour feathers cover the bird’s surface and fine down occurs on young birds and under the contour feathers of water birds. The only cutaneous gland is the single uropygial gland near the base of the tail. This produces an oily secretion that waterproofs the feathers when the bird preens. There are scales on the legs, feet and claws on the tips of the toes.
Main article: Mammal anatomy
Mammals are a diverse class of animals, mostly terrestrial but some are aquatic and others have evolved flapping or gliding flight. They mostly have four limbs but some aquatic mammals have no limbs or limbs modified into fins and the forelimbs of bats are modified into wings. The legs of most mammals are situated below the trunk, which is held well clear of the ground. The bones of mammals are well ossified and their teeth, which are usually differentiated, are coated in a layer of prismatic enamel. The teeth are shed once (milk teeth) during the animal’s lifetime or not at all, as is the case in cetaceans. Mammals have three bones in the middle ear and a cochlea in the inner ear. They are clothed in hair and their skin contains glands which secrete sweat. Some of these glands are specialized as mammary glands, producing milk to feed the young. Mammals breathe with lungs and have a muscular diaphragm separating the thorax from the abdomen which helps them draw air into the lungs. The mammalian heart has four chambers and oxygenated and deoxygenated blood are kept entirely separate. Nitrogenous waste is excreted primarily as urea.
Mammals are amniotes, and most are viviparous, giving birth to live young. The exception to this are the egg-laying monotremes, the platypus and the echidnas of Australia. Most other mammals have a placenta through which the developing foetus obtains nourishment, but in marsupials, the foetal stage is very short and the immature young is born and finds its way to its mother’s pouch where it latches on to a nipple and completes its development.
Further information: Human body § Human anatomy, and Outline of human anatomyModern anatomic technique showing sagittal sections of the head as seen by a MRI scanIn the human, the development of skilled hand movements and increased brain size is likely to have evolved simultaneously.
Generally, students of certain biological sciences, paramedics, prosthetists and orthotists, physiotherapists, occupational therapists, nurses, podiatrists, and medical students learn gross anatomy and microscopic anatomy from anatomical models, skeletons, textbooks, diagrams, photographs, lectures and tutorials, and in addition, medical students generally also learn gross anatomy through practical experience of dissection and inspection of cadavers. The study of microscopic anatomy (or histology) can be aided by practical experience examining histological preparations (or slides) under a microscope. 
Human anatomy, physiology and biochemistry are complementary basic medical sciences, which are generally taught to medical students in their first year at medical school. Human anatomy can be taught regionally or systemically; that is, respectively, studying anatomy by bodily regions such as the head and chest, or studying by specific systems, such as the nervous or respiratory systems. The major anatomy textbook, Gray’s Anatomy, has been reorganized from a systems format to a regional format, in line with modern teaching methods. A thorough working knowledge of anatomy is required by physicians, especially surgeons and doctors working in some diagnostic specialties, such as histopathology and radiology. 
Academic anatomists are usually employed by universities, medical schools or teaching hospitals. They are often involved in teaching anatomy, and research into certain systems, organs, tissues or cells.
Invertebrates constitute a vast array of living organisms ranging from the simplest unicellular eukaryotes such as Paramecium to such complex multicellular animals as the octopus, lobster and dragonfly. They constitute about 95% of the animal species. By definition, none of these creatures has a backbone. The cells of single-cell protozoans have the same basic structure as those of multicellular animals but some parts are specialized into the equivalent of tissues and organs. Locomotion is often provided by cilia or flagella or may proceed via the advance of pseudopodia, food may be gathered by phagocytosis, energy needs may be supplied by photosynthesis and the cell may be supported by an endoskeleton or an exoskeleton. Some protozoans can form multicellular colonies.
Metazoans are multicellular organism, different groups of cells of which have separate functions. The most basic types of metazoan tissues are epithelium and connective tissue, both of which are present in nearly all invertebrates. The outer surface of the epidermis is normally formed of epithelial cells and secretes an extracellular matrix which provides support to the organism. An endoskeleton derived from the mesoderm is present in echinoderms, sponges and some cephalopods. Exoskeletons are derived from the epidermis and is composed of chitin in arthropods (insects, spiders, ticks, shrimps, crabs, lobsters). Calcium carbonate constitutes the shells of molluscs, brachiopods and some tube-building polychaete worms and silica forms the exoskeleton of the microscopic diatoms and radiolaria. Other invertebrates may have no rigid structures but the epidermis may secrete a variety of surface coatings such as the pinacoderm of sponges, the gelatinous cuticle of cnidarians (polyps, sea anemones, jellyfish) and the collagenous cuticle of annelids. The outer epithelial layer may include cells of several types including sensory cells, gland cells and stinging cells. There may also be protrusions such as microvilli, cilia, bristles, spines and tubercles.
Marcello Malpighi, the father of microscopical anatomy, discovered that plants had tubules similar to those he saw in insects like the silk worm. He observed that when a ring-like portion of bark was removed on a trunk a swelling occurred in the tissues above the ring, and he unmistakably interpreted this as growth stimulated by food coming down from the leaves, and being captured above the ring.
Insects possess segmented bodies supported by a hard-jointed outer covering, the exoskeleton, made mostly of chitin. The segments of the body are organized into three distinct parts, a head, a thorax and an abdomen. The head typically bears a pair of sensory antennae, a pair of compound eyes, one to three simple eyes (ocelli) and three sets of modified appendages that form the mouthparts. The thorax has three pairs of segmented legs, one pair each for the three segments that compose the thorax and one or two pairs of wings. The abdomen is composed of eleven segments, some of which may be fused and houses the digestive, respiratory, excretory and reproductive systems. There is considerable variation between species and many adaptations to the body parts, especially wings, legs, antennae and mouthparts.
Spiders a class of arachnids have four pairs of legs; a body of two segments—a cephalothorax and an abdomen. Spiders have no wings and no antennae. They have mouthparts called chelicerae which are often connected to venom glands as most spiders are venomous. They have a second pair of appendages called pedipalps attached to the cephalothorax. These have similar segmentation to the legs and function as taste and smell organs. At the end of each male pedipalp is a spoon-shaped cymbium that acts to support the copulatory organ.
Other branches of anatomy
- Superficial or surface anatomy is important as the study of anatomical landmarks that can be readily seen from the exterior contours of the body. It enables physicians or veterinary surgeons to gauge the position and anatomy of the associated deeper structures. Superficial is a directional term that indicates that structures are located relatively close to the surface of the body.
- Comparative anatomy relates to the comparison of anatomical structures (both gross and microscopic) in different animals.
- Artistic anatomy relates to anatomic studies for artistic reasons.
Main article: History of anatomy
In 1600 BCE, the Edwin Smith Papyrus, an Ancient Egyptian medical text, described the heart, its vessels, liver, spleen, kidneys, hypothalamus, uterus and bladder, and showed the blood vessels diverging from the heart. The Ebers Papyrus (c. 1550 BCE) features a “treatise on the heart”, with vessels carrying all the body’s fluids to or from every member of the body.
Ancient Greek anatomy and physiology underwent great changes and advances throughout the early medieval world. Over time, this medical practice expanded by a continually developing understanding of the functions of organs and structures in the body. Phenomenal anatomical observations of the human body were made, which have contributed towards the understanding of the brain, eye, liver, reproductive organs and the nervous system.
The Hellenistic Egyptian city of Alexandria was the stepping-stone for Greek anatomy and physiology. Alexandria not only housed the biggest library for medical records and books of the liberal arts in the world during the time of the Greeks, but was also home to many medical practitioners and philosophers. Great patronage of the arts and sciences from the Ptolemy rulers helped raise Alexandria up, further rivalling the cultural and scientific achievements of other Greek states.An anatomy thangka, part of Desi Sangye Gyatso‘s The Blue Beryl, 17th century
Some of the most striking advances in early anatomy and physiology took place in Hellenistic Alexandria. Two of the most famous anatomists and physiologists of the third century were Herophilus and Erasistratus. These two physicians helped pioneer human dissection for medical research. They also conducted vivisections on the cadavers of condemned criminals, which was considered taboo until the Renaissance—Herophilus was recognized as the first person to perform systematic dissections. Herophilus became known for his anatomical works making impressing contributions to many branches of anatomy and many other aspects of medicine. Some of the works included classifying the system of the pulse, the discovery that human arteries had thicker walls than veins, and that the atria were parts of the heart. Herophilus’s knowledge of the human body has provided vital input towards understanding the brain, eye, liver, reproductive organs and nervous system, and characterizing the course of disease. Erasistratus accurately described the structure of the brain, including the cavities and membranes, and made a distinction between its cerebrum and cerebellum  During his study in Alexandria, Erasistratus was particularly concerned with studies of the circulatory and nervous systems. He was able to distinguish the sensory and the motor nerves in the human body and believed that air entered the lungs and heart, which was then carried throughout the body. His distinction between the arteries and veins—the arteries carrying the air through the body, while the veins carried the blood from the heart was a great anatomical discovery. Erasistratus was also responsible for naming and describing the function of the epiglottis and the valves of the heart, including the tricuspid. During the third century, Greek physicians were able to differentiate nerves from blood vessels and tendons  and to realize that the nerves convey neural impulses. It was Herophilus who made the point that damage to motor nerves induced paralysis. Herophilus named the meninges and ventricles in the brain, appreciated the division between cerebellum and cerebrum and recognized that the brain was the “seat of intellect” and not a “cooling chamber” as propounded by Aristotle  Herophilus is also credited with describing the optic, oculomotor, motor division of the trigeminal, facial, vestibulocochlear and hypoglossal nerves.Surgical instruments were invented for the first time in history by Abulcasis in the 11th centuryAnatomy of the eye for the first time in history by Hunayn ibn Ishaq in the 9th century13th century anatomical illustration
Great feats were made during the third century in both the digestive and reproductive systems. Herophilus was able to discover and describe not only the salivary glands, but the small intestine and liver. He showed that the uterus is a hollow organ and described the ovaries and uterine tubes. He recognized that spermatozoa were produced by the testes and was the first to identify the prostate gland.
The anatomy of the muscles and skeleton is described in the Hippocratic Corpus, an Ancient Greek medical work written by unknown authors. Aristotle described vertebrate anatomy based on animal dissection. Praxagoras identified the difference between arteries and veins. Also in the 4th century BCE, Herophilos and Erasistratus produced more accurate anatomical descriptions based on vivisection of criminals in Alexandria during the Ptolemaic dynasty.
In the 2nd century, Galen of Pergamum, an anatomist, clinician, writer and philosopher, wrote the final and highly influential anatomy treatise of ancient times. He compiled existing knowledge and studied anatomy through dissection of animals. He was one of the first experimental physiologists through his vivisection experiments on animals. Galen’s drawings, based mostly on dog anatomy, became effectively the only anatomical textbook for the next thousand years. His work was known to Renaissance doctors only through Islamic Golden Age medicine until it was translated from the Greek some time in the 15th century.
Medieval to early modern
Anatomy developed little from classical times until the sixteenth century; as the historian Marie Boas writes, “Progress in anatomy before the sixteenth century is as mysteriously slow as its development after 1500 is startlingly rapid”.:120–121 Between 1275 and 1326, the anatomists Mondino de Luzzi, Alessandro Achillini and Antonio Benivieni at Bologna carried out the first systematic human dissections since ancient times. Mondino’s Anatomy of 1316 was the first textbook in the medieval rediscovery of human anatomy. It describes the body in the order followed in Mondino’s dissections, starting with the abdomen, then the thorax, then the head and limbs. It was the standard anatomy textbook for the next century.
Leonardo da Vinci (1452–1519) was trained in anatomy by Andrea del Verrocchio. He made use of his anatomical knowledge in his artwork, making many sketches of skeletal structures, muscles and organs of humans and other vertebrates that he dissected.
Andreas Vesalius (1514–1564) (Latinized from Andries van Wezel), professor of anatomy at the University of Padua, is considered the founder of modern human anatomy. Originally from Brabant, Vesalius published the influential book De humani corporis fabrica (“the structure of the human body”), a large format book in seven volumes, in 1543. The accurate and intricately detailed illustrations, often in allegorical poses against Italianate landscapes, are thought to have been made by the artist Jan van Calcar, a pupil of Titian.
In England, anatomy was the subject of the first public lectures given in any science; these were given by the Company of Barbers and Surgeons in the 16th century, joined in 1583 by the Lumleian lectures in surgery at the Royal College of Physicians.
Further information: History of anatomy in the 19th century
In the United States, medical schools began to be set up towards the end of the 18th century. Classes in anatomy needed a continual stream of cadavers for dissection and these were difficult to obtain. Philadelphia, Baltimore and New York were all renowned for body snatching activity as criminals raided graveyards at night, removing newly buried corpses from their coffins. A similar problem existed in Britain where demand for bodies became so great that grave-raiding and even anatomy murder were practised to obtain cadavers. Some graveyards were in consequence protected with watchtowers. The practice was halted in Britain by the Anatomy Act of 1832, while in the United States, similar legislation was enacted after the physician William S. Forbes of Jefferson Medical College was found guilty in 1882 of “complicity with resurrectionists in the despoliation of graves in Lebanon Cemetery”.
The teaching of anatomy in Britain was transformed by Sir John Struthers, Regius Professor of Anatomy at the University of Aberdeen from 1863 to 1889. He was responsible for setting up the system of three years of “pre-clinical” academic teaching in the sciences underlying medicine, including especially anatomy. This system lasted until the reform of medical training in 1993 and 2003. As well as teaching, he collected many vertebrate skeletons for his museum of comparative anatomy, published over 70 research papers, and became famous for his public dissection of the Tay Whale. From 1822 the Royal College of Surgeons regulated the teaching of anatomy in medical schools. Medical museums provided examples in comparative anatomy, and were often used in teaching. Ignaz Semmelweis investigated puerperal fever and he discovered how it was caused. He noticed that the frequently fatal fever occurred more often in mothers examined by medical students than by midwives. The students went from the dissecting room to the hospital ward and examined women in childbirth. Semmelweis showed that when the trainees washed their hands in chlorinated lime before each clinical examination, the incidence of puerperal fever among the mothers could be reduced dramatically.An electron microscope from 1973
Before the modern medical era, the main means for studying the internal structures of the body were dissection of the dead and inspection, palpation and auscultation of the living. It was the advent of microscopy that opened up an understanding of the building blocks that constituted living tissues. Technical advances in the development of achromatic lenses increased the resolving power of the microscope and around 1839, Matthias Jakob Schleiden and Theodor Schwann identified that cells were the fundamental unit of organization of all living things. Study of small structures involved passing light through them and the microtome was invented to provide sufficiently thin slices of tissue to examine. Staining techniques using artificial dyes were established to help distinguish between different types of tissue. Advances in the fields of histology and cytology began in the late 19th century along with advances in surgical techniques allowing for the painless and safe removal of biopsy specimens. The invention of the electron microscope brought a great advance in resolution power and allowed research into the ultrastructure of cells and the organelles and other structures within them. About the same time, in the 1950s, the use of X-ray diffraction for studying the crystal structures of proteins, nucleic acids and other biological molecules gave rise to a new field of molecular anatomy.
Equally important advances have occurred in non-invasive techniques for examining the interior structures of the body. X-rays can be passed through the body and used in medical radiography and fluoroscopy to differentiate interior structures that have varying degrees of opaqueness. Magnetic resonance imaging, computed tomography, and ultrasound imaging have all enabled examination of internal structures in unprecedented detail to a degree far beyond the imagination of earlier generations.
- ^ Merriam Webster Dictionary
- ^ Rotimi, Booktionary. “Anatomy”.
- ^ Jump up to:a b c d e f “Introduction page, “Anatomy of the Human Body”. Henry Gray. 20th edition. 1918″. Archived from the original on 16 March 2007. Retrieved 19 March 2007.
- ^ Arráez-Aybar et al. (2010). Relevance of human anatomy in daily clinical practice. Annals of Anatomy-Anatomischer Anzeiger, 192(6), 341–348.
- ^ O.D.E. 2nd edition 2005
- ^ Jump up to:a b Bozman, E. F., ed. (1967). Everyman’s Encyclopedia: Anatomy. J. M. Dent & Sons. p. 272. ASIN B0066E44EC.
- ^ “Anatomy”. The Free Dictionary. Farlex. 2007. Retrieved 8 July 2013.
- ^ Gribble N, Reynolds K (1993). “Use of Angiography to Outline the Cardiovascular Anatomy of the Sand Crab Portunus pelagicus Linnaeus”. Journal of Crustacean Biology. 13 (4): 627–637. doi:10.1163/193724093×00192. JSTOR 1549093.
- ^ Benson KG, Forrest L (1999). “Characterization of the Renal Portal System of the Common Green Iguana (Iguana iguana) by Digital Subtraction Imaging”. Journal of Zoo and Wildlife Medicine. 30 (2): 235–241. PMID 10484138.
- ^ “Magnetic Resonance Angiography (MRA)”. Johns Hopkins Medicine.
- ^ “Angiography”. National Health Service. Retrieved 29 April 2014.
- ^ Dorit, R. L.; Walker, W. F.; Barnes, R. D. (1991). Zoology. Saunders College Publishing. pp. 547–549. ISBN 978-0-03-030504-7.
- ^ Jump up to:a b c Ruppert, Edward E.; Fox, Richard, S.; Barnes, Robert D. (2004). Invertebrate Zoology, 7th edition. Cengage Learning. pp. 59–60. ISBN 978-81-315-0104-7.
- ^ Dorland’s (2012). Illustrated Medical Dictionary. Elsevier Saunders. p. 203. ISBN 978-1-4160-6257-8.
- ^ Dorland’s (2012). Illustrated Medical Dictionary. Elsevier Saunders. p. 1002. ISBN 978-1-4160-6257-8.
- ^ McGrath, J.A.; Eady, R.A.; Pope, F.M. (2004). Rook’s Textbook of Dermatology (7th ed.). Blackwell Publishing. pp. 3.1–3.6. ISBN 978-0-632-06429-8.
- ^ Bernt, Karen (2010). “Glandular epithelium”. Epithelial Cells. Davidson College. Archived from the original on 22 July 2016. Retrieved 25 June 2013.
- ^ Ruppert, Edward E.; Fox, Richard, S.; Barnes, Robert D. (2004). Invertebrate Zoology, 7th edition. Cengage Learning. p. 103. ISBN 978-81-315-0104-7.
- ^ Ruppert, Edward E.; Fox, Richard, S.; Barnes, Robert D. (2004). Invertebrate Zoology, 7th edition. Cengage Learning. p. 104. ISBN 978-81-315-0104-7.
- ^ Johnston, T.B; Whillis, J, eds. (1944). Grey’s Anatomy: Descriptive and Applied (28 ed.). Langmans. p. 1038.
- ^ Ruppert, Edward E.; Fox, Richard, S.; Barnes, Robert D. (2004). Invertebrate Zoology, 7th edition. Cengage Learning. pp. 105–107. ISBN 978-81-315-0104-7.
- ^ Moore, K.; Agur, A.; Dalley, A. F. (2010). “Essesntial Clinical Anatomy”. Nervous System (4th ed.). Inkling. Retrieved 30 April 2014.
- ^ Waggoner, Ben. “Vertebrates: More on Morphology”. UCMP. Retrieved 13 July 2011.
- ^ Romer, Alfred Sherwood (1985). The Vertebrate Body. Holt Rinehart & Winston. ISBN 978-0-03-058446-6.
- ^ Liem, Karel F.; Warren Franklin Walker (2001). Functional anatomy of the vertebrates: an evolutionary perspective. Harcourt College Publishers. p. 277. ISBN 978-0-03-022369-3.
- ^ “What is Homology?”. National Center for Science Education. 17 October 2008. Retrieved 28 June 2013.
- ^ Jump up to:a b Dorit, R. L.; Walker, W. F.; Barnes, R. D. (1991). Zoology. Saunders College Publishing. pp. 816–818. ISBN 978-0-03-030504-7.
- ^ “The fish heart”. ThinkQuest. Oracle. Archived from the original on 28 April 2012. Retrieved 27 June2013.
- ^ Jump up to:a b Kotpal, R. L. (2010). Modern Text Book of Zoology: Vertebrates. Rastogi Publications. p. 193. ISBN 978-81-7133-891-7.
- ^ Stebbins, Robert C.; Cohen, Nathan W. (1995). A Natural History of Amphibians. Princeton University Press. pp. 24–25. ISBN 978-0-691-03281-8.
- ^ Dorit, R. L.; Walker, W. F.; Barnes, R. D. (1991). Zoology. Saunders College Publishing. pp. 843–859. ISBN 978-0-03-030504-7.
- ^ Stebbins, Robert C.; Cohen, Nathan W. (1995). A Natural History of Amphibians. Princeton University Press. pp. 26–35. ISBN 978-0-691-03281-8.
- ^ Dorit, R. L.; Walker, W. F.; Barnes, R. D. (1991). Zoology. Saunders College Publishing. pp. 861–865. ISBN 978-0-03-030504-7.
- ^ Jump up to:a b c Dorit, R. L.; Walker, W. F.; Barnes, R. D. (1991). Zoology. Saunders College Publishing. pp. 865–868. ISBN 978-0-03-030504-7.
- ^ Dorit, R. L.; Walker, W. F.; Barnes, R. D. (1991). Zoology. Saunders College Publishing. p. 870. ISBN 978-0-03-030504-7.
- ^ Dorit, R. L.; Walker, W. F.; Barnes, R. D. (1991). Zoology. Saunders College Publishing. p. 874. ISBN 978-0-03-030504-7.
- ^ Jump up to:a b Dorit, R. L.; Walker, W. F.; Barnes, R. D. (1991). Zoology. Saunders College Publishing. pp. 881–895. ISBN 978-0-03-030504-7.
- ^ Jump up to:a b Dorit, R. L.; Walker, W. F.; Barnes, R. D. (1991). Zoology. Saunders College Publishing. pp. 909–914. ISBN 978-0-03-030504-7.
- ^ “Hand”. Encyclopædia Britannica 2006 Ultimate Reference Suite DVD.
- ^ “Studying medicine”. Medschools Online. Archived from the original on 28 January 2013. Retrieved 27 June 2013.
- ^ Publisher’s page for Gray’s Anatomy. 39th edition (UK). 2004. ISBN 978-0-443-07168-3. Retrieved 19 March 2007.
- ^ Publisher’s page for Gray’s Anatomy. 39th edition (US). 2004. ISBN 978-0-443-07168-3. Retrieved 19 March 2007.
- ^ Jump up to:a b “American Association of Anatomists”. Retrieved 27 June 2013.
- ^ Ruppert, Edward E.; Fox, Richard, S.; Barnes, Robert D. (2004). Invertebrate Zoology, 7th edition. Cengage Learning. pp. 23–24. ISBN 978-81-315-0104-7.
- ^ “Exoskeleton”. Encyclopædia Britannica. Retrieved 2 July 2013.
- ^ Ebling, F. J. G. “Integument”. Encyclopædia Britannica. Retrieved 2 July 2013.
- ^ Arber, Agnes (1942). “Nehemiah Grew (1641–1712) and Marcello Malpighi (1628–1694): an essay in comparison”. Isis. 34 (1): 7–16. doi:10.1086/347742. JSTOR 225992.
- ^ Britannica Concise Encyclopaedia 2007
- ^ “O. Orkin Insect zoo”. Mississippi State University. 1997. Archived from the original on 2 June 2009. Retrieved 23 June 2013.
- ^ Gullan, P.J.; Cranston, P. S. (2005). The Insects: An Outline of Entomology (3 ed.). Oxford: Blackwell Publishing. pp. 22–48. ISBN 978-1-4051-1113-3.
- ^ Ruppert, Edward E.; Fox, Richard, S.; Barnes, Robert D. (2004). Invertebrate Zoology, 7th edition. Cengage Learning. pp. 218–225. ISBN 978-81-315-0104-7.
- ^ Marieb, Elaine (2010). Human Anatomy & Physiology. San Francisco: Pearson. p. 12.
- ^ Porter, R. (1997). The Greatest Benefit to Mankind: A Medical History of Humanity from Antiquity to the Present. Harper Collins. pp. 49–50. ISBN 978-0-00-215173-3.
- ^ Jump up to:a b c Longrigg, James (December 1988). “Anatomy in Alexandria in the Third Century B.C”. The British Journal for the History of Science. 21 (4): 455–488. doi:10.1017/s000708740002536x. JSTOR 4026964. PMID 11621690.
- ^ Bay, Noel Si Yang; Bay, Boon-Huat (2010). “Greek Anatomists Herophilus: The Father of Anatomy”. Anatomy and Cell Biology. 43 (3): 280–283. doi:10.5115/acb.2010.43.4.280. PMC 3026179. PMID 21267401.
- ^ Von Staden, H (1992). “The Discovery of the Body: Human Dissection and Its Cultural Contexts in Ancient Greece”. The Yale Journal of Biology and Medicine. 65 (3): 223–241. PMC 2589595. PMID 1285450.
- ^ Bay, Noel Si Yang; Bay, Boon- Huat (2010). “Greek Anatomist Herophilus: The Father of Anatomy”. Anatomy & Cell Biology. 43 (3): 280–283. doi:10.5115/acb.2010.43.4.280. PMC 3026179. PMID 21267401.
- ^ Eccles, John. “Erasistratus Biography (304B.C-250B.C)”. faqs.org. faqs.org. Retrieved 25 November2015.
- ^ Britannica. “Erasistratus of Ceos: Greek Physician”. britannica.com. The Encyclopedia of Britannica. Retrieved 25 November 2015.
- ^ Wiltse, LL; Pait, TG (1 September 1998). “Herophilus of Alexandria (325-255 B.C.) The Father of Anatomy”. Spine. 23 (17): 1904–1914. doi:10.1097/00007632-199809010-00022. PMID 9762750.
- ^ Bay, Noel Si Yang; Bay, Boon-Huat (2010). “Greek Anatomist Herophilus: The Father of Anatomy”. Anatomy & Cell Biology. 43 (3): 280–283. doi:10.5115/acb.2010.43.4.280. PMC 3026179. PMID 21267401.
- ^ Wills, Adrian (1999). “Herophilus, Ersasistratus, and the birth of neuroscience”. The Lancet. 354 (9191): 1719–1720. doi:10.1016/S0140-6736(99)02081-4. PMID 10568587. Retrieved 25 November 2015.
- ^ Jump up to:a b c Von Staden, Heinrich (October 2007). Herophilus: The Art of Medicine in Early Alexandria. Cambridge University Press. ISBN 9780521041782. Retrieved 25 November 2015.
- ^ Gillispie, Charles Coulston (1972). Dictionary of Scientific Biography. VI. New York: Charles Scribner’s Sons. pp. 419–427.
- ^ Lang, Philippa (2013). Medicine and Society in Ptolemaic Egypt. Brill NV. p. 256. ISBN 978-9004218581.
- ^ “Alexandrian Medicine”. Antiqua Medicina – from Homer to Vesalius. University of Virginia.
- ^ Jump up to:a b Hutton, Vivien. “Galen of Pergamum”. Encyclopædia Britannica 2006 Ultimate Reference Suite DVD.
- ^ Charon NW, Johnson RC, Muschel LH (1975). “Antileptospiral activity in lower-vertebrate sera”. Infect. Immun. 12 (6): 1386–1391. PMC 415446. PMID 1081972.
- ^ Brock, Arthur John (translator) Galen. On the Natural Faculties. Edinburgh, 1916. Introduction, page xxxiii.
- ^ Jump up to:a b c d e f Boas, Marie (1970) [first published by Collins, 1962]. The Scientific Renaissance 1450–1630. Fontana. pp. 120–143.
- ^ Zimmerman, Leo M.; Veith, Ilza (1993). Great Ideas in the History of Surgery. Norman. ISBN 978-0-930405-53-3.
- ^ Crombie, Alistair Cameron (1959). The History of Science From Augustine to Galileo. Courier Dover Publications. ISBN 978-0-486-28850-5.
- ^ Thorndike, Lynn (1958). A History of Magic and Experimental Science: Fourteenth and fifteenth centuries. Columbia University Press. ISBN 978-0-231-08797-1.
- ^ Mason, Stephen F. (1962). A History of the Sciences. New York: Collier. p. 550.
- ^ “Warwick honorary professor explores new material from founder of modern human anatomy”. Press release. University of Warwick. Retrieved 8 July 2013.
- ^ Vesalius, Andreas. De humani corporis fabrica libri septem. Basileae [Basel]: Ex officina Joannis Oporini, 1543.
- ^ O’Malley, C.D. Andreas Vesalius of Brussels, 1514–1564. Berkeley: University of California Press, 1964.
- ^ Boas, Marie (1970) [first published by Collins, 1962]. The Scientific Renaissance 1450–1630. Fontana. p. 229.
- ^ Sappol, Michael (2002). A traffic of dead bodies: anatomy and embodied social identity in nineteenth-century America. Princeton, NJ: Princeton University Press. ISBN 978-0-691-05925-9.
- ^ Rosner, Lisa. 2010. The Anatomy Murders. Being the True and Spectacular History of Edinburgh’s Notorious Burke and Hare and of the Man of Science Who Abetted Them in the Commission of Their Most Heinous Crimes. University of Pennsylvania Press
- ^ Richardson, Ruth (1989). Death, Dissection, and the Destitute. Penguin. ISBN 978-0-14-022862-5.
- ^ Johnson, D.R. “Introductory Anatomy”. University of Leeds. Retrieved 25 June 2013.
- ^ “Reproduction of Portrait of Professor William S. Forbes”. Jefferson: Eakins Gallery. Archived from the original on 16 October 2013. Retrieved 14 October2013.
- ^ Waterston SW, Laing MR, Hutchison JD (2007). “Nineteenth century medical education for tomorrow’s doctors”. Scottish Medical Journal. 52 (1): 45–49. doi:10.1258/rsmsmj.52.1.45. PMID 17373426.
- ^ Waterston SW, Hutchison JD (2004). “Sir John Struthers MD FRCS Edin LLD Glasg: Anatomist, zoologist and pioneer in medical education”. The Surgeon. 2 (6): 347–351. doi:10.1016/s1479-666x(04)80035-0. PMID 15712576.
- ^ McLachlan, J. & Patten, D. 2006. Anatomy teaching: ghosts of the past, present and future. Medical Education, 40(3), pp. 243–253.
- ^ Reinarz, J. 2005. The age of museum medicine: The rise and fall of the medical museum at Birmingham’s School of Medicine. Social History of Medicine, 18(3), pp. 419–437.
- ^ “Ignaz Philipp Semmelweis”. Encyclopædia Britannica. Retrieved 15 October 2013.
- ^ Jump up to:a b “Microscopic anatomy”. Encyclopædia Britannica. Retrieved 14 October 2013.
- ^ “Anatomical Imaging”. McGraw Hill Higher Education. 1998. Archived from the original on 3 March 2016. Retrieved 25 June 2013.
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