Mechano-Growth Factor Reduces Loss of Cardiac Function in Acute Myocardial Infarction

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Cardiac Injury

Cardiac injury models are applicable to both large and small animals. These models frequently result in MIs of variable size. Lack of reproducibly is a limitation of use. The techniques employed involve either coronary occlusion or direct myocardial injury from cytotoxics electrical or cryoinjury (7-29). The MI models will be discussed in detail. 1:2-2. Models involving alteration in cardiac loading Hypertension is associated with a 3-fold risk for the development of HF (30). The progression of hypertension to HF involves several distinct yet overlapping entities, namely, initial LV hypertrophy, collagen deposition with matrix remodelling, suboptimal LV relaxation, and ultimately, diastolic and systolic dysfunction (30). Techniques used to impose a pressure overload in large animal models have included renal artery constriction, aortic stenosis, and pulmonary artery or aortic banding (31-34). In adult guinea pigs, banding of the descending thoracic aorta has led to HF (35). Banding of the ascending aorta in rodents has also been used to induce LV hypertrophy and HF (36,37) (Figure 1:1). Whilst left ventricular banding techniques adequately produce marked LV hypertrophy, they fail to evoke significant neurohormonalactivation or LV systolic dysfunction. Nevertheless, the increased LV stiffness and reduced LV relaxation and filling associated with these models render them ideal settings in which to investigate diastolic dysfunction, a common cause of HF (38).
Arteriovenous shunts are used to create volume overload leading to a dilated cardiomyopathy and subsequent HF. Carotid artery to jugular vein shunts have been successfully performed in large animal models, such as dogs and goats (39-41). However, these models often require adjunctive doxorubicin administration to develop HF. Other investigators have used femoral artery to femoral vein fistulas in rodents, and demonstrated HF without the need for cytotoxic agents (42). Despite a reported mortality with arteriovenous shunts in excess of 25%, the shunt model appears to be a viable method of studying volume overload induced HF (39-42).
Volume overload of the LV can also be induced by creation of severe mitral regurgitation (26,43-47). Canine models of mitral regurgitation have been used to elucidate numerous abnormalities at the cellular level associated with developing LV dysfunction (43-45). Severe mitral regurgitation is created by disruption of the mitral valve chordal apparatus using catheterbased techniques in a closed chest model (46). This results in a volume-overloaded LV with dilatation and ultimately LV dysfunction and HF. LV dilation, neurohormonal activation, and volume overload hypertrophy are consistently generated (45,46). The model has been used to examine the effects of angiotensin II (type 1) and b-receptor blockade on LV failure (45,47).

Pacing

Tachyarrhythmias have long been recognized as contributing to the progression and/or exacerbation of HF (48). Tachycardia induced by chronic pacing has subsequently emerged as a frequent method by which to induce HF (49-59). Rapid pacing of either the atria or ventricles has been used in sheep, pigs, and dogs to create models of HF (39,50,53,57-59). Sustained heart rates between 210 to 240 beats/min typically generate low-output biventricular spherical dilation (60,61). Rapid pacing induces LV failure, as evidenced by reduced cardiac output, and intense neurohormonal activation (49,50).
The rapid pacing model has many advantages. Model creation is relatively uncomplicated and requires simple instrumentation. Pacing induced neurohormonal alterations occur which closely parallel those observed in humans with HF (49,50). Importantly, rapid pacing generates progressive and predictable degrees of LV dilation, pump dysfunction, and neurohormonal activation (49-59). However, it must be recognized that rapid pacing models fail to manifest the complete spectrum of HF. Specifically, rapid pacing results in LV dilation and dysfunction similar to those observed in patients with dilated cardiomyopathy. The changes, which occur in myocardial structure, are distinctly different from those observed in HF due to other causes, including IHD. One unusual feature of the rapid pacing model is the absence of hypertrophy before remodelling, an association consistently seen in humans (62). Finally, once pacing is terminated, function is reported as returning toward normal, a feature unique to the pacing model of HF (56,63). Concerns therefore exist regarding the applicability of the rapid pacing model to more frequent clinical conditions, which result in HF, including MI.

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Genetic Models of HF

Given the numerous challenges of large animal models, many investigators have focused on the development of small animal models, which have shorter breeding cycles, require less animal husbandry, and permit the use of transgenic or knockout animals. To date, the introduction of genetically engineered mice prone to develop atherosclerosis, to serve as models of IHD-related HF, has been impaired by the unpredictable timing and location of intracoronary plaque formation and occlusion (64). Coronary ligation MI models are increasingly used in combination with transgenic or gene-targeting technologies (65-66). Knockout models have the potential to identify proteins associated with myocardial injury and reperfusion. Blockade of injurious proteins or exogenous delivery of beneficial proteins may attenuate the effects of an acute MI (67,68).

Chapter 1: Animal Models of Myocardial Infarction and Heart Failure
1:1 Introduction
1:2 Methods of Producing Heart Failure
1:2-1. Cardiac Injury
1:2-2. Models involving alteration in cardiac loading
1:2-3. Pacing
1:2-4. Genetic Models of HF
1:2-5. Naturally occurring
1:2-6 Myocardial Infarction Models
1:2-6-1 Coronary Artery Occlusion
1:2-6-2 Coronary artery ligation
1:2-6-3 Coronary artery embolisation
1:3 Conclusions
Chapter 2: The Ovine Model of Myocardial Infarction
2:1 Introduction
2:2 Ovine Anatomy
2:3 Methods
2:4 Problems Encountered with Model Development
2:5 Result
2:6 Conclusions
Chapter 3: The Growth-Hormone–Insulin-Like Growth Factor-I Axis and Cardiovascular Disease
3:1 Introduction
3:2 The Growth-Hormone–Insulin-Like Growth Factor-I Axis
3:3 The GH–IGF-I axis and Cardiovascular Disease
Chapter 4: Insulin-Like Growth Factor-I and the Heart
4:1 Introduction
4:2 Insulin-Like Growth Factor-I: Structure and Signall
4:3 The IGF Axis Post Myocardial Infarction
4:4 Why is Insulin-Like Growth Factor-I Increased in Peri-Infarction Tissue?
4:4-1 IGF-I Prevents Death of Cardiomyocytes
4:4-2 IGF-I Promotes Regeneration of Human Cardiomyocytes
4:4-3 IGF-I deficiency and human heart failure
Chapter 5: Insulin-Like Growth Factor-I Administration in the Post Myocardial Infarction Hea
Failure Ovine Model
5:1 Introduction
5:2 Aim
5:3 Methods
5:3-1 The Animal Model
5:3-2 Radioimmunoassay—IGF-I Protein
5:3-3 IGF-I Administration
5:3-4 Echocardiography
5:4 Statistical Analysis
5:5 Results
5:5-1 Ejection Fraction
5:5-2 Radioimmunoassay
5:6 Discussion
5:7 Conclusion and Implications
Chapter 6: Mechano-Growth Factor: An Insulin-Like Growth Factor–I Splice Variant
6:1 Introduction
6:2 Mechano-Growth Factor: Structure and Signalling
6:3 Mechano-Growth Factor and Non-Cardiac Target Organs
6:4 Mechano- Growth Factor and the Heart
6:5 Conclusions
Chapter 7: Mechano-Growth Factor Reduces Loss of Cardiac Function in Acute Myocardial Infarction
7:1 Introduction
7:2 Materials and Methods
7:2-1 Animal Model
7:2-2 Infarct Quantification
7:2-3 Echocardiography
7:2-4 Tissue Sampling
7:2-5 Immunohistochemistry
7:3 Statistical Analysis
7:4 Results
7:4-1 Echocardiography
7:4-2 Infarct Quantification
7:4-3 Histology and Immunohistochemistry
7:5 Discussion
7:6 Conclusion
Chapter 8: Final Discussion
References