Appendix M. 
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development of neoangiogenesis within the myocardial infarct scar 
, a process reguiring activation of latent collagenase and other 
proteinases Under normal circumstances, the contribution of 
neoangiogenesis to the infarct bed capillary network is insufficient to 
keep pace with the tissue growth required for contractile 
compensation and is unable to support the greater demands of the 
hypertrophied, but viable, myocardium. The relative lack of oxygen 
and nutrients to the hypertrophied myocytes may be an important 
etiological factor in the death of otherwise viable myocardium, 
resulting in progressive infarct extension and fibrous replacement. 
Since late reperfusion of the infarct vascular bed in both humans and 
experimental animal models significantly benefits ventricular 
remodelling and survival we have postulated that methods to 
successfully augment vascular bed neovascularization might improve 
cardiac function by preventing loss of hypertrophied, but otherwise 
viable, cardiac myocytes. 
Inability Of Damaged Myocardium To Undergo Repair Due To Cell 
Cycle Arrest Of Adult Cardiomyocytes. Cardiomyocytes undergo 
terminal differentiation soon after birth, and are thought by most 
investigators to irreversibly withdraw from the cell cycle. Analysis of 
cardiac myocyte growth during early mammalian development 
indicates that cardiac myocyte DNA synthesis occurs primarily in 
utero, with proliferating cells decreasing from 33% at mid-gestation 
to 2% at birth While ventricular karyokinesis and cytokinesis are 
coupled during fetal growth, resulting in increases in mononucleated 
cardiac myocytes, karyokinesis occurs in the absence of cytokinesis 
for a transient period during the post-natal period, resulting in 
binucleation of ventricular myocytes without an overall increase in 
cell number. A similar dissociation between karyokinesis and 
cytokinesis characterizes the primary adult mammalian cardiac 
response to ischemia, resulting in myocyte hypertrophy and increase 
in nuclear ploidy rather than myocyte hyperplasia Moreover, in 
parallel with an inability to progress through cell cycle, ischemic 
adult cardiomyocytes undergo a high degree of apoptosis. 
When cells proliferate, the mitotic cycle progression is tightly 
regulated by an intricate network of positive and negative signals. 
Progress from one phase of the cell cycle to the next is controlled by 
the transduction of mitogenic signals to cyclically expressed proteins 
known as cyclins and subsequent activation or inactivation of several 
members of a conserved family of serine/threonine protein kinases 
known as the cyclin-dependent kinases (cdks) Growth arrest 
observed with such diverse processes as DNA damage, terminal 
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