Gap Junctions in Cardiac Disease

In this chapter changes in the distribution of gap junctions within the myocardial tissue, alterations of the distribution of special isoforms in the course of heart disease are described. Thus, changes in gap junction pattern for Cx43 and for Cx40 in the border zone of a chronic infarction are pointed out. Changes with growing age and in the course of heart failure are discussed as well. 

However, an enhanced extracellular potassium concentration and depolarization of the fibers besides the other factors lead to a reduced sodium channel availability, to a reduced maximum depolarization velocity, shortened action potentials and to a slowing of conduction. These changes result in an alteration in the activation patterns [Dhein et al., 1994] and an increase in dispersion of action potential duration, which is even more pronounced in the presence of neutrophilic leukocytes [Dhein et al., 1995a], 

There are two forms of arrhythmia in acute myocardial ischemia. Type-la arrhythmias occur 2-10 min after the onset of ischemia with a peak at 5-6 min. These arrhythmias are often of the reentrant type and are caused by diastolic bridging (details see chapter 1). It is also possible that premature ventricular depolarizations occur in this phase and initiate reentry. 

Besides these, type-lb arrhythmia can occur at 12-30 min after the onset of ischemia with a peak at 15-20 min. These type-lb arrhythmias are either due to a partial recovery of the cell excitability (partial recovery of dU/dt and of the action potential duration), which may be ascribed to the release of catecholamines [for review see, Janse and Wit, 1989] or are due to gap junctional 

6 min of ischemia and was considered the main trigger for uncoupling. In a similar setup, Yamada et al. [1994] demonstrated that the accumulation of long-chain acylcarnitines contributed to cellular uncoupling in the course of ischemia and was delayed by inhibition of acylcarnitine transferase I. Interes- 

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What about the real turnover rate of gap junction proteins as the basis of changes in gap junction pattern in the course of cardiac disease There are several reports on a considerably high and rapid turnover of connexins both in vivo and in vitro. 

Another cardiac disease often associated with cardiac arrhythmias is heart failure. Many factors including high catecholamine levels, dilated tissue geometry, changes in the [3-adrenoceptor population, impairment of the regulation of the intracellular (diastolic) calcium concentration, possibly enhanced endo-thelin levels and many more contribute to altered cardiac function and make the heart more prone to arrhythmia. However, the question was whether, in addition to the well-known structural changes, gap junction alterations may also partially form the arrhythmogenic substrate. Thus, researchers were interested in whether in the course of heart failure gap junctional alterations may occur. 

However, it is well known that with increasing age microfibrosis is observed which in turn will seperate the fibers from each other and thereby enhance the degree of nonuniformity as discussed in the first chapter of this book. This is accompanied by a reduction in side-to-side connections [Spach and Dolber, 1986]. Thus, with increasing age the intercellular communication can be expected to be reduced probably due to structural changes in the tissue with deposition of collagenous fibers. Concomitant changes in the gap junction distribution are probably secondary to cardiac diseases, although at present an effect of age per se cannot be excluded. 

A possible novel therapeutic strategy for heart failure following myocardial infarction may be to increase the number of functional myocytes within the diseased area by the implantation of exogenous myogenic cells. Early studies used neonatal rat cardiomyocytes for transplantation, as these cells have cardiac phenotype and still retain some proliferation capacity [2-4]. Fetal cardiomyocyte cell grafts showed the formation of cell-to-cell contacts, complete with gap junction proteins [4]. Moreover, cultured human fetal cardiomyocytes were shown to survive, and fetal rat cardiomyocytes were shown to be present in the infarcted rats hearts for up to 6 months after transplantation [5]. Further studies in animal models of myocardial infarction showed that grafting of cardiomyocytes from fetal and neonatal sources was asso-... 

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