Regional workload induced changes in electrophysiology and immediate early gene expression in intact in situ porcine...

Cardiac remodelling and hypertrophy induced by chronic haemodynamic overload (stretch) eventually leads to a decrease in cardiac function, an increased incidence of ventricular arrhythmia and mortality. The mechanisms by which myocytes sense haemodynamic stress and activate growth signals are largely unknown. Nuclear immediate early genes may act as third messengers, converting the stretch stimulus into long-term changes of gene expression via cytoplasmic signal transduction. However, previous studies have used cell cultures and isolated hearts, neither of which are ideal models. We have developed a new in situ porcine heart model where local strain (stretch) can be applied, for several hours if required, thus allowing the comparison of changes in electrophysiology and gene expression with unstrained myocardium in the same preparation. A pneumatically controlled stretch-device was attached to a portion of the right ventricle of an anaesthetized animal using suction. Chronic stretch was applied for 30 min or 1 h. Regional loading produced (i) a transient decrease in monophasic action potential duration (3.5+/-0.8%; P<0.05), followed by (ii) an elongation by 15 min, despite maintained stretch (3.4+/-1.5%; P<0.05 compared to the pre-stretch situation). A control segment of the right ventricle did not show these changes. Northern blot analysis showed that both c-fos and c-myc were induced in the areas sampled, but they were 12-fold and three-fold higher, respectively, in stretched compared with control tissue after 30 min. Thus, prolonged regional stretch can produce complex changes in cardiac electrophysiology and increase expression of some immediate early genes. Our model may be useful for studying the cascade of events that lead to remodelling, hypertrophy, and arrhythmia.