Transmural changes in size, contractile and electrical properties of SHR left ventricular myocytes during compensated hypertrophy.

Abstract

Some hypertrophic stimuli provoke responses from myocytes that vary across the thickness of the left ventricular wall. The Spontaneously Hypertensive Rat (SHR) is a well-established genetic model of hypertension and whole heart hypertrophy. Details of transmural responses to hypertension in the SHR are few, but are needed if the properties of this model are to be fully understood. We therefore tested the hypothesis that left ventricular myocytes of the SHR do not respond uniformly to their hypertensive environment. The volume, contraction and action potentials of enzymically isolated sub-epicardial (EPI) mid-myocardial (MID) and sub-endocardial (ENDO) myocytes from the left ventricle of 20-week-old SHR and normotensive Wistar-Kyoto (WKY) control rats were compared. Compared to WKY, as a single population, SHR myocytes displayed concentric hypertrophy (larger volumes with smaller length:width) increased t-tubule spacing, larger and prolonged cell shortening and intracellular calcium ([Ca2+]i) transients and longer action potentials. However, these responses differed across the left ventricular wall. MID myocytes showed significantly less hypertrophy than EPI and ENDO myocytes. EPI myocytes showed the largest (and significant) increases in cell shortening, [Ca2+]i transients and action potential duration, whilst MID myocytes showed the smallest (and non-significant) changes in these parameters. Real time reverse transcription polymerase chain reaction analysis on cardiac tissue suggest that increased expression of mRNA for fibronectin-1 and protein kinase Cepsilon are involved in the hypertrophic response of the whole heart. Our findings show that in the SHR, the effect of hypertension upon the morphology, mechanical activity and electrical activity of left ventricular myocytes is dependent upon their transmural location. Therefore, in addition to the overall compensating response to hypertension, i.e. increased contractility, there are likely to be regionally specific alterations in mechano-electric interactions that may influence the properties of this important model, e.g. its pre-disposition to arrhythmia whilst still in a compensated state.