Paradoxical cellular Ca2+ signaling in severe but compensated canine left ventricular hypertrophy.

In conscious dogs with severe left ventricular (LV) hypertrophy (H) (doubling of LV/body weight), which developed gradually over 1 to 2 years after aortic banding, baseline LV function was well compensated. The LV was able to generate twice the LV systolic pressure without an increase in LV end-diastolic pressure, or decrease in LV dP/dt or LV wall thickening. However, LV myocytes isolated from LVH dogs exhibited impaired contraction at baseline and in response to Ca2+. There was no change in L-type Ca2+ channel current (ICa) density but the ability of ICa to trigger Ca2+ release from the sarcoplasmic reticulum (SR) was reduced. Immunoblot analysis revealed a 68% decrease in SERCA2a, and a 35% decrease in the number of ryanodine receptors (RyR2), with no changes in protein level of calsequestrin, Na+/Ca2+ exchanger or phospholamban (PLB), but with both RyR2 and PLB hyperphosphorylated. Spontaneous Ca2+ sparks in LVH cells were found to have prolonged duration but similar intensities despite the reduced SR Ca2+ load. A higher Ca2+ spark rate was observed in LVH cells, but this is inconsistent with the reduced SR Ca2+ content. However, Ca2+ waves were found to be less frequent, slower and were more likely to be aborted in Ca2+-challenged LVH cells. These paradoxical observations could be accounted for by a nonuniform SR Ca2+ distribution, RyR2 hyperphosphorylation in the presence of decreased global SR Ca2+ load. We conclude that severe LVH with compensation masks cellular and subcellular Ca2+ defects that remain likely contributors to the limited contractile reserve of LVH.