Pressure overload-induced hypertrophy is a key step leading to heart failure. 
The Ca(2+)-induced Ca(2+) release (CICR) process that governs cardiac 
contractility is defective in hypertrophy/heart failure, but the molecular 
mechanisms remain elusive. To examine the intermolecular aspects of CICR during 
hypertrophy, we utilized loose-patch confocal imaging to visualize the signaling 
between a single L-type Ca(2+) channel (LCC) and ryanodine receptors (RyRs) in 
aortic stenosis rat models of compensated (CHT) and decompensated (DHT) 
hypertrophy. We found that the LCC-RyR intermolecular coupling showed a 49% 
prolongation in coupling latency, a 47% decrease in chance of hit, and a 72% 
increase in chance of miss in DHT, demonstrating a state of "intermolecular 
failure." Unexpectedly, these modifications also occurred robustly in CHT due at 
least partially to decreased expression of junctophilin, indicating that 
intermolecular failure occurs prior to cellular manifestations. As a result, 
cell-wide Ca(2+) release, visualized as "Ca(2+) spikes," became desynchronized, 
which contrasted sharply with unaltered spike integrals and whole-cell Ca(2+) 
transients in CHT. These data suggested that, within a certain limit, termed the 
"stability margin," mild intermolecular failure does not damage the cellular 
integrity of excitation-contraction coupling. Only when the modification steps 
beyond the stability margin does global failure occur. The discovery of "hidden" 
intermolecular failure in CHT has important clinical implications.