Objective: The development of congestive heart failure (CHF) is accompanied by left ventricular (LV) and myocyte contractile dysfunction. However, time-dependent cellular and ionic events which contribute to the initiation and progression of CHF remain unclear. This study tested the central hypothesis that changes in L-type Ca2+ channel current (ICa) and abundance (Bmax) are early events in the transition to CHF.
Methods: LV fractional shortening by echocardiography, isolated LV myocyte shortening velocity by videomicroscopy, ICa by voltage-clamp, and Bmax by [3H]nitrendipine binding were determined at each week during the progression of pacing-induced CHF in pigs (240 bpm; n = 6/week for 3 weeks). Myocyte and L-type Ca2+ channel function were determined under basal conditions and after beta-adrenergic receptor stimulation with 25 nM isoproterenol.
Results: After 1 week of pacing, myocyte and L-type Ca2+ current responses to beta-adrenergic receptor stimulation were reduced by 20% from control values and was accompanied by over a 210% increase in plasma catecholamine levels. After 2 weeks of pacing, reductions in LV fractional shortening and myocyte shortening velocity from control values (20 +/- 1 vs. 34 +/- 2% and 36.7 +/- 2.9 vs. 50.6 +/- 2.4 microns/s, respectively, P < 0.05) were paralleled by decreased ICa (2.47 +/- 0.10 vs. 3.63 +/- 0.25 pA/pF, P < 0.02) and Bmax (149 +/- 16 vs. 180 +/- 12 fmol/mg, P < 0.03). After 3 weeks of pacing, LV fractional shortening was reduced by over 50%, myocyte shortening velocity by 37%, and ICa and Bmax were reduced by over 25% from control values. Furthermore, after 3 weeks of pacing, the ICa/Bmax ratio was reduced from control values (16.2 +/- 0.9 vs. 20.6 +/- 1.2 [fA/pF]/[fmol/mg], P < 0.03), which suggests functional defects in the remaining L-type Ca2+ channels.
Conclusions: An early event during the transition to pacing-induced CHF was diminished beta-adrenergic receptor augmented L-type Ca2+ current, which was followed by an absolute loss of steady-state L-type Ca2+ current and channel abundance. The development of severe CHF was accompanied by a loss of Ca2+ carrying capacity through residual channels. These unique findings suggest that a contributory molecular mechanism for the initiation and progression of CHF is changes in the structure and function of the L-type Ca2+ channels.