Abstract 17308: Mechanical Unloading of Failing Hearts Normalises Calcium-Induced Calcium Release by Reverse Remodelling of the T-Tubule System.
Ca2+ -induced Ca2+ release (CICR) is critical for contraction in cardiomyocytes. The t-tubule system guarantees the proximity of the triggers for Ca2+ release (L-type Ca2+ channel) and the sarcoplasmic reticulum Ca2+ release channels (Ryanodine receptors). T-tubule disruption is implicated in the pathogenesis of heart failure (HF). Clinical studies of left ventricular assist devices in HF indicate that mechanical unloading induces reverse remodeling. However, the role of t-tubule remodelling during unloading is unknown. We hypothesise that unloading of failing hearts normalises t-tubule structure and improves CICR. HF was induced in Lewis rats by left coronary artery ligation for 12 weeks; Sham operated animals were used as control. Failing hearts were mechanically unloaded for 4 weeks by heterotopic abdominal heart transplantation (MUHF). LV myocytes were enzymatically isolated. HF reduced the t-tubule density measured by Di-8-ANEPPS staining, and this was reversed by unloading (Sham: 43.61 ± 1.43 %, n=35; HF: 27.09 ± 2.8 %, n=22; MUHF: 38.04 ± 2.19 %, n=32; HF vs MUHF p<0.01). The deterioration in the regularity of the t-tubule system in HF, as measured by the power of the dominant frequency of the Fourier transform, was also reversed in MUHF (Sham: 3.83 ± 0.39 X 107, n=35; HF: 4.39 ± 0.4 X 106, n=22; MUHF: 1.93 ± 2.41 X 107, n=32; HF vs MUHF p<0.001). Scanning ion conductance microscopy showed the reappearance of normal surface striations in MUHF. L-type Ca2+ current density, measured using whole cell patch clamping, was reduced in HF but unaffected by unloading (Sham: −7.85 ± 0.21 pA/pF, n=33; HF: −6.85 ± 0.367 pA/pF, n=26; MUHF: −7.53 ± 0.320 pA/pF, n=30). Ca2+ transients and sparks were measured using Fluo-4. The variance of the time to peak of the Ca2+ transient, an index of CICR synchronicity, which was increased in HF was normalised by unloading (Sham: 154.9 ± 17.8 ms2, n=41 vs. HF: 278.7 ± 30.7 ms2, n=37; MUHF: 158.2 ± 14.90 ms2, n=36; HF vs. MUHF p=0.001). The increased spark frequency observed in HF was reduced in MUHF (Sham: 0.908 ±0.19 sp/s, n=45; HF: 1.56 ±0.28 sp/s, n=52; MUHF: 0.92 ± 0.16 sp/s, n=36; HF vs MUHF p=0.01). Our data show that mechanical unloading of the failing heart reverses the pathological remodelling of the t-tubule system and normalises CICR.
- © 2010 by American Heart Association, Inc.