TRB3 function in cardiac endoplasmic reticulum stress.

RATIONALE: Tribbles (TRB)3 is an intracellular pseudokinase that modulates the activity of several signal transduction cascades. TRB3 has been reported to inhibit the activity of Akt protein kinases. TRB3 gene expression is highly regulated in many cell types, and amino acid starvation, hypoxia, or endoplasmic reticulum (ER) stress promotes TRB3 expression in noncardiac cells. OBJECTIVE: The objective of this work was to examine TRB3 expression and function in cultured cardiac myocytes and in mouse heart. METHODS AND RESULTS: Agents that induced ER stress increased TRB3 expression in cultured cardiac myocytes while blocking insulin-stimulated Akt activation in these cells. Knockdown of TRB3 in cultured cardiac myocytes reversed the effects of ER stress on insulin signaling. Experimental myocardial infarction led to increased TRB3 expression in murine heart tissue in the infarct border zone suggesting that ER stress may play a role in pathological cardiac remodeling. Transgenic mice with cardiac-specific overexpression of TRB3 were generated and they exhibited normal contractile function but altered cardiac signal transduction and metabolism with reduced cardiac glucose oxidation rates. Transgenic TRB3 mice were also sensitized to infarct expansion and cardiac myocyte apoptosis in the infarct border zone after myocardial infarction. CONCLUSIONS: These results demonstrate that TRB3 induction is a significant aspect of the ER stress response in cardiac myocytes and that TRB3 antagonizes cardiac glucose metabolism and cardiac myocyte survival.

Adaptive Cardiac Resynchronization Therapy Effect on Electrical Dyssynchrony (aCRT-ELSYNC): A randomized controlled trial.

BACKGROUND: Adaptive cardiac resynchronization therapy (aCRT) is known to have clinical benefits over conventional CRT, but the mechanisms are unclear. OBJECTIVE: Compare effects of aCRT and conventional CRT on electrical dyssynchrony. METHODS: A prospective, double-blind, 1:1 parallel-group assignment randomized controlled trial in patients receiving CRT for routine clinical indications. Participants underwent cardiac computed tomography and 128-electrode body surface mapping. The primary outcome was change in electrical dyssynchrony measured on the epicardial surface using noninvasive electrocardiographic imaging before and 6 months post-CRT. Ventricular electrical uncoupling (VEU) was calculated as the difference between the mean left ventricular (LV) and right ventricular (RV) activation times. An electrical dyssynchrony index (EDI) was computed as the standard deviation of local epicardial activation times. RESULTS: We randomized 27 participants (aged 64 ± 12 years; 34% female; 53% ischemic cardiomyopathy; LV ejection fraction 28% ± 8%; QRS duration 155 ± 21 ms; typical left bundle branch block [LBBB] in 13%) to conventional CRT (n = 15) vs aCRT (n = 12). In atypical LBBB (n = 11; 41%) with S waves in V5-V6, conduction block occurred in the anterior RV, as opposed to the interventricular groove in strict LBBB. As compared to baseline, VEU reduced post-CRT in the aCRT (median reduction 18.9 [interquartile range 4.3-29.2 ms; P = .034]), but not in the conventional CRT (21.4 [-30.0 to 49.9 ms; P = .525]) group. There were no differences in the degree of change in VEU and EDI indices between treatment groups. CONCLUSION: The effect of aCRT and conventional CRT on electrical dyssynchrony is largely similar, but only aCRT harmoniously reduced interventricular dyssynchrony by reducing RV uncoupling.