BackgroundMechanical assist device therapy has emerged recently as an important and rapidly expanding therapy in advanced heart failure, triggering in some patients a beneficial reverse remodeling response. However, mechanisms underlying this benefit are unclear.Methods and ResultsIn a model of mechanical unloading of the left ventricle, we observed progressive myocyte atrophy, autophagy, and robust activation of the transcription factor FoxO3, an established regulator of catabolic processes in other cell types. Evidence for FoxO3 activation was similarly detected in unloaded failing human myocardium. To determine the role of FoxO3 activation in cardiac muscle in vivo, we engineered transgenic mice harboring a cardiomyocyte‐specific constitutively active FoxO3 mutant (caFoxO3flox;αMHC‐Mer‐Cre‐Mer). Expression of caFoxO3 triggered dramatic and progressive loss of cardiac mass, robust increases in cardiomyocyte autophagy, declines in mitochondrial biomass and function, and early mortality. Whereas increases in cardiomyocyte apoptosis were not apparent, we detected robust increases in Bnip3 (Bcl2/adenovirus E1B 19‐kDa interacting protein 3), an established downstream target of FoxO3. To test the role of Bnip3, we crossed the caFoxO3flox;αMHC‐Mer‐Cre‐Mer mice with Bnip3‐null animals. Remarkably, the atrophy and autophagy phenotypes were significantly blunted, yet the early mortality triggered by FoxO3 activation persisted. Rather, declines in cardiac performance were attenuated by proteasome inhibitors. Consistent with involvement of FoxO3‐driven activation of the ubiquitin‐proteasome system, we detected time‐dependent activation of the atrogenes program and sarcomere protein breakdown.ConclusionsIn aggregate, these data point to FoxO3, a protein activated by mechanical unloading, as a master regulator that governs both the autophagy‐lysosomal and ubiquitin‐proteasomal pathways to orchestrate cardiac muscle atrophy.

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An integrated computational-experimental method was developed to characterize the global nonlinear elastic stress-strain behavior of a beating rat heart. This method combines finite element (FE) simulation with the experimental end-diastolic cavity pressure- balloon volume relationship of left ventricle (LV) to characterize the deformation resistance of a beating heart. In the FE simulations, the hyperelastic Ogden strain energy potential was used and geometric nonlinearity was also considered. The elastic moduli for the ex-vivo rat heart obtained through the study vary from 0.003 to 0.577 MPa.

Background: Mechanical unloading of the diseased ventricle has emerged as an important treatment strategy in advanced heart failure. In rare instances, dramatic improvements in ventricular performance are seen, yet little is known regarding underlying mechanisms. Histone deacetylases (HDACs) are implicated in the control of cell growth and remodeling. Recent studies have demonstrated that HDAC inhibition (HDACi) suppresses pathological cardiac hypertrophy and attenuates re-induction of the fetal gene program. We hypothesized that HDACi would accelerate unloading-induced cardiac atrophy. Methods: Mechanical unloading of murine hearts was accomplished by heterotopic transplantation into the abdomen of same-strain recipients (7 days). Two days prior to surgery, mice were randomized to daily sq injections of either trichostatin A (TSA, 1 mg/kg) or vehicle. Left ventricular (LV) cardiomyocyte area was measured from H&E sections (100 myocytes/heart), and LV transcript abundance was measured by quantitative real-time RT-PCR. Native hearts from recipient mice served as controls. Results: Consistent with a role for HDACs in cardiac atrophy, the protein abundance of HDAC-1 (54%; p<0.05), -2 (52%; p<0.01) and -3 (40%; p<0.05) were significantly increased in untreated donor hearts. Unloading-induced cardiomyocyte atrophy was accelerated in hearts transplanted into TSA-treated mice (25±4% atrophy, TSA vs 13±1% atrophy, vehicle; p<0.05). Remarkably, TSA treatment did not blunt (p=NS) the dramatic (72-fold, p<0.05) up-regulation of fetal β MHC seen in vehicle-treated hearts, despite significant increases in the rate of atrophy development. The cyclin dependent kinase inhibitors (CDKIs) p21(Cip1/Waf1) and p27(Kip1), which are known to negatively regulate cardiac hypertrophy, were each increased (p21, 45%, p<0.1; p27, 31%, p<0.1) in TSA-treated hearts relative to control. Conclusions: HDAC inhibition elicits a bona fide cardiomyocyte atrophy response during ventricular unloading in association with up-regulation of CDKI transcript expression. HDAC inhibition, however, does not blunt re-activation of the fetal gene program. These findings may have important implications for heart failure patients undergoing LV assist device support. This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).