MAFbx/Atrogin-1 is required for atrophic remodeling of the unloaded heart.

BACKGROUND: Mechanical unloading of the failing human heart induces profound cardiac changes resulting in the reversal of a distorted structure and function. In this process, cardiomyocytes break down unneeded proteins and replace those with new ones. The specificity of protein degradation via the ubiquitin proteasome system is regulated by ubiquitin ligases. Over-expressing the ubiquitin ligase MAFbx/Atrogin-1 in the heart inhibits the development of cardiac hypertrophy, but the role of MAFbx/Atrogin-1 in the unloaded heart is not known. METHODS AND RESULTS: Mechanical unloading, by heterotopic transplantation, decreased heart weight and cardiomyocyte cross-sectional area in wild type mouse hearts. Unexpectedly, MAFbx/Atrogin-1(-/-) hearts hypertrophied after transplantation (n=8-10). Proteasome activity and markers of autophagy were increased to the same extent in WT and MAFbx/Atrogin-1(-/-) hearts after transplantation (unloading). Calcineurin, a regulator of cardiac hypertrophy, was only upregulated in MAFbx/Atrogin-1(-/-) transplanted hearts, while the mTOR pathway was similarly activated in unloaded WT and MAFbx/Atrogin-1(-/-) hearts. MAFbx/Atrogin-1(-/-) cardiomyocytes exhibited increased calcineurin protein expression, NFAT transcriptional activity, and protein synthesis rates, while inhibition of calcineurin normalized NFAT activity and protein synthesis. Lastly, mechanical unloading of failing human hearts with a left ventricular assist device (n=18) also increased MAFbx/Atrogin-1 protein levels and expression of NFAT regulated genes. CONCLUSIONS: MAFbx/Atrogin-1 is required for atrophic remodeling of the heart. During unloading, MAFbx/Atrogin-1 represses calcineurin-induced cardiac hypertrophy. Therefore, MAFbx/Atrogin-1 not only regulates protein degradation, but also reduces protein synthesis, exerting a dual role in regulating cardiac mass.

Acute type I aortic dissection with or without antegrade stent delivery: Mid-term outcomes.

OBJECTIVE: We determined the effect of antegrade stent delivery in the descending thoracic aorta on short- and mid-term clinical and imaging outcomes for patients who underwent repair of acute DeBakey type I aortic dissection. METHODS: Outcomes were evaluated for 178 patients who underwent acute type I aortic dissection between 2005 and 2016 (standard repair, n = 115 [64.6%]; antegrade stent delivery, n = 63 [35.4%]). Propensity score match and multivariable analyses were performed to assess outcomes. RESULTS: The stent and standard repair groups had similar rates of operative mortality (30-day or in-hospital) (12.7% vs 17.4%, P = .41), persistent stroke (6.3% vs 5.3%, P = .75), and persistent paraplegia/paraparesis (1.6% vs 0.9%, P = 1.0). Propensity score match analysis indicated that the operative mortality rate was higher in the standard repair group (P = .059), which the multivariable analysis confirmed. The persistent stroke rate was nonsignificantly higher in the stent group (P = .66). Persistent paraplegia/paraparesis rates were similar in both groups (P = 1.0), and the overall rates of spinal cord ischemia were nonsignificantly higher in the stent group (P = .18). During follow-up (mean duration, 4.6 ± 3.6 y), computed tomography showed that stented patients more often had remodeling of the descending thoracic aorta (P = .0002) and somewhat more often had remodeling of the thoracoabdominal aorta (P = .13). Stented patients also had fewer subsequent procedures (P = .25). The 3- and 5-year survivals were 73.3% ± 6.9% and 49.9% ± 7.6% in the matched stented group and 66.3% ± 9.4% and 41.6% ± 7.7% in the matched standard group, respectively (P = .015 for overall survival). CONCLUSIONS: In the short term, antegrade stent delivery was associated with less operative mortality. In the mid-term, promising remodeling of the false lumen was seen in stented patients, as were (nonsignificantly) lower rates of subsequent procedures in the thoracoabdominal aorta. Mid-term survival was also greater in the stented patients.