From an Unfolding Emergency Treatment to a Universal Shift in Therapy: The History and Evolution of the Catheter-Based Treatment of Aortic Valve Stenosis.

Aortic valve stenosis (AVS) is the most frequent valvular heart disease in industrialized countries, presenting with very high mortality if left untreated. While drug treatment can sometimes alleviate symptoms, it fails to stop progression or cure the underlying disease. Until the first decade of this millennium, surgical aortic valve replacement (SAVR) remained the only available therapy option with a positive impact on mortality and morbidity. Even though several studies reported highly positive effects of SAVR regarding the improved quality of life and better physical performance, SAVR remained an intervention that, due to its remarkable complexity and the need for heart-lung machine and cardioplegia, was limited by the patients' comorbid profile. While unsatisfying hemodynamic results after transcatheter aortic balloon valvuloplasty in high-risk surgical patients limited its adoption as an alternative treatment, it provided the impetus for further interventional approaches to the therapy of AVS. This review considers the invention and development of transcatheter aortic valve implantation (TAVI), which established itself as a catheter-based, minimally invasive procedure over the past decade, and has become an equivalent treatment method for high-risk surgical patients. For that matter, early TAVI concepts, their amendments, and the associated pioneers are recognized for paving the way to a revolutionary diversification in AVS treatment.

PRAS40 suppresses atherogenesis through inhibition of mTORC1-dependent pro-inflammatory signaling in endothelial cells.

Endothelial pro-inflammatory activation plays a pivotal role in atherosclerosis, and many pro-inflammatory and atherogenic signals converge upon mechanistic target of rapamycin (mTOR). Inhibitors of mTOR complex 1 (mTORC1) reduced atherosclerosis in preclinical studies, but side effects including insulin resistance and dyslipidemia limit their clinical use in this context. Therefore, we investigated PRAS40, a cell type-specific endogenous modulator of mTORC1, as alternative target. Indeed, we previously found PRAS40 gene therapy to improve metabolic profile; however, its function in endothelial cells and its role in atherosclerosis remain unknown. Here we show that PRAS40 negatively regulates endothelial mTORC1 and pro-inflammatory signaling. Knockdown of PRAS40 in endothelial cells promoted TNFα-induced mTORC1 signaling, proliferation, upregulation of inflammatory markers and monocyte recruitment. In contrast, PRAS40-overexpression blocked mTORC1 and all measures of pro-inflammatory signaling. These effects were mimicked by pharmacological mTORC1-inhibition with torin1. In an in vivo model of atherogenic remodeling, mice with induced endothelium-specific PRAS40 deficiency showed enhanced endothelial pro-inflammatory activation as well as increased neointimal hyperplasia and atherosclerotic lesion formation. These data indicate that PRAS40 suppresses atherosclerosis via inhibition of endothelial mTORC1-mediated pro-inflammatory signaling. In conjunction with its favourable effects on metabolic homeostasis, this renders PRAS40 a potential target for the treatment of atherosclerosis.