Review Question - QID 211453

The development of thoracic aortic aneurysms (TAA) in patients with Marfan syndrome (MFS) is thought to be secondary to a synergistic interaction between transforming growth factor-beta (TGF-β) and the renin-angiotensin system (RAS).

MFS is consequent to mutations in FBNI, which encodes the extracellular matrix microfibrillar protein fibrillin-1. Fibrillin is essential for the formation of elastic fibers found in connective tissue, including blood vessels. Loss of vascular wall integrity leads to the development of TAAs characteristic of MFS. Initially, the development of TAAs was thought to be driven by abnormal TGF-β signaling secondary to impaired sequestration of TGF-β by mutant fibrillin-1. TGF-β can both positively and negatively regulate cell proliferation and vascular remodeling. While TGF-β is essential for the development of the cardiovascular system, later in life, TGF-β is expressed in reaction to injury, mediating a fibrotic response for repair. Rather than an effect and not a cause, recent evidence has suggested that loss of vascular elasticity initially results in activation of the RAS system. This produces angiotensin II (AngII) which acts to increase and maintain normal blood pressure. AngII can directly induce smooth muscle remodeling with resultant wall dilation, as well as directly cause TGF-β synthesis and receptor expression. TGF-β subsequently creates a positive feedback loop through the Smad signaling pathway. Thus, increased levels of TGF-β and Smad2 levels in MFS may both result from increased AngII-mediated signaling. Therefore Losartan, an angiotensin II receptor antagonist (ARB), has been proposed as a pharmacologic means of preventing TAA progression.

Yu and Jeremy 2018 provided a review that examines current knowledge about the interactions of Ang II and TGFβ signaling in the vasculature. They discuss the use of Losartan as a proposed treatment to blunt this synergism and prevent the progression of TAA. They report that initial animal models of MFS demonstrated promising results and led to its use in clinical trials. They conclude that the literature has demonstrated mixed results with some reporting reduced TAA progression while others have found no apparent benefit of Losartan over conventional treatment (i.e., beta-blockers).

Franken et al. 2015 performed a retrospective cohort study to determine the role of TGF-β as a therapeutic biomarker for the effectiveness of losartan on aortic root dilatation rate (AoDR). They reported that patients with MFS had significantly higher TGF-β levels compared with healthy controls at baseline, and that patients who had a decrease in TGF-β at one month of Losartan therapy had significantly higher AoDR at 3 years follow up compared with patients who had an initial increase TGF-β. They concluded that TGF-β levels may be considered as a readout of the disease state of the aorta (which would explain their misleading results), and that increased angiotensin II is the initiator of aorta dilatation and responsible for increased TGF-β levels in MFS.

Incorrect Answers:
Answer 2: C-reactive protein (CRP) is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Studies have largely demonstrated that CRP levels are normal in patients with MFS and it has not been identified to play any role in the development of TAA secondary to MFS.
Answers 3-5: Interferon-gamma is a cytokine that is critical for innate and adaptative immunity against viral, some bacterial and protozoan infections. It has no role in the pathophysiology of MFS.