Editorial : Improved Understanding of Marfan Syndrome

Most primary care physicians are probably familiar with Marfan syndrome. It is inherited as an autosomal dominant condition (meaning there is a 50% chance for each offspring of an affected individual to also have Marfan syndrome). Some of the clinical features include tall stature, joint laxity, diminished muscle mass and lens dislocation. But the most concerning, and life-threatening, complication is dilation and rupture of the aortic root. Although there is no cure for Marfan syndrome, the standard of care for decades has been to use beta-blockers to slow the progression of aortic dilation. While this approach has definitely shown clinical benefit in delaying progression of aortic diameter, it unfortunately fails to prevent the need for surgical intervention in many patients.

In recent years, Dr. Harry C. Dietz and his colleagues at Johns Hopkins University, Baltimore, have made great strides in elucidating the underlying pathophysiology of Marfan syndrome and identifying potential new therapies. In April, the group published two articles in Science that report additional findings regarding the process of aortic aneurysm formation in a mouse model of Marfan syndrome (Science 2011;332:358-61 and Science 2011;332:361-5).

Marfan syndrome is caused by mutations in the gene FBN1, which result in reduced production of fibrillin-1, a major scaffold protein important in creating and stabilizing connective tissue. For years, it was thought that deficiency of fibrillin-1 contributed to aneurysm formation because of poor structural integrity of the connective tissue in arterial walls.

However, it now appears that aneurysm formation is caused by excess signaling through the transforming growth factor–beta (TGF-beta) pathway. Fibrillin-1 normally functions in the extracellular matrix to sequester TGF-beta. In Marfan syndrome, there is insufficient fibrillin-1 to adequately sequester TGF-beta, and pathologic excessive signaling occurs.

It turns out that losartan, and likely other angiotensin receptor blockers (ARBs), effectively reduce TGF-beta signaling and in the mouse model can prevent – and even reverse – aortic root dilation. This discovery is not only useful as a research tool but also has obvious clinical implications in the management of Marfan syndrome. In addition to the obvious suggestion of treating Marfan syndrome patients with losartan, there is a natural question about whether ACE inhibitors might be similarly effective in reducing TGF-beta signaling and protecting the aorta. While some small studies have suggested that ACE inhibitors may be of clinical benefit, knowledge of biochemical pathways and the recent reports by Dr. Dietz and his colleagues may suggest otherwise.

There are actually two angiotensin II receptors. The type 1 receptor (AT1) increases TGF-beta signaling and contributes to aortic aneurysm formation. The type 2 receptor (AT2) is less well understood, and there has been debate about its effect on TGF-beta signaling. Losartan and other ARBs are specific inhibitors of AT1 and have no effect on AT2.

In the recent reports, Marfan mice lacking the AT2 receptor had greater TGF-beta signaling and more aortic root dilation than did Marfan mice with intact AT2 receptors. Furthermore, losartan was much less effective in reducing TGF-beta signaling or protecting the aortas among Marfan mice lacking the AT2 receptor. This implies that the AT2 receptor actually downregulates TGF-beta signaling and can be protective with respect to aortic root aneurysm formation.

It then follows that ACE inhibitors, which act upstream of angiotensin II, and therefore decrease activity of both AT1 and AT2, may not be as effective as ARBs are in reducing TGF-beta signaling or protecting the aorta in Marfan syndrome. Indeed, in the reports by Dr. Dietz, enalapril was able to slow the progression of aortic root diameter in the mouse model but was not able to match the reversal of aneurysm size achieved by losartan.

The other important finding in these latest studies is further identification of the specific pathways downstream from TGF-beta that are involved in aneurysm formation. The critical players appear to be extracellular signal–regulated kinases (ERK) and c-Jun amino-terminal kinases (JNK). This knowledge brings us one step closer to a complete understanding of exactly how aneurysms develop in Marfan syndrome and serves as an excellent example of how basic science and clinical research can overlap and synergize. In the mouse studies, losartan shut down the excess ERK signaling, while enalapril had no effect on this pathway. This lends further support to the idea that ARB may be superior to ACE inhibitors as a clinical treatment. Even more significantly, the inhibitors of ERK and JNK used by Dr. Dietz’s group in their research are under evaluation for clinical application, and they – or drugs modeled after them – might ultimately prove extremely valuable in the treatment of patients with Marfan syndrome.