A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.

Elife. 2015 Oct 27;4. pii: e08648. doi: 10.7554/eLife.08648.

A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.
 

Doyle JJ1,2Doyle AJ1,3Wilson NK1Habashi JP1,4Bedja D5,6Whitworth RE7Lindsay ME8Schoenhoff F9,10Myers L1Huso N1Bachir S1Squires O1,Rusholme B1Ehsan H2Huso D11Thomas CJ12Caulfield MJ3Van Eyk JE10Judge DP13Dietz HC1,4,13GenTAC Registry ConsortiumMIBAVA Leducq Consortium.

Comment by Benjamin Landis

Abstract

There has been tremendous progress toward unraveling the molecular mechanisms of aortopathy associated with Marfan syndrome (MFS), which has translated to major advances in medical care for these patients.  Current medical management, aimed at reducing progressive aortic dilation and risk for dissection, often includes the use of beta blockers (BBs) or angiotensin II type 1 receptor blockers (ARBs).  Calcium channel blockers (CCBs) are considered to be another reasonable therapy option for these patients with the intent of lowering hemodynamic aortic wall stress, particularly when side effects or comorbid conditions prevent the use of BBs or ARBs.  In this recent article, Doyle and colleagues convincingly demonstrate that in fact CCBs may have detrimental effects for these patients.  In their well characterized knock-in mouse model of MFS (Fbn1C1039G/+), they show that CCBs lead to more rapid dilation of the aortic root and the ascending aorta and, strikingly, a 40% mortality rate secondary to aortic rupture over the course of 3 months.  These observations correlated with histological evidence of severely disrupted aortic architecture and were particularly prominent in the ascending aorta.  Both CCBs tested (amlodipine and verapamil) showed deleterious effects.  Mechanistically, the damaging effects of CCBs appear to be due to increased PKCĪ²-mediated activation of ERK1/2 and were abrogated by inhibitors of PKCĪ² or ERK1/2.  The authors proceeded to show that hydralazine, which is known to reduce PKC-mediated ERK1/2 activation, reduced aortic dilation and architectural disruption compared with placebo in MFS mice. Finally, MFS patients who had ever taken CCBs were observed to have increased risk for aortic dissection in the NHLBI’s GenTAC registry.  Taken together, this study provides strong evidence that CCBs should be removed from the armamentarium for treating MFS-related aortopathy and that hydralazine is an attractive consideration for these patients.  Whether these observations are applicable to other genetic etiologies of aortopathy remains to be determined