A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome
Doyle, J. J., Doyle, A. J., Wilson, N. K., Habashi, J. P., Bedja, D., Whitworth, R. E., Lindsay, M. E., Schoenhoff, F., Myers, L., Huso, N., Bachir, S., Squires, O., Rusholme, B., Ehsan, H., Huso, D., Thomas, C. J., Caulfield, M. J., Van Eyk, J. E., Judge, D. P., ... MIBAVA Leducq Consortium (2015). A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome. eLife, 4, Article 08648. https://doi.org/10.7554/eLife.08648
Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKC beta) as a critical mediator of this pathway and demonstrate that the PKC beta inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCa and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.