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

Abstract

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 (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ 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.DOI: http://dx.doi.org/10.7554/eLife.08648.001

Medical management of aortic disease in Marfan syndrome

“…Marfan patients who received CCB (n=531) prior to or at the time of their diagnosis (followed up for a mean time of 50.8±1.6 months), when compared to groups not taking CCBs, were found more likely to have acute aortic dissections [odds ratio (OR) =12.5; P=0.032] (32). Patients on CCBs had greater odds of having surgery than those on other hypertensive regimens (OR =5.5, P=0.001) (32). Findings from this study revealed that patients on amlodipine had worse outcomes than those taking verapamil, which may be explained by the known selectivity of verapamil for cardiac tissue (32).…”

“…Ann Cardiothorac Surg 2017;6(6):654-661 www.annalscts.com Recent animal studies demonstrated a detrimental effect of CCB on Marfan mice, as mice treated with CCBs exhibited higher rates of dissection on 3-month follow-up compared to those given placebo (32). This discovery was also found to have relevance in humans, as retrospective trials of CCB agents aiming to evaluate adverse outcomes displayed similar results.…”

“…Patients on CCBs had greater odds of having surgery than those on other hypertensive regimens (OR =5.5, P=0.001) (32). Findings from this study revealed that patients on amlodipine had worse outcomes than those taking verapamil, which may be explained by the known selectivity of verapamil for cardiac tissue (32). CCBs are hypothesized to cause this damage via activation of the TGF-β dependent signaling cascades (32).…”

2016 Presidential Address: Let’s Make Human Genetics Great (Again): The Importance of Beauty in Science 1

“…8 While studying the ability of various classes of antihypertensive agents to modify the aneurysm phenotype in mouse models of Marfan syndrome, we observed that calcium channel blockers unexpectedly led to hyperacute acceleration of aneurysm growth and tear, literally tripling aneurysm size within 5 weeks and causing death due to aortic rupture within 6 weeks of treatment initiation. Mechanistic characterization led to appreciation of a pathogenic role for the PLC-IP3-PKC axis and a protective role for the PKC inhibitor enzastaurin in Marfan mice that had-or had not-received calcium channel blockers.…”

Etiology and pathogenesis of the Marfan syndrome: current understanding

“…Surprisingly, first in the mouse model treated with either amlodipine or verapamil, and subsequently in retrospective analysis of humans, calcium-channel blockade was found to be harmful, probably through protein kinase C (PKC) activation (23). Interestingly, hydralazine inhibits PKC and might be an alternative therapy for those patients who cannot tolerate β-blockade or AT1 blockade.…”