Attenuation of Aortic Remodeling with Low Doses of Neprilysin/Angiotensin II Receptor Blockers Sacubitril/Valsartan in a Fibrillin‐1‐Deficient Model of Marfan Syndrome

Abstract

Introduction Sacubitril is a neprilysin inhibitor indicated for heart failure patients with reduced ejection fraction (HFReF), which causes protective natriuretic peptide accumulation. To maximize efficacy and minimize side effects, sacubitril is administered in combination with valsartan, a blood pressure‐lowering angiotensin II receptor blocker (ARB). We and others have shown that ARBs are capable of blood pressure lowering‐independent effects on vascular and lung remodeling, but whether the sacubitril/ARB combination shows greater anti‐vascular and lung remodeling effects is unknown. Objective Since ARBs are routinely prescribed to patients with Marfan syndrome, which is a fibrillin‐1 mutation‐induced connective tissue disease that causes aortic widening, dissection and lung emphysema, we sought to test the anti‐remodeling effects of low‐doses sacubitril/valsartan combination on the vascular and pulmonary complications associated with Marfan syndrome in mice. Results Treatment with low dose valsartan and sacubitril/valsartan (pure forms in drinking water) did not significantly lower blood pressure when compared with vehicle group in the C1039G fibrillin‐1 model of Marfan syndrome. There was a non‐significant inhibitory trend of Marfan‐associated aortic root widening with valsartan and especially sacubitril/valsartan, whereas only the latter induced a significant and near‐complete (74%) inhibition of Marfan‐associated ascending aorta widening (P<0.008). None of the treatment groups significantly reduced emphysema, loss of lung volume, change in hysteresis, tissue damping and resistance associated with Marfan syndrome. Conclusion Sacubitril/valsartan combination may be more clinically relevant than valsartan alone in settings of aortic dilation, even at low doses. Support or Funding Information Supported by Novartis Canada

An Overview of Investigational and Experimental Drug Treatment Strategies for Marfan Syndrome

“…Preliminary data suggest that a low dose of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan can inhibit ascending aorta dilation in the Fbn1 C1039G/+ mouse model to a greater extent than the ARB valsartan alone. 166 Since the doses of both the ARNI and the ARB were titrated to a level not affecting blood pressure, additional neprilysin inhibition is likely to afford additional protection due to its anti-remodeling effects. A first case report of the use of sacubitril/valsartan in an MFS patient showed that this treatment can improve MFS-related cardiomyopathy.…”