Background: Sacubitril/Valsartan is an angiotensin receptor neprilysin inhibitor used for heart failure (HF) therapy. Sacubitril/Valsartan aims to promote effects of natriuretic peptides by inhibiting neprilysin with Sacubitril, and mitigate effects of angiotensin II by blocking angiotensin II type-1 receptors with Valsartan. While treatment with Sacubitril/Valsartan reduces morbidity and CV related mortality in patients with HF and reduced EF compared with ACE inhibition with Enalapril, the mechanisms of action leading to this benefit are not well understood.
Methods: All studies were approved by the IACUC at CBSET Inc (Lexington, MA). The dilated cardiomyopathy model (DCM) was created by inducing volume-overload via partial disruption of the aortic valve. Pharmacologic therapy began 4 weeks after valve disruption and lasted to 8 weeks (N=8). Drugs were administered daily via oral gavage (Sacubitril/Valsartan 68 mg/kg, N=8, or Enalapril 30 mg/kg, N=8). After 4 weeks of therapy, hemodynamic assessments were conducted using intraventricular MillarTM technology, and an exercise tolerance test was conducted using a rodent treadmill.
Results: Rats with volume-overload developed DCM with left ventricular hypertrophy, dilatation, and dysfunction (EF, max dP/dt, end-systolic pressure-volume relationship after transient vena cava occlusion [ESPVR], min dP/dt) by 4 weeks, which progressed by 8 weeks. Therapy of DCM with Sacubitril/Valsartan but not Enalapril improved LV contractility (max dP/dt, ESPVR), relaxation (min dP/dt), and exercise tolerance. Moreover therapy with Sacubitril/Valsartan was superior to therapy with Enalapril in terms of LV relaxation (Figure 1A) and exercise tolerance (Figure 1B). Neither therapy improved LV morphology, EF, or cardiac output.
Conclusion: Therapy with Sacubitril/Valsartan is superior to Enalapril in improving LV relaxation and preservation of exercise tolerance in rats with DCM.