Advertisement

Vasomera™, a Novel VPAC2-Selective Vasoactive Intestinal Peptide Agonist, Improves Ventriculo-Arterial Coupling and Decreases Myocardial Demand in Sheep with Induced Ischemic Heart Failure

      Background

      The natural vasoactive intestinal peptide (VIP) has been proposed as a therapeutic agent for heart failure via the activation of the G-protein-coupled VPAC1 and VPAC2 receptors; however, VIP's clinical utility is limited due to its short half-life and VPAC1-mediated side-effects. Vasomera™ is a novel long-acting biopolymer-based selective VPAC2-eceptor agonist, which may circumvent the limitation(s) of traditional VIP agonists. Here, the acute effects of Vasomera in load-independent function and ventriculo-arterial coupling were evaluated in sheep with failing ischemic ventricles.

      Methods

      Sheep (n = 5) were instrumented for the determination of systemic/left-ventricular hemodynamic as well as for the evaluation of cardiac-output (via thermo-dilution), load-independent left-ventricular (LV) inotropy/lusitropy and ventriculo-arterial coupling (via pressure-volume relationships), as well as for the assessment of myocardial oxygen extraction. All animals had heart failure induced (prior to instrumentation) via serial (weekly) coronary embolizations, resulting in depressed LV function (EF: 28 ± 1%) and elevated filling pressures (EDP: 22 ± 2mmHg). LV mechano-energetics were evaluated before/after a single-dose continuous IV infusion of Vasomera (0.3 μg/kg/min IV).

      Results

      Vasomera decreased the estimated arterial elastance (Ea: -24 ± 5%, 2.3 ± 0.2 to 1.9 ± 0.9 mmHg/mL, P < 0.05) with negligible changes in heart rate (114 ± 4 to 111 ± 6 bpm). Steeper ESPVR (Ees: 1.2 ± 0.1 to 1.9 ± 0.2 mmHg/mL, P < 0.05) and PRSW slopes (45 ± 4 to 61 ± 7 mmHg*, P < 0.05) were observed post-treatment, suggesting positive (load independent) inotropy and improved ventriculo-arterial coupling (Ea/Ees: 2.0 ± 0.3 to 1.1 ± 0.2, P < 0.05). Concomitantly, cardiac output (CO: 4.3 ± 0.2 to 4.9 ± 0.4 L/min, P < 0.05) increased while myocardial oxygen extraction decreased (O2ex: 41 ± 5 to 20 ± 4%, P < 0.05); the LV pressure-volume area, a correlate of myocardial demand, also decreased (PVA: 15.3 ± 2.2 to 6.0 ± 1.0 mmHg*L, P < 0.05).

      Conclusions

      Vasomera, a novel VPAC2 agonist, decreased myocardial loading and energetic demand, while improving LV function and ventriculo-arterial coupling in the setting of ischemic heart failure.