Abstract
Abstract 13204: Acute Effects of a Small-Molecule Direct Myosin-Attenuator (MYK-581) in a Mini-Pig Genetic Model of Non-Obstructed Hypertrophic Cardiomyopathy: In Vivo Evidence for Contractile Regulation With Improved Compliance and Functional Reserve
Circulation (New York, N.Y.), Vol.138(Suppl_1 Suppl 1), pp.A13204-A13204
11/06/2018
Abstract
IntroductionHypertrophic cardiomyopathy (HCM) is a heritable disease characterized by hyper-contractility, impaired filling, and exertional intolerance. Direct myosin-modulation with Mavacamten can normalize contractility and improve exercise capacity in patients with obstructed HCM. However, myosin-modulation could also limit residual cross-bridges during diastole, improving LV compliance and relaxation. This in vivo study evaluated the systolic/diastolic effects of direct myosin-attenuation in a novel genetic large-animal model of non-obstructed HCM.MethodsJuvenile Yucatan mini-pigs with a heterozygous MYH7 R403Q mutation and wild-type (WT) herd-mates were studied. Cardiac output, load-independent systolic and diastolic function (via LV pressure-volume relationships), and β-adrenergic (β-AR) cardiac reserve (dobutamine, 10 ug/kg/min IV) were assessed under anesthesia (R403Qn = 10, WTn = 8) both before and during treatment with MYK-581 (IV), a cardio-selective allosteric myosin modulator (mavacamten surrogate). The acute oral (PO) effects of metoprolol (METO, 2 mg/kg) and MYK-581 were also compared in conscious pigs with telemetered LV pressures (R403Qn = 4, WTn = 3).ResultsMutant pigs were hyper-contractile (e.g., LVEF+24 ± 5% and PRSW+21 ± 3% vs. WT), had elevated end-diastolic pressures (EDP23 ± 2 vs. 9.0 ± 1 mmHg in WT, P<0.05), stiffer ventricles, and blunted β-AR stroke volume recruitment (SV+5 ± 2% vs. +33 ± 5% in WT, P<0.05). In HCM, MYK-581 normalized EF (-8 ± 1%) and improved LV compliance, increasing end-diastolic dimensions (EDV+6 ± 1%) and lowering EDP (-9 ± 3%) (all P < 0.05 vs. pre-dose). MYK-581 also improved β-AR reserve (SV+21 ± 7%, P<0.05). In conscious pigs, MYK-581, but not METO, improved relaxation and decreased EDP (tau-12 ± 3 vs. +2 ± 1% in METO, and EDP-4 ± 1 vs. +2 ± 1 mmHg in METO; both P < 0.05).ConclusionsDirect myosin attenuation in genetic HCM normalized systolic function, while improving ventricular compliance in vivo. This cardiovascular profile, supported by a right-/down-ward shift in LV pressure-volume relationships, also led to improved cardiac reserve, and therefore could have salutary effects in patients with HCM and/or impaired ventricular filling.
Details
- Title: Subtitle
- Abstract 13204: Acute Effects of a Small-Molecule Direct Myosin-Attenuator (MYK-581) in a Mini-Pig Genetic Model of Non-Obstructed Hypertrophic Cardiomyopathy: In Vivo Evidence for Contractile Regulation With Improved Compliance and Functional Reserve
- Creators
- Carlos del Rio - Pharmacology, MyoKardia, San Francisco, CAAprajita Yadav - DMPK, MyoKardia, San Francisco, CANeal Huang - Formulations Development, MyoKardia, San Francisco, CAGail Geist - Safety Pharmacology, QTest Labs, Columbus, OHYukie Ueyama - Safety Pharmacology, QTest Labs, Columbus, OHBrad Youngblood - Safety Pharmacology, QTest Labs, Columbus, OHMarc Evanchik - Pharmacology, MyoKardia, San Francisco, CAEric Green - Pharmacology, MyoKardia, San Francisco, CAAbhay Divekar - Supreme Council Of HealthFerhaan Ahmad - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.138(Suppl_1 Suppl 1), pp.A13204-A13204
- Publisher
- by the American College of Cardiology Foundation and the American Heart Association, Inc
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/06/2018
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine; Radiology; Stead Family Department of Pediatrics
- Record Identifier
- 9984303001002771
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