A Small Molecule Inhibitor of Sarcomere Contractility Acutely Relieves Left Ventricular Outflow Tract Obstruction in Feline Hypertrophic Cardiomyopathy

Autor: Joshua A. Stern, Peter J Pascoe, Samantha P. Harris, Svetlana Markova, Eric M. Green, Yu Ueda, Marc J. Evanchik, Jae B. Kim
Přispěvatelé: Sadayappan, Sakthivel
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
Benzylamines
Muscle Physiology
Physiology
Cardiomyopathy
lcsh:Medicine
030204 cardiovascular system & hematology
Cardiovascular
Diagnostic Radiology
0302 clinical medicine
Myofibrils
Animal Cells
Heart Rate
Mitral valve
Ultrasound Imaging
Medicine and Health Sciences
2.1 Biological and endogenous factors
Ventricular outflow tract
Aetiology
lcsh:Science
Mammals
Multidisciplinary
Pharmaceutics
Radiology and Imaging
Hypertrophic cardiomyopathy
Drugs
3. Good health
Heart Disease
medicine.anatomical_structure
Echocardiography
Vertebrates
Cardiology
cardiovascular system
Calcium Antagonist Therapy
Cellular Types
Anatomy
medicine.symptom
Research Article
Muscle Contraction
Sarcomeres
medicine.medical_specialty
Alcohol septal ablation
Beta-Adrenergic Antagonist Therapy
Imaging Techniques
Systole
General Science & Technology
Heart Ventricles
Muscle Tissue
Ventricular outflow tract obstruction
Research and Analysis Methods
Contractility
03 medical and health sciences
Drug Therapy
Diagnostic Medicine
Internal medicine
medicine
Animals
cardiovascular diseases
Cardiac Surgical Procedures
Uracil
Pharmacology
Muscle Cells
business.industry
Animal
lcsh:R
Organisms
Isoproterenol
Hemodynamics
Biology and Life Sciences
Cell Biology
Cardiomyopathy
Hypertrophic
medicine.disease
Septal myectomy
Disease Models
Animal
Biological Tissue
030104 developmental biology
Hypertrophic
Amniotes
Disease Models
Cats
lcsh:Q
business
Receptor Antagonist Therapy
Zdroj: PloS one, vol 11, iss 12
PLoS ONE
PLoS ONE, Vol 11, Iss 12, p e0168407 (2016)
Popis: Hypertrophic cardiomyopathy (HCM) is an inherited disease of the heart muscle characterized by otherwise unexplained thickening of the left ventricle. Left ventricular outflow tract (LVOT) obstruction is present in approximately two-thirds of patients and substantially increases the risk of disease complications. Invasive treatment with septal myectomy or alcohol septal ablation can improve symptoms and functional status, but currently available drugs for reducing obstruction have pleiotropic effects and variable therapeutic responses. New medical treatments with more targeted pharmacology are needed, but the lack of preclinical animal models for HCM with LVOT obstruction has limited their development. HCM is a common cause of heart failure in cats, and a subset exhibit systolic anterior motion of the mitral valve leading to LVOT obstruction. MYK-461 is a recently-described, mechanistically novel small molecule that acts at the sarcomere to specifically inhibit contractility that has been proposed as a treatment for HCM. Here, we use MYK-461 to test whether direct reduction in contractility is sufficient to relieve LVOT obstruction in feline HCM. We evaluated mixed-breed cats in a research colony derived from a Maine Coon/mixed-breed founder with naturally-occurring HCM. By echocardiography, we identified five cats that developed systolic anterior motion of the mitral valve and LVOT obstruction both at rest and under anesthesia when provoked with an adrenergic agonist. An IV MYK-461 infusion and echocardiography protocol was developed to serially assess contractility and LVOT gradient at multiple MYK-461 concentrations. Treatment with MYK-461 reduced contractility, eliminated systolic anterior motion of the mitral valve and relieved LVOT pressure gradients in an exposure-dependent manner. Our findings provide proof of principle that acute reduction in contractility with MYK-461 is sufficient to relieve LVOT obstruction. Further, these studies suggest that feline HCM will be a valuable translational model for the study of disease pathology, particularly LVOT obstruction.
Databáze: OpenAIRE
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