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 |
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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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