Method for ameliorating or preventing arrhythmic risk associated with cardiomyopathy
Inventors
Assignees
US Department of Veterans Affairs • University of Illinois System
Publication Number
US-9220720-B2
Publication Date
2015-12-29
Expiration Date
2028-10-17
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Abstract
A method for reducing arrhythmic risk associated with cardiomyopathy includes administering a composition containing NAD+ or a mitochondrial targeted antioxidant to an individual in need thereof.
Core Innovation
The invention provides a method for reducing arrhythmic risk associated with cardiomyopathy by administering a composition containing NAD+ or a mitochondrial targeted antioxidant to an individual in need thereof. The invention is based on the discovery that mitochondria are the main source of NADH-dependent reactive oxygen species (ROS) that downregulate sodium channel current (INa) in cardiomyopathic cells, and that mitochondrial superoxide release is responsible for this downregulation.
The problem addressed is that cardiomyopathy and related cardiac metabolic derangements, such as heart failure or ischemia, are accompanied by a substantial risk of arrhythmic sudden death. While implantable cardiac defibrillators reduce sudden death risk, they have complications, are expensive, and do not address underlying pathology. There is a need for therapies that target the molecular basis for increased arrhythmic risk.
The invention demonstrates that elevation of intracellular NADH activates protein kinase C (PKC) and causes mitochondrial complex III to release ROS through the mitochondrial inner membrane anion channel (IMAC), leading to a reduction in cardiac sodium current (INa). Inhibition of mitochondrial ROS overproduction with NAD+ or mitochondrial targeted antioxidants, such as MitoTEMPO, prevents or suppresses this INa downregulation. Thus, the invention suggests therapeutic approaches to reduce or prevent arrhythmic risk associated with cardiomyopathy by restoring INa to normal levels via administration of NAD+ or mitochondrial antioxidants.
Claims Coverage
The patent includes three independent claims directed to methods for reducing arrhythmic risk associated with cardiomyopathy by administering a mitochondrial targeted antioxidant. Below are the main inventive features extracted from these claims.
Reducing arrhythmic risk by administering a mitochondrial targeted antioxidant
A method for reducing arrhythmic risk associated with cardiomyopathy characterized by an enlarged chamber, involving administering a mitochondrial targeted antioxidant to an individual in need thereof.
Restoring cardiac sodium current to normal levels via antioxidant administration
A method for reducing arrhythmic risk and restoring the cardiac sodium current (INa) to a normal level in an individual with cardiomyopathy characterized by an enlarged chamber, by administering a mitochondrial targeted antioxidant.
Reducing arrhythmic risk in cardiomyopathy with reduced ejection fraction
A method for reducing arrhythmic risk in an individual with cardiomyopathy characterized by an enlarged chamber and a cardiac ejection fraction of less than 50%, comprising administering a mitochondrial targeted antioxidant.
The claims focus on therapeutic methods for preventing or ameliorating arrhythmic risk in cardiomyopathy by administering mitochondrial targeted antioxidants that reduce mitochondrial ROS, thereby preventing or reversing the reduction of cardiac sodium current (INa). The claims cover different subject populations defined by cardiomyopathy characteristics and ejection fraction.
Stated Advantages
The methods may provide a more effective and less invasive therapy for arrhythmic risk compared to implantable cardiac defibrillators.
Administration of NAD+ or mitochondrial targeted antioxidants can restore cardiac sodium current (INa) to normal levels in cardiomyopathic cells.
Treatment with mitochondrial antioxidants reduces mitochondrial reactive oxygen species (ROS) production, which is responsible for arrhythmogenic sodium channel downregulation.
Documented Applications
Reducing arrhythmic risk associated with cardiomyopathy, including nonischemic cardiomyopathy with enlarged cardiac chambers.
Restoring cardiac sodium current to normal levels in individuals with cardiomyopathy.
Treatment of individuals with cardiomyopathy characterized by a cardiac ejection fraction of less than 50% to reduce arrhythmic risk.
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