Method for ameliorating or preventing arrhythmic risk associated with cardiomyopathy by improving conduction velocity
Inventors
Assignees
US Department of Veterans Affairs • University of Illinois System
Publication Number
US-9211301-B2
Publication Date
2015-12-15
Expiration Date
2028-10-17
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Abstract
A method for reducing arrhythmic risk associated with cardiomyopathy by improving conduction velocity, includes administering a composition containing NAD+ or a mitochondrial targeted antioxidant to an individual or person in need thereof.
Core Innovation
The invention provides a method for reducing arrhythmic risk associated with cardiomyopathy by improving conduction velocity. This method includes administering a composition containing NAD+ or a mitochondria-targeted antioxidant to an individual in need thereof. The underlying mechanism involves the restoration of cardiac sodium current (INa) through the reduction or suppression of mitochondrial reactive oxygen species (ROS) that are produced due to elevated intracellular reduced nicotinamide adenine dinucleotide (NADH) in cardiomyopathic cells.
The problem addressed is that conditions associated with deranged cardiac metabolism, such as heart failure or ischemia, carry a substantial risk of arrhythmic sudden death. Existing therapies like implanted cardiac defibrillators reduce sudden death risk but have physical and psychological complications, are expensive, and do not address the underlying pathology. Cardiac injury often results in downregulation of the cardiac Na+ channel (Nav1.5) mediated by increased intracellular NADH and mitochondrial ROS production, leading to reduced INa, conduction block, and increased arrhythmic risk.
The invention demonstrates that mitochondria are the main source of NADH-dependent ROS that downregulates INa in cardiomyopathic cells, adversely affecting conduction velocity. It shows that elevation of intracellular NADH activates protein kinase C (PKC) and causes mitochondrial complex III release of ROS through the mitochondrial inner membrane anion channel (IMAC), contributing to decreased conduction velocity. Inhibition of mitochondrial ROS overproduction by NAD+, mitochondrial targeted antioxidants such as MitoTEMPO, PKC inhibitors, or PKA activators prevents, suppresses, or reverses INa downregulation, thereby improving conduction velocity and reducing arrhythmic risk.
Claims Coverage
The patent contains three independent claims focused on methods to reduce arrhythmic risk in individuals with cardiomyopathy by improving conduction velocity through mitochondria-targeted antioxidant administration.
Method to reduce arrhythmic risk by improving conduction velocity using mitochondria-targeted antioxidants
A method of reducing arrhythmic risk in individuals with cardiomyopathy characterized by enlarged chamber and reduced conduction velocity, comprising administering a therapeutic amount of a mitochondria-targeted antioxidant to improve conduction velocity to a predetermined normal level, where this improvement reduces arrhythmic risk.
Method to restore sodium channel current and reduce arrhythmic risk by administering mitochondria-targeted antioxidants
A method of reducing arrhythmic risk in individuals with cardiomyopathy characterized by enlarged chamber and reduced sodium channel current, comprising administering mitochondria-targeted antioxidants to restore sodium channel current to a predetermined normal by improving conduction velocity, thereby reducing arrhythmic risk.
Method to reduce arrhythmic risk in cardiomyopathy patients with low ejection fraction by mitochondria-targeted antioxidant administration
A method of reducing arrhythmic risk in individuals with cardiomyopathy characterized by enlarged chamber and cardiac ejection fraction less than 50%, comprising administering mitochondria-targeted antioxidants to restore ejection fraction to more than 50% by improving conduction velocity, thereby reducing arrhythmic risk.
The claims focus on therapeutic methods employing mitochondria-targeted antioxidants, particularly MitoTEMPO, to improve conduction velocity by restoring or preserving cardiac sodium current in cardiomyopathy patients, resulting in reduced arrhythmic risk.
Stated Advantages
The method reduces arrhythmic risk associated with cardiomyopathy by improving conduction velocity.
It addresses underlying metabolic pathology causing sodium channel downregulation, unlike implants which do not.
Administration of NAD+ or mitochondria-targeted antioxidants restores sodium current (INa) and conduction velocity.
The approach is potentially less invasive and more effective than existing treatments like implanted cardiac defibrillators.
Documented Applications
Amelioration or prevention of arrhythmic risk in individuals with cardiomyopathy by improving conduction velocity.
Improvement of conduction velocity by restoring cardiac sodium current to normal levels in individuals with cardiomyopathy.
Reduction of arrhythmic risk in individuals with cardiomyopathy having cardiac ejection fraction less than 50% through improved conduction velocity.
Therapeutic administration of NAD+ or mitochondria-targeted antioxidants such as MitoTEMPO to individuals with cardiomyopathy.
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