Cardiac arrhythmia treatment methods

Abstract

Disclosed are methods of preventing or treating cardiac arrhythmia. In one embodiment, the methods include administering to an amount of at least one polynucleotide that modulates an electrical property of the heart. The methods have a wide variety of important uses including treating cardiac arrhythmia.

1 . A method of preventing or treating cardiac arrhythmia comprising administering to a mammal a therapeutically effective amount of at least one polynucleotide capable of modulating an electrical property in a standard cardiac electrophysiological assay; and expressing the polynucleotide in the mammal to prevent or treat the cardiac arrhythmia.  
     
     
         2 - 11 . (Cancelled)  
     
     
         12 . The method of  claim 1 , wherein the polynucleotide encodes a K channel subunit, Na channel subunit, Ca channel subunit, an inhibitory G protein subunit, a connexin; or a functional fragment thereof.  
     
     
         13 - 20 . (Cancelled)  
     
     
         21 . The method of  claim 12 , wherein the inhibitory G protein subunit is Gα i2  or a functional fragment thereof.  
     
     
         22 .- 26 . (Cancelled)  
     
     
         27 . A method of preventing or treating ventricular rate or pulse during atrial fibrillation comprising administering to a mammal a therapeutically effective amount of at least one polynucleotide encoding a Gα i2  or a functional fragment thereof; and expressing the polynucleotide in the mammal to prevent or treat the atrial fibrillation.  
     
     
         28 . The method of  claim 27 , wherein the method further comprises overexpressing the Gα i2  or a functional fragment thereof sufficient to decrease speed of conduction through the atrioventricular (AV) node (A-H interval) or His-Purkinje system as determined by a standard electrophysiological assay.  
     
     
         29 . The method of  claim 28 , wherein the decrease in the A-H interval is accompanied by a decrease in AV node refractory period (AVNERP).  
     
     
         30 . The method of  claim 28  or  29 , wherein the decrease in the A-H interval is at least about 10% as determined by the assay.  
     
     
         31 . The method of  claim 29 , wherein the increase in AVNERP is at least about 10% relative as determined by the assay.  
     
     
         32 . The method of  claim 27 , wherein overexpression of the Gα i2  or a functional fragment thereof is capable of decreasing pulse rate or ventricular rate during atrial fibrillation as determined by a standard cardiac electrophysiological assay.  
     
     
         33 . The method of  claim 32 , wherein the decrease in pulse rate or ventricular rate during atrial fibrillation is at least about 10% as determined by the assay.  
     
     
         34 . The method of  claim 27 , wherein the polynucleotide encoding the Gα i2  subunit hybridizes to the nucleic acid sequence shown in SEQ ID No. 1; or the complement thereof under high stringency hybridization conditions.  
     
     
         35 . The method of  claim 34 , wherein the polynucleotide comprises the nucleic acid shown in SEQ ID NO. 1 (FIG. 9); or a functional fragment of that sequence.  
     
     
         36 . The method of  claim 1  or  27 , wherein the administration step comprises injecting the polynucleotide into myocardium.  
     
     
         37 . The method of  claim 1  or  27 , wherein the administration step comprises perfusing the polynucleotide into cardiac vasculature.  
     
     
         38 . The method of  claim 36 , wherein the administration step further comprises perfusing the polynucleotide into cardiac vasculature.  
     
     
         39 . The method of  claim 37 , wherein the administration step further comprises increasing microvascular permeability.  
     
     
         40 . The method of  claim 34 , wherein the method further comprises administering at least one vascular permeability agent prior to or during administration of the gene transfer vector.  
     
     
         41 . The method of  claim 40 , wherein the vascular permeability agent is serotonin, vascular endothelial growth factor (VEGF), or a functional VEGF fragment to increase the permeability.  
     
     
         42 . The method of  claim 37 , wherein the perfusion is sufficient to transfer the polynucleotide to at least about 10% of cardiac myocytes in the mammal.  
     
     
         43 . The method of  claim 42 , wherein the infusion volume is between from about 0.5 to about 500 ml, and the coronary flow rate is between from about 0.5 to about 500 ml/min.  
     
     
         44 . The method of  claim 42 , wherein the perfusion is into the AV nodal artery and the cardiac myocytes comprising the polynucleotide are positioned at or near the AV node.  
     
     
         45 - 47 . (Cancelled)  
     
     
         48 . The method of claim  47 , wherein the viral vector comprises operably linked in sequence a cytomeglovirus (CMV) promoter and nucleic acid sequence encoding a full-length Gα i2 subunit gene.  
     
     
         49 - 59 . (Cancelled)