Atrial SERCA2a Overexpression Has No Affect on Cardiac Alternans but Promotes Arrhythmogenic SR Ca2+ Triggers.
BACKGROUND
Atrial fibrillation (AF) is the most common arrhythmia in humans, yet; treatment has remained sub-optimal due to poor understanding of the underlying mechanisms. Cardiac alternans precede AF episodes, suggesting an important arrhythmia substrate. Recently, we demonstrated ventricular SERCA2a overexpression suppresses cardiac alternans and arrhythmias. Therefore, we hypothesized that atrial SERCA2a overexpression will decrease cardiac alternans and arrhythmias.


METHODS
Adult rat isolated atrial myocytes where divided into three treatment groups 1) Control, 2) SERCA2a overexpression (Ad.SERCA2a) and 3) SERCA2a inhibition (Thapsigargin, 1μm). Intracellular Ca2+ was measured using Indo-1AM and Ca2+ alternans (Ca-ALT) was induced with a standard ramp pacing protocol.


RESULTS
As predicted, SR Ca2+ reuptake was enhanced with SERCA2a overexpression (p< 0.05) and reduced with SERCA2a inhibition (p<0.05). Surprisingly, there was no difference in susceptibility to Ca-ALT with either SERCA2a overexpression or inhibition when compared to controls (p = 0.73). In contrast, SERCA2a overexpression resulted in increased premature SR Ca2+ (SCR) release compared to control myocytes (28% and 0%, p < 0.05) and concomitant increase in SR Ca2+ load (p<0.05). Based on these observations we tested in-vivo atrial arrhythmia inducibility in control and Ad.SERCA2a animals using an esophageal atrial burst pacing protocol. There were no inducible atrial arrhythmias in Ad.GFP (n = 4) animals though 20% of Ad.SERCA2a (n = 5) animals had inducible atrial arrhythmias (p = 0.20).


CONCLUSIONS
Our findings suggest that unlike the ventricle, SERCA2a is not a key regulator of cardiac alternans in the atrium. Importantly, SERCA2a overexpression in atrial myocytes can increase SCR, which may be arrhythmogenic.
Heart and Vascular Research Center, Case Western Reserve University, Cleveland, OH, United States of America; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, United States of America.
Michelle M J
MM
Nassal
Heart and Vascular Research Center, Case Western Reserve University, Cleveland, OH, United States of America.
Xiaoping
X
Wan
Heart and Vascular Research Center, Case Western Reserve University, Cleveland, OH, United States of America.
Kenneth R
KR
Laurita
Heart and Vascular Research Center, Case Western Reserve University, Cleveland, OH, United States of America; Intermountain Heart Institute, Salt Lake City, Utah, United States of America.
Michael J
MJ
Cutler
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053840:Brugada Syndrome; D002118:Calcium / Q000378:metabolism*; D000075224:Cardiac Conduction System Disease; D005786:Gene Expression Regulation; D005936:Glucans / Q000378:metabolism; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006329:Heart Conduction System / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D019284:Thapsigargin / Q000008:administration & dosage
C506948:Atp2a2 protein, rat; D005936:Glucans; C439358:alternan; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium