Alterations In Gene Expression Of Calcium Handling Proteins In Patients With Chronic Atrial Fibrillation

Objective:To evaluate the molecular mechanisms involved in the atrial calcium homeostasis and calpains which occur in patients with atrial fibrillation(AF)and to investigate their effects on the initiation and maintenance of AF.Methods:The right atrial appendages were obtained from 16 patients with atrial fibrillation(cases)and from 12 matched controls with sinus rhythm.The mRNA expression of proteins including the calcium homeostasis and calpain1,calpain2,calpastatin was measured by semi-quantitative reverse transcription-polymerase chain reaction(RT-PCR)and normalized to the mRNA level of glyceraldehyde-3-phosphate dehydrogenase.Electron microscopy was applied to observe atrial muscle cell in tissue sample from fibrillating atria and normal atrium.The left atrial diameter(LAD),mitral valvular area(MVA)and systolic pulmonary arterial pressure were obtained by echocardiography before surgery.Results: Compared to sinus rhythm group,the mRNA levels of L-type calcium channel alc,sarcoplasmic reticulum(SR)calcium adenosine triphosphatase(Ca²⁺-ATPase)and ryanodine receptor type-2(R_YR₂)were significantly decreased(P＜0.01),the mRNA level of inositol triphosphate receptor type-1(IP₃R₁)was significantly increased(P＜0.05).No changes in the mRNA expression of phospholamban and calsequestrin were observed between cases and controls(P＞0.05).Correlations were found between MVA and mRNA levels of LVDCCalc,SR Ca²⁺-ATPase(r=0.719,P=0.003;r=0.625, P=0.013).The mRNA level of SR Ca²⁺-ATPase was negatively correlated with LAD (r=-0.573,P=0.032).The mRNA level of calpainl was significantly increased(P＜0.05). The mRNA level of LVDCCalc was negatively correlated with calpain1(r=-0.583, P=0.019).No changes in the mRNA expression of calpain2 and calpastatin were observed between cases and controls(P＞0.05).On electron microscopy,variation was apparent in the atrial ultramicrostructure.Conclusion:The mRNA levels of LVDCCalc,SRCa²⁺-ATPase and R_YR₂ were significantly decreased,the mRNA level of IP₃R₁ was significantly increased,suggesting that calcium loading may be responsible for the occurrence and maintenance of atrial fibrillation,abnormal regulation in the mRNA expression may be the molecular mechanism of intracellular Ca²⁺overload.The correlation between altered expression of Ca²⁺handling peotein and LAD,MVA suggests that the progressive nature of AF involves structural change.Calpains may influence cadiocyte structure and channel protein level and are related to both electrical remolding and structural change.