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The pathogenesis of atrial fibrillation (AF) and underlying mechanisms remain poorly understood. It is well known that a deficit in the mitochondrial energy metabolism can contribute to the progression of the substrate for AF. During AF the activity of the res-piratory chain alters and the myocardial oxygen extraction increases, resulting in a state of relative hypoxia. Cytochrome c oxidase (EC 220.127.116.11., CytOx), representing complex IV of the respiratory chain, catalyzes the rate-limiting step in the electron transfer to Dioxygen. Therein, subunit 4 of the enzyme is the key regulatory subunit and funda-mentally required for the enzymatic activity. Accordingly, it has control function for the entire process of oxidative phosphorylation. Expression of isoform 4.2 is dependent on cellular oxygen content and optimizes the efficiency of respiration at low oxygen levels. This study is to address the mRNA expression of subunit 4 isoforms of the cytochrome c oxidase in case of AF.
Examining a HeLa-cell-line cell culture under normoxia and conditions of oxygen depri-vation, an increase in the expression of isoform 4.2 became apparent.
Myocardial biopsies of the right atrium were taken from 42 cardiac surgery patients. 11 patients suffered from permanent AF, whereas 31 patients with sinus rhythm represent-ed the control group. The mRNA expressions of isoforms 4.1 and 4.2 of the cytochrome c oxidase were quantified. In order to evaluate hypoxic response, mRNA expressions of HIF-1α and VEGF-B were examined.
The evaluation of cytochrome c oxidase isoform 4.2/4.1 ratio revealed an elevated iso-form 4.2 expression accompanied by a decrease of the expression of isoform 4.1 in the patient group with permanent AF. Due to the known mitochondrial dysfunction, pa-tients with diabetes mellitus were not considered. In this study the elevation of the ex-pression of isoform 4.2 appeared independently of the severity of coronary artery dis-ease. The suggestion is made that statin therapy and the consequential change in lipid metabolism lead to an altered isoform 4.2 expression. Supposedly, an increased isoform 4.2 expression is accompanied by an extended left atrial diameter in AF.
In conclusion, alterations in CytOx subunit 4 isoform expression during relative hypoxia in myocardial tissue (increase of VEGF-B expression) may serve as a compensatory mechanism. The increase of isoform 4.2 within cytochrome c oxidase results in an opti-mized efficiency of the energy metabolism and a limitation of ROS production. All in all, the switch of isoform expression pattern may represent a reparatory and/or regenera-tory mechanism during AF.