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EXPERIMENTAL STUDY

Relationship of myocardial remodeling to the genesis of serum autoantibodies to cardiac beta₁-adrenoceptors and muscarinic type 2 acetylcholine receptors in rats

Hui-Rong Liu, MD, PhD^*, Rong-Rui Zhao, MD, PhD^*, Xiang-Ying Jiao, MD, PhD^*, Ying-Yuan Wang, MD, PhD^* and Michael Fu, MD, PhD^,*

^* Laboratory of Cardiovascular Physiology, Shanxi Medical University, Taiyuan, China
Wallenberg Laboratory, Sahlgrenska University Hospital, Göteborg, Sweden

Manuscript received May 18, 2001; revised manuscript received February 13, 2002, accepted February 28, 2002.

^* Reprint requests and correspondence: Prof. Rong-Rui Zhao, Lab of Cardiovascular Physiology, Shanxi Medical University, Taiyuan, China.

OBJECTIVES: We sought to investigate the mechanism responsible for the occurrence of anticardiac receptor autoantibodies.

BACKGROUND: Increasing evidence suggests the involvement of autoimmune mechanisms in the pathogenesis of a number of cardiovascular diseases. Among them, the biologic, functional and pathogenic properties of anticardiac receptor antibodies have been extensively investigated. However, the mechanism responsible for the occurrence of anticardiac receptor autoantibodies remains poorly understood.

METHODS: Two rat models (aortic banding [AB] and adriamycin [ADR] groups) were constructed. Determination of cardiac function and morphology and T-lymphocyte subtypes, enzyme-linked immunosorbent assay and cardiomyocyte cultures were performed.

RESULTS: It was shown, in the AB and ADR groups, that the frequency and titer of autoantibodies to beta₁ and muscarinic type 2 receptors were increased when myocardial remodeling occurred, as evidenced by significant cardiac morphologic changes, deposition of collagen and obvious functional impairment. This suggests that cardiac remodeling itself, in two disparate models of heart failure and cardiomyopathy, was able to trigger the genesis of anticardiac receptor autoantibodies. These autoantibodies have biologic effects similar to those seen in human autoantibodies. They have also shown a characteristic self-growth, as well as a time-course decline, suggesting that a negative finding of anticardiac receptor autoantibodies in sera of patients with heart disease does not necessarily imply that there is no autoimmune reaction involved in the pathogenesis.

CONCLUSIONS: Our results demonstrated that myocardial damage was able to trigger the occurrence of an autoimmune reaction, resulting in the genesis of anticardiac receptor autoantibodies with properties similar to those seen in patients with idiopathic dilated cardiomyopathy.

Abbreviations and Acronyms   AB   aortic banding   ADR   adriamycin   Bmax   maximal number of receptor binding sites   CD4+/CD8+   ratio of helper to suppressor peripheral blood T lymphocytes   CVF   collagen volume fraction   DCM   dilated cardiomyopathy   ±dP/dtmax   maximal rate of rise and/or decline in left ventricular pressure   ELISA   enzyme-linked immunosorbent assay   FITC   fluorescein isothiocyanate   LV   left ventricle/ventricular   Kd   dissociation constant   M2   muscarinic type 2

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