Immunization against the beta1-adrenergic receptor second extracellular loop and transfer of these antibodies induced progressive severe left ventricular dilatation and dysfunction in rats.
Does an autoimmune attack directed against the cardiac β1-adrenergic receptor cause dilated cardiomyopathy in an animal model?
This study provides direct evidence that an autoimmune attack against the cardiac β1-adrenergic receptor can cause dilated cardiomyopathy, suggesting it should be categorized as an autoimmune disease.
p-value: p=<0.001
Today, dilated cardiomyopathy (DCM) represents the main cause of severe heart failure and disability in younger adults and thus is a challenge for public health.About 30% of DCM cases are genetic in origin; however, the large majority of cases are sporadic, and a viral or immune pathogenesis is suspected.Following the established postulates for pathogenesis of autoimmune diseases, here we provide direct evidence that an autoimmune attack directed against the cardiac 1 -adrenergic receptor may play a causal role in DCM.First, we immunized inbred rats against the second extracellular 1 -receptor loop ( 1 -EC II ; 100% sequence identity between human and rat) every month.All these rats developed first, receptorstimulating anti- 1 -EC II Ab's and then, after 9 months, progressive severe left ventricular dilatation and dysfunction.Second, we transferred sera from anti- 1 -EC II -positive and Ab-negative animals every month to healthy rats of the same strain.Strikingly, all anti- 1 -EC II -transferred rats also developed a similar cardiomyopathic phenotype within a similar time frame, underlining the pathogenic potential of these receptor Ab's.As a consequence, 1 -adrenergic receptor-targeted autoimmune DCM should now be categorized with other known receptor Ab-mediated autoimmune diseases, such as Graves disease or myasthenia gravis.Although carried out in an experimental animal model, our findings should further encourage the development of therapeutic strategies that combat harmful anti- 1 -EC II in receptor Ab-positive DCM patients.Nonstandard abbreviations used: 1-adrenergic receptor (1-AR); 1-AR second extracellular receptor loop (1-ECII); body weight (BW); cAMP-dependent protein kinase (PKA); cardiac output (CO); dilated cardiomyopathy (DCM); glutathione-Stransferase (GST); human embryonal kidney (HEK); immunofluorescence microscopy (IFM); 125 I-labeled cyanopindolol ( 125 I-CYP); isobutylmethylxanthine (IBMX); left ventricular (LV); LV end-diastolic diameter (LVED); LV end-diastolic pressure (LVEDP); LV area (LVA); LV cavity area (LVCA); LV wall area (LVWA); peak change in LV pressure per time (interval) (dp/dtmax); velocity-time integral (VTI).
Jahns et al. (Sat,) conducted a other in Idiopathic dilated cardiomyopathy (n=61). beta1-ECII immunization and antibody transfer vs. GST or NaCl was evaluated on Left ventricular dilatation and dysfunction (p=<0.001). Immunization against the beta1-adrenergic receptor second extracellular loop and transfer of these antibodies induced progressive severe left ventricular dilatation and dysfunction in rats.