Human cardiac myosin autoantibodies impair myocyte contractility: a cause-and-effect relationship.
The functional relevance of autoantibodies (Abs) against cardiac myosin (CM) in clinical idiopathic dilated cardiomyopathy (DCM) remains controversial. The study sought to determine effects of human Abs affinity-purified (AF) by immunoaffinity column chromotography on excitation-contraction coupling in isolated myocytes. Effects of CM-Abs from heart failure patients with DCM (n=19) and ischemic heart disease (IHD, n=19) on contractility, L-type Ca2+ current, and Ca2+ transients in continuously perfused rat ventricular myocytes were studied. Immunofluorescence studies using confocal microscopy were carried out to determine whether Abs were internalized. AF-Abs from either group did not differ in IgG titer but differed in their elution profiles. The IgG3 subclass response was higher in AF fractions from DCM (21%) than IHD (5%) patients. The Abs reduced the capacity of field-stimulated myocytes to contract in a dose-dependent manner. Inhibition of contraction, as a percentage of untreated cells, was greater with DCM than IHD-Abs (P=0.004), and the effect was independent of Ab titer. An increase in frequency of the beating myocytes (0.2 to 3.0 Hz) raised peak systolic and diastolic levels of [Ca2+]i of cells treated with DCM but not IHD-Abs (P<0.005). The AF-Abs were not internalized by myocytes and had no effect on L-type Ca2+ currents. The altered sensitivity of the myofilaments to [Ca2+]i by CM-Abs may represent a potential mechanism of autoantibody-mediated impairment in clinical DCM.
Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College School of Medicine, Royal Brompton and Harefield Trust, Harefield Hospital, Middlesex, UK. rwarraich@lycos.com
Rahat S
RS
Warraich
Elinor
E
Griffiths
Andrew
A
Falconar
Vijay
V
Pabbathi
Chris
C
Bell
Gianni
G
Angelini
M-Saadeh
MS
Suleiman
Magdi H
MH
Yacoub
D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D024722:Cardiac Myosins / Q000276:immunology*; D002311:Cardiomyopathy, Dilated / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000276:immunology; D051381:Rats
D001323:Autoantibodies; D024722:Cardiac Myosins; D002118:Calcium