Human cardiac myosin autoantibodies impair myocyte contractility: a cause-and-effect relationship Rahat S. Warraich * ,1 , Elinor Griffiths † , Andrew Falconar ‡ , Vijay Pabbathi † , Chris Bell † , Gianni Angelini † , M.-Saadeh Suleiman † and Magdi H. Yacoub * * Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College School of Medicine, Royal Brompton and Harefield Trust, Harefield Hospital, Middlesex, UK; † Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, England UK; and ‡ London School of Hygiene and Tropical Medicine, London, UK 1 Correspondence: Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College School of Medicine, Royal Brompton and Harefield Trust, Harefield Hospital, Middlesex UB9 6JH, UK. E-mail: rwarraich@lycos.com 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 Ca 2+ current, and Ca 2+ 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 Ca 2+ 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 Ca 2+ currents. The altered sensitivity of the myofilaments to Ca 2+ i by CM-Abs may represent a potential mechanism of autoantibody-mediated impairment in clinical DCM.—Warraich, R. S., Griffiths, E., Falconar, A., Pabbathi, V., Bell, C., Angelini, G., Suleiman, M.-S., Yacoub, M. H. Human cardiac myosin autoantibodies impair myocyte contractility: a cause-and-effect relationship. Key Words: dilated cardiomyopathy • antimyosin autoantibodies • myocyte contractility
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Human cardiac myosin autoantibodies impair myocyte contractility: a cause-and-effect relationship
Warraich, Rahat S.; Griffiths, Elinor; Falconar, Andrew; Pabbathi, Vijay; Bell, Chris; Angelini, Gianni; Suleiman, M.-Saadeh; Yacoub, Magdi H.
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, Volume 20 (6): 651
Fed of American Socs for Experimental Biology – Apr 1, 2006
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