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179 PATHOPHYSIOLOGIC ROLE OF M2 MUSCARINIC RECEPTOR AUTOANTIBODIES IN PATIENTS WITH DIABETIC CARDIOMYOPATHY.
  1. S. Stavrakis1,
  2. X. Yu1,
  3. S. Huang1,
  4. A. Baba1,
  5. B. Szabo1,
  6. M. W. Cunningham1,
  7. D. C. Kem1
  1. 1University of Oklahoma College of Medicine and VAMC, Oklahoma City, OK; Kitasato Institute Hospital, Tokyo, Japan.

Abstract

Background Activating autoantibodies to the M2 muscarinic (AAM2) and to the β-adrenergic receptors (AAβARs) have been described in patients with idiopathic dilated cardiomyopathy, ischemic cardiomyopathy, and hypertensive heart disease.

Methods We identified three patients with diabetic cardiomyopathy (DBCM) complicated with hypertension and examined their sera for pathophysiologic evidence of AAM2 and/or AAβAR. The chronotropic and inotropic effects of IgG from these patients were studied in an isolated perfused canine Purkinje fiber preparation. We measured the amplitude of stimulated contractions at 2 kHz and the rate of spontaneous contractions during perfusion with buffer containing either control or purified IgG from these patients. Isoproterenol (ISO) was used as a positive control.

Results Patient 1, with poorly controlled type 1 diabetes, was diagnosed in 2000 with DBCM. Sera from 2000 and 2006 were positive at ELISA titers of 1:12,800 and 1:3,200, respectively, against β1/2AR. Serum from 2006 was positive by ELISA for AAM2 at a titer of 1:160 (p < .05 vs control). The 2006 serum demonstrated a significant increase in the amplitude of stimulated contractions (114% vs baseline, p < .05) by 2 minutes, followed by a prominent decrease, which was then maintained at a steady state (74% vs baseline, p < .05). The rate of spontaneous contractions decreased to 73% at steady state (p < .05). Patients' 2 and 3 sera were positive at ELISA titers of 1:3,200 against β1/2AR. Patient 2's serum showed a biphasic amplitude response (rise = 120% and nadir = 76%, p < .05) and a steady decline in rate (83% vs baseline, p < .05). Patient 3's serum, which was also positive for AAM2 at a titer of >1:3,200 (p < .05 vs control), demonstrated a steady decrease in amplitude of 84% (p < .05) and a variable response in rate, with an initial rise to 112% (p < .05) and subsequent decrease to 73% versus baseline (p < .05). IgG compromised but did not abolish the positive chronotropic and inotropic effects of ISO.

Conclusions We have demonstrated that AAM2 in the diabetic patient is capable of suppressing the positive inotropic and chronotropic effect of AAβAR in isolated Purkinje fibers. These studies are time and patient dependent. They raise the issue that the cumulative effects of increased intrinsic activation of the βAR and the M2 receptors can increase the substrate for generation of tachyarrhythmias in a population with poorly controlled diabetes mellitus.

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