Development of cardiomyopathy and atrial tachyarrhythmias associated with activating autoantibodies to beta-adrenergic and muscarinic receptors

Abstract

A 71-year-old male with well-controlled hypertension developed atrial tachyarrhythmias in 2002 and a restrictive cardiomyopathy in 2006 to 2007. Sera from 1992, 2001, and 2006 to 2008 demonstrated activating autoantibodies against beta-adrenergic (AAbetaAR) and M2 muscarinic receptors (AAM2R). These sera have been characterized for bioactivity using in vitro assays of cardiac contractility and automaticity using a canine cardiac Purkinje fiber assay as well as protein kinase assay activation in H9c2 cells. These assays demonstrated concurrent positive betaAR and inhibitory M2R effects that were blocked by nadolol and atropine, respectively. In a canine pulmonary vein atrial sleeve preparation, sera diluted 1:100 produced atrial hyperpolarization that was blocked by atropine. Atrial tachyarrhythmias developed in 2002 in the presence of a persistent bradycardia. Serial echocardiograms demonstrated progressive diastolic dysfunction in the absence of cardiac hypertrophy between 2006 and 2007. A dual-chamber pacemaker was installed with combined betaAR (nadolol) and M2<3R (oxybutynin) blockade, resulting in marked suppression of atrial ectopy and improved diastolic function. The estimated pulmonary artery pressure decreased and exercise tolerance returned. Blood pressure has remained normal with beta-blockade. AAbetaAR and AAM2R prospectively influenced atrial and ventricular function in this patient, and specific receptor blockade was associated with improved cardiac function.

Figure 1

The ELISA titers for antibodies against β1AR, M2R, and CM in patient sera between 1992 and 2007. β1AR, β1-adrenergic receptor; CM, cardiac myosin; ELISA, enzyme-linked immunosorbent assay; M2R, M2 muscarinic receptor.

Figure 2

The effect of purified IgG from 2001 sera on canine Purkinje fiber contractility. Data are expressed as percent of basal buffer control (dashed line) (mean ± SD). IgG alone induced a positive inotropic response of isolated Purkinje fibers (*P < .005 vs. control IgG). IgG in the presence of ATR increased the contractile response (** P< .05 vs. IgG alone). The nonselective β-blocker NAD decreased the IgG-mediated contractile response (*P < .005 vs. IgG alone). Combined blockade with atropine and nadolol eliminated any change in contractility. The normal control IgG did not demonstrate any significant contractile response, either alone or in the presence of atropine, nadolol and their combination. The positive control, ISO (10 nmol/L), significantly increased Purkinje fiber contractility (*P < .001 vs. control IgG). ATR, atropine; IgG, immunoglobulin; ISO, isoproterenol; NAD, nadolol; SD, standard deviation.

Figure 3

The effect of the 2001 sera on Purkinje fiber automaticity. Each value represents the mean of 20 consecutive contractions and was measured after the preparation had stabilized. The data are expressed as the percentage of basal levels of the buffer control (dashed line; mean ± SD). This effect was similar to the contractility data. The presence of ATR significantly increased the rate (*P < .001 vs. sera alone), and this accelerated response again was completely eliminated by previous treatment with the nonselective β-blocker NAD. The positive control, ISO (10 nmol/L) significantly increased Purkinje fiber automaticity (**P < .01 vs. control sera). ATR, atropine; ISO, isoproterenol; NAD, nadolol; SD, standard deviation.

Figure 4

The effect of patient sera on PKA activation. Values are expressed as percent of basal levels of PKA in medium control (dashed line) in the H9c2 cardiac cells (mean ± SD, n = 3). (A) Comparison between sera from 1992, 2001, and 2007. The serum-induced PKA activation was increased in the presence of muscarinic blocker ATR (**P < .05 vs. sera alone). The PKA activity was returned toward baseline when the β-blocker NAD was added (*P < .005 vs. sera alone), indicating the concurrent presence of activating antibodies to βAR and M2R in the patient sera. Isoproterenol (ISO, 100 nmol/L) was used as a positive control to activate PKA (*P < .005 vs. control sera). (B) Comparison between the sera from 2008, taken after βAR and M2<3R blockade had been established, and IgG purified from the same sera, which did not contain the blocking agents. The serum and purified IgG both demonstrated residual βAR activity approximately 160% to 180% of basal levels. The serum containing the blocking agents failed to increase activity when atropine was added, suggesting that inherent βAR blockade was present. In the presence of atropine, the IgG preparation from the same serum had a robust increase in βAR activity (*P < .005 vs. IgG alone), strongly suggesting that the diluted sera still contained sufficient β-blocker to block the expected increase in βAR activity. The addition of nadolol to the in vitro assay suppressed this observed increase of βAR activity but only back to the level observed with serum or IgG alone. ATR, atropine; IgG, immunoglobulin; NAD, nadolol; PKA, protein kinase A; SD, standard deviation.

Figure 5

The effect of patient sera on atrial action potentials and production of EAD. Serum from the patient caused hyperpolarization and shortening of action potential duration, which was blocked by muscarinic blocker atropine, indicating the presence of cholinergic agonistic autoantibodies in the patient serum. The same serum also induced an EAD during rapid pacing. No EAD was present with treatment of control serum. EAD, early after depolarization.