DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model

Abstract

Myotonic dystrophy (DM) is the most common form of muscular dystrophy and is caused by expansion of a CTG trinucleotide repeat on human chromosome 19. Patients with DM develop atrioventricular conduction disturbances, the principal cardiac manifestation of this disease. The etiology of the pathophysiological changes observed in DM has yet to be resolved. Haploinsufficiency of myotonic dystrophy protein kinase (DMPK), DM locus-associated homeodomain protein (DMAHP) and/or titration of RNA-binding proteins by expanded CUG sequences have been hypothesized to underlie the multi-system defects observed in DM. Using an in vivo murine electrophysiology study, we show that cardiac conduction is exquisitely sensitive to DMPK gene dosage. DMPK-/- mice develop cardiac conduction defects which include first-, second-, and third-degree atrioventricular (A-V) block. Our results demonstrate that the A-V node and the His-Purkinje regions of the conduction system are specifically compromised by DMPK loss. Importantly, DMPK+/- mice develop first-degree heart block, a conduction defect strikingly similar to that observed in DM patients. These results demonstrate that DMPK dosage is a critical element modulating cardiac conduction integrity and conclusively link haploinsufficiency of DMPK with cardiac disease in myotonic dystrophy.

Figure 1

PR intervals of DMPK-mutant and wild-type mice. (a) Scatter diagram of individual P–R intervals on resting electrocardiograms from mature homozygote DMPK^–/–, heterozygote DMPK^+/–, and wild-type DMPK^+/+ mice. The majority of adult mutant mice had a P–R interval > 35 ms, whereas the majority of wild-type mice had a P–R interval ≤ 35 ms. The mean P–R interval was significantly longer in both heterozygote and homozygote adult mice, compared with control mice (P < 0.05). (b) Mean (± standard deviation) P–R interval (in ms) from two distinct age groups of DMPK^–/–, DMPK^+/–, and DMPK^+/+ mice. There was no significant difference in mean P–R interval among the 1–2-month-old mice. The DMPK-deficient mice over 5 months old had a significantly prolonged mean P–R duration. WT, wild type.

Figure 2

Selected examples of ECG and intracardiac electrogram tracings from DMPK^–/– mice with varying degrees of atrioventricular (A–V) block. (a) First-degree A–V block. The P–R interval on ECG is prolonged to 47 ms, coincident with a long A–V interval on intracardiac recordings from right atrium and ventricle. (b) An example of Mobitz type I second-degree A–V block (Wenckebach phenomenon) in a DMPK^–/– mouse, with gradual P–R prolongation on surface ECG and A–V prolongation on intracardiac electrograms on each successive cycle until the atrial impulse is not conducted to the ventricle. (c) An example of third degree A–V block in a DMPK^–/– mouse, with complete dissociation of the P waves from the QRS complexes. (d) Representative composite telemetered ECG samples from 3 different mice during unrestrained, unanesthetized ambulation. (a) A control DMPK^+/+ mouse has an SCL of 102 ms and a P–R interval of 30 ms on the frontal ECG lead. (b) An example of a telemetered ECG from a DMPK^+/– mouse, with an SCL of 112 ms and a P–R interval of 40 ms. (c) A tracing from a DMPK^–/– mouse, with an SCL of 115 ms and a P–R interval of 43 ms. IEGM, intracardiac electrogram; RA, right atrium; RV, right ventricle; SCL, sinus cyle length.

Figure 3

Schematic mechanistic model of DMPK mouse A–V conduction abnormalities. The diagram illustrates the possible ionic and cellular interactions and effects of DMPK deficiency on the modulation of cardiac conduction.