Also: Amyotrophic Lateral Sclerosis & Gait in Mice in JNER.
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Dystrophin-deficiency cardiac phenotype
Victor Chu**, Ajit Kale*, Peter Mueller, Ivo Amende, and
Thomas G. Hampton. Mouse Specifics, Inc., **Beth Israel Deaconess Medical Center, and *The CuraVita Corporation, Boston, MA.
Note: this report includes data from Muscle & Nerve 26(4):513-519, 20021 , supported in part by NHLBI Program for Genomic Applications HL066582 (Genomics of Cardiovascular Development, Adaptation, and Remodeling) to V. Chu.
Web published: October/November, 2002*
* Due to large volume of web-traffic to this feature, it has been extended through November.
Abstract
The muscular dystrophies are associated with autonomic nervous disorders that may contribute to the sequelae of cardiac disorders common in patients. We tested whether dystrophin-deficient mice (mdx), a mouse model of Duchenne muscular dystrophy (DMD), exhibit electrocardiographic disturbances consistent with observations in patients with DMD. Since dystrophin-deficiency may be associated with reductions in neuronal nitric oxide synthase (nNOS), we also recorded ECGs in nNOS-deficient mice (nNOS-/-) to see how closely they resemble observations in mdx mice. Results indicate autonomic nervous disturbances in dystrophin-deficient mice that reflect those seen in DMD patients, but do not appear to be linked with nNOS deficiency.
Methods
Figure 1.
Adult male mdx mice (n=15), nNOS-/- mice (n=7), and their appropriate controls (C57BL/10ScSn [C57, n=15] and B6129SF2/J [B6129, n=6]), were obtained from The Jackson Laboratory. The AnonyMOUSETM ECG screening system was used to record ECGs.2 No surgery was required. Data were acquired at 2kHz for at least 2 seconds to provide equivalent continuous recordings of 20 to 30 beats. e-MOUSETM was used to interpret the signals.2 Time domain indices of HRV were calculated as described previously.3
Results
Heart rate was nearly 15% faster in mdx mice than in C57 controls (P<0.05). HRV and CV were significantly lower in mdx mice than in C57 mice ((P<0.05). nNOS deficiency resulted in neither elevated heart rates nor reduced heart rate variability compared to B6129 controls. In fact, there was a trend for higher HR, lower HRV, and lower CV in the B6129 control mice compared to nNOS-/- mice. As a result, HR was significantly higher and heart rate variability indices significantly lower in dystrophin-deficient mice in comparison to nNOS-deficient mice (P<0.05), although AV conduction times were equivalent (see Table 1).
Table 1. ECG indices in mdx and nNOS -/- mice.
mdx (n=15)
nNOS-/- (n=7)
P value
HR (bpm)
809 ± 5
686 ± 22
0.05
HRV (bpm)
6 ± 1
18 ± 2
0.05
CV (%)
0.7 ± 0.1
2.7 ± 0.8
0.05
QRS (ms)
27.2 ± 0.4
27.7 ± 0.4
NS
Values are Means ± SEM.
Discussion
mdx mice demonstrated marked tachycardia and decreased heart rate variability, findings also present in patients with Duchenne muscular dystrophy.4,5 Although the mdx mouse was first described in 1984,6 the electrocardiographic phenotype may have been unreported because of the confounding effects of anesthesia or in vitro preparations used in previous studies of mdx cardiac properties. Others have documented a link between loss of myocardial dystrophin and loss of nNOS activity.7 However, nNOS deficiency results in neither elevated heart rates nor reduced heart rate variability compared to B6129 controls. Moreover, HR was significantly lower and HRV indices were significantly greater in nNOS-/- mice compared to mdx mice. This suggests that decreased myocardial nNOS per se does not alone account for the heightened sympathetic tone and reduced parasympathetic tone reflected in the mdx baseline ECG. To what extent chronic tachycardia and aberrant autonomic tone contribute to the sequelae of cardiac failure in young men with DMD remains to be determined. Electrocardiographic monitoring and interventions that correct autonomic tone may be beneficial.
References
Chu, V. et al. 2002. Muscle and Nerve, 26:513-519.
Chu, V. et al. 2001. BMC Physiology 1:6.
Germann, J. et al. 2000. Am. J. Physiol. 279:H733-H740.
Maruyama, T. et al.1995. Jpn. Heart J. 36:741-750.
Yotsukura, M. et al. 1998. Am. Heart J. 136:289-296.
Bulfield, G. et al. 1984. Proc. Nat. Acad. Sci. U.S.A. 81:1189-1192.
Bia, B.L. et al. 1999. J. Mol. Cell Cardiol. 31:1857-1862.
