We developed a technology for heart rate (HR) variability (HRV) analysis in the mouse for characterization of HR dynamics, modulated by vagal and sympathetic activity. The mouse is the principal animal model for studying biological processes. Mouse strains are now available harboring gene mutations providing fundamental insights into molecular mechanisms underlying cardiac electrical diseases. Future progress depends on enhanced understanding of these fundamental mechanisms and the implementation of methods for the functional analysis of mouse cardiovascular physiology. By telemetric techniques, standard time and frequency-domain measures of HRV were computed with and without autonomic blockade, and baroreflex sensitivity testing was performed. HR modulation in the high-frequency component is predominantly mediated by the parasympathetic nervous system, whereas the low-frequency component is under the influence of both the parasympathetic and sympathetic systems. The presented technology and protocol allow for assessment of autonomic regulation of the murine HR. Phenotypic screening for HR regulation in mice will further enhance the value of the mouse as a model of heritable electrophysiological human disease.

Activation of I(KACh) predisposed to AF and lack of I(KACh) prevented AF. It is likely that I(KACh) plays a crucial role in the generation of AF in mice. Specific I(KACh) blockers might be useful for the treatment of AF without significant adverse effects on the atrioventricular node or the ventricles.

The disorders of skeletal muscle and cardiac function observed in myotonic dystrophy (DM) occur as a consequence of a CTG repeat expansion (1, 2) located in the 3′ untranslated region of a protein kinase, myotonic dystrophy protein kinase (DMPK; 3, 4), on chromosome 19q13.3. The molecular mechanisms by which expanded CTG sequences produce DM pathophysiology remain unresolved, though three models prevail. First, partial loss of DMPK resulting as a consequence of nuclear retention of the mutant DMPK mRNA may contribute to DM (5-8). Second, decreased transcription of a neighboring homeodomain-encoding gene, DMAHP, occurring possibly due to altered chromatin structure near the CTG expansion, may play a role in DM (9, 10). Lastly, transdominant effects associated with expression of expanded CUG repeats and modulation of splicesite recognition may contribute to DM pathology (11-13).The primary clinical cardiac manifestation in DM is the development of conduction disturbances, with progressive atrioventricular (A-V) block and bradycardia. Prolonged A-V conduction (first-degree A-V block) is common, and higher-grade A-V block is a significant cause of death (14-17). The His-Purkinje system may also be affected, with bundle branch block and intraventricular conduction delay (18,19).To test the hypothesis that partial DMPK loss contributes to DM pathology, we developed a mouse strain lacking functional DMPK (DMPK -/-). We have shown that DMPK -/-mice develop late-onset skeletal myopathy as a consequence of abnormal excitation/contraction coupling (20). In this study we demonstrate that DMPK dosage modulates cardiac conduction. On electrocardiogram (ECG), a prolonged P-R interval (first-degree A-V block) was present in adult DMPK -/-mice compared to wild-type controls. Electrophysiological evaluation of DMPK -/-mice demonstrated more serious conduction disturbances including second and third-degree A-V block. Adult DMPK +/-mice also exhibited firstdegree A-V block similar to DMPK -/-mice. Thus, heterozygous animals have a quantifiable cardiac phenotype reminiscent of DM patients. Our results show that DMPK gene disruption causes A-V conduction abnormalities in both homozygous and heterozygous DMPK-deficient mice, and support loss of DMPK as playing a dominant role in the characteristic DM cardiac phenotype. MethodsAnimal care. A total of 27 male and 20 female adult 129/BS strain mice were studied. The mean age was 63.9 ± 21 weeks, with no differences between genotypes. The average weight was 37.7 ± 9 grams. Another 18 young mice were studied to assess age-related alterations in conduction properties. Death occurred in 6 animals due to procedural complications. Mice were housed in a diurnal facility, in compliance with the American Association for the Accreditation of Laboratory Animal Care and each center's Institutional Animal Care and Use Committee. Mice were anesthetized with intraperitoneal ketamine hydrochloride and pentobarbital (0.033 mg/gm each). Myotonic dystrophy (DM) is the most common form of muscular dystrophy...