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Chronic methamphetamine use, a widespread drug epidemic, has been
associated with cardiac morphological and electrical remodeling, leading
to the development of numerous cardiovascular diseases. While
methamphetamine has been documented to induce arrhythmia, most results
originate from clinical trials from users who experienced different
durations of methamphetamine abuse, providing no documentation on the use
of methamphetamine in standardized settings. Additionally, the underlying
molecular mechanism on how methamphetamine affects the cardiovascular
system remains elusive. A relationship was sought between cardiotoxicity
and arrhythmia with associated methamphetamine abuse in zebrafish to
identify and to understand the adverse cardiac symptoms associated with
methamphetamine. Zebrafish were first treated with methamphetamine 3 times
a week over a 2-week duration. Immediately after treatment, zebrafish
underwent electrocardiogram (ECG) measurement using an in-house developed
acquisition system for electrophysiological analysis. Subsequent analyses
of cAMP expression and Ca2+ regulation in zebrafish cardiomyocytes were
conducted. cAMP is vital to development of myocardial fibrosis and
arrhythmia, prominent symptoms in the development of cardiovascular
diseases. Ca2+ dysregulation is also a factor in inducing arrhythmias.
During the first week of treatment, zebrafish that were administered with
methamphetamine displayed a decrease in heart rate, which persisted
throughout the second week and remained significantly lower than the heart
rate of untreated fish. Results also indicate an increased heart rate
variability during the early stage of treatment followed by a decrease in
the late stage for methamphetamine-treated fish over the duration of the
experiment, suggesting a biphasic response to methamphetamine exposure.
Methamphetamine-treated fish also exhibited reduced QTc intervals
throughout the experiment. Results from the cAMP and Ca2+ assays
demonstrate that cAMP was upregulated and Ca2+ was dysregulated in
response to methamphetamine treatment. Collagenic assays indicated
significant fibrotic response to methamphetamine treatment. These results
provide potential insight into the role of methamphetamine in the
development of fibrosis and arrhythmia due to downstream effectors of
cAMP.
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