Skyclarys helps to normalize heartbeat, stabilize rhythm: Study
Mouse work also found sex differences in heart activity, treatment response
Skyclarys (omaveloxolone) improves heart function in Friedreich’s ataxia (FA) by reducing abnormal heartbeats and stabilizing heart rhythm, a study in a mouse disease model of severe cardiomyopathy concluded.
Data also revealed sex-specific disturbance in the heart’s electrical activity and responses to Skyclarys treatment in these mice.
The study, “Poincaré plot analysis of electrocardiogram uncovers beneficial effects of omaveloxolone in a mouse model of Friedreich’s ataxia,” was published in the journal Heart Rhythm.
Hypertrophic cardiomyopathy can lead to irregular heartbeats with FA
Heart abnormalities are a common FA symptom, found in about three-quarters of all patients, and come with a severity that ranges from mild and asymptomatic to life-threatening. The most common heart-related change is hypertrophic cardiomyopathy, in which the muscles lining the heart become thick and enlarged. Over time, this can lead to irregular heartbeats, such as tachycardia (fast heart rate) or bradycardia (slow heart rate).
Skyclarys, an oral treatment approved to slow or prevent disease progression in people ages 16 and older, is designed to activate NrF2, a protein whose signaling is impaired in FA patients. In clinical trials, the therapy significantly improved scores on the modified Friedreich’s Ataxia Rating Scale (mFARS), a standard evaluation of FA progression.
Still, Skyclarys’ impact on the heart’s electrical activity, as assessed by an electrocardiogram or ECG, is unclear.
To address this, a team led by scientists at the University of California, Davis, performed ECG in mice, while under anesthesia, that were specifically bred to develop FA cardiomyopathy, with and without Skyclarys treatment.
ECG recordings from untreated FA mice showed extended R-R intervals, meaning the time between some heartbeats was longer than others, which was more common in males than females. Recordings also detected an abnormality in both sexes called the torsades de pointes. This dangerous type of tachycardia starts in the ventricles, the heart’s lower chambers, and is characterized by a prolonged QT interval, the time it takes the heart muscle to contract and recover.
Skyclarys’ use did not significantly affect the averaged ECG parameters. Still, in female FA mice, it shortened the PR interval, the time between the P wave, the electrical activity that starts in the atria in the heart’s upper chambers, and the QRS complex, representing the beginning of ventricular contraction and the heartbeat. In male mice, Skyclarys reduced the number of abnormal P-wave intervals, the time it takes for an electrical impulse to travel from the atria to the ventricles.
The therapy normalized most corrected QT intervals in male mice. However, two distinct peaks in QT intervals were observed in female mice. Treatment reduced the number of shorter than normal R-R intervals solely in males, and restored the so-called J wave, an ECG pattern found in mice but not humans.
“Altogether, these data indicate a significant sex-specific disturbance in ECG signals and sex-specific response to [Skyclarys] treatment in [FA] mice,” the scientists wrote.
Skyclarys use diminished heart rate variability in affected mice
Researchers then measured heart rate variability, the difference in time intervals between adjacent heartbeats, to assess autonomic nervous system activity, which governs involuntary processes like heart rate.
In untreated FA mice, two measures of heart rate variability significantly increased over time: the standard deviation of all normal R-R intervals and the square root of the mean squared between successive differences in R-R intervals. In contrast, these values were significantly reduced in mice given Skyclarys, “indicating its beneficial effect on heart rhythm stability,” the team noted.
Looking more closely, FA mice displayed a clustering of R-R intervals away from normal, toward tachycardia in male mice and bradycardia in female mice. Notably, Skyclarys prevented abnormal clustering in both sexes of FA mice.
“Our study revealed that [Skyclarys] treatment abolished disparate heart rhythms from occurring, restoring single oscillatory beats in individual [FA] mice,” the scientists concluded.
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