Repolarization and contractility in hypertrophic cardiomyopathy patients

Aims: Arrhythmia mechanisms in hypertrophic cardiomyopathy remain
uncertain. Preclinical models suggest hypertrophic cardiomyopathy-linked
mutations perturb sarcomere length-dependent activation, alter cardiac
repolarization in rate-dependent fashion and potentiate triggered
electrical activity. This study was designed to assess rate-dependence of
clinical surrogates of contractility and repolarization in humans with
hypertrophic cardiomyopathy. Methods: All participants had a cardiac
implantable device capable of atrial pacing. Cases had clinical diagnosis
of hypertrophic cardiomyopathy, controls were age-matched. Continuous
electrocardiogram and blood pressure were recorded during and immediately
after 30 second pacing trains delivered at increasing rates. Results: Nine
hypertrophic cardiomyopathy patients and 10 controls were enrolled (47%
female, median 55 years), with similar baseline QRS duration, QT interval
and blood pressure. Median septal thickness in hypertrophic cardiomyopathy
patients was 18mm; 33% of hypertrophic cardiomyopathy patients had peak
sub-aortic velocity >50mmHg. Ventricular ectopy occurred during or
immediately after pacing trains in 4/9 hypertrophic cardiomyopathy
patients and 0/10 controls (P=0.03). At faster drive trains, hypertrophic
cardiomyopathy patients showed a non-significant trend towards a shallower
QT-RR slope than controls. After normalization to the preceding pacing
train QT interval, the normalized QT interval of the first post-pause
recovery beat after pacing trains was similar between cohorts. No
statistically significant differences were seen in surrogate measures for
cardiac contractility. Conclusion: Rapid pacing trains triggered
ventricular ectopy in hypertrophic cardiomyopathy patients, but not
controls. This finding aligns with pre-clinical descriptions of excessive
cardiomyocyte calcium loading during rapid pacing, increased post-pause
sarcoplasmic reticulum calcium release, and subsequent calcium-triggered
activity. Normal contractility at all diastolic intervals argues against
clinical significance of altered length-dependent myofilament activation.