Abstract
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. 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. 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). During delivery of steady rate pacing across a range of cycle lengths, the QT-RR relationship was not statistically different between HCM and control groups; no differences were seen in subgroup analysis of patients with or without intact AV node conduction. Similarly, there was no difference between groups in the QT interval of the first post-pause recovery beat after pacing trains. No statistically significant differences were seen in surrogate measures for cardiac contractility. 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.
Highlights
Patients with familial hypertrophic cardiomyopathy (HCM) are at risk of sudden cardiac death from malignant ventricular arrhythmias [1]
This may be a direct effect of the HCM-causing mutation, increased myofilament calcium sensitivity may act independent of the underlying HCM mutation, secondary to reduced phosphorylation of myofilament proteins such as protein kinase A targets [4]
We sought for the first time to systematically, non-invasively compare dynamic cardiac contractility and repolarization of patients with HCM to that of age-matched controls using a pacing protocol designed to test the effect of increasing pacing rates and pauses
Summary
Patients with familial hypertrophic cardiomyopathy (HCM) are at risk of sudden cardiac death from malignant ventricular arrhythmias [1]. There has been an increasing appreciation for the role of myofilament calcium sensitization in human HCM. Some data suggests this may be a mutation-independent mechanism that alters length-dependent sarcomere activation and effects contractility [4]. Preclinical mouse models demonstrate increased intracellular calcium buffering producing cardiomyocyte calcium loading during rapid pacing, increased calcium transients following pauses, and subsequent prolongation of the action potential duration, early afterdepolarizations and triggered beats [5]. Increased cytosolic calcium buffering with subsequent alterations in calcium homeostasis and action potentials were found in human cardiomyocytes derived from induced pluripotent stem cells carrying a pathogenic HCM mutation in troponin T [6]. The current pilot study sought to explore whether clinical surrogates of contractility and repolarization are altered in humans with HCM in a manner that is concordant with the growing preclinical understanding
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