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  • 1.
    Dahlberg, Pia
    et al.
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Region Vaestra Goetaland, Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Axelsson, Karl-Jonas
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Region Vaestra Goetaland, Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lundahl, Gunilla
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Gransberg, Lennart
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Bergfeldt, Lennart
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Region Vaestra Goetaland, Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Spatiotemporal repolarization dispersion before and after exercise in patients with long QT syndrome type 1 versus controls: probing into the arrhythmia substrate2023In: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 325, no 6, p. H1279-H1289Article in journal (Refereed)
    Abstract [en]

    Congenital long QT syndrome (LQTS) carries an increased risk for syncope and sudden death. QT prolongation promotes ventricular extrasystoles, which, in the presence of an arrhythmia substrate, might trigger ventricular tachycardia degenerating into fibrillation. Increased electrical heterogeneity (dispersion) is the suggested arrhythmia substrate in LQTS. In the most common subtype LQT1, physical exercise predisposes for arrhythmia and spatiotemporal dispersion was therefore studied in this context. Thirty-seven patients (57% on β-blockers) and 37 healthy controls (mean age, 31 vs. 35; range, 6-68 vs. 6-72 yr) performed an exercise test. Frank vectorcardiography was used to assess spatiotemporal dispersion as Tampl, Tarea, the ventricular gradient (VG), and the Tpeak-end interval from 10-s signal averages before and 7 ± 2 min after exercise; during exercise too much signal disturbance excluded analysis. Baseline and maximum heart rates as well as estimated exercise intensity were similar, but heart rate recovery was slower in patients. At baseline, QT and heart rate-corrected QT (QTcB) were significantly longer in patients (as expected), whereas dispersion parameters were numerically larger in controls. After exercise, QTpeakcB and Tpeak-endcB increased significantly more in patients (18 ± 23 vs. 7 ± 10 ms and 12 ± 17 vs. 2 ± 6 ms; P < 0.001 and P < 0.01). There was, however, no difference in the change in Tampl, Tarea, and VG between groups. In conclusion, although temporal dispersion of repolarization increased significantly more after exercise in patients with LQT1, there were no signs of exercise-induced increase in global dispersion of action potential duration and morphology. The arrhythmia substrate/mechanism in LQT1 warrants further study.

    NEW & NOTEWORTHY: Physical activity increases the risk for life-threatening arrhythmias in LQTS type 1 (LQT1). The arrhythmia substrate is presumably altered electrical heterogeneity (a.k.a. dispersion). Spatiotemporal dispersion parameters were therefore compared before and after exercise in patients versus healthy controls using Frank vectorcardiography, a novelty. Physical exercise prolonged the time between the earliest and latest complete repolarization in patients versus controls, but did not increase parameters reflecting global dispersion of action potential duration and morphology, another novelty.

  • 2.
    Winbo, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Department of Physiology, University of Auckland, Auckland, New Zealand; Manaaki Manawa Centre for Heart Research, University of Auckland, Auckland, New Zealand; Department of Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand; Cardiac Inherited Disease Group (CIDG), Auckland, New Zealand.
    Ramanan, Suganeya
    Eugster, Emily
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jovinge, Stefan
    Skinner, Jonathan R.
    Montgomery, Johanna M.
    Functional hyperactivity in long OT syndrome type 1 pluripotent stem cell-derived sympathetic neurons2021In: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 321, no 1, p. H217-H227Article in journal (Refereed)
    Abstract [en]

    Sympathetic activation is an established trigger of life-threatening cardiac events in long QT syndrome type 1 (LQT1). KCNQ1 loss-of-function variants, which underlie LQT1, have been associated with both cardiac arrhythmia and neuronal hyperactivity pathologies. However, the LQT1 sympathetic neuronal phenotype is unknown. Here, we aimed to study human induced pluripotent stem cell (hiPSC)-derived sympathetic neurons (SNs) to evaluate neuronal functional phenotype in LQT1. We generated hiPSC-SNs from two patients with LQT1 with a history of sympathetically triggered arrhythmia and KCNQ1 loss-of-function genotypes (c.781_782delinsTC and p.S349W/p.R518X). Characterization of hiPSC-SNs was performed using immunohistochemistry, enzyme-linked immunosorbent assay, and whole cell patch clamp electrophysiology, and functional LQT1 hiPSC-SN phenotypes compared with healthy control (WT) hiPSC-SNs. hiPSC-SNs stained positive for tyrosine hydroxylase, peripherin, KCNQ1, and secreted norepinephrine. hiPSC-SNs at 60 +/- 2.2 days in vitro had healthy resting membrane potentials (-60 +/- 1.3 mV), and fired rapid action potentials with mature kinetics in response to stimulation. Significant hyperactivity in LQT1 hiPSC-SNs was evident via increased norepinephrine release, increased spontaneous action potential frequency, increased total inward current density, and reduced afterhyperpolarization, compared with age-matched WT hiPSC-SNs. A significantly higher action potential frequency upon current injection and larger synaptic current amplitudes in compound heterozygous p.S349W/p.R518X hiPSC-SNs compared with heterozygous c.781_782delinsTC hiPSC-SNs was also observed, suggesting a potential genotype-phenotype correlation. Together, our data reveal increased neurotransmission and excitability in heterozygous and compound heterozygous patient-derived LQT1 sympathetic neurons, suggesting that the cellular arrhythmogenic potential in LQT1 is not restricted to cardiomyocytes. NEW & NOTEWORTHY Here, we present the first study of patient-derived LQT1 sympathetic neurons that are norepinephrine secreting, and electrophysiologically functional, in vitro. Our data reveal a novel LQT1 sympathetic neuronal phenotype of increased neurotransmission and excitability. The identified sympathetic neuronal hyperactivity phenotype is of particular relevance as it could contribute to the mechanisms underlying sympathetically triggered arrhythmia in LQT1.

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