Patients with the genetic heart disease catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) are advised against intensive exercise. The PhD thesis of Ravinea Manotheepan, however, indicates that some patients with CPVT1 might benefit from exercise.


MAIN RESULTS:

  1. Individualized exercise training increases fitness and threshold heart rate for ventricular arrhythmias in patients with CPVT1.
  2. Two weeks of high intensity interval training improves calcium handling in mice with the genetic mutation causing CPVT1.
  3. The arrhythmia in CPVT are dependent on adrenergic effect  and high heart rate, although adrenergic stimulation seems to be the essential factor for arrhythmia initiation.

THESIS DEFENCE:

Thesis: Arrhythmia-preventive effects of exercise training in catecholaminergic polymorphic ventricular tachycardia type 1. From experimental models to patients
Candidate: Ravinea Manotheepan
Time: May 28, 2018 at 13:15
Place: Oslo University Hospital, Ullevål: Kreftsenteret, Auditorium 1
Link to university website (in Norwegian)


SUMMARY:

CPVT1 is an inherited cardiac disorder in which patients have increased risk of stress-induced ventricular arrhythmias and sudden cardiac death.

(1) Three months of intensive aerobic exercise improved the heart rate threshold for ventricular arrhythmia in patients with CPVT1, compared to a group of patients who did not exercise. In total, 13 patients participated, and six of them exercised. Three months after the exercise period, the threshold for arrhythmia had returned to baseline levels.

The patients exercised under close supervision. Every session consisted of four intervals of six minutes each at an intensity of 80 to 90 % of the threshold heart rate for ventricular arrhythmia. The patients improved their aerobic capacity with 13 % following exercise.

(2) Exercised mice with the genetic mutation for CPVT1 had fewer episodes of ventricular tachycardia and improved cardiomyocyte calcium handling compared to sedentary mice. The exercise consisted of six weekly interval sessions at high intensity for two weeks.

The genetic mutation that causes CPVT1 results in abnormally increased leak of calcium though ryanodine receptors in the cardiomyocytes’ sarcoplasmic reticulum in diastole. Cardiomyocytes isolated from exercised mice were far less prone to calcium waves, calcium leaks and calcium sparks, compared to untrained cardiomyocytes. Furthermore, the improvements are probably caused by an exercise-induced reduction in the levels of oxidized CaMKII, preventing CaMKII-dependent phosphorylation of the ryanodin receptor.

(3) Patients with CPVT and a pacemaker exercised on a bicycle until the heart rate threshold for arrhythmia. When the heart frequency was increased by speeding up the pacemaker, the arrhythmia threshold was significantly higher than during exercise.

Also, the leak of calcium was much higher when cardiomyocytes from mice were electrically stimulated to contract with adrenaline present, compared to only electrical stimulation.


REFERENCES:

(1) Manotheepan, R., Saberniak, J., Danielsen, T. K., Edvardsen, T., Sjaastad, I., Haugaa, K. H., & Stokke, M. K. (2014). Effects of individualized exercise training in patients with catecholaminergic polymorphic ventricular tachycardia type 1American Journal of Cardiology113(11), 1829-1833.

(2) Manotheepan, R., Danielsen, T. K., Sadredini, M., Anderson, M. E., Carlson, C. R., Lehnart, S. E., Sjaastad, I. & Stokke, M. K. (2016). Exercise training prevents ventricular tachycardia in CPVT1 due to reduced CaMKII-dependent arrhythmogenic Ca2+ releaseCardiovascular research, cvw095.

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