Arrhythmogenic mechanisms in the isolated perfused hypokalaemic murine heart.
OBJECTIVE
Hypokalaemia is associated with a lethal form of ventricular tachycardia (VT), torsade de pointes, through pathophysiological mechanisms requiring clarification.


METHODS
Left ventricular endocardial and epicardial monophasic action potentials were compared in isolated mouse hearts paced from the right ventricular epicardium perfused with hypokalaemic (3 and 4 mm [K(+)](o)) solutions. Corresponding K(+) currents were compared in whole-cell patch-clamped epicardial and endocardial myocytes.


RESULTS
Hypokalaemia prolonged epicardial action potential durations (APD) from mean APD(90)s of 37.2 +/- 1.7 ms (n = 7) to 58.4 +/- 4.1 ms (n =7) and 66.7 +/- 2.1 ms (n = 11) at 5.2, 4 and 3 mm [K(+)](o) respectively. Endocardial APD(90)s correspondingly increased from 51.6 +/- 1.9 ms (n = 7) to 62.8 +/- 2.8 ms (n = 7) and 62.9 +/- 5.9 ms (n = 11) giving reductions in endocardial-epicardial differences, DeltaAPD(90), from 14.4 +/- 2.6 to 4.4 +/- 5.0 and -3.4 +/- 6.0 ms respectively. Early afterdepolarizations (EADs) occurred in epicardia in three of seven spontaneously beating hearts at 4 mm [K(+)](o) with triggered beats followed by episodes of non-sustained VT in nine of 11 preparations at 3 mm. Programmed electrical stimulation never induced arrhythmic events in preparations perfused with normokalemic solutions yet induced VT in two of seven and nine of 11 preparations at 4 and 3 mm [K(+)](o) respectively. Early outward K(+) current correspondingly fell from 73.46 +/- 8.45 to 61.16+/-6.14 pA/pF in isolated epicardial but not endocardial myocytes (n = 9) (3 mm [K(+)](o)).


CONCLUSIONS
Hypokalaemic mouse hearts recapitulate the clinical arrhythmogenic phenotype, demonstrating EADs and triggered beats that might initiate VT on the one hand and reduced transmural dispersion of repolarization reflected in DeltaAPD(90) suggesting arrhythmogenic substrate on the other.
Killeen
M J
MJ
Physiological Laboratory, University of Cambridge, Cambridge, UK. mjk42@cam.ac.uk
Thomas
G
G
Gurung
I S
IS
Goddard
C A
CA
Fraser
J A
JA
Mahaut-Smith
M P
MP
Colledge
W H
WH
Grace
A A
AA
Huang
C L-H
CL
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D001919:Bradycardia / Q000503:physiopathology; D004558:Electric Stimulation; D004699:Endocardium / Q000503:physiopathology; D005260:Female; D007008:Hypokalemia / Q000150:complications / Q000503:physiopathology*; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000502:physiology; D018408:Patch-Clamp Techniques; D010496:Pericardium / Q000503:physiopathology; D011188:Potassium / Q000502:physiology; D012307:Risk Factors; D017180:Tachycardia, Ventricular / Q000503:physiopathology; D016171:Torsades de Pointes / Q000209:etiology / Q000503:physiopathology; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*
D011188:Potassium