Humanised drug evaluation system for LQT2 sufferers

Researchers at Nottingham University have developed a humanised drug evaluation model for congenital long QT syndromes, to explore possible drug therapies for LQT2. Long QT syndrome is characterised by prolonged QT-interval or abnormal ventricular repolarisation, along with palpitations, fainting and seizures.

Skin fibroblasts from a Long QT sufferer were reprogrammed into stem cells (hiPSCs), and differentiated into spontaneously beating, functional cardiomyocytes; control cells was generated from the patient's mother- an asympotmatic carrier for the mutation.

(European Heart Journal doi:10.1093/eurheartj/ehr073 Feb 2011)

Microelectrode array and patch-clamp recordings were used to determine the patient, and control, cardiomyoctyes response to different pharmacological agents. Spontaneously beating clusters of the cardiomyocytes were cultured on a 60-electrode microelectrode array, which was recorded using a Multi Channel Systems MEA1060 amplifier with 60-electrode arrays; while individual cardiomyocytes were generated for single cell patch clamping. Analysis from the beating clusters and single cells matched the clinical ECG data confirming the prolonged action potential duration symptomatic of the condition in the patient.

The team first induced pluripotent stem cell derived cardiomyocytes reflecting the proarrhythmic potential of the LQT2 syndrome of the donor. Upon application of β-blockers Nadolol and Propranolol. They observed the cardiomyocytes return to normal beating patterns after the β-blockers was administered. These results support current use of β-blockers to regulate cardiac episodes in LQT2 patients.

They also explored the LQT2 cardiac myocytes response to potassium channel blockers and openers, as a suggested model for treating patients with the condition. They demonstrated the effectiveness of potassium channel activators to normalise the prolonged repolarisation of myocytes, and hypothesised their use in conjunction with β-blocker treatment.

There is a great deal more work to be done to determine safe use of these drugs to treat LQT2 sufferers but the model proposed by Matsa et al provides crucial data to support further high through put analysis and paves the way to a more personalised approach to anti-arrhythmic therapy.

Matsa et al Drug evaluation in cardimyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation.

European Heart Journal doi:10.1093/eurheartj/ehr073 Feb 2011