Critical Volume of Human Myocardium Necessary to Maintain Ventricular Fibrillation

BACKGROUND: Abnormal QT intervals, long QT or short QT, have been epidemiologically linked with sudden cardiac death because of ventricular fibrillation (VF). Consequently, Food and Drug Administration recommends testing all pharmacological agents for QT toxicity as a risk factor for cardiac toxicity. Such tests assess QT/QTc interval, which represents ventricular depolarization and repolarization. However, the current QT toxicity analysis does not account for the well-known anisotropy in cardiac tissue conductivity. Mines demonstrated in 1913 that cardiac wavelength (lambda) determines inducibility of reentrant arrhythmia, where both repolarization time or action potential duration and conduction velocity determine lambda=action potential durationxconduction velocity. We aimed to determine the role of anisotropic wavelength in inducibility of VF in explanted human left ventricular preparations. We tested the hypothesis that 3-dimensional cardiac wavelength, which takes into account anisotropic cardiac tissue conductivity, can accurately predict VF sustainability. METHODS: We conducted panoramic optical mapping of coronary perfused human left ventricular wedge preparations subjected to pharmacologically induced shortening and prolongation of action potential duration, by I(K,ATP )agonist pinacidil and antagonist glybenclamide, respectively. This measured action potential duration, conduction velocity, and thus determined pacing cycle length-dependent wavelengths in longitudinal (lambda(L)), transverse (lambda(TV)), and transmural (lambda(TM)) directions using S1S1 pacing protocol, from which wavelength volume (V-lambda) was determined, as V-lambda =lambda(L)x lambda(TV)x lambda(TM), and compared with tissue volume We tested a hypothesis that tissue volume/V-lambda, ratio can predict VF sustainability. RESULTS: At baseline, at pacing rate of 240 beats per minute, the wavelengths were lambda(L)=9.6 +/- 0.6 cm, lambda(TV)=4.2 +/- 0.3 cm, and lambda(TM)=5.8 +/- 0.2 cm, respectively (n=7), and thus V-lambda=246.4 +/- 42.1 cm(3). Administration of pinacidil at escalating concentrations progressively decreased V-lambda, and VF became sustained, when tissue volume/V-lambda, was above safety factor kappa=4.4 +/- 0.6 (n=9) during rapid pacing. Treatment with glybenclamide decreased V-T/V-lambda below kappa at any pacing rate and prevented VF sustainability. CONCLUSIONS: Sustained VF was only sustained in ventricular volume exceeding critical V-lambda=lambda(L)x lambda(TV)x lambda(TM).