DTI-0017

Endogenous adenosine (ADO) is known to be cardioprotective during acute myocardial ischemia. Coronary sinus ADO concentration has recently been shown to increase nearly 13-fold over baseline levels after 5 min of untreated ventricular fibrillation (VF). The role of ADO in VF has never been previously examined. The objective of this study was to determine the effect of ADO receptor antagonism, as measured by the scaling exponent (ScE), on the degeneration of VF over time during the circulatory phase of cardiac arrest.

A well-established swine model of prolonged VF arrest was used for this experiment. Eighteen domestic mixed-breed swine were assigned by block randomization to receive either DTI-0017 (5mg/kg), a potent ADO A(1) receptor antagonist or placebo in a double-blind fashion. The animals were instrumented under general anesthesia and acclimatized. The assigned solution was infused over 5 min. One minute after the infusion was completed, VF was induced with a 3s, 60 Hz, 100 mA transthoracic shock and left untreated. Lead II ECG was monitored continuously and recorded at 1000 samples/s. It was determined a priori that evaluation of the plots would be limited to a previously observed plateau phase historically occurring between 5 and 8 min corresponding to the circulatory phase of cardiac arrest. The scaling exponent values over this period were calculated for each of the 18 recordings using custom MATLAB routines. Using the Wald statistic to produce the Chi square distributions the null hypothesis, that there was no difference between the two groups, was tested. The Wald statistic calculation based on eight epochs from 300 to 475 s in placebo and DTI groups was significant to reject the null hypothesis of no difference in the groupxtime interaction at the 0.015 level (Chi square distribution for Wald=17.49, d.f.=7).

In this swine model, adenosine A(1) receptor antagonism accelerated the natural decay in the ECG VF waveform during the circulatory phase of cardiac arrest. Our findings would suggest that endogenous adenosine has cardioprotective effects during sudden cardiac arrest by slowing the time-dependent degeneration of VF.