DOES VT BEGET VT? REMODELING IN HEALED INFARCTION

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Protracted atrial fibrillation (AF) conditions the atrium through electrical remodeling to perpetuate AF (AF begets AF). Whether this is true for episodic ventricular tachycardia (VT) due to healed myocardial infarction (MI) is not known so this proposal asks whether VT begets VT. A related issue is how VT electrically remodels the infarcted ventricle. Experimental and clinical evidence indicates that post-NG VT is reentrant. While VT maintenance mechanisms are controversial, the role of refractoriness in VT initiation is usually not disputed. We therefore propose to study whether episodic VT affects VT inducibility and remodels refractoriness. Study hypotheses were based on the distinct properties of the infarcted (1Z), border (13Z), and normal (NZ) zone tissues associated with MI and on the phenomena of repolarization remodeling due to cardiac memory, failure or hypertrophy. Hypothesis 1 is that VT remodels refractoriness even in hearts already remodeled by MI. Hypothesis 2 is that refractoriness remodeling in the IZ, BZ and NZ differentially responds to the influence of VT rate versus site of origin. Hypothesis 3 is that VT-dependent changes in inducibility result from differences in refractoriness remodeling of the BZ with respect to the IZ or to the NZ. Hypothesis 4 is that changes in BZ and NZ plateau and repolarization currents are responsible for refractoriness remodeling in these tissues. To test these hypotheses we will use swine having healed MI caused by bead embolization. Fast or slow ventricular pacing (VP) from 1 of 3 test sites will simulate episodic VT. VT inducibility and peri-infarct endocardial refractoriness; will be assessed in vivo using CARTO electro-anatomic catheter mapping before and after MI and after VP of MI. Terminal in vitro studies will use whole cell voltage clamp to correlate remodeled BZ and NZ refractoriness with changes in plateau ion currents. We will measure steady state, peak activated and kinetic properties of Ik and ICaL and the current-voltage relations of Ik1 and InaCa. Indo-1 and fluo-3 recordings of the calcium transient will be used to determine the direction and relative magnitude of InaCa flux. Refractoriness due to INa reactivation will be detected via voltage and time-dependent recovery of upstroke velocity. If the study hypotheses are true then the labile and inhomogeneous remodeling properties of the post-MI heart may cause episodic VT to have either a positive or negative effect on VT inducibility. If the latter occurs then novel therapy based on pacing may be possible. If the former is true then preventive therapy could be directed against such remodeling.