Increased Afterload Following Myocardial Infarction Promotes Conduction-Dependent Arrhythmias That Are Unmasked by Hypokalemia

• Although the pathophysiological significance of hypertension in post-MI patients is established, mechanisms by which increased afterload alters the electrophysiological substrate and promotes arrhythmias after MI is unknown. • We developed a new porcine model of MI/iAL that exhibits widespread interstitial fibrosis, increased profibrotic gene expression, and propensity to pacing-induced arrhythmias when challenged with hypokalemia. • Investigation of the electrophysiological substrate revealed the dependence of these arrhythmias on hypokalemia-mediated conduction and not repolarization abnormalities. • A steep negative slope of rate-dependent conduction slowing in MI/iAL is consistent with a high safety factor for propagation of slow wavefronts before onset of sustained ventricular tachycardia/ventricular fibrillation. • Fibrosis in MI/iAL promotes the successful propagation of critically slow wavefronts leading to re-entrant arrhythmias that are unmasked by hypokalemia. Although the pathophysiological significance of resistant hypertension in post–myocardial infarction (MI) patients is established, the mechanisms by which increased afterload in that setting worsens outcome are unclear. With regard to sudden cardiac death, whether increased afterload alters the electrophysiological substrate after MI is unknown. We established a new large animal model of chronic post-MI remodeling with increased afterload that exhibits widespread deposition of fibrosis in remote areas from the anterior MI, mimicking the disease phenotype of patients with advanced ischemic heart disease. We identified the mode of initiation and mechanism of arrhythmias that were consistently unmasked by hypokalemia in this clinically relevant model.