Xiaobo Wu's Dissertation Defense (12/1/2022): The Role of the Perinexus in Long QT Syndrome Type 3

About this Dissertation

Cardiovascular disease remains the leading cause of death around the world, and over 40% of those deaths are attributable to sudden cardiac death by ventricular arrhythmias. It has been demonstrated that sudden cardiac death is associated with prolonged QT interval measured by an electrocardiogram. The etiology of prolonged QT interval has been extensively described in a group of cardiac diseases known as the Long QT Syndromes (LQTS). As an exemplar of LQTS, Long QT Syndrome Type 3 (LQT3), which is caused by a gain-of- function of cardiac voltage-gated sodium channel (Nav1.5), has a high risk of sudden cardiac death relative to other types of LQTS. This gain of function leads to disruption of Nav1.5 inactivation, which increases the late sodium current (I_NaL) to prolong action potential duration (APD, equivalent to QT interval). However, LQT3 patients can have normal QT intervals, which hasn’t been clinically interpreted. Dr. Poelzing’s lab recently found in a drug-induced LQT3 guinea pig heart model that this concealed LQT3 phenotype may be caused by narrow perinexi, which are intercalated-disc nano-meter spaces that densely express Nav1.5. The putative mechanism states that narrowing the perinexus decreases the amount of local sodium ions in the perinexus, and Nav1.5 activation rapidly depletes perinexal sodium ions to decrease I_NaL and thereby shorten APD. In other words, widening the perinexus increases the amount of sodium ions to increase I_NaL and prolong APD. Logically and technically, the increase in the perinexal sodium ion availability can also be achieved by elevating sodium concentration without widening the perinexus. Poelzing's lab found that elevating extracellular sodium concentration alone prolonged APD and together with perinexal expansion synergistically exacerbated APD relative to the individual effects of high sodium or perinexal widening alone in drug-induced LQT3 guinea pig hearts, which suggests that managing sodium intake and preventing intercellular edema could benefit LQT3 patients. Furthermore, they also found that the perinexus narrows with aging to conceal the LQT3 phenotype, and importantly, widening the perinexus in aged LQT3 hearts increases the susceptibility to arrhythmias, which suggests that the increased incidence of sudden cardiac death in aged LQT3 patients may be associated with perinexal expansion. Furthermore, to rule out the off-targets of the drug that is commonly used to induce LQT3 phenotype in guinea pig hearts, the team further investigated the individual and combined effects of high sodium and perinexal expansion in a genetically modified LQT3 (ΔKPQ) mouse heart model. Surprisingly, they found that high sodium shortened APD, instead of prolonging it, in both wild-type and ΔKPQ hearts. Although perinexal expansion significantly prolonged APD in ΔKPQ hearts, the combined effect of high sodium and perinexal expansion on APD was not synergistic, likely due to the shortening effect of high sodium. Patch clamping on isolated mouse cardiomyocytes showed that high sodium increased transient outward potassium current (I_to), which is responsible for early repolarization. Overall, Poelzing's lab results showed that high sodium regulates both I_to and I_NaL in ΔKPQ hearts, and produces opposing effects on APD. Since the electrophysiological properties of the mouse heart are distinct to human heart, selection of a proper animal model which functionally expresses I_to channels and has similar electrophysiology as the human heart is very important. Overall, the whole project deeply and diversely investigated the role of the perinexus in LQT3 under different conditions including sodium stress, aging and species. 

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