Effects of Kv1.3 inhibition in type 2 diabetes-induced cardiac electrical remodeling

  1. ZAYAS ARRABAL, JULIAN FERNANDO
Supervised by:
  1. Mónica Gallego Muñoz Director
  2. Oscar Casis Sáenz Director

Defence university: Universidad del País Vasco - Euskal Herriko Unibertsitatea

Fecha de defensa: 13 July 2021

Committee:
  1. Enrique Echevarría Orella Chair
  2. Carmen Delgado Canencia Secretary
  3. Erkan Tuncay Committee member
Department:
  1. Fisiología

Type: Thesis

Abstract

Background: Diabetic patients have prolonged cardiac repolarization and a higher risk ofarrhythmia. Besides, diabetes activatesthe innate immune system, resulting in higher levels of plasmatic proinflammatory cytokinessuch as TNFa and IL1b, which are described to prolong ventricular repolarization.Methods: Most of the current knowledge on diabetic cardiac electrical remodeling derivesfrom type 1 diabetic animals. Here, we characterize a metabolic model of type 2 diabetes withprolonged cardiac repolarization. Sprague-Dawley rats were fed on high fat diet (45% Kcalfrom fat) for 6 weeks, and a low dose of streptozotozin was intraperitoneally injected at week2. Body weight and fasting blood glucose were measured and electrocardiograms to consciousanimals were recorded weekly. Plasmatic lipid profile, insulin, cytokines and arrhythmiasusceptibility were determined at the end of the experimental period. The transient outwardK+ current and action potentials were recorded in isolated ventricular myocytes by patchclamp.Animals were also treated with PAP-1, an inhibitor of Kv1.3 channel that has animmunomodulatory role. Results: Type 2 diabetic animals showed insulin resistance,hyperglycemia and higher levels of plasma cholesterol, triglycerides, TNFa and IL1b thancontrols. They also developed bradycardia and prolonged QTc-interval duration that resultedin increased susceptibility to severe ventricular tachycardia under cardiac challenge. Actionpotential duration (APD) was prolonged in control cardiomyocytes incubated 24h with plasmaisolated from diabetic rats. However, adding TNFa and IL1b receptor blockers to the serum ofdiabetic animals prevented the increased APD. Inhibition of Kv1.3 reduced the circulaitingcytokines including TNFa and IL1B. It had an antidiabetic effect improving insulin resistanceand controlling the glucose while reduced the prolongation of QTc and the susceptibility toarrhythmia in the diabetic rats.Conclusions: The elevation of the circulating levels of TNFa and IL1b are responsible forimpaired ventricular repolarization and higher susceptibility to cardiac arrhythmia in ourmetabolic model of type 2 diabetes. Thus, immunomodulation by inhibition of Kv1.3 hasantidiabetic effects while improving the electrical alterations of the diabetic heart. Theseresults make the immune system a potential target for the treatment of diabetes and itsassociated alterations.