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Regulation of Cardiac Conduction

Kirstine Boisen Olsen

Summary

Cardiac arrhythmia is a major cause of morbidity and mortality in the western world and is frequently associated with underlying cardiac and systemic diseases. Cardiac gap junctions facilitate rapid and coordinated spread of the electrical impulse and in this way gap junctions are major determinants of conduction velocity (CV). Gap junctional uncoupling results in slowing of CV, and slow CV is recognized as a key mechanism in the generation of certain cardiac arrhythmias. 

The aim of this thesis was to investigate CV and mechanical properties under pharmacological manipulations and in relation to chronic and acute pathophysiological conditions in the heart. The work constitutes three projects – one made in cooperation with a collaboration group. 

Slow CV is believed to play an important role in the pathogenesis to atrial fibrillation (AF). Angiotensin II (Ang II) reduces gap junctional coupling and its levels are increased in AF indicating an important role in the pathogenesis to AF. The effect of Ang II on atrial CV was examined using in vitro measurements of isolated left atrial strips from healthy rats and rats subjected to myocardial infarction (MI). Stimulation with Ang II did not affect atrial CV in either healthy rats or rats with left ventricular MI. Acute metabolic stress did not change the sensitivity to Ang II stimulation. CV measurements in rats with left ventricular MI revealed a reduced atrial CV. In conclusion, Ang II does not mediate acute conduction slowing in the atria. Stressing the atrial conduction properties using metabolic stress or structural heart disease does not change the sensitivity to Ang II stimulation. 

Losartan provides cardioprotection against ischemic reperfusion damage and against the generation of arrhythmias. The cardioprotective effect of losartan is suspected to be linked to bradykinin. Binding studies performed by the collaboration group revealed that losartan acts as a partial agonist on the bradykinin B2 receptor. The comparative effects of losartan, candesartan and bradykinin on CV and mechanical properties were evaluated in atrial tissue strips subjected to metabolic stress. Both losartan and bradykinin improved recovery of force development after the stress period – an ability candesartan did not share. These results were consistent with the results from the binding studies. None of the tested drugs had any effect on conduction properties.

 In conclusion, the beneficial effects of losartan can be attributed to partial agonism at the bradykinin B2 receptor. 

Type 2 diabetes is associated with increased risk for cardiac arrhythmias including ventricular fibrillation (VF). The diabetic heart has a reduced conduction reserve making the diabetic heart 48 sensitive to further uncoupling. Acute uncoupling of gap junctions during ischemia is suspected to play an important role in the genesis of VF. The antiarrhythmic peptide analogue AAP10 increases gap junctional intercellular communication and the drug has been shown to prevent ischemia induced VF. 

CV properties were investigated using ventricular strips from the right ventricle from a Type 2 diabetic rat. CV was measured during simulated ischemia and the effect of AAP10 was evaluated. CV measurements revealed that baseline CV was lower and more sensitive to ischemia in the diabetic heart. AAP10 significantly increased CV during the ischemic period in the diabetic right ventricle.

 In conclusion, Type 2 diabetes reduces CV significantly probably making the diabetic heart vulnerable to arrhythmia. AAP10 is effective in increasing CV under an ischemic episode in the diabetic heart indicating a therapeutic potential for gap junction modifying peptides in treatment of ventricular tachyarrhythmias in the diabetic patient.