A translational approach to dyssynchrony

  • Graeme Kirkwood

Student thesis: Phd


Normal cardiac function is dependent on a healthy conduction system to maintain coordinated and synchronised activity. In the presence of heart failure, dyssynchronous ventricular activation due to left bundle branch block or right ventricular pacing can result in worsening symptoms and increased mortality; cardiac resynchronisation therapy in the form of biventricular pacing has therefore become an established and effective treatment. However, it also appears that right ventricular pacing can be a cause of heart failure in some individuals, even when there is no evidence of associated pre-existing cardiac disease. A better understanding of the processes leading to dyssynchrony-induced cardiomyopathy will allow better identification and treatment of patients who are at risk, and will contribute to our knowledge about heart failure in general.This PhD adopted a translational approach to cardiac dyssynchrony, by developing a novel model of atrial-synchronous ventricular pacing in adult Welsh Mountain sheep. The right ventricle was paced from the apex continuously for 3 months at a rate that was determined by the intrinsic atrial rate; this allowed the ventricular activation pattern to be altered without changing the heart rate. In parallel, a previously-developed model of rapid ventricular pacing was studied. In this model, the heart was paced continuously at a fixed rate of 210 bpm, which led to the development of symptomatic heart failure.In vivo parameters were characterised using standard clinical techniques of electrocardiography and echocardiography. Autonomic nervous system activity was investigated by examining the heart rate responses to pharmacological blockade using atropine and propranolol, and to beta-adrenergic stimulation using dobutamine. Heart rate variability was analysed in the time and frequency domains. In vitro, patch clamping studies were performed on ventricular myocytes isolated through enzymatic digestion from the interventricular septum and left ventricular free wall. Using the perforated patch current clamp technique at 37 C, action potential duration was measured and the associated triggered calcium transient was analysed using the calcium-sensitive fluorescent indicator Fura-2AM.Heart failure was associated with in vivo evidence of autonomic dysfunction, including a 38 % increase in the resting heart rate, blunting of the heart rate response to dobutamine, and almost complete loss of vagal tonic heart rate control. This pattern was not present in dyssynchrony. At a cellular level, normal sheep had heterogeneity of action potential duration, which was longer in the septum than the free wall. Heart failure disrupted this pattern, and was also associated with approximately a 40 % reduction in the magnitude of the calcium transient in both the septum and the free wall. Dyssynchrony was associated with a similar reduction in the calcium transient, but this was isolated to the free wall.RV apical pacing therefore induced a phenotype that resembled a localised cardiomyopathy, but without the associated autonomic dysfunction of the heart failure model. However, it was possible to identify a subgroup within these subjects that displayed a pattern of autonomic changes similar to those seen in heart failure, and this appeared to be associated with the most profound cellular changes. This raises the possibility that early dyssynchrony-induced cardiomyopathy may manifest as changes in the autonomic profile, which may be detectable in clinical practice.
Date of Award31 Dec 2014
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorAndy Trafford (Supervisor)


  • Dyssynchrony
  • Pacemaker
  • Heart failure
  • Cardiac
  • Cellular
  • Action potential

Cite this