Modification of Infarct Morphology and Arrhythmogenicity by Peri-Infarction Modulation of Gap Junctional Function
Lead Research Organisation:
Imperial College London
Department Name: National Heart and Lung Institute
Abstract
Ventricular arrhythmias (life-threatening heart rhythm disturbances) are responsible for the majority of 100,000 annual sudden deaths in the UK. Following a heart attack (myocardial infarction), the surviving heart muscle undergoes multiple changes during the healing process that subsequently predispose to these ventricular arrhythmias.
One such change involves gap junctions, which are proteins that connect individual heart muscle cells. They are responsible for regular transmission of electrical impulses through the heart muscle and for maintenance of regular heart rhythm. Abnormal changes in gap junctions, termed gap junction remodelling, have been shown to occur in the healing process after myocardial infarction, and is associated with ventricular arrhythmias.
We will assess if administering pharmacological agents that modify gap junctional function during the crucial time-window around an episode of myocardial infarction in rats, can influence the healing process by beneficially modifying the process of gap junction remodelling, thereby fundamentally reducing the risk of developing ventricular arrhythmias in the long-term.
If results are positive, these pharmacological agents may be introduced into clinical practice. The prospect of a short-term treatment given at the time of myocardial infarction that provides lasting protection from lethal arrhythmias is compelling, intriguing, and accords with the concept of an ideal treatment.
One such change involves gap junctions, which are proteins that connect individual heart muscle cells. They are responsible for regular transmission of electrical impulses through the heart muscle and for maintenance of regular heart rhythm. Abnormal changes in gap junctions, termed gap junction remodelling, have been shown to occur in the healing process after myocardial infarction, and is associated with ventricular arrhythmias.
We will assess if administering pharmacological agents that modify gap junctional function during the crucial time-window around an episode of myocardial infarction in rats, can influence the healing process by beneficially modifying the process of gap junction remodelling, thereby fundamentally reducing the risk of developing ventricular arrhythmias in the long-term.
If results are positive, these pharmacological agents may be introduced into clinical practice. The prospect of a short-term treatment given at the time of myocardial infarction that provides lasting protection from lethal arrhythmias is compelling, intriguing, and accords with the concept of an ideal treatment.
Technical Summary
Ventricular arrhythmias are responsible for the majority of the 100,000 annual sudden deaths in the UK. Myocardial infarction is associated with an increased risk of these life-threatening ventricular tachyarrhythmias, with a peak in sudden death during the first 24 hours, and second peak during the first weeks post-infarction.
Multiple changes occur to the myocardial electrical properties post-infarction, contributing to this pro-arrhythmic substrate. One such change is gap junctional remodelling within the infarct border zone. Post-myocardial infarction, changes occur in the localisation of connexin, an important gap junction protein responsible for conduction of electrical impulses. This remodelling process modifies the electrical properties of the infarct border zone, leading to conduction slowing and providing the substrate required to sustain re-entrant circuits and ventricular tachycardias.
Gap junctions represent a novel therapeutic target to prevent ventricular tachyarrhythmias and sudden death post-infarction. Modulating gap junctional coupling early during myocardial infarction may have the potential to beneficially impact upon adverse electrical remodelling and reduce the long-term risk of fatal ventricular arrhythmias. Studies so far have produced conflicting results, suggesting that both increasing and decreasing gap junctional coupling peri-infarction may produce beneficial effects by reducing arrhythmogenicity and infarct size.
We plan to systematically administer pharmacological agents that increase (rotigaptide) and decrease (carbenoxolone) gap junctional coupling during the peri-infarction period in an established rodent model of myocardial infarction. Two protocols will be used. Firstly, we will study the impact of pre-treatment with gap junctional modulators on acute arrhythmia incidence in the first few days post-infarction. Secondly and more importantly, we will determine the effect of peri-infarction gap junction modulation on longer-term arrhythmogenicity, assessed over weeks.
For both protocols, we will assess the effects of gap junctional modulation on arrhythmogenicity by recording the incidence of ventricular arrhythmias in vivo using continuous ECG-telemetry, and by assessing arrhythmia threshold ex vivo using programmed electrical stimulation on isolated, perfused hearts. We will also determine the impact of gap junctional modulation on infarct size by systematic histological examination, and its effect on gap junctional remodelling by connexin immunohistochemistry and immunoblotting.
Our study will help to determine if gap junction modulators have the potential to affect the healing and remodelling process following myocardial infarction to fundamentally change the risk of developing ventricular tachyarrhythmias. The prospect of a short-term treatment at the time of myocardial infarction that provides lasting protection from lethal arrhythmias is compelling, intriguing, and accords with the concept of an ideal treatment.
Multiple changes occur to the myocardial electrical properties post-infarction, contributing to this pro-arrhythmic substrate. One such change is gap junctional remodelling within the infarct border zone. Post-myocardial infarction, changes occur in the localisation of connexin, an important gap junction protein responsible for conduction of electrical impulses. This remodelling process modifies the electrical properties of the infarct border zone, leading to conduction slowing and providing the substrate required to sustain re-entrant circuits and ventricular tachycardias.
Gap junctions represent a novel therapeutic target to prevent ventricular tachyarrhythmias and sudden death post-infarction. Modulating gap junctional coupling early during myocardial infarction may have the potential to beneficially impact upon adverse electrical remodelling and reduce the long-term risk of fatal ventricular arrhythmias. Studies so far have produced conflicting results, suggesting that both increasing and decreasing gap junctional coupling peri-infarction may produce beneficial effects by reducing arrhythmogenicity and infarct size.
We plan to systematically administer pharmacological agents that increase (rotigaptide) and decrease (carbenoxolone) gap junctional coupling during the peri-infarction period in an established rodent model of myocardial infarction. Two protocols will be used. Firstly, we will study the impact of pre-treatment with gap junctional modulators on acute arrhythmia incidence in the first few days post-infarction. Secondly and more importantly, we will determine the effect of peri-infarction gap junction modulation on longer-term arrhythmogenicity, assessed over weeks.
For both protocols, we will assess the effects of gap junctional modulation on arrhythmogenicity by recording the incidence of ventricular arrhythmias in vivo using continuous ECG-telemetry, and by assessing arrhythmia threshold ex vivo using programmed electrical stimulation on isolated, perfused hearts. We will also determine the impact of gap junctional modulation on infarct size by systematic histological examination, and its effect on gap junctional remodelling by connexin immunohistochemistry and immunoblotting.
Our study will help to determine if gap junction modulators have the potential to affect the healing and remodelling process following myocardial infarction to fundamentally change the risk of developing ventricular tachyarrhythmias. The prospect of a short-term treatment at the time of myocardial infarction that provides lasting protection from lethal arrhythmias is compelling, intriguing, and accords with the concept of an ideal treatment.