Targeting soluble guanylate cyclase as a novel strategy to treat and prevent cardiac arrhythmias: efficacy and mechanisms
Lead Research Organisation:
University of Manchester
Department Name: School of Medical Sciences
Abstract
Context:
Heart diseases are a leading cause of death and, once diagnosed, often have survival outcomes worse than the common cancers. A major factor contributing to death in patients with heart disease is dangerous heart rhythms (arrhythmias) leading to sudden cardiac death. Whilst many patients are prescribed drugs to control their heart rhythm, the so-called antiarrhythmic drugs, there are some significant problems with these drugs that ultimately means many patients do not benefit from their use and remain at risk of sudden cardiac death. Amongst the factors that limit the effectiveness of currently prescribed drugs are patients not being able to tolerate their side effects when they are given at clinically effective doses and that some of the best drugs at preventing arrhythmias are contraindicated where there is structural heart disease such as following a heart attack (myocardial infarction).
In this programme of work, we intend to take a major step forward in overcoming the significant limitations associated with current antiarrhythmic treatments by using a novel approach to target cardiac arrhythmias and evaluate a new class of antiarrhythmic drugs. The approach involves targeting a signalling pathway, the cGMP signalling cascade, which is famously the site of action of drugs used for erectile dysfunction such as Viagra. Here we will use drugs that target the cGMP signalling cascade upstream of the Viagra type drugs. Our proposed approach thereby confers a number of advantages resulting, we predict, in the antiarrhythmic effect we are interested in being retained or even potentially enhanced, in the setting of diseases such as heart failure and following a heart attack.
Our preliminary data convincingly shows that our proposed approach is highly effective in a variety of situations including in heart failure and an inherited arrhythmia syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT).
Aims and objectives:
The overarching aims and objectives that we will address involve demonstrating the effectiveness of this new class of drugs and understanding the mechanisms by which the antiarrhythmic effect is achieved. We will evaluate these questions using a series of carefully considered models of human diseases known to be associated with a high risk of cardiac arrhythmias such as CPVT, heart failure and myocardial infarction. We will also evaluate the effectiveness of the proposed new antiarrhythmic approach versus a first-line antiarrhythmic drug, nadolol, which is used in the management of CPVT. In doing so we will use a platform of state-of-the-art approaches with techniques and methods that span the whole organism, intact heart, single cell and gene level. This highly integrative approach will primarily inform us as to how the antiarrhythmic effect is brought about. However, the experiments will also give important insight into the potential suitability of this class of drugs as novel approaches to slow the progression of, or even reverse some of the changes that occur in the heart in heart failure or following a heart attack such as scar formation or the structure of heart cells.
Applications and benefits:
The programme of work is highly translational in nature and our firm intention is to take the expected positive outcomes from this study and rapidly deploy them in first in-man clinical trials.
Based on our preliminary data, we envisage that our proposed novel antiarrhythmic approach will be effective against cardiac arrhythmias arising from a wide range of causes. Our study will investigate three major challenge areas in clinical practice for current antiarrhythmic medications and includes the inherited arrhythmia syndrome CPVT, in heart failure and following a heart attack. Moreover, as noted above, we also anticipate future studies investigating the utility of this drug class in managing and treating other abnormalities that occur in the diseased heart.
Heart diseases are a leading cause of death and, once diagnosed, often have survival outcomes worse than the common cancers. A major factor contributing to death in patients with heart disease is dangerous heart rhythms (arrhythmias) leading to sudden cardiac death. Whilst many patients are prescribed drugs to control their heart rhythm, the so-called antiarrhythmic drugs, there are some significant problems with these drugs that ultimately means many patients do not benefit from their use and remain at risk of sudden cardiac death. Amongst the factors that limit the effectiveness of currently prescribed drugs are patients not being able to tolerate their side effects when they are given at clinically effective doses and that some of the best drugs at preventing arrhythmias are contraindicated where there is structural heart disease such as following a heart attack (myocardial infarction).
In this programme of work, we intend to take a major step forward in overcoming the significant limitations associated with current antiarrhythmic treatments by using a novel approach to target cardiac arrhythmias and evaluate a new class of antiarrhythmic drugs. The approach involves targeting a signalling pathway, the cGMP signalling cascade, which is famously the site of action of drugs used for erectile dysfunction such as Viagra. Here we will use drugs that target the cGMP signalling cascade upstream of the Viagra type drugs. Our proposed approach thereby confers a number of advantages resulting, we predict, in the antiarrhythmic effect we are interested in being retained or even potentially enhanced, in the setting of diseases such as heart failure and following a heart attack.
Our preliminary data convincingly shows that our proposed approach is highly effective in a variety of situations including in heart failure and an inherited arrhythmia syndrome known as catecholaminergic polymorphic ventricular tachycardia (CPVT).
Aims and objectives:
The overarching aims and objectives that we will address involve demonstrating the effectiveness of this new class of drugs and understanding the mechanisms by which the antiarrhythmic effect is achieved. We will evaluate these questions using a series of carefully considered models of human diseases known to be associated with a high risk of cardiac arrhythmias such as CPVT, heart failure and myocardial infarction. We will also evaluate the effectiveness of the proposed new antiarrhythmic approach versus a first-line antiarrhythmic drug, nadolol, which is used in the management of CPVT. In doing so we will use a platform of state-of-the-art approaches with techniques and methods that span the whole organism, intact heart, single cell and gene level. This highly integrative approach will primarily inform us as to how the antiarrhythmic effect is brought about. However, the experiments will also give important insight into the potential suitability of this class of drugs as novel approaches to slow the progression of, or even reverse some of the changes that occur in the heart in heart failure or following a heart attack such as scar formation or the structure of heart cells.
Applications and benefits:
The programme of work is highly translational in nature and our firm intention is to take the expected positive outcomes from this study and rapidly deploy them in first in-man clinical trials.
Based on our preliminary data, we envisage that our proposed novel antiarrhythmic approach will be effective against cardiac arrhythmias arising from a wide range of causes. Our study will investigate three major challenge areas in clinical practice for current antiarrhythmic medications and includes the inherited arrhythmia syndrome CPVT, in heart failure and following a heart attack. Moreover, as noted above, we also anticipate future studies investigating the utility of this drug class in managing and treating other abnormalities that occur in the diseased heart.
Technical Summary
The long-term aim from this programme of work is deployment of a novel class of antiarrhythmic drugs that overcome the significant limitations associated with current therapies. Our proposal is to achieve this through activation of cyclic soluble guanylate cyclase (sGC) mediated guanosine monophosphate (cGMP) production. The objectives are inter-related yet independent and will provide; i) a detailed understanding of the mechanisms by which sGC activation produces antiarrhythmic effects and, ii) demonstrate antiarrhythmic efficacy in a range of translationally relevant situations. This latter objective is strongly supported by our preliminary data.
We have carefully selected arrhythmia prone preclinical models to address these objectives including an inherited arrhythmia syndrome (CPVT), myocardial infarction and heart failure. For each model, robustness, reproducibility, experimental and statistical design are key considerations and form the cornerstone of our approach. Where treatments are administered, subjects will be randomly allocated and the investigator blinded to treatment and genotype until data analysis is completed.
Using an integrative quantitative physiology approach and state-of-the-art equipment, data will be generated at the whole organism, intact organ (heart), single cell (myocyte) and gene level (myocytes and hearts). The types of data generated will include cardiac ECG parameters, cellular ion channel function and intracellular calcium measurements, gene expression levels and cellular ultrastructural parameters (e.g. ryanodine receptor cluster area).
We will pursue intellectual property and commercial opportunities through our Innovation Office. We anticipate our results will lead immediately to follow-on, first in-man studies funded via, e.g., the Developmental Pathways Funding Scheme.
We have carefully selected arrhythmia prone preclinical models to address these objectives including an inherited arrhythmia syndrome (CPVT), myocardial infarction and heart failure. For each model, robustness, reproducibility, experimental and statistical design are key considerations and form the cornerstone of our approach. Where treatments are administered, subjects will be randomly allocated and the investigator blinded to treatment and genotype until data analysis is completed.
Using an integrative quantitative physiology approach and state-of-the-art equipment, data will be generated at the whole organism, intact organ (heart), single cell (myocyte) and gene level (myocytes and hearts). The types of data generated will include cardiac ECG parameters, cellular ion channel function and intracellular calcium measurements, gene expression levels and cellular ultrastructural parameters (e.g. ryanodine receptor cluster area).
We will pursue intellectual property and commercial opportunities through our Innovation Office. We anticipate our results will lead immediately to follow-on, first in-man studies funded via, e.g., the Developmental Pathways Funding Scheme.
