Targeting soluble guanylate cyclase as a novel strategy to treat and prevent cardiac arrhythmias: efficacy and mechanisms

靶向可溶性鸟苷酸环化酶作为治疗和预防心律失常的新策略：功效和机制

• 批准号: MR/Y003594/1
• 负责人: Andrew Trafford
• 金额: $ 94.79万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY003594%2F1
• 关键词: Targeting; soluble; guanylate; cyclase; novel

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.

背景：心脏病是死亡的主要原因，一旦被诊断出，通常会比普通癌症更糟。心脏病患者导致死亡的主要因素是危险的心律（心律不齐）导致心脏猝死。尽管许多患者被处方用于控制其心律的药物，但所谓的抗心律失常药物，这些药物存在一些重大问题，最终意味着许多患者无法从使用中受益，并且仍处于心脏突然死亡的危险中。在限制当前处方药有效性的因素中，患者在临床上有效剂量时无法忍受其副作用，并且在临床上有效的某些药物预防心律不齐的最佳药物是在结构性心脏病中偶然引起的，例如在心脏病发作（心脏梗塞）上具有重要的限制，我们就可以在这一重要的一步中加以限制，而是在这种工作中进行了限制。使用一种新的方法来靶向心律不齐，并评估一类新的抗心律失常药物。该方法涉及靶向信号通路，即CGMP信号级联，这是著名的用于勃起功能障碍（例如伟哥）的药物的作用部位。在这里，我们将使用针对伟哥型药物上游CGMP信号级联的药物。我们预测，我们预测，在抗心律失常的效果中，我们有兴趣保留甚至有可能增强的抗心律失常效应，在心力衰竭和心脏病发作之后的疾病环境中，我们的初步数据令人信服地表明，我们所提出的方法表明，我们所提出的方法在包括心脏失败的各种情况下是高效心室心动过速（CPVT）。目的和目标：我们将解决的总体目标和目标涉及证明这一新药物的有效性，并了解实现抗心律失常效应的机制。我们将使用一系列认真考虑的人类疾病模型来评估这些问题，这些模型已知与心律不齐的高风险有关，例如CPVT，心力衰竭和心肌梗塞。我们还将评估拟议的新抗心律失常方法与一线抗心律失常药物Nadolol的有效性，该药物用于CPVT的管理。这样一来，我们将使用跨越整个生物体，完整心脏，单细胞和基因水平的技术和方法的最先进方法平台。这种高度综合的方法将主要告知我们如何产生抗心律失常效应。但是，这些实验还将为这类药物的潜在适合性提供重要的见解，因为新颖的方法是减慢心脏失败或心脏病发作（例如心脏病形成或心脏细胞结构）的心脏病或心脏病结构的新方法。根据我们的初步数据，我们设想我们提出的新型抗心律失常方法将有效地抵抗因广泛原因而引起的心律不齐。我们的研究将研究当前抗心律失常药物的临床实践中的三个主要挑战领域，并包括遗传性心律失常综合征CPVT，心力衰竭和心脏病发作。此外，如上所述，我们还期望将来的研究研究该药物类别在管理和治疗患病心脏中发生的其他异常情况方面的实用性。