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：心脏病是导致死亡的主要原因，一旦确诊，其生存结果往往比常见癌症更差。导致心脏病患者死亡的一个主要因素是危险的心律（心律失常），导致心源性猝死。虽然许多患者服用了控制心律的药物，即所谓的抗心律失常药物，但这些药物存在一些重大问题，最终意味着许多患者无法从其使用中受益，并且仍然面临心源性猝死的风险。限制目前处方药物有效性的因素包括，患者在服用临床有效剂量时无法忍受其副作用，并且一些预防心律失常的最佳药物在患有结构性心脏病的情况下是禁忌的，例如：心脏病发作（心肌梗塞）。在这项工作计划中，我们打算通过使用一种针对心脏的新方法，在克服当前抗心律失常治疗相关的重大局限性方面迈出重要一步。心律失常并评估一类新型抗心律失常药物。该方法涉及针对信号通路，即 cGMP 信号级联，众所周知，该信号通路是用于治疗勃起功能障碍的药物（例如伟哥）的作用位点。在这里，我们将使用针对伟哥类药物的 cGMP 信号级联上游的药物。因此，我们提出的方法具有许多优势，我们预测，在心力衰竭和心脏病发作等疾病的情况下，我们有兴趣保留甚至潜在增强抗心律失常作用。我们的初步数据令人信服地表明我们提出的方法在多种情况下都非常有效，包括心力衰竭和遗传性心律失常综合征，即儿茶酚胺能多形性室性心动过速（CPVT）。目的和目标：我们要解决的总体目的和目标包括证明此类新型药物的有效性并了解实现抗心律失常作用的机制。我们将使用一系列经过仔细考虑的人类疾病模型来评估这些问题，这些疾病与心律失常的高风险相关，如 CPVT、心力衰竭和心肌梗塞。我们还将评估所提出的新抗心律失常方法与用于治疗 CPVT 的一线抗心律失常药物纳多洛尔的有效性。在此过程中，我们将使用最先进的方法平台，其技术和方法涵盖整个有机体、完整的心脏、单细胞和基因水平。这种高度综合的方法将主要告诉我们抗心律失常作用是如何产生的。然而，这些实验还将对这类药物的潜在适用性提供重要的见解，作为减缓心力衰竭或心脏病发作后心脏发生的一些变化（例如疤痕）进展的新方法，甚至逆转这些变化。应用和益处：该工作计划本质上是高度转化的，我们坚定的意图是从这项研究中获得预期的积极成果，并将其快速部署到首次人体临床试验中。根据我们的初步数据，我们预计我们提出的新型抗心律失常方法将有效对抗多种原因引起的心律失常。我们的研究将调查当前抗心律失常药物临床实践中的三个主要挑战领域，包括遗传性心律失常综合征 CPVT、心力衰竭和心脏病发作后的情况。此外，如上所述，我们还预计未来的研究将调查此类药物在管理和治疗患病心脏中发生的其他异常方面的效用。