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

背景：心脏病是死亡的主要原因，一旦确诊，其生存结局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失常（心律失常），导致心脏性猝死。虽然许多患者被处方药物来控制他们的心律，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获益，并且仍然存在心源性猝死的风险。限制目前处方药物有效性的因素包括，当以临床有效剂量给药时，患者无法耐受其副作用，以及一些预防心律失常的最佳药物在存在结构性心脏病（如心脏病发作后）的情况下禁忌使用在本工作方案中，我们打算通过使用一种新的靶向心脏的方法，心律失常和评估一类新的抗心律失常药物。该方法涉及靶向信号通路，cGMP信号级联，这是用于勃起功能障碍的药物（如伟哥）的著名作用部位。在这里，我们将使用针对伟哥类药物上游cGMP信号级联的药物。因此，我们提出的方法赋予了许多优势，我们预测，我们感兴趣的是保留甚至潜在地增强的抗肿瘤效果，我们的初步数据令人信服地表明，我们提出的方法在各种情况下都非常有效，包括心力衰竭和被称为儿茶酚胺能的遗传性心律失常综合征。多形性室性心动过速（CPVT）。目的和目标：我们将讨论的总体目的和目标涉及证明这类新药物的有效性和了解实现抗肿瘤作用的机制。我们将使用一系列经过仔细考虑的已知与心律失常高风险相关的人类疾病模型（如CPVT、心力衰竭和心肌梗死）来评估这些问题。我们还将评估所提出的新的抗心律失常方法与用于CPVT管理的一线抗心律失常药物纳多洛尔相比的有效性。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生物体，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如何产生抗肿瘤作用。然而，这些实验也将提供重要的见解，了解这类药物作为新方法的潜在适用性，以减缓心力衰竭或心脏病发作后心脏中发生的一些变化（如瘢痕形成或心脏细胞结构）的进展，甚至逆转这些变化。应用和益处：该工作方案具有高度的转化性质，我们的坚定意图是从这项研究中取得预期的积极成果，并迅速将其应用于首次人体临床试验。根据我们的初步数据，我们设想，我们提出的新的抗心律失常的方法将是有效的，对心律失常所产生的广泛的原因。我们的研究将调查目前抗心律失常药物临床实践中的三个主要挑战领域，包括心力衰竭和心脏病发作后的遗传性心律失常综合征CPVT。此外，如上所述，我们还期待未来的研究调查这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。

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.