Cardiac regulatory mechanisms: from cardiac mechanisms to novel therapeutic approaches

This Special Issue on cardiac regulatory mechanisms originated from the 2018 Gordon Research Conference (GRC) on the same topic, a conference that has met every 2 years since 1982. The Cardiac Regulatory Mechanisms GRC is centred on the fundamental physiological mechanisms that control normal cardiac function and how they are altered by disease, with the goal of discovering novel mechanisms to protect or restore function of the failing, injured or arrhythmic heart. Supported in part by The Journal of Physiology, the 2018 GRC was organized by Brian O'Rourke, Johns Hopkins University, USA and Thomas Eschenhagen, University Medical Centre Hamburg-Eppendorf, Germany, and took place June 3–8, 2018 at Colby-Sawyer College in New London, NH, USA. The GRC brought together over 180 scientists from different disciplines who discussed how fundamental molecular processes can be leveraged for therapeutic intervention using cutting-edge approaches. The conference covered recent advances in understanding cardiac function/dysfunction in the areas of heart failure, metabolic disease, cardiac signal transduction, regulation by non-coding DNA/RNA, calcium signalling and myocyte/non-myocyte communication. For this special issue, conference participants contributed 12 symposium reviews and two original research articles on six different scientific topics that relate basic physiology of the heart to cardiovascular diseases. The first set of reviews and original articles discusses aberrant calcium signalling and arrhythmia mechanisms. The symposium review by Wleklinski, Kannankeril and Knollmann introduces the concept of pathological calcium signalling as an arrhythmia mechanism. The authors discuss the molecular and tissue mechanisms of catecholaminergic polymorphic ventricular tachycardia, a genetic arrhythmia disorder in which ventricular tachycardia is caused by aberrant calcium signalling (Wleklinski et al. 2020). Christopher Johnson then reviews how the cardiac Na+ channels are regulated by calcium, and what can go wrong in heart disease (Johnson, 2020). The symposium reviews are complemented by two research papers reporting on how adrenergic signalling can generate calcium-dependent arrhythmia susceptibility in heart hypertrophy and in heart failure. Hamilton and others studied calcium activated small conductance K+ channels (SK2 channels) which play an important role in the regulation of the cardiac membrane potential (Hamilton et al. 2020). The authors discovered that protein kinase A (PKA) underlies the functional recruitment of sarcolemmal SK2 channels. This regulation of SK2 channels by PKA has important implications not only for hypertrophic heart disease but also during normal physiology, where it contributes to repolarization under conditions of enhanced adrenergic drive. Dries and others discovered that in heart failure caused by myocardial infarction, an altered adrenergic response in the infarct borderzone is responsible for in vivo triggered activity and repolarization instability (Dries et al. 2020). Together, the reviews and research articles raise provocative new concepts on the role of aberrant calcium signalling in arrhythmogenesis. The second set of reviews is on regulation of myofilaments in health and disease where recent discoveries have advanced our understanding of contractile physiology. Striated muscle contraction is regulated by calcium-dependent modulation of myosin cross-bridge binding to F-actin by the thin filament troponin-tropomyosin complex. Schmidt and Cammarato delve deep into the structural aspects of myofilament function and discuss recent advances of contractile regulation by the F-actin tropomyosin interaction (Schmidt & Cammarato, 2020). Recent advances have made it possible to generate induced pluripotent stem cells (iPSCs) from skin or blood cells (Takahashi & Yamanaka, 2006). As a result, the number of experimental studies utilizing this approach to generate human cardiomyocytes from iPSCs and study the pathophysiology of genetic heart diseases is increasing steadily. The symposium review by Sewanan and Campbell provides the reader with provocative new ideas on modelling sarcomeric cardiomyopathies with human cardiomyocytes derived from iPSCs (Sewanan & Campbell, 2020). The third set of reviews deals with the role of non-myocytes in heart development and cardiovascular disease. Colliva, Braga, Giacca and Zacchigna propose that endothelial-cardiomyocyte cross-talk is critically important both in heart development and in several heart diseases (Colliva et al. 2020). Their review provides the reader with recent insights into how endothelial cell–cardiomyocyte interactions control not only heart development, but also several processes affecting the heart in normal and pathological conditions, including ischaemia, remodelling and metabolic dysfunction. The authors also introduce in vitro models to help define the mechanism underlying the endothelial-cardiomyocyte crosstalk. In the second review, Kannan and Kwon tackle the problem of cardiomyocyte maturation during cardiac development (Kannan & Kwon, 2020). In vivo, cardiomyocytes undergo many adaptive structural, functional and metabolic changes during maturation. A major challenge in the field is that cardiomyocytes derived in vitro from pluripotent stem cells fail to develop to maturity in similar fashion. To address this challenge, the authors review what is known about the key processes that regulate normal maturation in vivo and provide practical guidance on developing experimental strategies to produce mature cardiomyocytes in a dish. In the third paper, Bardsley and Paterson review recent discoveries of the cellular and molecular mechanisms that contribute to neural regulation of the heart (Bardsley & Paterson, 2020). Given the recent discoveries highlighting the importance of acutely regulated cyclic nucleotides and their effectors in the control of intracellular calcium and exocytosis, the authors review how impaired cyclic nucleotide signalling and altered receptor-coupled G-protein activation contribute to sympathetic hyperactivity in heart disease. The review also raises provocative ideas for molecular targeted therapy aimed at preventing sympathetic overactivity. The fourth topic covered in this issue is the role of metabolic and mitochondrial dysfunction in diabetic heart disease. Diabetes, obesity and insulin resistance are interrelated diseases and their incidence is increasing rapidly in the developed world. The resulting diabetic cardiomyopathy is characterized by high levels of intramyocardial lipid deposits. Nakamura and Sadoshima discuss recent insights into the molecular mechanisms of diabetic cardiomyopathy (Nakamura & Sadoshima, 2020). Their review summarizes the mechanisms leading to cardiac lipotoxicity and discusses the role of peroxisome proliferator-activated receptor α and dysregulated fatty acid metabolism as potential therapeutic targets. The fifth set of reviews explores outside-the-box ideas about the regulation of the heart by non-coding RNAs and chromatin in heart failure. Challenging the classical neuroendocrine hypothesis, Kreutzer, Fiedler and Thum propose that small non-coding RNAs (ncRNA)and ncRNA-derived micropeptide are key players in heart failure (Kreutzer et al. 2020). Based on recent reports that ncRNAs such as microRNAs, long non-coding RNAs or circular RNAs can be selectively targeted via pharmacological approaches, the authors discuss the main ncRNA classes and how they influence cardiac biology. In the second review on this topic, Padmanabhan and Haldar provide an overview of efforts using small molecules to treat abnormal chromatin regulation and transcriptional activity in heart failure (Padmanabhan & Haldar, 2020). Based on the new idea of disrupting altered transcription by targeting chromatin-associated proteins, the review focuses on modulating bromo- and extra-terminal domain (BET) family of chromatin co-activator proteins in the context of heart failure. The final set of papers explores new concepts in pathophysiological signal transduction in myocardial remodelling. Cardiovascular disease and cancer are the two leading causes of death worldwide. Only recently has a connection between both diseases been recognized, with rates of cancer being higher in patients with heart failure, and rates of cancer higher in heart failure patients (Meijers et al. 2018). The review by Brancaccio, Hirsch and Ghigo summarizes the current knowledge on the mechanisms underlying the bidirectional communication between the failing heart and the cancer (Brancaccio et al. 2020). Although little is currently known on the underlying molecular mechanisms, the authors speculate on which molecular mediators released by either the tumour or the heart can link heart failure and cancer. The final review by Gildart, Kapiloff and Dodge-Kafka closes the loop to adrenergic signalling discussed in the first set of symposium reviews and focuses on the regulation of protein kinase A by anchoring proteins (AKAPs) and calcineurin (Gildart et al. 2020). Recent experimental evidence suggests that calcineurin anchoring by AKAPs confers specificity to calcineurin function in the cardiomyocyte. The authors speculate that targeting of the calcineurin ‘signalosomes’ may provide a rationale for inhibiting the phosphatase in heart disease.