Cardiac regulatory mechanisms: new concepts and challenges

This Journal of Physiology Special Issue on Cardiac Regulatory Mechanisms originated from the 2016 Gordon Research Conference (GRC) on the same topic. The Cardiac Regulatory Mechanism GRC has met every two years since 1982. Supported in part by The Journal of Physiology, the 2016 GRC was organized by Björn Knollmann (Vanderbilt University, USA) and Barbara Casadei (Oxford University, UK), and took place on June 5–10, 2016 at Colby‐Sawyer College in New London, NH, USA. The GRC brought together 180 scientists from different disciplines with a common interest in elucidating regulatory mechanisms of the normal heart and how they become dysfunctional in disease. The 2016 meeting focused on cutting edge research that ranged from the molecular scale to the use of ‘big data’ to help understand cardiac function in health and disease. For this Special Issue, conference participants contributed 20 Topical Reviews and eight original research articles describing the latest experimental approaches, research findings and open questions on eight different scientific topics that range from the basic physiology of excitation–contraction coupling in the heart to latest translational topics such as cardiac aging, mechanisms underlying atrial fibrillation, molecular signalling of cardiac hypertrophy and how to use databases of electronic medical records to study functional genomics in humans.

The first two reviews discuss novel approaches to cardiac aging repair and rejuvenation. Wolfram Zimmerman reports on the advances and remaining challenges of repairing the diseased heart with myocardial remuscularization (Zimmerman, 2017). Based on provocative results from studies in Drosophila and mice, Melkani and Panda propose a different approach to rejuvenate the aged heart: Time‐restricted feeding, which attenuates age and diet‐induced cardiac dysfunction without altering caloric intake (Melkani & Panda, 2017).

The second set of reviews and original articles is on mitochondrial function and myocardial metabolism, where recent discoveries have revolutionized our understanding of mitochondrial physiology. Jennifer Kwong focuses on the mitochondrial calcium uniporter complex, an inner membrane calcium transporter and major pathway of mitochondrial calcium entry (Kwong, 2017). The molecular identification of uniporter constituents made it possible to examine its function in vivo using targeted genetic models. The Topical Review by Kohlhaas, Nickel and Maack provides the reader with provocative new ideas on the coupling of mitochondrial energetics and calcium and how dysfunctional calcium‐energetics coupling can contribute to the progression of heart failure (Kohlhaas et al. 2017b). The Topical Reviews are complemented by three original articles reporting that inhibition of malate–aspartate shuttle preserves mitochondrial function after ischaemia–reperfusion (Jespersen et al. 2017), that endogenous nitric oxide formation in cardiac myocytes does not control mitochondrial respiration during β‐adrenergic stimulation (Kohlhaas et al. 2017a), and that K_ATP channel inhibition protects against electromechanical decline of the heart during hypoxia (Garrott et al. 2017).

The third set of papers deals with new concepts of excitation‐contraction coupling and calcium signalling in the heart. Leonard Sacconi proposes that electrical defects in the transverse‐axial tubular systems – cell membrane invaginations that are considered the principal site of excitation–contraction coupling in cardiomyocytes – are significant contributors to heart disease (Crocini et al. 2017). The next Topical Review raises the possibility that neuronal sodium channels may play a heretofore unrecognized role in cardiac excitation–contraction coupling (Veeraraghavan et al. 2017). In a provocative original paper, the Blatter lab reports that excitation–contraction coupling in atrial cardiomyocytes requires dual activation of ryanodine receptor calcium release channels by cytosolic and sarcoplasmic reticulum luminal calcium (Maxwell & Blatter, 2017). Two other original articles examine the role of calcium‐activated potassium channels in cardiac pacemaker activity (Torrente et al. 2017) and calcium signalling in a model of diastolic dysfunction (Gattoni et al. 2017).

The fourth set of reviews explores new ideas on how cardiac function is regulated by myocyte to non‐myocyte crosstalk: Ulrike Mende describes bioengineered tissue models that enable studies of the microenvironment of myocyte to non‐myocyte crosstalk (Kofron & Mende, 2017), Charalambos Antoniades reviews the role of epicardial fat tissue in cardiac biology (Antonopoulos & Antoniades, 2017), and Marco Mongillo challenges the classic view of cardiac sympathetic innervation based on recent results from optogenic experiments (Zaglia & Mongillo, 2017).

The fifth set of reviews explores outside‐the‐box ideas about the regulation of contractile function in health and disease. Challenging a classical myofilament‐centric view, Robison and Prosser propose that microtubules play a critical role in regulating myocyte contractility (Robison & Prosser, 2017). Sabine Huke discusses mechanisms how myofilament dysfunction can create susceptibility to ventricular arrhythmia and sudden death (Huke, 2017). Based on her elegant approach studying myocyte mechanics in vitro, Ye Chen‐Izu suggests a novel mechano‐chemo signal transduction pathway that occurs during cardiac myocyte contraction (Chen & Izu, 2017). Complementing the Topical Reviews, Friedrich et al. report on the efficacy of a calcium channel blocker in a mouse model of hypertrophic cardiomyopathy (Flenner et al. 2017).

The sixth set of papers explores scientific controversies regarding the molecular mechanisms of atrial fibrillation. In a pro–con debate, Dobrev and Wehrens present strong evidence supporting the mechanistic role of hyperactive calcium release in atrial fibrillation (Dobrev & Wehrens, 2017). Maura Greiser challenges this concept based on her recent work and proposes a novel mechanism of calcium signalling silencing instead (Greiser, 2017). Fabritz and coworkers tackle the controversies surrounding the PITX2 gene in atrial fibrillation (Syeda et al. 2017). Based on genome‐wide association studies, the PITX2 gene locus is near many single nucleotide polymorphisms linked to high atrial fibrillation risk, but its mechanistic role in atrial fibrillation remains enigmatic.

The seventh set of papers raises new concepts in molecular signalling in myocardial remodelling that could be relevant for the prevention or treatment of chronic heart disease. Gil Bub reports on interactions of cardiac risk factors in hypertension‐induced cardiac remodelling (Tomek & Bub, 2017). Paula Da Costa Martins provides an in‐depth discussion on the regulation of myocardial hypertrophy by non‐coding RNA (Ottaviani & da Costa Martins, 2017). Gilda and Gomes review the proteasome dysfunction that occurs in cardiomyopathies and may contribute mechanistically to myocardial remodelling (Gilda & Gomes, 2017). Lorenz and coworkers propose a new pathway – the endogenous Raf kinase inhibitor protein – as a better and safer way to activate β‐adrenergic receptor signalling in heart failure (Lorenz et al. 2017). In an original research article, the Palomeque group identified the calcium–calmodulin dependent protein kinase as the mediator of cardiac apoptosis in mice with impaired glucose tolerance (Federico et al. 2017).

The final Topical Review introduces the reader to a new approach toward harnessing big clinical data for basic discovery. A common study design in experimental research for examining the functional role of a gene or a genetic variant is to introduce that genetic variant into a model organism (such as yeast or mouse) and then to search for phenotypic consequences. In his Topical Review, Dan Roden explains how the development of DNA biobanks linked to dense phenotypic information available in the electronic medical record enables such an experiment to be applied to human subjects in the form of a phenome‐wide association study (Roden, 2017).