Current matters of the heart

Cardiac function and the development and adaption of the cardiovascular system are among the classics in physiology and, as such, are also among the flagship topics in Acta Physiologica. We regularly revisit according topics as, for example, arterial hypertension, renal function and channelopathies, to provide you with an overview of the latest novel developments in the field. Cardiovascular disease accounts for a major disease burden and has for the recent decades been among the most intensively researched (and funded) topics in biomedicine. However, there have been repeated warnings of the "waning knowledge and expertise in integrative physiology," a gap which had grown into a veritable risk factor when Sipido et al1 aimed at identifying current "needs and opportunities for advancing translational research in cardiovascular disease". In 2002, John Hall, in a short editorial note, had already coined the term "translational physiology".2 Therein, he explained that, through a translational approach in physiology, observations from basic science settings would "translate into improved patient care",2 as results obtained initially in both clinical trials and population studies would be tested in preclinical models. What's the big news, one might ask—Douglas R. Seals explained how translational physiology did indeed differ notably from traditional integrative and/or clinical physiology mainly by its "broad investigative scope of basic research to community health".3 Cardiac physiology is undoubtedly of high translational potential. In 2002, Hall had noted a gap between, on the one hand, breakthrough advances in basic science, which, on the other, would only inadequately translate into a successful novel treatment strategies. He postulated three underlying causes: (i) a gradual decline in integrative physiology and clinical physiology over the previous years, (ii) the emergence of "two-track systems, with a research track and a clinical track, in academic medical centres" and (iii) a gradual decline of "integrative physiologists working at the whole animal level" in favour of a rise in research done at the cellular level and beyond.2 Acta Physiologica continues to provide a forum for both integrative and (sub)cellular approaches to cardiac physiology. Let us have a look at the latest news. As the first organ that develops during organogenesis, the development of the heart is critical for subsequent organ development. In a recent study, Vostarek et al4 identified the pacemaker and AV canal as most temperature-sensitive segments of the developing (avian) heart, which may reflect the effect of changing metabolic demands. Spontaneous Ca2+ release triggers rhythmic beating activity already in the very young vertebrate embryo, while action potential configurations in embryonic hearts differ significantly from adult, but are well adapted to the developing embryo's demands at each developmental stage.5 Cardiac growth is not limited to the developmental stage. External stressors, which occur repeatedly or chronically change the shape, function, and/or structure of the heart, while, however, not all remodelling is maladaptive. Heinzel and Oeing 6 review recent insights on the physiology and pathophysiology of cardiac growth and remodelling and their emerging mechanisms. The isolated perfused heart, the so-called Langendorff Heart apparatus, named after Oskar Langendorff (1853-1908), is still the predominant ex vivo set-up for the assessment of cardiac contractile strength and heart rate, a set-up which is still continuously being refined. Anttila et al7 recently described the effects of a decrease in oxygen concentration of the perfusate on BNP release, while Bliksøen et al8 describe an influence of the intraventricular balloon used for pressure measurements on endocardial coronary flow and subsequent cell death in the isolated perfused rat heart, both of which may interfere with transferable experimental results. Recently, Gary Tse9 and Jeevaratnam10 discussed in detail the assessment of monophasic action potentials with regard to the mechanism of ventricular arrhythmogenesis. Osadchii11 reviews mechanisms of cardiac electrical instability, which can be attributed to abnormal repolarization, including repolarization-related surrogates currently used to assess arrhythmic propensity, arrhythmogenic electrolyte dysbalance and drug-induced arrhythmia.11 Drug-provoked arrhythmias are a common problem in a number of non-cardiac medications, as reviewed in.12 Junctophilins (JP) are cardiac junctional membrane complex proteins anchored to both the T-tubule system and the sarcoplasmic reticulum. Feng et al13 recently described for the first time how JP2 associates with and regulates the SK2 channel. Gaburjakova et al14 have, based on bioinformatic data, taken first steps to identify the cytosolic Ca2+-binding sites responsible for activation and inhibition in the ryanodine receptor 1 channel. Myocardial contractile function is determined by factors such as heart rate, activity of the conduction system, calcium influx causing myocardial fibre shortening and several other modulating factors. Genetic mutations in the SCN5A gene, which encodes the cardiac voltage-gated sodium channel NaV1.5, may be involved in the pathophysiology of heart failure, in which abnormal NaV1.5 plasma membrane expression and/or sodium current (INa) density have been observed.15, 16 Excessive sympatho-excitation characterizes heart failure and contributes to disease progression in CHF. The mechanisms causing the increase in renal sympathetic nerve activity remain to be elucidated. Wang et al17 have recently described how c-Jun N-terminal Kinase reduces GAD1 and GABRA1 expression, thereby mediating prostaglandin-induced sympatho-excitation in a rat model of chronic heart failure. Lu et al18 describe that renal denervation benefits cardiac angiogenesis during sustained pressure overload by a regulation of VEGF and VEGFR2 expression and eNOS activation. Left ventricular (LV) dysfunction is a potential consequence of obesity–insulin resistance. In a pre-diabetic animal model, fibroblast growth factor 21 therapy improved LV function and metabolic symptoms.19 Post-ischaemic LV dysfunction could be improved by a combined therapeutic inotropic support (dobutamine) and selective heart rate reduction (ivabradine).20 In post-ischaemic reperfusion injury, vagal nerve stimulation reduces infarct size. Kiss et al21 recently described that the cardioprotective effect of vagal nerve stimulation is mediated via a reduction in cardiac arginase activity. Both cardiac and renal diseases are common and frequently coexist, together often significantly increasing mortality, morbidity and both complexity and cost of care.22, 23 Oosterhuis et al24 studied the effects of a multidrug regimen, which decreased cardiac fibrosis and stabilized systolic function in a rodent model of chronic renocardiac syndrome. Cardiac fibrosis is the result of a pathophysiological remodelling process not only in cardiorenal syndromes, but which occurs in a multitude of cardiac diseases. Bilirubin had until recently been considered to be a cytotoxic waste product. Very surprisingly at first, recent studies have shown bilirubin to have cardioprotective effects, potentially exerted through its antioxidant, anti-inflammatory, vasodilatory, antiapoptotic and antiproliferative properties.25, 26 Greiwe et al27 recently described differential lymphangiogenesis in cardiac tissue, which is of special importance for tissue homeostasis and regeneration, for example, in post-transplantation settings. Successful translation of research results into the clinics has always had to overcome obstacles attributable to both study limitations,28 but also to external factors.29 Lately, systematic analyses have helped map the definitions and steps in translational research,30 to refine the processes necessary to successfully transfer questions from the bedside to the bench, and come back with useful answers. None.