ABC | Volume 112, Nº5, May 2019

Viewpoint Resident Macrophages Orchestrating Heart Rate Diego Santos Souza, 1 Tatiane de Oliveira Barreto, 2 Michael Nadson Santos Santana, 1 José Evaldo Rodrigues Menezes-Filho, 1 J ader Santos Cruz, 2 Carla Maria Lins de Vasconcelos 1 Universidade Federal de Sergipe – Fisiologia, 1 São Cristóvão, SE – Brazil Universidade Federal de Minas Gerais - Bioquímica e Imunologia, 2 Belo Horizonte, MG – Brazil Mailing Address: Jader Santos Cruz • Universidade Federal de Minas Gerais - Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, 4º andar, Avenida Antônio Carlos, 6627, Postal Code 31270-901, Belo Horizonte, MG – Brazil E-mail: jcruz@icb.ufmg.br Manuscript received June 26, 2018, revised manuscript October 15, 2018, accepted November 14, 2018 Keywords Macrophages; Heart Conduction System; Heart Rate; Myocites, cardiac; Fibroblasts; Connexins; Arrhythmias, Cardiac. DOI: 10.5935/abc.20190041 Introduction The electrical conduction system of the heart is essential for maintaining normal heart rhythm and function. This is due to the presence of specialized cells that generate electrical impulses that propagate throughout the heart tissue, quickly and efficiently. This electrical impulse starts at the sinoatrial node (SAN) and propagates sequentially to atrioventricular node (AVN), subsequently being transmitted to the ventricles via specialized conduction pathways. The electrical signals are conducted from cell to cell through a cardiomyocyte permeability control system formed by proteins called connexins, and connexin-43 is the type found in the heart and is associated with the formation of so-called gap junctions. By providing the single electrical connection between the atria and the ventricles, AVN plays an essential role in the dynamics of cardiac contraction. Clinically, when the PR interval is observed in the electrocardiographic recordings, we can correlate the electrical impulse conduction time from its generation in the SAN to the delay in the AVN region, which is called "decremental conduction". 1 When prolongation of the PR interval or an AV block occurs, which delays excessively or even eliminates the conduction of the electrical impulse from the atria to the ventricles, will result in hemodynamic deterioration, syncope and death, in case the patient is not submitted to the brand heart. 2 Over the years, several studies have described the macrophages as cells of phagocytic functions that would exclusively act in the immune system protecting the organism against pathogens. However, more recently this paradigm was mainly questioned about the origin of macrophages. Several studies have provided evidence that a subpopulation of macrophages, which originated from embryonic development and do not come from the bloodstream, reside and proliferate in virtually all body tissues and apparently act specifically on each organ. For example, resident macrophages of adipose tissue contribute to the regulation of thermogenesis, 3 iron recycling in the spleen and liver, 4 and participate in the process of synaptic maturation in the healthy brain. 5 Such non-canonical activities emphasize the functional diversity of macrophages and their ability to perform specific tasks in the various tissues, in addition to host defence. 6 In cardiac tissue, macrophages are intrinsic components of the myocardium in normal functioning, where they appear as spindle cells intercalated between cardiomyocytes, fibroblasts and endothelial cells. 7 Macrophages and the heartbeat Cardiac function depends on the appropriate moment of contraction in several distinct regions, as well as the heart rate. 8 Hulsmans et al. 9 observed that mice that had their macrophage fauna weakened, had bradycardia and irregular beats. It is known that connexin-43 is predominant in ventricles of humans and that its reduction promotes bradycardia and AV block, 8 thus, in observing specialized cells in non-muscular electrical conduction, they found that macrophages are electrically coupled to cardiomyocytes and that these resident macrophages facilitate electrical conduction through the AV node. Such conducting cells interleave with macrophages expressing connexin-43 forming additional gap junctions between cardiomyocytes (Figure 1). The investigators observed that the animals that had a reduction of resident macrophages, besides having bradycardia, had AV blockade of 2nd and 3rd degrees (Figure 2), 9 whose cause in humans is still unknown. 10 Another intriguing point is that cardiac macrophages have a resting membrane potential of -35 mV on average and depolarize in synchrony with cardiomyocytes. This makes the membrane potential at the rest of the cardiomyocytes more positive and according to the results obtained by computational simulation, accelerate both depolarization and repolarization phases. 9 The cardioprotective role of cardiac resident macrophages can go beyond the modulation of the electrophysiological properties of the coupled cardiomyocytes. The perivascular localization of cardiac macrophages makes them uniquely positioned to interpret systemic signals in the bloodstream. 10 Macrophages and cardiovascular diseases Monnerat et al. 11 demonstrated that inflammation caused by type I diabetes causes resident macrophages to secrete interleukin 1 β (IL-1 β ), acting in a paracrine manner, increasing oxidative stress in the surrounding cells and destabilizing the electrical activity of cardiomyocytes provoking lethal ventricular arrhythmias. Moreover, atherosclerotic lesions are currently understood as inducers of important inflammatory processes, which comprise components of the innate and acquired immune systems. Clinical data showed that increased leukocyte count, interleukin-6 (IL-6), tumour necrosis factor (TNF) and IL-1 β were at risk of more severe cardiovascular events. In fact, IL-6 is locally regulated during the coronary occlusion process in patients with acute myocardial infarction with ST-segment elevation. 12-14 588