The role of the cardiac lymphatic system has been recently appreciated since lymphatic disturbances take part in various heart pathologies. This review presents the current knowledge about normal anatomy and structure of lymphatics and their prenatal development for a better understanding of the proper functioning of this system in relation to coronary circulation. Lymphatics of the heart consist of terminal capillaries of various diameters, capillary plexuses that drain continuously subendocardial, myocardial, and subepicardial areas, and draining (collecting) vessels that lead the lymph out of the heart. There are interspecies differences in the distribution of lymphatic capillaries, especially near the valves, as well as differences in the routes and number of draining vessels. In some species, subendocardial areas contain fewer lymphatic capillaries as compared to subepicardial parts of the heart. In all species there is at least one collector vessel draining lymph from the subepicardial plexuses and running along the anterior interventricular septum under the left auricle and further along the pulmonary trunk outside the heart and terminating in the right venous angle. The second collector assumes a different route in various species. In most mammalian species the collectors run along major branches of coronary arteries, have valves and a discontinuous layer of smooth muscle cells.
The existence and importance of cardiac lymphatics has been neglected for many years. Recently more attention has been devoted to this system since it was discovered that besides helping maintain intramyocardial pressure and preventing tissue edema it plays an important role in many heart pathologies, such as atherosclerosis and interstitial fibrosis [
Nowadays, due to improved techniques that make it possible to distinguish blood vessels from lymphatics, the lymphatic system is no longer considered as secondary to the blood circulatory system [
Knowledge of the structure and location of capillary lymphatic system and major draining branches in the heart in various species as well as its relationship with the circulatory system would help in understanding the proper functioning of the heart. Additionally, due to an immense development of modern technologies and the use of transgenic animals in many research tasks, a better understanding of normal cardiac lymphatic vessel embryogenesis is also in progress. Thus, the aim of this paper is to summarize the current knowledge on cardiac lymphatic anatomy in various species and discuss the basic steps of lymphatic vessel development and maturation.
The techniques for visualization of gross anatomy of lymphatics vary. A useful method to demonstrate location of lymphatics is to inject India-ink to subepicardium, myocardium, or subendocardium, areas of the conduction system and atrioventricular valves, via a needle, glass pipette, or syringe. Additionally, other filling substances have been used by investigators in the past such as radiopaque iodized oil, latex or vital dye (trypan blue), Evans blue, resins, micropulverized barium sulfate, and carbon (very small carbon particles) combined with polyvinylpyrrolidone [
Nowadays, modern techniques allow lymphatic endothelial cells (LEC) with specific markers to be easily demonstrated in various species on histological, confocal microscope sections and by the use of the “whole mount” immunohistochemical method [
The earliest detailed data on cardiac lymphatics has been described by Patek [
Shimada and colleagues noted that the lymphatic plexus was less extensive in the atria than in the ventricles [
The capillary lymphatic system has been demonstrated by various techniques to be present in the conduction tissue of mammalian hearts: in the sinoatrial node of man, dog, and rabbit [
Adventitial lymphatics have been reported to be rather extensive along the aorta as well as along the coronary arteries in mammalian species. Our work indicated that by the end of the prenatal life an extensive adventitial lymphatic plexus was developed at the roots of the aorta and the pulmonary trunk in mouse hearts [
The myocardial lymphatic capillaries were less numerous as compared to blood capillaries. The ventricular myocardium of cat, rabbit, and human hearts possessed an average of 1,029 blood capillaries per 1,000 muscle cells ([
In some species, only fragments of myocardium were studied. For example, some authors studied the myocardium of the septomarginal band in lamb hearts [
Terminal vessels (lymphatic capillaries) were irregular in shape and diameter, possessed many branches, and exhibited tortuous courses. The caliber of lymphatic capillaries varied, depending on the author, animal species, or technique used, and ranged from 20 to 100
The smaller lymphatic capillaries of the myocardial plexus converged forming larger drainage lymphatic vessels that contained valves. These drainage vessels coursed in the subepicardial space [
In Macaca monkeys the pattern of cardiac lymphatics has been reported to be comparable to that of man, dog, and pig [
The structure and course of precollectors and collecting subepicardial vessels were demonstrated in our lab by injecting mouse hearts with India ink mixed with gelatin and showing their course as dividing branches and merging branches. These vessels vary in size and diameter along their course. The left major collector in murine hearts corresponds to the major cardiac trunk in other mammalian species. It drains the paraconal interventricular sulcus around the left conal vein towards the left side of the pulmonary trunk and upwards to the mediastinum via the nearest lymph node (corresponding to the tracheobronchial node in other species) (Figure
(a) A photography of an India-ink-injected adult mouse heart demonstrating the structure and the route of the major lymphatic collector; (b) a scheme showing the extracardiac route of this collector terminating in a regional lymph node (in red); ra—right auricle; pt—pulmonary trunk; rpa—right pulmonary artery; ao—aorta.
Contrary to human, pig, and dog heart where major lymphatic precollectors/collectors accompany coronary artery branches, in the mouse and rat hearts these vessels accompany branches of cardiac veins (are in a close proximity to major cardiac veins).
Patek [
Cardiac lymphatic flow has been suggested to be propelled by a passive pumping [
The development of cardiac lymphatic vessels has been the subject of a few studies. As development of lymphatics commonly followed blood vessel formation in the body of the embryo, the same sequence was observed in developing organs, such as the heart; that is, the lymphatics occurred later than blood vessels. The species studied were rats, mice, and birds such as quail and chicken [
Development and structure of lymphatics in the avian heart (chicken, quail) have been studied fragmentarily. Only a few papers dealing with injection techniques and with the use of lymphatic markers have been published [
Confocal microscopy images of a 13-dpc mouse heart stained with DAPI (blue), anti-Prox-1 (red), anti-Lyve-1 (green), and anti-CD31 (white). Prox-1+/CD31+/Lyve-1− vessels (white arrows) are present along the great arteries; ao—aorta; pt—pulmonary trunk; scale bars = 100
Confocal microscopy images of a 14-dpc mouse heart stained with DAPI (blue), anti-Prox-1 (red), and anti-Lyve-1 (green). Lyve-1-positive cells (green arrows), Prox-1-positive cells (red arrows), and Lyve-1/Prox-1-double positive vessels (yellow arrows) are visible along the great arteries; ao—aorta; pt—pulmonary trunk; scale bars = 100
It has been demonstrated by our group that cells bearing macrophage phenotypes were incorporated to lymphatic vascular walls during prenatal and early postnatal development of cardiac mouse lymphatics [
Ultrastructure of a developing subepicardial lymphatic vessel in a 4-day postnatal mouse heart. A tortuous appearance of LEC and anchoring filaments are visible.
An immense interest in biology and development of cardiac lymphatic vessels is nowadays justified because they are involved in normal functioning of the cardiovascular system and play a role in various pathologies. Understanding interspecies differences in normal structure and development of lymphatics is important for comparison of those structures in transgenic animals. Animal models with modification of selected genes help pursue a developmental process of lymphatic vessel formation and its regulatory mechanisms. Our recent work on mouse cardiac lymphatics using multiple markers of the lymphatic endothelium points to interspecies differences in capillary plexus location and in the course of major draining vessels. The lymphatics of a normal adult mouse heart, contrary to those in other mammalian species, are restricted to the outer zone of the myocardial wall (as has been previously suggested by Böger and Hort with the use of old techniques) [
The authors declare that there is no conflict of interests regarding the publication of this paper.
This paper was funded by the National Science Centre (Grant no. 2701/B/P01/2010/39) and by internal funds of The Medical University of Warsaw (no. 1M11/NM1/2013, Student Grant, received by GG). The excellent technical help of Anna Podbielska is greatly appreciated. The authors would like to thank Professor Artur Kamiński, the Head of the Tissue Banking Center, for generously making a confocal microscope accessible for the purposes of this project.