Heinrich Ewald Hering's discovery of the heart pacemaker: Hering, Tawara and Aschoff's search for its morphological basis, the sinoatrial node, and why they failed.

Two groups of investigators investigated the heart pacemaker and its morphological basis in the early twentieth century. The first group was formed by Henrich Ewald Hering (physiologist), Sunao Tawara and Ludwig Aschoff (morphologists). The second group was composed of James Mackenzie (general practitioner and clinical investigator), Arthur Keith and Martin Flack (morphologists). These groups were formed almost at the same time in 1903. Their work resulted in the discovery of the atrioventricular node and Purkinje network (Sunao Tawara, in 1906), heart pacemaker (H E Hering, in 1907) and sinoatrial node (Keith and Flack, in 1907). Here, it is shown how the interconnections of the concurrent works of these groups resulted in the discovery not only of the function, but also of the structure of the sinoatrial node.

Miniseries 1-Part II: the comparative anatomy of the atrioventricular conduction axis.

AIMS: The arrangement of the conduction axis is markedly different in various mammalian species. Knowledge of such variation may serve to question the validity of using animals as prospective models for design of systems for clinical use. METHODS AND RESULTS: We compared the arrangement of the atrioventricular conduction axis in human, murine, canine, porcine, and bovine hearts, examining serially sectioned datasets from 20 human, 16 murine, 3 porcine, 5 canine, and 1 bovine hearts. We also analysed computed tomographic datasets obtained from bovines and one human heart. Unlike the situation in the human heart, there is no formation of an atrioventricular fibrous membranous septum in the murine, canine, porcine, nor bovine hearts. Canine, porcine, and bovine hearts also lack an infero-septal recess, when defined as a fibrous plate supporting the buttress of the atrial septum. In these species, half of the non-coronary leaflet is directly opposed to the ventricular septal surface. CONCLUSION: There is a long right-sided non-branching component of the axis, which skirts the attachment of the non-coronary sinus of the aortic root. In the bovine heart, moreover, the left bundle branch usually extends intramyocardially as a solitary tape before surfacing and ramifying on the left ventricular septal surface. The difference in the atrioventricular conduction axis between species may influence the anatomical substrates for atrioventricular re-entry tachycardia, as well as providing inferences for assessing the risks of transcatheter implantation of the aortic valve. Further studies are now needed to assess these possibilities.

The atrioventricular conduction axis and the aortic root-Inferences for transcatheter replacement of the aortic valve.

Conduction problems still occur following transcatheter aortic valvar replacement. With this in mind, we have assessed the relationship of the conduction axis to the aortic root. We used serial histological sections, made perpendicular to the base of the triangle of Koch in nine hearts, and perpendicular to the aortic root in 11 hearts. We first defined the extent of the fibrous tissues forming the boundaries of an infero-septal recess of the subaortic outflow tract, found in all datasets but one. When the recess was present, the axis penetrated through its rightward wall, giving rise to the left bundle branch prior to entering the outflow tract. The axis itself was usually on the crest of the ventricular septum, but could be deviated leftward or rightward. Its proximity to the virtual basal plane reflected the angulation of the muscular septum. On average, the superior edge of the left bundle was within 3.3 mm of the hinge of the right coronary leaflet, with a range from 0.4 to 10.2 mm. The arrangement was markedly different in the case lacking an infero-septal recess. Our findings necessitated a redefinition of the right fibrous trigone and the central fibrous body. The atrioventricular conduction axis, having entered the aortic root, is usually closest at the hinge of the right coronary leaflet. Knowledge of the depth of the infero-septal recess, and the angulation of the muscular ventricular septal, may help to avoid conduction problems following transcatheter implantation of the aortic valve.

Similarities and differences in the arrangement of the atrioventricular conduction axis in the canine compared to the human heart.

BACKGROUND: Subtle differences exist between dog and human, despite use of the dog as a model for cardiac surgical and electrophysiological research. OBJECTIVE: The purpose of this study was to investigate the differences in the atrioventricular conduction axis and adjacent structures between dogs and humans. METHODS: We prepared 33 human and 5 canine hearts for serial histologic sections of the atrioventricular conduction axis, making correlations with gross anatomic findings. We additionally examined and photographed 15 intact normal human hearts obtained from infants undergoing autopsy. Furthermore, we interrogated a computed tomographic dataset from a human adolescent and from 2 autopsied canine hearts, both with normal cardiac anatomy. RESULTS: All canine hearts lacked an inferoseptal recess, with the noncoronary leaflet of the aortic valve and the right fibrous trigone having direct attachments to the septal surface of the left ventricular outflow tract. This correlated with an extensive nonbranching component of the ventricular conduction axis, which skirted half of the noncoronary aortic sinus. This anatomic arrangement was observed in 2 of 15 of autopsied infant hearts. In the human hearts with an inferoseptal recess, the relatively shorter nonbranching bundle is embedded within the fibrous tissue forming its right wall. CONCLUSION: We found a major difference between canine and the majority of human hearts, namely, the presence or absence of an inferoseptal recess. When this recess is absent, as in the canine heart and in some human hearts, a greater proportion of the atrioventricular conduction axis is found within the circumference of the subaortic outflow tract.

Three-dimensional visualization of the bovine cardiac conduction system and surrounding structures compared to the arrangements in the human heart.

In the human heart, the atrioventricular node is located toward the apex of the triangle of Koch, which is also at the apex of the inferior pyramidal space. It is adjacent to the atrioventricular portion of the membranous septum, through which it penetrates to become the atrioventricular bundle. Subsequent to its penetration, the conduction axis is located on the crest of the ventricular septum, sandwiched between the muscular septum and ventricular component of the membranous septum, where it gives rise to the ramifications of the left bundle branch. In contrast, the bovine conduction axis has a long non-branching component, which penetrates into a thick muscular atrioventricular septum having skirted the main cardiac bone and the rightward half of the non-coronary sinus of the aortic root. It commonly gives rise to both right and left bundle branches within the muscular ventricular septum. Unlike the situation in man, the left bundle branch is long and thin before it branches into its fascicles. These differences from the human heart, however, have yet to be shown in three-dimensions relative to the surrounding structures. We have now achieved this goal by injecting contrast material into the insulating sheaths that surround the conduction network, evaluating the results by subsequent computed tomography. The fibrous atrioventricular membranous septum of the human heart is replaced in the ox by the main cardiac bone and the muscular atrioventricular septum. The apex of the inferior pyramidal space, which in the bovine, as in the human, is related to the atrioventricular node, is placed inferiorly relative to the left ventricular outflow tract. The bovine atrioventricular conduction axis, therefore, originates from a node itself located inferiorly compared to the human arrangement. The axis must then skirt the non-coronary sinus of the aortic root prior to penetrating the thicker muscular ventricular septum, thus accounting for its long non-branching course. We envisage that our findings will further enhance comparative anatomical research.

The membranous septum revisited: A glimpse of our anatomical past.

The so-called membranous septum is the fibrous component of the septal structures within the heart. It is relatively subtle in its appearance, but of considerable significance to the understanding of cardiac function and cardiac disease, both congenital and acquired. Surprisingly, its existence was seemingly unknown until the early decades of the 19th century. At this time, those writing in the English language described it as the "undefended space," recognizing its importance in the setting of its aneurysmal dilation, and as the site of septal defects. By the initial decade of the 20th century, it had come to be recognized as the landmark to the site of atrioventricular bundle. Over the first decade of the 21st century, its clinical significance has been emphasized in the context of transcutaneous replacement of the aortic valve. In this review, we describe our own recent investigations of this fibrous part of the septal structures. At the same time, we provide a glimpse of our anatomic past, explaining how its initial description relied on the observations of young physicians taking their first steps in the investigation of cardiac anatomy.

Tumor cell death in orthotopic breast cancer model by NanoALA: a novel perspective on photodynamic therapy in oncology.

Aim: Nano-5-aminolevulic acid (NanoALA)-mediated photodynamic therapy (PDT), an oil-in-water polymeric nanoemulsion of ALA, was evaluated in a murine model of breast cancer. Materials & methods: Analysis of ALA-derived protoporphyrin IX production and acute toxicity test, biocompatibility and treatment efficacy, and long-term effect of NanoALA-PDT on tumor progression were performed. Results: The nanoformulation favored the prodrug uptake by tumor cells in a shorter time (1.5 h). As a result, the adverse effects were negligible and the response rates for primary mammary tumor control were significantly improved. Tumor progression was slower after NanoALA-PDT treatment, providing longer survival. Conclusion: NanoALA is a good proactive drug candidate for PDT against cancer potentially applied as adjuvant/neoadjuvant intervention strategy for breast cancer.

Sunao Tawara : further musings on his tribulations in providing the basis for the modern-day understanding of cardiac electrophysiology.

Sunao Tawara, who was born in 1873 and died in 1952, is considered the father of modern cardiac electrophysiology. He published his monumental monograph describing the atrioventricular conduction axis in 1906. He achieved this task in the face of multiple tribulations as a doctoral student working in a cultural environment that was not his own. Although his letters underscoring the publication of the monograph have been published, little emphasis has been placed on the potential problems he encountered in bringing his task to fruition. For example, it was not until the final 6 months of his studies that he resolved the issue of the connection between the atrioventricular bundle and the so called "Purkinje cardiomyocytes". His exchanges with his mentor, Ludwig Aschoff, emphasized that the difficulties he encountered in making the connection caused him quite some turmoil. We believe that this issue, and others that he identified in his correspondence, are worthy of further attention.

Human subpulmonary infundibulum has an endocardial network of specialized conducting cardiomyocytes.

BACKGROUND: The right ventricular outflow tract is the most common source of ventricular arrhythmias in nonstructural heart disease. Most of these arrhythmias are of endocardial origin, but their morphologic substrate is mostly unknown. OBJECTIVE: The purpose of this study was to identify potential morphologic substrates for such arrhythmias originating within the right ventricular outflow tract. METHODS: Three adult human hearts that had been fixed in 4% formaldehyde were examined. In 2 of the hearts, which were obtained subsequent to necropsies, the base of the anterior papillary muscle of the tricuspid valve was removed at the site of its fusion with the moderator band. The block of removed myocardium was submitted to routine histologic processing and sectioned at 5-µm thickness. The free-standing subpulmonary infundibulum also was removed as a series of macroscopic preparations, which were sectioned in their short axis at 5-µm thickness. The third heart was assessed using microcomputed tomography after it had been stained with 7.5% I2KI contrast agent for 14 days, with the contrast agent refreshed on the seventh day. RESULTS: Specialized conducting cardiomyocytes from the base of the anterior papillary muscle to the supraventricular crest and subpulmonary infundibulum were identified and tracked using histology in 2 hearts and microcomputed tomography in the other. Transitional cells were also found at these sites. CONCLUSION: The existence of such specialized cardiomyocytes within the infundibulum is of clinical significance because they could be the morphologic substrate for arrhythmias known to originate from these sites.

The ox atrioventricular conduction axis compared to human in relation to the original investigation of sunao tawara.

It was Sunao Tawara who, in 1906, established the foundations for knowledge of the arrangement of the atrioventricular conduction axis in man and other mammals. Study of the hearts of ungulates was a central part in his investigation, which assessed other species, including man. He described several subtle differences between the mammals. We have now ourselves studied the cardiac conduction tissue of the ox heart, comparing our findings with our knowledge of the arrangement in man, and providing new insights into the differences illustrated by Tawara. It is, perhaps, surprising that these differences, although subtle, have not attracted more attention. We show that the major difference is the fact that the noncoronary aortic sinus in the ox heart is mainly supported by the myocardium of the ventricular septum, whereas in the human heart the sinus, and its leaflet, are in fibrous contiguity with the aortic leaflet of the mitral valve. It is this feature that determines the difference in the arrangement of the conduction axis between the species. We also show that the emergence of the left bundle branch on the left ventricular aspect of the muscular septum is more variable than previously described. Clin. Anat. 33:383-393, 2020. © 2019 Wiley Periodicals, Inc.

The influence of female mice age on biodistribution and biocompatibility of citrate-coated magnetic nanoparticles.

BACKGROUND: Magnetic nanoparticles (MNPs) have been successfully tested for several purposes in medical applications. However, knowledge concerning the effects of nanostructures on elderly organisms is remarkably scarce. PURPOSE: To fill part of this gap, this work aimed to investigate biocompatibility and bio-distribution aspects of magnetic nanoparticles coated with citrate (NpCit) in both elderly and young healthy mice. METHODS: NpCit (2.4 mg iron) was administered intraperitoneally, and its toxicity was evaluated for 28 days through clinical, biochemical, hematological, and histopathological examinations. In addition, its biodistribution was evaluated by spectrometric (inductively coupled plasma optical emission spectrometry) and histological methods. RESULTS: NpCit presented age-dependent effects, inducing very slight and temporary biochemical and hematological changes in young animals. These changes were even weaker than the effects of the aging process, especially those related to the hematological data, tumor necrosis factor alpha, and nitric oxide levels. On the other hand, NpCit showed a distinct set of results in the elderly group, sometimes reinforcing (decrease of lymphocytes and increase of monocytes) and sometimes opposing (erythrocyte parameters and cytokine levels) the aging changes. Leukocyte changes were still observed on the 28th day after treatment in the elderly group. Slight evidence of a decrease in liver and immune functions was detected in elderly mice treated or not treated with NpCit. It was noted that tissue damage or clinical changes related to aging or to the NpCit treatment were not observed. As detected for aging, the pattern of iron biodistribution was significantly different after NpCit administration: extra iron was detected until the 28th day, but in different organs of elderly (liver and kidneys) and young (spleen, liver, and lungs) mice. CONCLUSION: Taken together, the data show NpCit to be a stable and reasonably biocompatible sample, especially for young mice, and thus appropriate for biomedical applications. The data showed important differences after NpCit treatment related to the animals' age, and this emphasizes the need for further studies in older animals to appropriately extend the benefits of nanotechnology to the elderly population.

Why do we break one of the first rules of anatomy when describing the components of the heart?

A rule of human anatomy is that all structures within the body should be described relative to the so-called "anatomical position." Along with those describing structures such as the skull and liver, those accounting for the components of the heart consistently break this rule, describing the organ as if removed from the body and positioned on its apex, the so-called "Valentine position." Although potentially appropriate to some animal species, this approach produces problems when used in human anatomy, even if the right and left ventricles are only viewed in truly right-sided and left-sided positions when assessed in the Valentine fashion. The names of the ventricles, of course, are never going to change. This is not necessarily the case with other cardiac components. Consider the artery that extends between the ventricles on their diaphragmatic surface. Blockage produces inferior myocardial infarction, which is to be expected, since the vessel is located in inferior and interventricular position. It is incorrect to describe the artery as being posterior and descending. Such infelicities are now the more obvious with the advent of techniques that, in clinical cardiology, show the components of the heart as it lies within the chest. In this review, we have assessed the frequency of use of the Valentine approach in popular textbooks used by students of human anatomy. We show that, using the conduction tissues as a model, this system also being incorrectly described in the majority of the textbooks, the situation can be improved by use of attitudinally appropriate description. Clin. Anat. 32:585-596, 2019. © 2019 Wiley Periodicals, Inc.

Crista Supraventricularis Purkinje Network and Its Relation to Intraseptal Purkinje Network.

Using transparent specimens with a dual color injection, microscopy, and computer tomography, this report shows that the right and left ventricular subendocardial Purkinje networks are connected by an extensive septal network in the bovine heart. The septal network is present along the entire septum except at a free zone below ventricular valves. Being the only communication of the basal right septum with the right free wall, the supraventricular crest is an enigmatic but not, by any means, hidden muscular structure. It is one of the last structures to be activated in human heart. It is shown here that the supraventricular crest Purkinje network connects the anterosuperior right ventricular basal free wall Purkinje network to anterior right ventricular basal septal Purkinje network. It is suggested that the stimulus initiated at middle left ventricular endocardium will activate the supraventricular crest. The intraseptal connection found between the basal left ventricular subendocardial septal Purkinje network and the right ventricular basal septal Purkinje network is, probably, the pathway for the stimulus. An anatomic basis is provided to explain why the inflow tract contracts earlier than the outflow tract in the right ventricle systole. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:1793-1801, 2017. © 2017 Wiley Periodicals, Inc.