In keeping with an existing and ongoing focus in cardiology - this article (brief opinion) is also on the use of advanced technology in cardiovascular medicine:

In a normal human life-span, the heart beats 2.5 billion times, made possible by a specialized heart cell type (cardiomyocyte) collectively known as the cardiac conduction system (CCS)¹. The specialized CCS is anatomically distinct from the working myocardium, with its natural capacity to generate electrical impulses and function as biological pacemakers² (Fig 1).  

Structurally, the CCS constitutes of -

1. The sinus node in the right atrium (SA) - the primary pacemaker,
2. The atrioventricular conduction axis (AV) – the only pathway allowing excitation to pass between the atria and the ventricles, and
3. The Purkinje network – allowing fast/coordinated conduction in the ventricles³. 

The electrical activity of the CCS typically results in an electrocardiogram (ECG/EKG) signal (Fig 2), clinically used to monitor the heart’s wiring system. Pathophysiological remodelling of the specialized cardiomyocytes often accompany cardiac arrhythmias and conduction disturbances. However, even with existing advanced imaging techniques, intricate knowledge of the three-dimensional (3D) microanatomy and cellular orientation of the human CCS has remained unknown^3,4. 

In August 2017, a study culminating over seven years, combined existing methods of contrast-enhanced micro-computed tomography (micro-CT) and software systems, to produce high-resolution cellular maps of the human heart’s wiring system².  The technique is yet only useful with post-mortem whole heart tissue, due to the high dose of iodine-based contrast agent and a diffusion period of 2 weeks required for CCS visualization. Ideally, this imaging technique could be optimized to guide surgeons during real-time surgery since the conduction system is currently invisible at such interventions². The clinical dysfunctions of the conduction system, usually result from acquired conditions of myocardial ischemia/infarction, age-related degeneration, procedural complications, and drug toxicity¹; therefore a 3D window to the CCS can provide first-hand insight to clinicians and researchers in cardiovascular research.    

RE-EXAMINING THE CARDIAC ANATOMY

In the last decade, immunohistochemistry with combined imaging techniques transformed medical knowledge of the human CCS by revealing the sinoatrial node (SA) to be anatomically distinct from the earlier medical-textbook version^2,3. Studies further investigated the hearts of rat and rabbit models with micro-CT thereafter, to gain additional insight to the function of specialized cardiomyocytes that generate pumping functions of the heart⁴. In the present study, Stephenson et al combined 3D reconstruction to mathematical modelling based on micro-CT images, for anatomically precise, unprecedented reconstruction of the human CCS ex-vivo². 

The non-invasive, non-destructive, contrast-enhanced imaging technique known as micro-CT enabled 3D representations of the cardiac conduction system, segmented from a single data set [Fig 3a, sinus node-blue, paranodal area-turquoise, atrioventricular conduction axis-green, and Purkinje networks-the right (red) and left (purple)]. The CCS was then superimposed on a semi-transparent or ‘ghosted’ rendering of the intact whole heart (Fig 3b, RA-right atrium, LA-left atrium, RV-right ventricle, LV-left ventricle). 

After identifying regions of interest on the micro-CT images, models were reconstructed in 3D using volume rendering and segmentation software (Fig 4). The imaging technique clearly differentiated the specialized cardiomyocytes conducting electricity (Fig 3C) from the normal working cardiomyocytes. Subsequent computational simulations were developed with electrophysiologically accurate electrical activity using mathematical modelling software (Fig 3D). Further work remains to incorporate the morphological detail of Purkinje fibers gathered from the data set into an accurate cellular model of the Purkinje system². 

CLINICAL APPLICATIONS OF THE VIRTUAL ANATOMY

The 3D models have a variety of practical applications starting with the ability to form the basis of 4-dimensional (4D) conductance simulations, based on normal and abnormal electrocardiograms (ECGs). The imaging procedure can also allow micro-structural evaluation of arrhythmias (heart rhythm problems) and target identification for catheter-ablation (a procedure used to destroy selective areas of the heart responsible for arrhythmia)⁵. Additionally, the models have potential to mimic drug effects and demonstrate the impact of pharmacotherapy on ion-channel activity in drug discovery studies². Beyond the immediate functionalities listed, the knowledge can be broadly incorporated to refine the biological position during heart valve implantation and prevent stenosis⁶. Furthermore, if proven comparable in congenital studies, the technique could guide reconstruction surgery plans in pediatric cardiovascular medicine, enabling certainty to locate impaired conduction tissue². While the use of micro-CT for virtual archival of post-mortem fetal heart tissue has proven potential in congenital malformation studies⁷, the present techniques can allow high-resolution, 3D anatomical detail of the conduction system in such malformations. Pediatric cardiac surgery increasingly relies on anatomically accurate printed models at present, and will benefit from 3D models representing the microanatomy of the CCS in future.   

The findings confirmed previous investigations and demonstrated the relationship between conducting tissues and the surrounding cardiac anatomy in 3D for the first time, in a single human heart^2,8. The high-resolution data was in agreement with previous observations made with immunohistochemistry and histology - predominant techniques in standard pathology^9,10. In contrast to standard 2-D sectioning in histology, however, the virtual, non-destructive re-slicing allowed accurate segmentation in multiple directions to achieve the 3D data (Fig 5, virtually sliced in the longitudinal axis). Preceding virtual models on human disease in the 3D atria, had only integrated morphological data from histology and from models of disparate species¹¹, highlighting the importance of whole heart high-resolution data discussed here.  

While the 3D technique will not replace tissue-slicing/staining histology techniques that have existed for more than a century, the group hopes it will evolve to allow visualization of the conduction system’s location in the heart, in real-time. This further includes interior access at the molecular and cellular level, to understand functionality of proteins and cell populations in the functional heart. The findings currently conclude that 'commonly accepted anatomical representations of the CCS are oversimplified' as recapped on an interview with the researchers available online.

Poster Image: The first 3D imaging technique of the intricate human Cardiac Conduction System. Published as Seeing the Heart’s Power, American Scientist 2017 (reference 2).

References:

1.  Park, D.S. & Fishman, G.I. The Cardiac Conduction System. Circulation 123, 904-915 (2011).
2. Stephenson, R.S., et al. High resolution 3-Dimensional imaging of the human cardiac conduction system from microanatomy to mathematical modeling. Scientific Reports 7, 7188 (2017).
3. Boyett, M.R. 'And the beat goes on.' The cardiac conduction system: the wiring system of the heart. Experimental physiology 94, 1035-1049 (2009).
4. Jarvis, J.C. & Stephenson, R. Studying the microanatomy of the heart in three dimensions: a practical update. Frontiers in pediatrics 1, 26 (2013).
5. Wazni, O. & Chung, M.K. Catheter Ablation for Rate Controlled Atrial Fibrillation: New Horizon in Heart Failure Treatment. Journal of the American College of Cardiology (2017).
6. Patel, A. & Kirtane, A.J. Aortic valve stenosis. JAMA Cardiology 1, 623-623 (2016).
7. Hutchinson, J.C., et al. Clinical utility of postmortem microcomputed tomography of the fetal heart: diagnostic imaging vs macroscopic dissection. Ultrasound in Obstetrics & Gynecology 47, 58-64 (2016).
8. Chandler, N., et al. Computer Three-Dimensional Anatomical Reconstruction of the Human Sinus Node and a Novel Paranodal Area. The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology 294, 970-979 (2011).
9. Matsuyama, T.-a., et al. Anatomical diversity and age-related histological changes in the human right atrial posterolateral wall. EP Europace 6, 307-315 (2004).
10. Oosthoek, P.W., Virágh, S., Lamers, W.H. & Moorman, A.F. Immunohistochemical delineation of the conduction system. II: The atrioventricular node and Purkinje fibers. Circulation Research 73, 482-491 (1993).
11. Aslanidi, O.V., et al. 3D virtual human atria: A computational platform for studying clinical atrial fibrillation. Progress in Biophysics and Molecular Biology 107, 156-168 (2011).