BACKGROUND: His bundle pacing (HBP) is a relatively new treatment modality for patients experiencing issues with the cardiac conduction system. The treatment is thought to be an advantageous therapy compared with the standard treatment because it uses the native conduction pathway instead of introducing a non-physiological correction pathway which has been documented to increase the risk of heart failure. First carried out in humans in 2000 (Deshmukh, Casavant, Romanyshyn, & Anderson, 2000), HBP has been shown to be superior to right ventricular pacing and equivalent to cardiac resynchronization therapy. Because of the relative recency of the application of this technique in humans, there is a need for more studies to understand the long-term effectiveness and to guide training for new clinicians. 
OBJECTIVES: The objectives of this study were to (1) define the utility of three-dimensional mapping as a guiding tool for lead placement in HBP, (2) investigate the electroanatomical imaging of the atrioventricular (AV) septum, bundle of His, and other areas of the conduction system, (3) apply these observations to guide optimal pacing lead placement in the clinical setting, and (4) describe the correction of right and left bundle branch blocks by HBP. METHODS: Patients with pacemaker indication due to diseased conduction system were identified and recommended to undergo His bundle lead implantation. The lead was navigated into the heart by fluoroscopy and progressing the catheter through the axillary, subclavian, and cephalic veins. During the procedure, electroanatomical mapping was conducted by a quadripolar catheter to guide lead placement. His cloud, non-selective capture, and selective capture areas were marked and used to generate a 3D model layering the patient conduction system onto the physical anatomy. Pacemapping was then utilized to identify the most suitable area for disease correction.
Results: HBP mapping data were available in 24 patients. Several different responses to pacemapping were observed in the area of the AV septum including selective HBP (S-HBP), non-selective HBP (NS-HBP) (with upper, lower, and common variants), and right bundle branch (RBB) capture. Capture areas were superimposed onto the 3D model in real time and used to guide lead implantation for purposes of correcting various forms of conduction disease. The use of electroanatomical mapping (EAM) reduced the need for fluoroscopic guidance compared with the non-EAM-assisted procedure. Four common patterns were observed while mapping: (1) pattern 1, selective capture surrounded by upper and lower non-selective regions of capture; (2) pattern 2, selective capture surrounded by a common non-selective region of capture; (3) pattern 3, two separate non-selective capture areas with no selective capture; (4) pattern 4, common non-selective capture area with no selective capture. There was no correlation between capture threshold voltage and location of non-selective capture. Also, no correlation was found between capture threshold voltage and presence of common non-selective versus upper and lower non-selective capture areas. Patients with left bundle branch block (LBBB) and RBBB had similar His capture anatomy and were correctable by NS-HBP. CONCLUSIONS: HBP guided by electroanatomical mapping should be considered as a standard approach during pacemaker implantation. Because the underlying conduction anatomy is variable among patients, the use of EAM can direct lead positioning at a more physiologic location. In addition, EAM-guided implantation can reduce the need for fluoroscopy.

Thesis (M.S.)--University of Michigan, 1988.

Thesis (M.S.)--University of Michigan, 1988.

Cardiovascular disease is a leading cause of death in developed countries, and places a huge demand on healthcare services and economies across the globe. In this thesis computational models of the rabbit and mouse whole heart were developed and used to investigate a variety of phenomena related to cardiac electrophysiology. In part I, a heterogeneous family of single cell models was developed for the rabbit ventricles. The models were incorporated into a 3D anatomical reconstruction, and subsequently used to study the relationship between ventricular heterogeneity and the electrocardiographic T-wave. It was found that, in order of significance, apico-basal, inter-ventricular and transmural heterogeneity had a lead-dependent effect on the T-wave of the 12-lead electrocardiogram. Subsequently, a detailed model of the rabbit whole heart was developed using image data from X-ray computed tomography, from which detailed anatomical structures were segmented and myocardial architecture determined. The developed 3D whole heart model exhibited physiological fibre structure and experimentally justified patterns of activation. In part II, a mathematical model of the mouse atrioventricular node was developed. The model was validated by its ability to show physiological pacemaking and response to ion channel blocking. The model was subsequently adapted to consider the heterogeneous nature of the atrioventricular node, and incorporated into a 2D simplistic tissue model of the whole heart. The developed model exhibited physiological atrioventricular conduction, and provided insights into the nature of dual-pathway electrophysiology and the role of the funny current. Finally, an optimisation study was carried out for contrast enhancement of X-ray computed tomography, specifically for imaging the mouse heart, the results of which may be used to facilitate future high-throughput imaging of cardiac tissue.

Bradyarrhythmias are common clinical findings consisting of physiologic and pathologic conditions (sinus node dysfunction and atrioventricular [AV] conduction disturbances). Bradyarrhythmias can be benign, requiring no treatment; however, acute unstable bradycardia can lead to cardiac arrest. In patients with confirmed or suspected bradycardia, a thorough history and physical examination should include possible causes of sinoatrial node dysfunction or AV block. Management of bradycardia is based on the severity of symptoms, the underlying causes, presence of potentially reversible causes, presence of adverse signs, and risk of progression to asystole. Pharmacologic therapy and/or pacing are used to manage unstable or symptomatic bradyarrhythmias.

Familial amyloidosis with polyneuropathy (FAP) was first reported from Portugal in 1952, but since then this syndrome has been recognized in many countries including Sweden. In this investigation cardiac and pulmonary functions in the Swedish variety of FAP were studied. A retrospective survey of the ECG findings in 71 patients showed a high prevalence of atrioventricular (38%) and intraventricular (41%) conduction defects, and also a high prevalence of atrial fibrillation (14%). In several patients a progression in the conduction defects to advanced disturbances could be observed and 10 out of 71 patients (14%) in the present series required pacemaker treatment. A histopathological study of the atrioventricular part of the conduction system showed marked amyloid infiltration in each case, which may explain the high prevalence of conduction defects. In an échocardiographie study which emcompassed 22 consecutive patients, all but those two patients with the shortest duration of symptomatic disease showed abnormal features. The most frequent and characteristic findings were hypertrophy of the interventricular septum (86%) and a hyperrefractile appearance of the iryocardium (68%). This unusual association of échocardiographie features is considered almost diagnostic of cardiac amyloidosis. A hemodynamic study showed an essentially normal systolic heart function, but in several patients there were signs of impaired diastolic function with increased myocardial rigidity. Several patients showed signs of obstruction of the ventricular outflow tracts. This finding, as well as the échocardiographie features, is in accordance with altered anatomical and functional properties of the interventricular septum. The major pulmonary function abnormalities were decreased maximum respiratory pressure which indicate that the neuropathy in FAP involves the respiratory musculature, and impaired diffusing capacity consistent with an alveo-capillary block caused by amyloid deposits. / digitalisering@umu

Background: Experimental mapping and computer modelling provide important platforms to study the fundamental mechanisms underlying normal and abnormal activation of the heart. However, accurate computer modelling requires detailed anatomical models and needs support and validation from experimental data. Aims: 1) Construction of detailed anatomical heart models with the cardiac conduction system (CCS). 2) Mapping of the electrical activation sequence in rabbit atria to support and validate computer simulation. 3) Mapping of the spontaneous activity in the atrioventricular ring tissues (AV rings), which consist of nodal-like myocytes and can be a source of atrial tachycardia. Methods: High-resolution magnetic resonance imaging (MRI) and computed tomography (CT) were used to provide two-dimensional (2D) images for the construction of the detailed anatomical heart models. Immunohistochemistry and Masson’s trichrome staining were used to distinguish the CCS in the heart. LabVIEW was used in the development of a multi-electrode mapping system. The multi-electrode mapping technique was employed to map the electrical activation sequence of the rabbit atria. The cellular automaton model was used to simulate electrical activation of the rabbit atria. Results: 1) Three detailed anatomical models were constructed, including a detailed three dimensional (3D) anatomical model of the rabbit heart (whole of the atria and part of the ventricles), a 3D anatomical model of the rat heart with the CCS and AV rings, and a 3D anatomical model of the human atrioventricular node. 2) A multi-electrode mapping system was developed. 3) The electrical activation sequence of the rabbit atria was mapped in detail using the multi-electrode mapping system. The conduction velocity in the rabbit atria was measured. The mapping data showed the coronary sinus and the left superior vena cava do not provide an interatrial conduction route during sinus rhythm in the rabbit heart. 4) Electrical activation of the rabbit atria was simulated with the support of the 3D anatomical model of the rabbit atria and the experimental mapping data. 5) The spontaneous activity in the rat AV rings was mapped using the multi-electrode mapping system. Conclusions: The detailed anatomical models developed in this study can be used to support accurate computer simulation and can also be used in anatomical teaching and research. The experimental mapping data from the rabbit atria can be used to support and validate computer simulation. The computer simulation study demonstrated the importance of anatomical structure and electrophysiological heterogeneity. This study also demonstrated that the AV rings could potentially act as ectopic pacemakers.

Intracardiac pathways mediating the parasympathetic control of various cardiac functions are incompletely understood. Several intracardiac ganglia have been demonstrated to potently influence cardiac rate [the sinoatrial (SA) ganglion], atrioventricular (AV) conduction (the AV ganglion), or left ventricular contractility (the cranioventricular ganglion). However, there are numerous ganglia found throughout the heart whose functions are poorly characterized. One such ganglion, the posterior atrial (PA) ganglion, is found in a fat pad on the rostral dorsal surface of the right atrium. We have investigated the potential impact of this ganglion on cardiac rate and AV conduction. We report that microinjections of a ganglionic blocker into the PA ganglion significantly attenuates the negative chronotropic effects of vagal stimulation without significantly influencing negative dromotropic effects. Because prior evidence indicates that the PA ganglion does not project to the SA node, we neuroanatomically tested the hypothesis that the PA ganglion mediates its effect on cardiac rate through an interganglionic projection to the SA ganglion. Subsequent to micro-injections of the retrograde tracer fast blue into the SA ganglion, >70% of the retrogradely labeled neurons found within five intracardiac ganglia throughout the heart were observed in the PA ganglion. The neuroanatomic data further indicate that intraganglionic neuronal circuits are found within the SA ganglion. The present data support the hypothesis that two interacting cardiac centers, i.e., the SA and PA ganglia, mediate the peripheral parasympathetic control of cardiac rate. These data further support the emerging concept of an intrinsic cardiac nervous system.

In the heart, unidirectional blood flow depends on proper heart valve function. As, in mammals, regulatory mechanisms of early heart valve and bone development are shown to contribute to adult heart valve pathologies, we used the animal model zebrafish (ZF, Danio rerio) to investigate the microarchitecture and differentiation of cardiac valve interstitial cells in the transition from juvenile (35 days) to end of adult breeding (2.5 years) stages. Of note, light microscopy and immunohistochemistry revealed major differences in ZF heart valve microarchitecture when compared with adult mice. We demonstrate evidence for rather chondrogenic features of valvular interstitial cells by histological staining and immunodetection of SOX-9, aggrecan, and type 2a1 collagen. Collagen depositions are enriched in a thin layer at the atrial aspect of atrioventricular valves and the ventricular aspect of bulboventricular valves, respectively. At the ultrastructural level, the collagen fibrils are lacking obvious periodicity and orientation throughout the entire valve. (J Histochem Cytochem 67:361–373, 2019)

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