Browsing by Subject "Cardiac"

Impulse propagation in cardiac muscle is determined not only by the excitable properties of the myocyte membrane, but also by the gross and fine structure of cardiac muscle. Ionic diffusion pathways are defined by the muscle's interconnected myocytes and interweaving interstitial spaces. Resistive variations arising from spatial changes in tissue structure, including geometry, composition and electrical properties have a significant impact on the success or failure of impulse propagation. Although much as been learned about the impact of discrete resistive architecture of the intracellular space, the role of the interstitial space in the spread of electrical activity is less well understood or appreciated at the microscopic scale.

The interstitial space, or interstitium, occupies from 20-25% of the total heart volume.

The structural and material composition of the interstitial space is both complex and

heterogeneous, encompassing non-myocyte cell structures and a conglomeration of

extracellular matrix proteins. The spatial distribution of the interstitium can vary from confined spaces between abutting myocytes and tightly packed cardiac fibers to large gaps between cardiac bundles and sheets

This work presents a discrete multidomain formulation that describes the three-dimensional ionic diffusion pathways between connected myocytes within a variable interstitial physiology and morphology. Unlike classically used continuous and discontinuous models of impulse propagation, the intracellular and extracellular spaces are represented as spatially distinct volumes with dynamic and static boundary conditions that electrically couple neighboring spaces to form the electrically cooperative tissue model. The discrete multidomain model provides a flexible platform to simulate impulse propagation at the microscopic scale within a three-dimensional context. The three-dimensional description of the interstitial space that

encompasses a single cell improves the capability of the model to realistically investigate the impact of the discontinuous and electrotonic inhomogeneities of the myocardium's interstitium.

Under the discrete multidomain representation, a non-uniformly described interstitium

capturing the passive properties of the intravascular space or variable distribution and

composition of the extracellular space that encompasses a cardiac fiber creates an

electrotonic load perpendicular to the direction of the propagating wavefront. During

longitudinal propagation along a cardiac fiber, results demonstrate waveshape

alterations due to variations in loads experienced radially that would have been otherwise masked in traditional model descriptions. Findings present a mechanism for eliminating myocyte membrane participation in impulse propagation, as the result of decreased loading experienced radially from a non-uniformly resistive extracellular space. Ultimately, conduction velocity increases by decreasing the "effective" surface-to-volume ratio, as theoretically hypothesized to occur in the conducting Purkinje tissue.

Throughout vertebrate evolution, the cardiac outflow vasculature has changed from a branchial arch system to a systemic and pulmonary circulatory system. However, all vertebrate hearts and outflow tracts still develop from a single heart tube. In the chick and mouse, cardiac neural crest cells divide the single outflow tract into the aorta and pulmonary arteries. Additionally, cardiac neural crest cells provide the smooth muscle of the aortic arch arteries, help to remodel the aortic arch arteries into asymmetrical structures, and contribute cardiac ganglia. I review the major contributions of cardiac neural crest cells to the outflow vasculature of the chick and mouse and apply this information to study cardiac neural crest cell contributions to vertebrates that lack a divided circulatory system. I re-evaluate the role of cardiac neural crest cells in zebrafish vasculature and find that these cells do contribute to the gill arch arteries, the ventral aorta and cardiac ganglia, but they do not contribute to myocardium. I also study the outflow tract development of the turtle Trachemys scripta to understand the process of outflow septation in a vertebrate that has a divided outflow tract but an incomplete division of the ventricle. I compare the chick outflow tract to the turtle. The formation of the proximal versus distal cushions and the appearance of smooth muscle cells within the distal cushions of the turtle are very similar to the cushion position and cell types within the cushions of the chick. In the chick, the smooth muscle positive cells in the distal cushions are derived from cardiac neural crest cells. I hypothesize that cardiac neural crest cells are also responsible for the outflow tract septation of reptiles. These results demonstrate that the pattern of cardiac neural crest cell contribution to vertebrate vasculature remains predictable and consistent, enabling future studies to focus on changes in vascular patterning caused by cardiac neural crest cells among different vertebrate lineages.

This dissertation investigates the feasibility of a real-time transthoracic Acoustic Radiation Force Impulse (ARFI) imaging system to measure myocardial function non-invasively in clinical setting. Heart failure is an important cardiovascular disease and contributes to the leading cause of death for developed countries. Patients exhibiting heart failure with a low left ventricular ejection fraction (LVEF) can often be identified by clinicians, but patients with preserved LVEF might be undetected if they do not exhibit other signs and symptoms of heart failure. These cases motivate development of transthoracic ARFI imaging to aid the early diagnosis of the structural and functional heart abnormalities leading to heart failure.

M-Mode ARFI imaging utilizes ultrasonic radiation force to displace tissue several micrometers in the direction of wave propagation. Conventional ultrasound tracks the response of the tissue to the force. This measurement is repeated rapidly at a location through the cardiac cycle, measuring timing and relative changes in myocardial stiffness. ARFI imaging was previously shown capable of measuring myocardial properties and function via invasive open-chest and intracardiac approaches.

The prototype imaging system described in this dissertation is capable of rapid acquisition, processing, and display of ARFI images and shear wave elasticity imaging (SWEI) movies. Also presented is a rigorous safety analysis, including finite element method (FEM) simulations of tissue heating, hydrophone intensity and mechanical index (MI) measurements, and thermocouple transducer face heating measurements. For the pulse sequences used in later animal and clinical studies, results from the safety analysis indicates that transthoracic ARFI imaging can be safely applied at rates and levels realizable on the prototype ARFI imaging system.

Preliminary data are presented from in vivo trials studying changes in myocardial stiffness occurring under normal and abnormal heart function. Presented is the first use of transthoracic ARFI imaging in a serial study of heart failure in a porcine model. Results demonstrate the ability of transthoracic ARFI to image cyclically-varying stiffness changes in healthy and infarcted myocardium under good B-mode imaging conditions at depths in the range of 3-5 cm. Challenging imaging scenarios such as deep regions of interest, vigorous lateral motion and stable, reverberant clutter are analyzed and discussed.

Results are then presented from the first study of clinical feasibility of transthoracic cardiac ARFI imaging. At the Duke University Medical Center, healthy volunteers and patients having magnetic resonance imaging-confirmed apical infarcts were enrolled for the study. The number of patients who met the inclusion criteria in this preliminary clinical trial was low, but results showed that the limitations seen in animal studies were not overcome by allowing transmit power levels to exceed the FDA mechanical index (MI) limit. The results suggested the primary source of image degradation was clutter rather than lack of radiation force. Additionally, the transthoracic method applied in its present form was not shown capable of tracking propagating ARFI-induced shear waves in the myocardium.

Under current instrumentation and processing methods, results of these studies support feasibility for transthoracic ARFI in high-quality B-Mode imaging conditions. Transthoracic ARFI was not shown sensitive to infarct or to tracking heart failure in the presence of clutter and signal decorrelation. This work does provide evidence that transthoracic ARFI imaging is a safe non-invasive tool, but clinical efficacy as a diagnostic tool will need to be addressed by further development to overcome current challenges and increase robustness to sources of image degradation.