Three-Dimensional Impedance Tomographic Mapping of Metabolically Active Endolumen

Real-time detection of vulnerable atherosclerotic lesions, characterized by a high content of oxidized low-density lipoprotein (oxLDL)-laden macrophages or foam cells, remains an unmet clinical need. While fractional flow reserve (FFR)-guided revascularization in angiographically intermediate stenoses is utilized to assess hemodynamic significance, in vivo detection of oxLDL-rich plaques may provide a new paradigm for treating metabolically unstable lesions. Herein, we have demonstrated endoluminal mapping of lipid-laden lesions using 3-D electrical impedance spectroscopy-derived impedance tomography (EIT) in a pre-clinical swine model. We performed surgical banding of the right carotid arteries of Yucatan mini-pigs, followed by 16 weeks of high-fat diet, to promote the development of lipid-rich lesions. We implemented an intravascular sensor combining an FFR pressure transducer with a 6-point micro-electrode array for electrical impedance spectroscopy (EIS) measurements. 3-D EIT mapping was achieved using an EIS-based reconstruction algorithm. We demonstrated that EIT mapping corresponds to endoluminal histology for oxLDL-laden lesions. We further used computational models to theoretically predict and validate EIS measurements. Thus, our 3-D EIS-derived EIT provides in vivo detection of metabolically active plaques with the goal of guiding optimal intravascular intervention

Cellular Imaging of Human Atherosclerotic Lesions by Intravascular Electric Impedance Spectroscopy

Background: Newer techniques are required to identify atherosclerotic lesions that are prone to rupture. Electric impedance spectroscopy (EIS) is able to provide information about the cellular composition of biological tissue. The present study was performed to determine the influence of inflammatory processes in type Va (lipid core, thick fibrous cap) and Vc (abundant fibrous connective tissue while lipid is minimal or even absent) human atherosclerotic lesions on the electrical impedance of these lesions measured by EIS. Methods and Results: EIS was performed on 1 aortic and 3 femoral human arteries at 25 spots with visually heavy plaque burden. Severely calcified lesions were excluded from analysis. A highly flexible micro-electrode mounted onto a balloon catheter was placed on marked regions to measure impedance values at 100 kHz. After paraffin embedding, visible marked cross sections (n = 21) were processed. Assessment of lesion types was performed by Movats staining. Immunostaining for CD31 (marker of neovascularisation), CD36 (scavenger cells) and MMP-3 (matrix metalloproteinase-3) was performed. The amount of positive cells was assessed semi-quantitatively. 15 type Va lesions and 6 type Vc lesions were identified. Lesions containing abundant CD36-, CD31- and MMP-3-positive staining revealed significantly higher impedance values compared to lesions with marginal or without positive staining (CD36+455650 V vs. CD36- 346653 V, p = 0.001; CD31+436643 V vs. CD31- 340655 V, p = 0.001; MMP-3+ 400668 V vs. MMP-3- 323633 V, p = 0.03)

A basic study of electrical impedance spectroscopy for intravascular diagnosis and therapy monitoring of atherosclerosis

The thesis reports about the feasibility of electrical impedance spectroscopy with microsystems for the intravascular diagnosis of atherosclerosis. Based on a basic investigation on the cellular level, it describes how the impedance of vessel walls on the microscale is determined and how the cellular alteration related with atherosclerosis affects the measured impedance. For an intravascular impedance characterization of vessels, it shows the development of a balloon impedance catheter (BIC) equipped with a flexible microelectrode structure. BIC measurement proved to be sensitive enough to detect the thickness of vessel walls or plaque positions. From in situ animal experiments, it demonstrates the potential of BIC to characterize atheromatous vessels.Die vorliegende Arbeit beschäftigt sich mit Untersuchungen zum Einsatz von Mikrosystemen, basierend auf elektrischer Impedanzspektroskopie, für die intravaskuläre Diagnose von Atherosklerose. Auf zellulärer Ebene konnte zum einen die Impedanz von Gefäßwänden bestimmt sowie die Auswirkungen von zellulären Veränderungen auf diese gezeigt werden. Für die intravaskuläre Impedanzspektroskopie wurde ein Ballon-Katheter mit integrierten Mikroelektroden entwickelt. Durchgeführte Messungen zeigen eine ausreichend hohe Empfindlichkeit zur Detektion von Gefäßwandstärken oder zur Lokalisierung von Plaques. Abschließend konnte im Tierversuch die Charakterisierung von atherosklerotischen Gefäßen gezeigt werden

Electrical Impedance Based Spectroscopy and Tomography Techniques for Obesity and Heart Diseases

Despite advances in diagnosis and therapy, atherosclerosis cardiovascular disease remains the leading cause of morbidity and mortality. Predicting metabolically active atherosclerotic lesions has remained an unmet clinical need. Specially, atherosclerotic plaques that are prone to rupture are of extremely high-risk and can cause detrimental heart attacks and/or strokes, leading to sudden death. It has been shown that atheroscleroses is correlated to the level of obesity of an individual [1] Usually in clinical practice, the doctor will assess a patient's "risk factor" based on his or her Body Mass Index (BMS), and measurement of the waist circumference. Meanwhile the level of fatty droplet deposits in the liver is an important bio-marker to assess the patient's risk factor, however the patient will need to undergo radiation imaging such as CT scan or MRI scan. For the vulnerable plaques that can lead to sudden rupture, the ability to distinguish them at an early stage remains largely lacking. Therefore it is of great clinical interest to find improved diagnostic techniques to identify and localize such vulnerable plaques. Meanwhile, lipid has significantly lower electrical impedance than the rest of the vessel tissues in certain frequency bands [2]. In this thesis we explore spectroscopic and tomographic methods to characterize such plaques. In addition, with the Electrical Impedance Tomography method we will propose a novel method to detect fatty liver in an early stage with non-radiating and non-invasive manner.</p

Dual gated PET/CT imaging of heart

Coronary artery disease (CAD) resulting from atherosclerotic arterial changes, plaques, is a progressive process, which can be asymptomatic for many years. Asymptomatic CAD can cause a heart attack that leads to sudden death if the vulnerable coronary plaque ruptures and causes artery occlusion. The plaque inflammation plays an important role in the rupture susceptibility. Reliable anticipation of rupture is still clinically impossible for a single patient. Detection of the vulnerable coronary plaques before clinical signs remains a significant scientific challenge where positron emission tomography (PET) can play an important role. The aim of this dissertation was to find out whether a small, coronary plaque size, heart structures could be detected by a clinically available positron emission tomography and computed tomography (PET/CT) hybrid camera in realistically moving cardiac phantoms, a minipig model, and patients with CAD. Due to cardiac motions accurate detection of small heart structures are known to be problematic in PET imaging. Due to absence of commercial application at the beginning of the study, new dual gating method for cardiac PET imaging was developed and programmed that takes into account both contraction and respiratory induced cardiac motions. Cardiac phantom PET studies showed that small, active and moving plaques can be distinguished from myocardium activity and the gating methods improved the detection sensitivity and resolution of the plaques. In minipig and CAD patient cardiac PET studies small structures of myocardium and coronary arteries was detected more sensitive and accurately when using dual gating method than manufacturer gating methods. In cardiac patient PET study respiratory induced cardiac motions were shown to be linearly dependent with spirometry-measured respiratory volumes. Standard 3-lead electrocardiogram (ECG) measurement can be filtered by anesthesia monitor to detect lung impedance signal. In cardiac patient PET study this lung impedance signal were applied for respiratory gating. In this study was observed that the 3-lead ECG derived impedance signal gating method detects respiratory induced cardiac motion in PET as well as other externally used respiratory gating methods. In summary, the dual gated cardiac PET method is more sensitive and accurate to detect small cardiac structures, as coronary vessel wall pathology, than the commercial methods used in the study.Sydämen kaksoisliiketahdistettu PET/CT kuvantaminen Ateroskleroottisten valtimomuutosten, plakkien, seurauksena asteittain kehittyvä sepelvaltimotauti voi olla vuosia oireeton. Oireeton sepelvaltimotauti voi aiheuttaa äkkikuolemaan johtavan sydäninfarktin, mikäli sepelvaltimon seinämäplakin repeytymisestä aiheutuu verisuonen tukkiva hyytymä. Tutkimuksissa on osoitettu, että plakin tulehduksella on merkittävä rooli repeytymisalttiudelle. Repeytymisen luotettava ennakointi on yksittäisen potilaan kohdalla edelleen kliinisesti mahdotonta. Tulehtuneiden ja repeytymisalttiiden sepelvaltimoplakkien toteaminen ennen kliinisiä oireita on edelleen merkittävä tieteellinen haaste, missä positroniemissiotomografia (PET) kuvantamisella voi olla merkittävä rooli. Väitöskirjan tavoitteena oli selvittää, voidaanko kliinisessä käytössä olevalla positroniemissiotomografia ja tietokonetomografia (PET/TT) yhdistelmäkameralla havaita pieniä, sepelvaltimoplakkien kokoisia, sydämen rakenteita koneellisesti toimivissa todenmukaisissa sydänmalleissa, eläinmallissa ja sepelvaltimotautia sairastavilla potilailla. Sydämen pienten rakenteiden tarkka havaitseminen PET/TTkameroilla on haasteellista sydämen liikkumisen vuoksi. Tutkimuksessa kehitettiin ja ohjelmoitiin uusi sydämen PET-kuvantamisen liiketahdistusmenetelmä, joka ottaa huomioon sekä sydämen supistusliikkeen että hengitysliikkeen vaikutuksen sydämen PET kuvantamissa. Koneellisilla sydänmalleilla osoitettiin, että PET on riittävän herkkä havaitsemaan pieniä ja liikkuvia radioaktiivisia ”sepelvaltimoplakkeja”, ja että liiketahdistusmenetelmät parantavat plakkien havaitsemisherkkyyttä ja tarkkuutta. Eläinmallissa ja sepelvaltimotautipotilailla kaksoisliiketahdistusmenetelmän herkkyys ja tarkkuus havaita pieniä sydänlihaksen ja sepelvaltimoiden rakenteita todettiin kaupallisia tahdistusmenetelmiä paremmaksi. Potilastutkimuksissa todettiin hengityksen aiheuttama sydämen liike PET-kuvissa lineaarisesti riippuvaiseksi spirometrialla mitattujen hengitystilavuuksien kanssa. Tavallisesta 3-johtoisesta sydänsähkökäyrästä voidaan anestesiamonitorin avulla suodattaa keuhkojen impedanssisignaalia. Hengitysliikkeen aiheuttama potilaiden sydämen liike PETkuvissa havaittiin yhtä hyvin käyttämällä tätä keuhkojen impedanssisignaalia kuin muita yleisesti käytettäviä ulkoisia hengitystahdistussignaaleja. Todetaan, että kaksoisliiketahdistettu sydämen PET-kuvantamismenetelmä on tutkimuksessa käytettyjä kaupallisia menetelmiä herkempi ja tarkempi havaitsemaan sydämen pieniä rakenteita sekä sepelvaltimon seinämän tulehdusplakkeja

Removal of cardiovascular obstructions by spark erosion

Coronary atherosclerosis, leading to coronary artery stenosis, is the main cause for ischemic health disease in the Westem countries. Stenoses manifest themselves by limiting blood supply to the myocardium thus causing complaints. A long history of degenerative atherosclerotic disease of the intimal wall of the coronary vessels has usually preceded these events. Probably because of this long term process the composition of the accumulated obstructive tissue is quite heterogeneous and consists of a variety of cells and extra cellular material like lipid containing macrophages, smooth muscle cells, Illonocytes, collagen. cholesterol crystals and calcium. In addition, fresh or organized thrombi may have been deposited on these plaques. Regression of these lesions may be obtained by lifestyle changes or lipid lowering therapy. The acute invasive removal of such complex lesions, however, cannot be achieved by applying simple mechanical or chemical means

The development and applications of a system designed to quantify coronary arterial stenosis

The objective analysis of coronary artery stenosis is required for the assessment of interventions in the management of Coronary Artery Disease (CAD). This thesis presents a microcomputer-based system designed to meet this requirement which is easy to use and relatively cheap. The hardware consists of a standard 35 mm cine-projector (International General Electric Company), a rear projection graphics tablet (GTCO Corporation) and microcomputer (Vector Graphic Limited) with printer (Epson Limited). The graphics tablet and projector are mounted into a steel framework which allows an arteriographic image to be cast from the rear of the projector and focused, parallax free, onto the centre of the tablet. The tablet in turn communicates with the computer via a RS232 link. [Continues.

Dynamic Measures of Arterial Stiffness in a Rodent Model

Cardiovascular disease is one of the leading causes of death in Canada. Arterial stiffness is an important factor in the pathogenesis of cardiovascular disease. Cardiac failure, hypertension, renal failure, and dementia have all been linked to arterial stiffness. The arterial system is designed to dampen the pulses of blood from the heart's left ventricle and distribute the blood forward as steady flow in the small vessels. The pulse-dampening ability of the arterial system is reduced with age when the elastic fibers in the arterial wall degrade and fracture. The arterial stiffening process can accelerate from deposition of minerals within the arterial wall, such as calcium, from the endothelial layer becoming compromised or from fibrosis secondary to inflammation or turbulence. Arterial stiffness can be assessed post-mortem by microscopic examination of the arterial wall. However, for use in dynamic experiments and for therapeutic intervention, several ante-mortem techniques have been developed: pulse wave velocity (PWV), pulse waveform analysis (PWA), wave separation analysis (WSA), and carotid ultrasonography. Rats are important models for cardiovascular disease, toxicology, and pharmacological studies because of their convenient size and short life cycle. However, PWA and WSA have not been shown to be valid approaches for studying arterial stiffness in rat peripheral arteries. In this thesis, dynamic in vivo methods for PWA and WSA in rat peripheral arteries were developed to provide accurate measures of arterial stiffness. Software specific to the rat vasculature, PWanalyze and WSanalyze, was developed to measure PWA and WSA parameters, respectively. A comparison of these PWA and WSA methods in rat peripheral arteries was performed by creating a range of arterial stiffnesses through acute and chronic experiments. Arterial stiffness was measured in the femoral artery by a novel PWA parameter, the minimum time derivative of blood pressure dp/dt(min), as effectively as the established parameter the maximum time derivative of blood pressure dp/dt(max). A new method of WSA in femoral arteries was developed. Backward wave amplitude measured in the aorta was shown to increase as arteries stiffened and decrease as arteries relaxed with acute vasoactive drug injections. These experiments showed that dp/dt(min) and WSA are valid approaches to use when studying arterial stiffness in rats