Conduit Artery Photoplethysmography and its Applications in the Assessment of Hemodynamic Condition

Elektroniskā versija nesatur pielikumusPromocijas darbā ir izstrādāta maģistrālo artēriju fotopletizmogrāfijas (APPG) metode hemodinamisko parametru novērtējumam. Pretstatot referentām metodēm, demonstrēta iespēja iegūt arteriālo elasticitāti raksturojošus parametrus, izmantojot APPG signāla formas analīzi (atvasinājuma un signāla formas aproksimācijas parametri) un ar APPG iegūtu pulsa izplatīšanās ātrumu unilaterālā gultnē. Izstrādāta APPG reģistrācijas standartizācija, mērījuma laikā nodrošinot optimālo sensora piespiedienu. Šis paņēmiens validēts ārējās ietekmes (sensora piespiediens) un hemodinamisko stāvokļu (perifērā vaskulārā pretestība) izmaiņās femorālā APPG signālā, identificējot būtiskākos faktorus APPG pielietojumos. Veikta APPG validācija asinsrites fizioloģijas un preklīniskā pētījumā demonstrējot APPG potenciālu pētniecībā un diagnostikā. Izstrādāts pulsa formas parametrizācijas paņēmiens, saistot fizioloģiskās un aproksimācijas modeļa komponentes. Atslēgas vārdi: maģistrālā artērija, fotopletizmogrāfija, arteriālā elasticitāte, metodes standartizācija, pulsa formas kvantifikācija, vazomocija, sepseThe doctoral thesis features the development of a conduit artery photoplethysmography technique (APPG) for the evaluation of hemodynamic parameters. Contrasting referent methods, the work demonstrates the possibility to receive parameters characterizing the arterial stiffness by means of APPG waveform analysis (derivation and waveform approximation parameters) and APPG obtained pulse wave velocity in a unilateral vascular bed. In this work APPG standardization technique was developed providing optimal probe contact pressure conditions. It was validated by altering the external factors (probe contact pressure) and hemodynamic conditions (peripheral vascular resistance) on the femoral APPG waveform identifying the key factors in APPG applications. The APPG validation in blood circulation physiology and a pre-clinical trial was performed demonstrating APPG potential in the extension of applications. An arterial waveform parameterization was developed relating the physiological wave to approximation model components. Keywords: conduit artery, photoplethysmography, arterial stiffness, method standardization, waveform parametrization, vasomotion, sepsi

2-D and 3-D high frame-rate Pulse Wave Imaging for the characterization of focal vascular disease

Cardiovascular diseases are major causes of morbidity and mortality in Western-style populations. Atherosclerosis and Abdominal Aortic Aneurysms (AAAs) are two prevalent vascular diseases that may progress without symptoms and contribute to acute cardiovascular events such as stroke and AAA rupture, which are consistently among the leading causes of death worldwide. The imaging methods used in the diagnosis of these diseases, have been reported to present several limitations. Given that both are associated with mechanical changes in the arterial wall, imaging of the arterial mechanical properties may improve early disease detection and patient care. Pulse wave velocity (PWV) refers to the velocity at which arterial waves generated by ventricular ejection travel along the arterial tree. PWV is a surrogate marker of arterial stiffness linked to cardiovascular mortality. The foot-to-foot method that is typically used to calculate PWV suffers from errors of distance measurements and time-delay measurements. Additionally, a single PWV estimate is provided over a relatively long distance, thus inherently lacking the capability to provide regional arterial stiffness measurements. Pulse Wave Imaging (PWI) is a noninvasive, ultrasound-based technique for imaging the propagation of pulse waves along the wall of major arteries and providing a regional PWV value for the imaged artery. The aim of this work was to enable PWI to provide more localized PWV and stiffness measurements within the imaged arterial segment and to further extend it into a 2-D and 3-D technique for the detection and monitoring of focal vascular disease at high temporal and spatial resolution. The improved modality was integrated with blood flow imaging modalities aiming to render PWI a comprehensive methodology for the study of arterial biomechanics in vivo. Spatial information was increased with the introduction of piecewise PWI. This novel technique was used to measure PWV within small sub-regions of the imaged vessel in murine aneurysmal (n = 8) and atherosclerotic aortas (n = 11) in vivo. It provided PWV and stiffness maps while capturing the progressive arterial stiffening caused by atherosclerosis. PWI was further augmented with a sophisticated adaptive algorithm, enabling it to optimally partition the imaged artery into relatively homogeneous segments, automatically isolating arterial stiffness inhomogeneities. Adaptive PWI was validated in silicone phantoms consisting of segments of varying stiffness and then tested in murine aortas in vivo. Subsequently, the conventional tradeoff between spatial and temporal resolution was addressed with a plane wave compounding implementation of PWI, allowing the acquisition of full field of view frames at over 2000 Hz. A GPU-accelerated PWI post-processing framework was developed for the processing of the big bulk of generated data. The parameters of coherent compounding were optimized in vivo. The optimized sequences were then used in the clinic to assess the mechanical properties of atherosclerotic carotids (n=10) and carotids of patients after endarterectomy (n=7), a procedure to remove the plaque and restore blood flow to the brain. In the case of atherosclerotic patients undergoing carotid endarterectomy, the results were compared against the histology of the excised plaques. Investigation of the mechanical properties of plaques was also conducted for the first time with a high-frequency transducer (18.5 MHz). Additionally, 4-D PWI was introduced, utilizing high frame rate 3-D plane wave acquisitions with a 2-D matrix array transducer (16x16 elements, 2.5 MHz). A novel methodology for PWV estimation along the direction of pulse wave propagation was implemented and validated in silicone phantoms. 4-D PWI provided comprehensive views of the pulse wave propagation in a plaque phantom and the results were compared against conventional PWI. Finally, its feasibility was tested in the carotid arteries of healthy human subjects (n=6). PWVs derived in 3-D were within the physiological range and showed good agreement with the results of conventional PWI. Finally, PWI was integrated with flow imaging modalities (Color and Vector Doppler). Thus, full field-of-view, high frame-rate, simultaneous and co-localized imaging of the arterial wall dynamics and color flow as well as 2-D vector flow was implemented. The feasibility of both techniques was tested in healthy subjects (n=6) in vivo. The relationship between the timings of the flow and wall velocities was investigated at multiple locations of the imaged artery. Vector flow velocities were found to be aligned with the vessel’s centerline during peak systole in the common carotid artery and interesting flow patterns were revealed in the case of the carotid bifurcation Consequently, with the aforementioned improvements and the inclusion of 3-D imaging, PWI is expected to provide comprehensive information on the mechanical properties of pathological arteries, providing clinicians with a powerful tool for the early detection of vascular abnormalities undetectable on the B-mode, while also enabling the monitoring of fully developed vascular pathology and of the recovery of post-operated vessels

Toward simultaneous flow and pressure assessment in large arteries using non-invasive ultrasound

Ultrageluid wordt in de kliniek vaak toegepast om op een niet-invasieve manier geometrische eigenschappen van grote vaten, zoals diameter en wanddikte en hemodynamische variabelen zoals bloedstroomsnelheid te bepalen. Om biomechanische parameters en hemodynamische variabelen die karakteristiek zijn voor de ontwikkeling van hart en vaatziekten, zoals compliantie en impedantie, te bepalen, is de bepaling van geometrie en bloedstroomsnelheid alleen onvoldoende. Daarvoor is een gelijktijdige en bij voorkeur niet invasieve meting van debiet en druk vereist. Met de huidige ultrageluidstechnieken is het onmogelijk om gelijktijdig debiet en druk nauwkeurig te bepalen. Debiet wordt vaak bepaald aan de hand van twee metingen: een diametermeting (geluidsbundel loodrecht op het vat) en een meting van de maximale axiale bloedstroomsnelheid met behulp van Doppler ultrageluid (geluidsbundel onder een hoek met het vat). Door een theoretische snelheidsverdeling aan te nemen, bijvoorbeeld een Poiseuille of Womersley profiel, wordt hieruit vervolgens het debiet berekend. In-vivo zijn vaten zelden recht: vaten zijn taps toelopend, gekromd en hebben vertakkingen. Dientengevolge zijn er secundaire snelheidscomponenten aanwezig die de axiale snelheidverdeling be¨invloeden. Dit resulteert in asymmetrische axiale snelheidsverdelingen. Omdat de aangenomen snelheidsverdelingen slechts geldig zijn voor rechte vaten, geeft een dusdanige bepaling een onnauwkeurige afschatting van het debiet. Verder is het onmogelijk om gelijktijdig met de snelheidsmeting nauwkeurig de wandbeweging te bepalen, waardoor de debietmeting nog verder verslechtert en het gelijktijdig bepalen van druk uit wandbeweging en debiet onmogelijk wordt. In dit onderzoek worden Particle Image Velocimetry (PIV) gebaseerde algoritmen toegepast op RF-data die verkregen zijn met behulp van een commercieel beschikbaar, voor klinische toepassing goedgekeurd ultrageluidssysteem. Dit maakt het mogelijk om snelheidscomponenten loodrecht op de ultrageluidbundel, en dus gelijktijdig wandpositie en axiale snelheid nauwkeurig te meten. Deze snelheidsmeettechniek is gevalideerd door metingen van het snelheidsprofiel in een experimentele opstelling te vergelijken met resultaten van computational fluid dynamics (CFD) berekeningen, voor stationaire en instationaire stromingen in een recht vat. Er werd een goede overeenstemming gevonden voor het axiale snelheidsprofiel. Integratie van het gemeten axiale snelheidsprofiel leverde een nauwkeurige afschatting van het debiet op. Omdat in de praktijk de meeste vaten gekromd zijn is de snelheids meetmethode vervolgens gevalideerd voor toepassing op stromingen in dit soort geometrieën. In de experimentele opstelling zijn axiale snelheidsprofielen gemeten voor stationaire en instationaire stroming in kromme buizen. Opnieuw zijn de gemeten profielen vergeleken met resultaten van CFD-berekeningen. Ook hier werd een goede overeenstemming gevonden tussen de gemeten profielen en de met behulp van CFD berekende snelheidsprofielen. Om nauwkeurig debiet te bepalen op basis van de gemeten asymmetrische axiale snelheidsprofielen, is een analytische en een op CFD gebaseerde studie gedaan naar stroming in kromme vaten. Deze studie heeft geresulteerd in de cos ¿-methode. Toepassing van de cos ¿-methode op de gemeten asymmetrische axiale profielen gaf een nauwkeurige afschatting van het debiet, voor stationaire en instationaire flow. Vergeleken met de huidig toegepaste afschattingsmethode voor het debiet werd een grote verbetering gevonden. Voor een fysiologisch relevant debiet gaf de cos ¿-methode een gemiddelde afwijking van 5% ten opzichte van het referentiedebiet terwijl deze voor de huidig toegepaste Poiseuille en Womersley benaderingen gelijk was aan 20%. Tenslotte is getracht om de lokale druk te bepalen uit enkel een niet-invasieve ultrageluidsmeting door een meting van de diameter te combineren met een gelijktijdige bepaling van de lokale compliantie. De lokale compliantie is bepaald door de lokale golfsnelheid (PWV) te meten. Verschillende methoden om lokaal de PWV te meten zijn getest in de experimentele opstelling. Hieruit bleek dat de QA-methode, een methode waarbij de lokale PWV bepaald wordt uit de verhouding tussen veranderingen in debiet en veranderingen in oppervlak van de dwarsdoorsnede van het vat, het mogelijk maakt om lokaal nauwkeurig PWV te meten. Door de PWV meting te combineren met een gelijktijdige meting van de diameter werd de lokale druk nauwkeurig afgeschat. Dit geeft aan dat het haalbaar is om op een niet-invasieve manier in-vivo druk te meten met behulp van ultrageluid. Hoewel de meettechnieken besproken in deze studie alleen getest zijn voor toepassing in een gecontroleerde experimentele omgeving, zijn de vooruitzichten voor klinische toepassing veelbelovend. De gepresenteerde methoden maken het mogelijk om de toestand van het vaatbed nauwkeuriger te bepalen, waardoor in de toekomst informatie verkregen kan worden over het effect van therapeutische ingrepen en factoren ge¨identificeerd kunnen worden die karakteristiek zijn voor de ontwikkeling van hart- en vaatziekten

Validation of a 1D Algorithm That Measures Pulse Wave Velocity to Estimate Compliance in Blood Vessels

The purpose of this research is to determine if it is possible to validate the new 1D method for measuring pulse wave velocity in the aorta in vivo and estimate compliance. Arterial pressure and blood flow characterize the traveling of blood from the heart to the arterial system and have played a significant role in the evaluation of cardiovascular diseases. Blood vessel distensibility can give some information on the evolution of cardiovascular disease. A patient’s aorta cannot be explanted to measure compliance; therefore we are using a flow phantom model to validate the 1D pulse wave velocity technique to estimate compliance

Methods and Algorithms for Cardiovascular Hemodynamics with Applications to Noninvasive Monitoring of Proximal Blood Pressure and Cardiac Output Using Pulse Transit Time

Advanced health monitoring and diagnostics technology are essential to reduce the unrivaled number of human fatalities due to cardiovascular diseases (CVDs). Traditionally, gold standard CVD diagnosis involves direct measurements of the aortic blood pressure (central BP) and flow by cardiac catheterization, which can lead to certain complications. Understanding the inner-workings of the cardiovascular system through patient-specific cardiovascular modeling can provide new means to CVD diagnosis and relating treatment. BP and flow waves propagate back and forth from heart to the peripheral sites, while carrying information about the properties of the arterial network. Their speed of propagation, magnitude and shape are directly related to the properties of blood and arterial vasculature. Obtaining functional and anatomical information about the arteries through clinical measurements and medical imaging, the digital twin of the arterial network of interest can be generated. The latter enables prediction of BP and flow waveforms along this network. Point of care devices (POCDs) can now conduct in-home measurements of cardiovascular signals, such as electrocardiogram (ECG), photoplethysmogram (PPG), ballistocardiogram (BCG) and even direct measurements of the pulse transit time (PTT). This vital information provides new opportunities for designing accurate patient-specific computational models eliminating, in many cases, the need for invasive measurements. One of the main efforts in this area is the development of noninvasive cuffless BP measurement using patient’s PTT. Commonly, BP prediction is carried out with regression models assuming direct or indirect relationships between BP and PTT. However, accounting for the nonlinear FSI mechanics of the arteries and the cardiac output is indispensable. In this work, a monotonicity-preserving quasi-1D FSI modeling platform is developed, capable of capturing the hyper-viscoelastic vessel wall deformation and nonlinear blood flow dynamics in arbitrary arterial networks. Special attention has been dedicated to the correct modeling of discontinuities, such as mechanical properties mismatch associated with the stent insertion, and the intertwining dynamics of multiscale 3D and 1D models when simulating the arterial network with an aneurysm. The developed platform, titled Cardiovascular Flow ANalysis (CardioFAN), is validated against well-known numerical, in vitro and in vivo arterial network measurements showing average prediction errors of 5.2%, 2.8% and 1.6% for blood flow, lumen cross-sectional area, and BP, respectively. CardioFAN evaluates the local PTT, which enables patient-specific calibration and its application to input signal reconstruction. The calibration is performed based on BP, stroke volume and PTT measured by POCDs. The calibrated model is then used in conjunction with noninvasively measured peripheral BP and PTT to inversely restore the cardiac output, proximal BP and aortic deformation in human subjects. The reconstructed results show average RMSEs of 1.4% for systolic and 4.6% for diastolic BPs, as well as 8.4% for cardiac output. This work is the first successful attempt in implementation of deterministic cardiovascular models as add-ons to wearable and smart POCD results, enabling continuous noninvasive monitoring of cardiovascular health to facilitate CVD diagnosis

Impact of alpha adrenergic and myogenic control on forearm vasomotor properties

We tested the hypotheses that forearm vascular compliance (C) but not resistance (R) would be influenced by myogenic stimuli, and changing (A) forearm transmural pressure (TP) would influence the effect of a-adrenergic input on C and R. Continuous forearm blood flow was measured during Norepinephrine (NE; a-agonist) and during concurrent NE and Phentolamine (PH; a-antagonist) infusion with the arm above and below heart level (n=10). C was inversely related to TP (p\u3c0.05). NE decreased C and increased R (p\u3c0.05). PH abolished these responses. The effect of NE on AC was greater with the arm above versus below heart level (p\u3c0.05), while AR was only observed with the arm below the heart (p\u3c0.05). Conclusions: Myogenic changes affect forearm vascular C independent of changes in R. Alpha -adrenergic activation reduces C and increases R. Furthermore, with NE, AC requires a high starting value of C, while AR occurs under high T

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

Ultrasonic Pulse Wave Imaging for in vivo Assessment of Vascular Wall Dynamics and Characterization of Arterial Pathologies

Arterial diseases such as hypertension, carotid stenosis, and abdominal aortic aneurysm (AAA) may progress silently without symptoms and contribute to acute cardiovascular events such as heart attack, stroke, and aneurysm rupture, which are consistently among the leading causes of death worldwide. The arterial pulse wave, regarded as one of the fundamental vital signs of clinical medicine, originates from the heart and propagates throughout the arterial tree as a pressure, flow velocity, and wall displacement wave, giving rise to the natural pulsation of the arteries. The dynamic properties of the pulse wave are intimately related to the physical state of the cardiovascular system. Thus, the assessment of the arterial wall dynamics driven by the pulse wave may provide valuable insights into vascular mechanical properties for the early detection and characterization of arterial pathologies. The focus of this dissertation was to develop and clinically implement Pulse Wave Imaging (PWI), an ultrasound elasticity imaging-based method for the visualization and spatio-temporal mapping of the pulse wave propagation at any accessible arterial location. Motion estimation algorithms based on cross-correlation of the ultrasound radio-frequency (RF) signals were used to track the arterial walls and capture the pulse wave-induced displacements over the cardiac cycle. PWI facilitates the image-guided measurement of clinically relevant pulse wave features such as propagation speed (pulse wave velocity, or PWV), uniformity, and morphology as well as derivation of the pulse pressure waveform. A parametric study investigating the performance of PWI in two canine aortas ex vivo and 10 normal, healthy human arteries in vivo established the optimal image acquisition and signal processing parameters for reliable measurement of the PWV and wave propagation uniformity. Using this framework, three separate clinical feasibility studies were conducted in patients diagnosed with hypertension, AAA, and carotid stenosis. In a pilot study comparing hypertensive and aneurysmal abdominal aortas with normal controls, the AAA group exhibited significantly higher PWV and lower wave propagation uniformity. A “teetering” motion upon pulse wave arrival was detected in the smaller aneurysms ( 5.5 cm in diameter). While no significant difference in PWV or propagation uniformity was observed between normal and hypertensive aortas, qualitative differences in the pulse wave morphology along the imaged aortic segment may be an indicator of increased wave reflection caused by elevated blood pressure and/or arterial stiffness. Pulse Wave Ultrasound Manometry (PWUM) was introduced as an extension of the PWI method for the derivation of the pulse pressure (PP) waveform in large central arteries. A feasibility study in 5 normotensive, 9 pre-hypertensive, and 5 hypertensive subjects indicated that a significantly higher PP in the hypertensive group was detected in the abdominal aorta by PWUM but not in the peripheral arteries by alternative devices (i.e. a radial applanation tonometer and the brachial sphygmomanometer cuff). A relatively strong positive correlation between aortic PP and both radial and brachial PP was observed in the hypertensive group but not in the normal and pre-hypertensive groups, confirming the notion that PP variation throughout the arterial tree may not be uniform in relatively compliant arteries. The application of PWI in 10 stenotic carotid arteries identified phenomenon such as wave convergence, elevated PWV, and decreased cumulative displacement around and/or within regions of atherosclerotic plaque. Intra-plaque mapping of the PWV and cumulative strain demonstrated the potential to quantitatively differentiate stable (i.e. calcified) and vulnerable (i.e. lipid) plaque components. The lack of correlation between quantitative measurements (PWV, modulus, displacement, and strain) and expected plaque stiffness illuminates to need to consider several physiological and imaging-related factors such as turbulent flow, wave reflection, imaging location, and the applicability of established theoretical models in vivo. PWI presents a highly translational method for visualization of the arterial pulse wave and the image-guided measurement of several clinically relevant pulse wave features. The aforementioned findings collectively demonstrated the potential of PWI to detect, diagnose, and characterize vascular disease based on qualitative and quantitative information about arterial wall dynamics under pathological conditions