Design of a thermal diffusion sensor for noninvasive assessment of skin surface perfusion and endothelial dysfunction

Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2008.Includes bibliographical references (p. 105-121).The skin microcirculation performs a range of vital functions, such as maintaining nutritional perfusion to the tissues and overall thermoregulation. Not only does impairment to the skin blood supply lead to tissue necrosis and other disease complications, increasing evidence shows that dysfunctional vasoreactivity in the skin microcirculation is associated with multiple disease states, including hypertension, diabetes mellitus, hypercholesterolemia, peripheral vascular disease, and coronary artery disease, and it is one of the earliest indicators of systemic endothelial dysfunction, the precursor to atherosclerotic disease. Endothelial dysfunction is functionally characterized by abnormal vasomotor response to either a pharmacological or flow-mediated stimulus and can be demonstrated in the skin by measuring reperfusion following a period of ischemia, a phenomenon known as post-occlusive reactive hyperemia (PORH). In my research, I have reviewed the literature regarding endothelial dysfunction and its association with a wide range of cardiovascular risk factors. I have also described the mechanisms thought to link endothelial function in the central vascular beds (i.e. coronary) to that of peripheral conduit vessels and the microcirculation. The knowledge thus gathered confirmed that the microcirculation of the skin is an appropriate site for endothelial function assessment. The ultimate goal of my thesis is to design a noninvasive sensor that is capable of obtaining a quantitative measure of skin perfusion, continuously and in real-time, using the principle of thermal diffusion in perfused tissue. I performed preliminary noninvasive endothelial function testing with a modified Thermal Diffusion Probe (TDP), which has been previously validated for absolute perfusion measurement in an invasive setting.(cont.) Based on an initial analysis, I have shown that thermal surface perfusion measurements are feasible and reflect the natural perfusion and temperature fluctuations intrinsic to skin tissue. I also established guidelines for determining quantitative parameters of reactivity from tests of PORH as well as temporal parameters of perfusion variations over time through a spectral analysis of resting blood flow. After establishing the necessary thermal boundary conditions for obtaining surface perfusion measurements, I embarked on a process of computer-assisted modeling and rapid prototyping of various design iterations on an insulated sensor housing, with subsequent fabrication of first generation noninvasive sensors. As a result of these initial sensor designs, specifications for the sensor housing were created to ensure that the appropriate thermal field would be established at the skin measurement site - an important step as it permits the most accurate determination of tissue thermal properties. Finally, I propose a candidate design for an ideal sensor capable of improving the reproducibility of noninvasive perfusion measurements on skin. The development of a noninvasive measure of endothelial dysfunction in the skin is of great value in the early identification of individuals at risk for atherosclerotic complications. Furthermore, the nature of such a technique would provide quantitative information on the presence of a disorder, the extent of dysfunction, and the effectiveness of treatment interventions.by Vivian V. Li.M.Eng

Arterial Ultrasonography and Tonometry as Adjuncts to Cardiovascular Risk Stratification

Myocardial infarction and stroke often occur without prior warning in asymptomatic individuals. Identifying individuals at risk is important for cost-effective use of preventive therapies. Algorithms based on risk factors statistically associated with cardiovascular events classify individuals into high-risk, intermediate-risk, or low-risk categories. However, more than one-third of adults in the U.S. are in the intermediate-risk category, and decisions regarding therapy are challenging in this subset. Testing for alterations in arterial function and structure that predate cardiovascular events may help refine cardiovascular risk assessment in the intermediate-risk group and identify candidates for aggressive therapy. Vascular ultrasonography and tonometry are promising test modalities for assessment of arterial function and structure in asymptomatic subjects. Several prospective studies have shown that measures of arterial function and structure provide prognostic information incremental to conventional risk factors. Standardization of methodology and establishment of quality control standards in the performance of these tests could facilitate their integration into clinical practice as adjuncts to existing cardiovascular risk stratification algorithms

Thermal-based probe for testing endothelial dysfunction and possible implications for diagnosing atherosclerosis

Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2006.Includes bibliographical references (leaves 51-54).Endothelial dysfunction is a precursor to atherosclerosis. Thus, the vascular health of an individual can be assessed if endothelial dysfunction can be readily and unambiguously quantified. A thermal-based approach using temperature and blood perfusion measurements in conjunction with an arterial challenge has the potential to quantitatively assess endothelial dysfunction. This report includes a detailed review of previous attempts to characterize endothelial dysfunction and a preliminary evaluation of a thermal-based approach that relies on temperature and perfusion measurements. Two simple thermal models are used to contextualize results obtained from this technique. Results reveal that this thermal-based method serves as a valid indicator of endothelial assessment while at the same time reducing some of the mitigating factors of existing approaches to identifying endothelial dysfunction. More testing must be performed in order to optimize this thermal-based approach.by Muyinatu A. Lediju.S.B

Functional Evaluation of the Peripheral Vasculature Using Magnetic Resonance Imaging

Akin to cardiac stress testing, functional integrity of the peripheral vasculature can be interrogated by measuring the response to a stimulus. Recent reports suggest that the reactive hyperemia response, the physiologic reaction following induced ischemia, is associated with disease presence, correlated with disease severity, and may be a sensitive biomarker of pre-clinical disease. In this dissertation, an innovative, interleaved magnetic resonance imaging method is developed, termed Perfusion, Intravascular Venous Oxygen saturation, and T2* (PIVOT), which simultaneously measures microvascular perfusion, venous oxygen saturation (SvO2), and the blood-oxygen-level dependent (BOLD) signal. PIVOT is first applied in healthy subjects to demonstrate its ability to measure reactive hyperemia response dynamics. Next, reactive hyperemia perfusion is compared between the more temporally efficient pulsed arterial spin labeling (PASL) used in PIVOT and the more recently developed and preferred method for the brain, pseudo-continuous ASL (pCASL). Assessment of the impact of blood flow variability throughout the ischemia-reperfusion paradigm on pCASL perfusion quantification is investigated. Then, both PASL and pCASL sequences are used to measure reactive hyperemia perfusion in healthy subjects. No significant differences were detected between perfusion measured with PASL or pCASL despite different labeling strategies, temporal resolutions, and perfusion quantification models. Subsequently, PIVOT is combined with a velocity-encoded dual-echo GRE to create an interleaved three-slice sequence that provides quantification of bulk blood flow in the arteries and veins in addition to the traditional PIVOT measures. This new sequence, termed Velocity and PIVOT (vPIVOT) is used to investigate the relationship of blood flow in the macro- and microvasculature and muscle oxygen consumption during the transition from exercise to rest. Finally, PIVOT is applied clinically in a cohort of patients with varying degrees of severity of peripheral artery disease. Increasing disease severity was correlated with a prolongation of the hyperemic response time, measured as a lengthening of time to peak perfusion, SvO2 washout time, and time to peak T2*. In addition, peak perfusion and SvO2 upslope were significantly different between patients with PAD and healthy controls. These results suggest the potential for PIVOT to evaluate disease severity and may present a tool to assess response to therapeutic intervention

Vascular Function in Chronic Kidney Disease and in Renovascular Disease

Cardiovascular mortality is 15 to 30 times higher in patients with chronic kidney disease than in the age-adjusted general population. Even minor renal dysfunction predicts cardiovascular events and death in the general population. In patients with atherosclerotic renovascular disease the annual cardiovascular event and death rate is even higher. The abnormalities in coronary and peripheral artery function in the different stages of chronic kidney disease and in renovascular disease are still poorly understood, nor have the cardiac effects of renal artery revascularization been well characterized, although considered to be beneficial. This study was conducted to characterize myocardial perfusion and peripheral endothelial function in patients with chronic kidney disease and in patients with atherosclerotic renovascular disease. Myocardial perfusion was measured with positron emission tomography (PET) and peripheral endothelial function with brachial artery flow-mediated dilatation. It has been suggested that the poor renal outcomes after the renal artery revascularization could be due to damage in the stenotic kidney parenchyma; especially the reduction in the microvascular density, changes mainly evident at the cortical level which controls almost 80% of the total renal blood flow. This study was also performed to measure the effect of renal artery stenosis revascularization on renal perfusion in patients with renovascular disease. In order to do that a PET-based method for quantification of renal perfusion was developed. The coronary flow reserve of patients with chronic kidney disease was similar to the coronary flow reserve of healthy controls. In renovascular disease the coronary flow reserve was, however, markedly reduced. Flow-mediated dilatation of brachial artery was decreased in patients with chronic kidney disease compared to healthy controls, and even more so in patients with renovascular disease. After renal artery stenosis revascularization, coronary vascular function and renal perfusion did not improve in patients with atherosclerotic renovascular disease, but in patients with bilateral renal artery stenosis, flow-mediated dilatation improved. Chronic kidney disease does not significantly affect coronary vascular function. On the contrary, coronary vascular function was severely deteriorated in patients with atherosclerotic renovascular disease, possibly because of diffuse coronary artery disease and/or diffuse microvascular disease. The peripheral endothelial function was disturbed in patients with chronic kidney disease and even more so in patient with atherosclerotic renovascular disease. Renal artery stenosis dilatation does not seem to offer any benefits over medical treatment in patients with renovascular disease, since revascularization does not improve coronary vascular function or renal perfusion.Vaskulaarifunktio kroonisessa munuaisten vajaatoiminnassa ja renovaskulaaritaudissa Kuolleisuus sydän- ja verisuonisairauksiin kroonista munuaisten vajaatoimintaa sairastavilla potilailla on 15 – 30 -kertainen taustaväestöön verrattuna. On osoitettu, että jo lieväkin munuaisten vajaatoiminta ennustaa sydän- ja verisuonitauti tapahtumia ja kuolleisuutta väestössä. Ateroskleroottista renovaskulaaritautia sairastavilla vuotuinen kuolleisuus sydän- ja verisuonisairauksiin on vielä suurempi. Sepelvaltimoiden ja ääreisverenkierron toiminnasta on vain vähän tutkimustietoa niin munuaisten vajaatoimintaa kuin renovaskulaaritautiakin sairastavilla. Myöskään munuaisvaltimoahtauman laajentamisen aiheuttamia muutoksia sydämen ja ääreisverenkierron toimintaan ei ole juuri tutkittu. Tämän tutkimuksen tarkoituksena oli ensisijaisesti selvittää sydämen verenvirtausta, sepelvaltimoiden toiminnallista kapasiteettia eli sepelvaltimoiden virtausreserviä ja ääreisverenkierron toiminnan muutoksia niin kroonista munuaisten vajaatoimintaa sairastavilla kuin ateroskleroottista renovaskulaaritautia sairastavilla potilailla. Tutkimusmenetelminä käytettiin positroniemissiotomografiaa (PET) sydämen verenvirtauksen määrittämiseksi sekä ultraäänitutkimusta perifeerisen ääreisverenkierron toiminnan tutkimiseksi. Viime vuosina on arveltu, että kliinisten tutkimusten huonot tulokset munuaisvaltimoahtauman laajennuksen jälkeisesti liittyisivät munuaisten pienten verisuonten toiminnallisiin ja rakenteellisiin muutoksiin munuaisvaltimoahtauman vaikutuksesta. Muutoksia on havaittu erityisesti munuaisten kuorikerroksessa, joka käyttää noin 80 % munuaiseen ohjautuvasta verenvirtauksesta. Tutkimuksen toisena tavoitteena oli mitata mahdollisia muutoksia munuaisten verenvirtauksessa munuaisvaltimoahtauman laajentamisen jälkeisesti. Tätä varten kehitimme PET -metodin munuaisten verenvirtauksen määrittämiseksi. Sepelvaltimoiden virtausreservi kroonista munuaisten vajaatoimintaa sairastavilla ei eronnut tilastollisesti merkitsevästi terveiden verrokeiden virtausreservistä. Sen sijaan renovaskulaaritautipotilaiden virtausreservi oli vaikea-asteisesti huonontunut. Olkavarsivaltimon laajenemiskapasitetti oli huonontunut munuaisten vajaatoimintaa sairastavilla terveisiin verrattuna ja renovaskulaaritautipotilailla vielä enemmän. Munuaisvaltimoahtauman laajentamisen jälkeisesti renovaskulaaritautipotilaiden sepelvaltimoiden funktiossa tai munuaisten verenvirtauksessa ei havaittu parantumista. Kuitenkin molemminpuolisesta munuaisvaltimoahtaumasta kärsivillä ääreisverenkierron toiminta parantui tilastollisesti merkitsevästi toimenpiteen jälkeen. Johtopäätöksinä voidaan todeta, että munuaisten vajaatoiminta sinällään ei näyttäisi merkitsevästi huonontavan sepelvaltimoiden virtausreserviä. Sen sijaan renovaskulaaritautia sairastavilla virtausreservi on huono, todennäköisesti joko subkliinisen sepelvaltimotaudin ja/tai mikrovaskulaaritaudin aiheuttamana. Ääreisverenkierron toiminta sen sijaan oli huonontunut molemmissa potilasryhmissä, renovaskulaaritautipotilailla vielä enemmän. Munuaisvaltimoahtauman laajentaminen ei näytä tarjoavan hyötyä lääkehoitoon verrattuna, sillä toimenpiteen jälkeisesti ei havaittu muutoksia sydämen virtausreservissä sen paremmin kuin munuaisten verenvirtauksessakaan.Siirretty Doriast

Effects Of Peripheral Revascularization On Blood Pressure And Calf Muscle Oxygen Saturation In Peripheral Artery Disease

Peripheral artery disease (PAD) reduces oxygen supply to skeletal muscle that causes an exaggerated blood pressure response to exercise. Revascularization procedures have been important for treating impaired limb perfusion caused by PAD. However, to what extent these procedures improve tissue perfusion during exercise or normalize the exercise pressor reflex in PAD remains unknown. The purpose of the study was to examine whether revascularization reduces the exercise pressor reflex and improves skeletal muscle oxygen saturation (SmO2) measured using near-infrared spectroscopy (NIRS). Six PAD patients performed incremental supine plantar flexion exercise, starting at 0.5 kg and increased by 0.5 kg every minute for up to 14 minutes, pre- and one-month post peripheral revascularization procedure. SmO2 was measured continuously from the gastrocnemius muscle, while heart rate and blood pressure were measured beat-by-beat. Reductions in SmO2 from baseline to 1.5 kg were attenuated post-revascularization when compared to pre-intervention (-6.5 ± 6.2% vs. -39.8 ± 22.5%, P < .05). The change in mean arterial blood pressure was reduced post-revascularization (4 ± 4 mmHg vs. 16 ± 12 mmHg P < .05). These data suggest that revascularization reverses the rapid decline in SmO2 and attenuates the blood pressure response during exercise in patients with PAD

Noninvasive Blood Flow and Oxygenation Measurements in Diseased Tissue

The research presented in this dissertation focused on the application of optical imaging techniques to establish blood flow and oxygen saturation as effective biomarkers for two disease cases, Autism Spectrum Disorder (ASD) and Huntington’s Disease (HD). The BTBR mouse model of ASD was utilized to validate measurements of cerebral blood flow and oxygenation as biomarkers for autism. The R6/2 mouse model of juvenile HD was utilized to validate measurements of skeletal muscle blood flow following tetanic muscle contractions induced by electrical nerve stimulation. Next, a noncontact, camera-based system to measure blood flow and oxygen saturation maps was implemented to improve upon the previous HD mouse results by providing spatial heterogeneity in a wild-type mouse model. Finally, translational research was performed to validate a research design conducting concurrent grip strength force and skeletal muscle blood flow and oxygenation measurements in a healthy human population that will be used to establish HD biomarkers in humans in future clinical applications