Advancing Pulse Wave Velocity Methods - From Novel Ultrasonic Concepts to Ambulatory Monitoring

Introduction Cardiovascular diseases are the leading cause of death globally. They pose an insidious danger as those affected are typically free of symptoms until irreversible organ damage occurs, mostly with acute lethal consequences. Therefore, and in light of an immense health economic burden, prevention and early-stage detection of cardiovascular risk are of utmost importance. Since the early 20th century, blood pressure is the prevailing clinical marker of vascular health, wherefore hypertension is considered as a key risk factor for cardiovascular disease development. However, it is also undoubted that arterial stiffening is at the root of cardiovascular disease, triggering a vicious circle of progressive arterial damaging and increasing blood pressure. Arterial stiffness is assessed by the velocity of the pressure pulse wave propagating from the heart over the arterial tree. Over the past two decades, compelling evidence was gathered that pulse wave velocity (PWV) constitutes an independent predictor of cardiovascular disease beyond classical risk factors like blood pressure and was even suggested as a predictor of incident hypertension. Whereas PWV is a recognized marker in clinical research and epidemiology, its widespread clinical use is still hampered by limited practicality and methodological consensus. For instance, the gold standard for regional aortic stiffness (i.e., carotid-to-femoral PWV) requires multi-site arterial waveforms, while the standard measure for local arterial stiffness (i.e., Bramwell-Hill PWV) requires multi-modal pressure and diameter waveforms. Hence, both measures are cumbersome and highly operator-dependent, while any indirect surrogates based on peripheral sensors are considered as unreliable. Therefore, clinical and scientific experts advocate the development of practical, efficient and reproducible methods for broad application in clinical routines, not only to advance present cardiovascular risk assessment but also to expand the clinical evidence. Objectives The primary objective of the research in this thesis is the development of novel PWV-based techniques to facilitate cardiovascular health assessment in three respects. Firstly, we aim for practical and efficient ultrasound-based methods to assess central arterial PWV. Secondly, given the inherent pressure dependency of arterial stiffness, we aim to improve blood pressure estimation based on these novel PWV measures. Thirdly, we aim to develop a wearable system for continuous and unobtrusive 24-hour ambulatory blood pressure monitoring based on PWV. For the prospective deployment of the novel ultrasound-based PWV methods in an ambulatory monitoring system, it is a secondary objective of this research to evaluate the applicability of novel piezoelectric micromachined ultrasound transducers (pMUTs). An initial experimental series with phantom and in vivo measurements demonstrates that carotid artery imaging with pMUT arrays is essentially feasible and bears potential for versatile advancements in terms of array configurations and system miniaturization. Research Methodology & Results Following a thorough safety analysis and specific algorithm development for carotid artery tracking with high-frequency ultrasound, two novel methods are developed, respectively for the regional and local assessment of central arterial PWV. To provide proof-of-concept, both methods are evaluated in a small-scale cohort of healthy human subjects. The regional method is based on the segmentation of pulse arrival time, i.e., the time interval elapsing between the cardiac cycle onset and the arrival of a central or peripheral pressure pulse. If conventionally obtained from an electrocardiogram and a peripheral optical waveform, the pulse arrival time is typically biased by an unknown cardiac interval and inhomogeneities between central and peripheral vasculature. Instead, we use a characteristic fiducial point in the carotid distension waveform, signaling the cardiac isovolumic contraction onset, to segment the pulse arrival time into cardiac and vascular intervals. Subsequently, a central aortic-to-carotid PWV is computed from the vascular transit time interval and an estimated arterial path length. This unbiased central PWV estimate clearly outperforms the peripheral pulse arrival time-based estimate by demonstrating significantly higher correlations with Bramwell-Hill PWV and lower blood pressure estimation errors, even in conformity with the error margins of a blood pressure validation standard. Thereby this novel method may provide the basis for unilateral assessment of central arterial stiffness and potentially improve its clinical practicality. The local method is based on a mathematical model designed to take wave reflection phenomena into account. That is, wave reflections constitute a major error source in local PWV estimates by causing nonlinearities in the spatiotemporal propagation of distinct waveform fiducials. However, wave reflections are inevitable and should be taken into account, which is also confirmed by the initial development of a quality indicator that discards substantial amounts of PWV estimates exceeding a certain degree of nonlinearity. Therefore, the Double Gaussian Propagation Model is developed to take the confluence of incident and reflected waves into account by modelling carotid waveform complexes holistically. The spatiotemporal gradient of the decomposed forward propagating wave component then defines the local carotid PWV. This novel estimate clearly outperforms the fiducial-based spatiotemporal estimate by demonstrating significantly higher correlations with Bramwell-Hill PWV and blood pressure, even at two different waveform complexes and their incremental pressure level. Thereby this novel method may provide the basis for a practical assessment of (incremental) local carotid artery stiffness. Similar to PWV, the present means of blood pressure monitoring are suboptimal. Infrequent snapshot measurements at the doctor's office are often biased by masked or white-coat hypertension, while automated home blood pressure monitoring is considered inaccurate, particularly in the critical diagnostic range. Ambulatory 24-hour blood pressure monitoring is a valuable clinical tool to reduce diagnostic uncertainties and obtain individual patterns of high prognostic significance. However, frequent cuff inflations are causing discomfort for the patients and induce bias, particularly in the relevant night readings. Moreover, a wearable system for 24-hour blood pressure monitoring is developed, which exploits the pressure-dependency of PWV. In this case, PWV is estimated from the pulse arrival time interval, obtained from an integrated electrocardiogram and finger photoplethysmogram combination, and serves as key predictor in a multivariate statistical model. Adequate tracking performance is demonstrated in a small-scale cohort of healthy human subjects, with relative tracking errors well within the error margins of a blood pressure validation standard. An additional cuff-based calibration enables accurate estimation of absolute blood pressure levels over a wide range of diagnostically relevant thresholds. Thereby, without the exertion of mechanical forces on the body, the wearable system may constitute a user-friendly and unbiased alternative to conventional cuff-based ambulatory blood pressure monitoring. Conclusion Whereas the ideal solution for a practical, efficient and reproducible PWV measure has not yet emerged, the methods developed in this thesis provide an unprecedented compromise balancing practicality and the ability to obtain clinically significant central PWV. Despite of certain limitations in terms of the reference methods and small-scale cohorts, we provide solid proof-of-concept for three novel methods advancing PWV measurements for cardiovascular health assessment. Ultimately, all methods demonstrate an adequate technology readiness level and are readily transferable to clinical practice for further validation at proper scale. Prospectively, the novel methods may constitute viable screening tools to intercept arterial stiffening and incident hypertension at an early stage, shifting the focus towards prevention and thereby enable long-lasting cardiovascular health.

Publication year:2021

Accessibility:Embargoed