Skeletal muscle, exercise and activity in pulmonary hypertension

MD ThesisPulmonary Arterial hypertension (PAH) is a rare and progressive condition presenting with exercise intolerance, leading to right ventricle (RV) failure and death. There has been significant progress in understanding the basic pathophysiology leading to the development of a number of targeted therapies, resulting in improved prognosis. Despite this, patients remain limited in performing exertional activities with a poorer quality of life. Recent research has focused on PAH being a multi-systemic disease with skeletal muscle dysfunction contributing to exercise intolerance. There needs to be greater understanding of the physiological and behavioural mechanisms that limit daily functional capabilities in PAH patients. The aims of the thesis were to study the role of skeletal muscle mitochondrial function, the limitations in central and peripheral haemodynamics on maximum exercise, and develop a greater understanding of whether habitual daily physical activity levels are improved by current pharmaceutical treatments. Using 31Phosphorous-magnetic resonance spectroscopy (31P-MRS), oxygen delivery as opposed to impaired mitochondrial function would explain the abnormal skeletal muscle bioenergetics observed. This is further supported by analysing skeletal muscle biopsy samples demonstrating that mitochondrial protein expression and function was normal, therefore not contributing to impaired exercise capacity. Using continuous non-invasive cardiac output, chronotropic incompetence and reduced peripheral oxygen extraction are the predominant mechanisms leading to impaired peak oxygen consumption. Finally, in a pilot study targeted-therapies failed to change habitual daily physical activity and fatigue levels in PAH patients despite a significant observed change in submaximal exercise capacity. In conclusion, a number of physiological mechanisms that impair exercise capacity and habitual physical activity in PAH are beyond the currently available targeted therapies. Further research is needed into how best to improve exercise capacity, fatigue and activity levels that will directly lead to improvement in quality of life for PAH patients

Enabling Wearable Hemodynamic Monitoring Using Multimodal Cardiomechanical Sensing Systems

Hemodynamic parameters such as blood pressure and stroke volume are instrumental to understanding the pathogenesis of cardiovascular disease. Unfortunately, the monitoring of these hemodynamic parameters is still limited to in-clinic measurements and cumbersome hardware precludes convenient, ubiquitous use. To address this burden, in this work, we explore seismocardiogram-based wearable multimodal sensing techniques to estimate blood pressure and stroke volume. First, the performance of a multimodal, wrist-worn device capable of obtaining noninvasive pulse transit time measurements is used to estimate blood pressure in an unsupervised, at-home setting. Second, the feasibility of this wrist-worn device is comprehensively evaluated in a diverse and medically underserved population over the course of several perturbations used to modulate blood pressure through different pathways. Finally, the ability of wearable signals—acquired from a custom chest-worn biosensor—to noninvasively quantify stroke volume in patients with congenital heart disease is examined in a hospital setting. Collectively, this work demonstrates the advancements necessary towards enabling noninvasive, longitudinal, and accurate measurements of these hemodynamic parameters in remote settings, which offers to improve health equity and disease monitoring in low-resource settings.Ph.D

Multidimensional embedded MEMS motion detectors for wearable mechanocardiography and 4D medical imaging

Background: Cardiovascular diseases are the number one cause of death. Of these deaths, almost 80% are due to coronary artery disease (CAD) and cerebrovascular disease. Multidimensional microelectromechanical systems (MEMS) sensors allow measuring the mechanical movement of the heart muscle offering an entirely new and innovative solution to evaluate cardiac rhythm and function. Recent advances in miniaturized motion sensors present an exciting opportunity to study novel device-driven and functional motion detection systems in the areas of both cardiac monitoring and biomedical imaging, for example, in computed tomography (CT) and positron emission tomography (PET). Methods: This Ph.D. work describes a new cardiac motion detection paradigm and measurement technology based on multimodal measuring tools — by tracking the heart’s kinetic activity using micro-sized MEMS sensors — and novel computational approaches — by deploying signal processing and machine learning techniques—for detecting cardiac pathological disorders. In particular, this study focuses on the capability of joint gyrocardiography (GCG) and seismocardiography (SCG) techniques that constitute the mechanocardiography (MCG) concept representing the mechanical characteristics of the cardiac precordial surface vibrations. Results: Experimental analyses showed that integrating multisource sensory data resulted in precise estimation of heart rate with an accuracy of 99% (healthy, n=29), detection of heart arrhythmia (n=435) with an accuracy of 95-97%, ischemic disease indication with approximately 75% accuracy (n=22), as well as significantly improved quality of four-dimensional (4D) cardiac PET images by eliminating motion related inaccuracies using MEMS dual gating approach. Tissue Doppler imaging (TDI) analysis of GCG (healthy, n=9) showed promising results for measuring the cardiac timing intervals and myocardial deformation changes. Conclusion: The findings of this study demonstrate clinical potential of MEMS motion sensors in cardiology that may facilitate in time diagnosis of cardiac abnormalities. Multidimensional MCG can effectively contribute to detecting atrial fibrillation (AFib), myocardial infarction (MI), and CAD. Additionally, MEMS motion sensing improves the reliability and quality of cardiac PET imaging.Moniulotteisten sulautettujen MEMS-liiketunnistimien käyttö sydänkardiografiassa sekä lääketieteellisessä 4D-kuvantamisessa Tausta: Sydän- ja verisuonitaudit ovat yleisin kuolinsyy. Näistä kuolemantapauksista lähes 80% johtuu sepelvaltimotaudista (CAD) ja aivoverenkierron häiriöistä. Moniulotteiset mikroelektromekaaniset järjestelmät (MEMS) mahdollistavat sydänlihaksen mekaanisen liikkeen mittaamisen, mikä puolestaan tarjoaa täysin uudenlaisen ja innovatiivisen ratkaisun sydämen rytmin ja toiminnan arvioimiseksi. Viimeaikaiset teknologiset edistysaskeleet mahdollistavat uusien pienikokoisten liiketunnistusjärjestelmien käyttämisen sydämen toiminnan tutkimuksessa sekä lääketieteellisen kuvantamisen, kuten esimerkiksi tietokonetomografian (CT) ja positroniemissiotomografian (PET), tarkkuuden parantamisessa. Menetelmät: Tämä väitöskirjatyö esittelee uuden sydämen kineettisen toiminnan mittaustekniikan, joka pohjautuu MEMS-anturien käyttöön. Uudet laskennalliset lähestymistavat, jotka perustuvat signaalinkäsittelyyn ja koneoppimiseen, mahdollistavat sydämen patologisten häiriöiden havaitsemisen MEMS-antureista saatavista signaaleista. Tässä tutkimuksessa keskitytään erityisesti mekanokardiografiaan (MCG), joihin kuuluvat gyrokardiografia (GCG) ja seismokardiografia (SCG). Näiden tekniikoiden avulla voidaan mitata kardiorespiratorisen järjestelmän mekaanisia ominaisuuksia. Tulokset: Kokeelliset analyysit osoittivat, että integroimalla usean sensorin dataa voidaan mitata syketiheyttä 99% (terveillä n=29) tarkkuudella, havaita sydämen rytmihäiriöt (n=435) 95-97%, tarkkuudella, sekä havaita iskeeminen sairaus noin 75% tarkkuudella (n=22). Lisäksi MEMS-kaksoistahdistuksen avulla voidaan parantaa sydämen 4D PET-kuvan laatua, kun liikeepätarkkuudet voidaan eliminoida paremmin. Doppler-kuvantamisessa (TDI, Tissue Doppler Imaging) GCG-analyysi (terveillä, n=9) osoitti lupaavia tuloksia sydänsykkeen ajoituksen ja intervallien sekä sydänlihasmuutosten mittaamisessa. Päätelmä: Tämän tutkimuksen tulokset osoittavat, että kardiologisilla MEMS-liikeantureilla on kliinistä potentiaalia sydämen toiminnallisten poikkeavuuksien diagnostisoinnissa. Moniuloitteinen MCG voi edistää eteisvärinän (AFib), sydäninfarktin (MI) ja CAD:n havaitsemista. Lisäksi MEMS-liiketunnistus parantaa sydämen PET-kuvantamisen luotettavuutta ja laatua

Non-invasive monitoring of vital signs using recliner chair and respiratory pattern analysis

In-home monitoring has the potential to help track health changes for older adults with chronic health conditions, thereby making early treatment possible when exacerbations arise. A recliner chair is often used by older adults, even for sleeping at night, for those with breathing difficulty, neck and back problems, or other pain. Here, we present a sensor system for recliner chairs that can be used to monitor heart rate and respiration rate. The system uses two accelerometers placed strategically to capture these vital signs noninvasively and without direct contact with the body, while at same time being hidden from view. The system was tested with 45 subjects, with an average age of 78.8 years for both upright and reclined configurations of the chair. We also tested the system on 6 different types of recliner models. An accuracy of 99% for heart rate and 93% for respiratory rate was obtained. An analysis of the error distribution patterns according to age, gender and recliner configurations are considered. A validation study of a commercially available sensor, Murata SCA11H, which is primarily designed for use on the bed is tested on the chair and the results are presented in this thesis. We have also developed a measure known as the "Breathing Pattern Index" that can be useful in determining the respiratory health of the occupants on the chair. Initial studies of the effectiveness of this index and algorithm are evaluated and the results are presented. This new system and index have the potential to help in identifying very early health changes and improve health outcomes for older adults.Includes bibliographical reference

Comparison of Different Methods for Estimating Cardiac Timings: A Comprehensive Multimodal Echocardiography Investigation

Cardiac time intervals are important hemodynamic indices and provide information about left ventricular performance. Phonocardiography (PCG), impedance cardiography (ICG), and recently, seismocardiography (SCG) have been unobtrusive methods of choice for detection of cardiac time intervals and have potentials to be integrated into wearable devices. The main purpose of this study was to investigate the accuracy and precision of beat-to-beat extraction of cardiac timings from the PCG, ICG and SCG recordings in comparison to multimodal echocardiography (Doppler, TDI, and M-mode) as the gold clinical standard. Recordings were obtained from 86 healthy adults and in total 2,120 cardiac cycles were analyzed. For estimation of the pre-ejection period (PEP), 43% of ICG annotations fell in the corresponding echocardiography ranges while this was 86% for SCG. For estimation of the total systolic time (TST), these numbers were 43, 80, and 90% for ICG, PCG, and SCG, respectively. In summary, SCG and PCG signals provided an acceptable accuracy and precision in estimating cardiac timings, as compared to ICG

A pervasive body sensor network for monitoring post-operative recovery

Over the past decade, miniaturisation and cost reduction brought about by the semiconductor industry has led to computers smaller in size than a pin head, powerful enough to carry out the processing required, and affordable enough to be disposable. Similar technological advances in wireless communication, sensor design, and energy storage have resulted in the development of wireless “Body Sensor Network (BSN) platforms comprising of tiny integrated micro sensors with onboard processing and wireless data transfer capability, offering the prospect of pervasive and continuous home health monitoring. In surgery, the reduced trauma of minimally invasive interventions combined with initiatives to reduce length of hospital stay and a socioeconomic drive to reduce hospitalisation costs, have all resulted in a trend towards earlier discharge from hospital. There is now a real need for objective, pervasive, and continuous post-operative home recovery monitoring systems. Surgical recovery is a multi-faceted and dynamic process involving biological, physiological, functional, and psychological components. Functional recovery (physical independence, activities of daily living, and mobility) is recognised as a good global indicator of a patient’s post-operative course, but has traditionally been difficult to objectively quantify. This thesis outlines the development of a pervasive wireless BSN system to objectively monitor the functional recovery of post-operative patients at home. Biomechanical markers were identified as surrogate measures for activities of daily living and mobility impairment, and an ear-worn activity recognition (e-AR) sensor containing a three-axis accelerometer and a pulse oximeter was used to collect this data. A simulated home environment was created to test a Bayesian classifier framework with multivariate Gaussians to model activity classes. A real-time activity index was used to provide information on the intensity of activity being performed. Mobility impairment was simulated with bracing systems and a multiresolution wavelet analysis and margin-based feature selection framework was used to detect impaired mobility. The e-AR sensor was tested in a home environment before its clinical use in monitoring post-operative home recovery of real patients who have undergone surgery. Such a system may eventually form part of an objective pervasive home recovery monitoring system tailored to the needs of today’s post-operative patient.Open acces

The effects of pregnancy and weight changes on cardiovascular pathophysiology

Pregnancy is a major physiological stress of the cardiovascular system. Weight gain significantly contributes to physical limitations. This thesis examines the effects on both physical and cardiac performance of weight gain in pregnancy. Utilising cardiac power output at rest and maximal exercise, I measured the effects of (i) inert weight loading (ii) pregnancy and (iii) obesity in the non-pregnant state, to determine the acute, chronic and also reversible changes. Weight loading using a pregnancy simulator suit (“Empathy Belly”) showed reduced physical performance, whilst showing an improvement in cardiac performance, predominantly by increasing the pressure generating capacity of the heart. Additional load carriage with the “Empathy Belly” and a rucksack, showed further reduction in physical performance, but no further improvement in cardiac performance. Pregnancy revealed significant reductions in physical performance and maintenance in cardiac performance compared to the non-pregnant post-partum. Contrary to this, there were significant reductions in both physical and cardiac performance in pregnancy, compared to pre-conception. Changes in cardiac performance throughout pregnancy gradually improved, whilst there was a deterioration in overall physical performance. Obesity in the non-pregnant state, showed significant reduction in physical performance with a marked increase in cardiac performance. This was primarily driven by an increase in the flow generating capacity of the heart; the cardiac output. Inert weight loading, weight carriage in pregnancy and non-physiological weight gain in obesity in the non-pregnant state, all reduce physical performance. In contrast to this, both inert weight carriage and weight carriage in obesity increase cardiac performance. Acute weight loading induces an increase in pressure generating capacity, whilst chronic weight carriage leads to an increase in flow generating capacity. For the first time, I have shown that peak cardiac performance reduces in pregnancy from pre-conception, although this gradually improves throughout pregnancy and is likely to be in part caused by an increase in weight gain

Autonomic Cardiovascular Regulation in Children with Hypoplastic Left Heart Syndrome and the Fontan Circulation

Background: Hypoplastic left heart syndrome (HLHS) is a congenital heart disease phenotype where the left side of the heart is severely underdeveloped and cannot support systemic circulation. Children with HLHS undergo the Fontan operation, where the caval veins are attached to the pulmonary artery, and the right ventricle pumps blood through the aorta. Children with HLHS with Fontan circulation (HLHS-FC) have a reduced exercise tolerance and suffer from autonomic dysfunction. Understanding the role of autonomic dysfunction by studying the exercise pressor reflex through the stimulation of mechano- and metaboreceptors could provide further insight on potential mechanisms contributing to exercise intolerance. We hypothesized than children with HLHS-FC would have an augmented exercise pressor response resulting in increased sympathetic stimulation through mechno- and metaboreflex (handgrip) and metaboreflex only (post-exercise circulatory occlusion, PECO) as defined by change in mean arterial pressure (MAP) versus healthy controls (CTL). Methods and Results: Nine HLHS-FC (f=3, m=6; 134 y) and 9 CTL (f=3, m=6; 133 y) rested supine for 10 minutes to assess heart rate variability (HRV) and resting physiologic parameters, then performed 2 minutes of 40% maximal voluntary contraction isometric handgrip exercise, followed by 3 minutes of PECO on the exercised arm. Continuous blood pressure, heart rate (HR), ventilation, and forearm blood flow (FBF) of the contralateral limb were measured throughout the protocol. Children with HLHS-FC had lower resting heart rate variability (HRV) values of standard deviation of normal R-R intervals (31.932.4 vs. 70.424.0; P = 0.011), root mean square of successive R-R interval differences (31.932.3 vs. 70.324.0; P = 0.011), percentage of consecutive normal R-R intervals that differ by more than 50ms (19.828.2 vs. 44.718.8; P = 0.043), low frequency power percentage (21.85.4 vs. 35.710.4; P = 0.003), high frequency power percentage (31.515.4 vs. 46.89.7; P < 0.023) than CTL. Mean arterial pressure (MAP) increased significantly less during handgrip (55mmHg vs 1610mmHg; P < 0.001) and PECO (45mmHg vs 149mmHg P = 0.002) in HLHS-FC than CTL. There was a blunted exercise HR response in HLHS-FC compared to CTL (67 bpm vs. 248 bpm; P <0.001). Ventilation was lower in HLHS-FC than CTL during handgrip (0.321.15 L/min vs 3.363.94 L/min; P = 0.003). In HLHS-FC FBF increased substantially during PECO when compared to rest (0 mL/min/m2 vs 19.832.6 mL/min/m2; P = 0.012) and handgrip (2.916.7 mL/min/m2 vs 19.832.6 mL/min/m2; P = 0.036). Conclusion: Children with HLHS-FC suffer from autonomic dysfunction, with a sympathovagal balance favouring the sympathetic nervous system, and contrary to our hypothesis, have a blunted exercise pressor reflex response to increased sympathetic stimulation. The exercise pressor reflex may play a key role in the exercise intolerance encountered by children with HLHS-FC

Exercise intensity as a mediator of central and peripheral vascular integrity

Vascular homeostasis is a vital element of health. Exercise plays a role in maintaining the integrity of the vascular endothelium via transient increases in endothelial shear stress that accompany exercise-induced hyperaemia. This hyperaemia and stimulus it presents to the vasculature is governed by exercise intensity. Exercise is the primary therapy in cardiac rehabilitation contexts, a population with typically elevated cardiovascular risk factors and compromised vascular integrity. In the UK, cardiac rehabilitation may be ineffective for improving long-term health outcomes. This thesis demonstrates that the exercise intensities achieved by patients in UK cardiac rehabilitation were variable and generally low. The exercise performed had no impact upon indices of peripheral vascular structure or function and little effect upon short-term health outcomes. A service-level intervention was implemented to increase the dose of exercise achieved by patients via an increase in intensity and examine its effects upon the vasculature. In a subsequent cohort, the intervention was unsuccessful at modifying the exercise intensities that were achieved or indices of peripheral vascular structure or function. However, a positive relationship between the intensity achieved at the end of the programme and changes in vascular function was found. Although peripheral vascular integrity is easily studied it is perhaps less relevant to health compared to central vascular integrity. Assessments of the central circulation during exercise have previously relied upon high-risk, invasive techniques. Therefore, to understand the stimulus presented to the central vasculature by exercise at intensities akin to those achieved in cardiac rehabilitation, a novel technique was applied: using cardiac magnetic resonance imaging during cycling in a healthy cohort. This technique was unable to capture the changes in perfusion of the central circulation that should have occurred with exercise at different intensities but successfully demonstrated reproducible assessments of cardiac dynamics during exercise of different intensities