STIMULATE-ICP: A pragmatic, multi-centre, cluster randomised trial of an integrated care pathway with a nested, Phase III, open label, adaptive platform randomised drug trial in individuals with Long COVID: A structured protocol.

INTRODUCTION: Long COVID (LC), the persistent symptoms ≥12 weeks following acute COVID-19, presents major threats to individual and public health across countries, affecting over 1.5 million people in the UK alone. Evidence-based interventions are urgently required and an integrated care pathway approach in pragmatic trials, which include investigations, treatments and rehabilitation for LC, could provide scalable and generalisable solutions at pace. METHODS AND ANALYSIS: This is a pragmatic, multi-centre, cluster-randomised clinical trial of two components of an integrated care pathway (Coverscan™, a multi-organ MRI, and Living with COVID Recovery™, a digitally enabled rehabilitation platform) with a nested, Phase III, open label, platform randomised drug trial in individuals with LC. Cluster randomisation is at level of primary care networks so that integrated care pathway interventions are delivered as "standard of care" in that area. The drug trial randomisation is at individual level and initial arms are rivaroxaban, colchicine, famotidine/loratadine, compared with no drugs, with potential to add in further drug arms. The trial is being carried out in 6-10 LC clinics in the UK and is evaluating the effectiveness of a pathway of care for adults with LC in reducing fatigue and other physical, psychological and functional outcomes at 3 months. The trial also includes an economic evaluation which will be described separately. ETHICS AND DISSEMINATION: The protocol was reviewed by South Central-Berkshire Research Ethics Committee (reference: 21/SC/0416). All participating sites obtained local approvals prior to recruitment. Coverscan™ has UK certification (UKCA 752965). All participants will provide written consent to take part in the trial. The first participant was recruited in July 2022 and interim/final results will be disseminated in 2023, in a plan co-developed with public and patient representatives. The results will be presented at national and international conferences, published in peer reviewed medical journals, and shared via media (mainstream and social) and patient support organisations. TRIAL REGISTRATION NUMBER: ISRCTN10665760.

Measurement of Wall Shear Stress Exerted by Flowing Blood in the Human Carotid Artery: Ultrasound Doppler Velocimetry and Echo Particle Image Velocimetry.

Vascular endothelial cells lining the arteries are sensitive to wall shear stress (WSS) exerted by flowing blood. An important component of the pathophysiology of vascular diseases, WSS is commonly estimated by centerline ultrasound Doppler velocimetry (UDV). However, the accuracy of this method is uncertain. We have previously validated the use of a novel, ultrasound-based, particle image velocimetry technique (echo PIV) to compute 2-D velocity vector fields, which can easily be converted into WSS data. We compared WSS data derived from UDV and echo PIV in the common carotid artery of 27 healthy participants. Compared with echo PIV, time-averaged WSS was lower using UDV (28 ± 35%). Echo PIV revealed that this was due to considerable spatiotemporal variation in the flow velocity profile, contrary to the assumption that flow is steady and the velocity profile is parabolic throughout the cardiac cycle. The largest WSS underestimation by UDV was found during peak systole (118 ± 16%) and the smallest during mid-diastole (4.3± 46%). The UDV method underestimated WSS for the accelerating and decelerating systolic measurements (68 ± 30% and 24 ± 51%), whereas WSS was overestimated for end-diastolic measurements (-44 ± 55%). Our data indicate that UDV estimates of WSS provided limited and largely inaccurate information about WSS and that the complex spatiotemporal flow patterns do not fit well with traditional assumptions about blood flow in arteries. Echo PIV-derived WSS provides detailed information about this important but poorly understood stimulus that influences vascular endothelial pathophysiology.

Echo Particle Image Velocimetry for Estimation of Carotid Artery Wall Shear Stress: Repeatability, Reproducibility and Comparison with Phase-Contrast Magnetic Resonance Imaging.

Measurement of hemodynamic wall shear stress (WSS) is important in investigating the role of WSS in the initiation and progression of atherosclerosis. Echo particle image velocimetry (echo PIV) is a novel ultrasound-based technique for measuring WSS in vivo that has previously been validated in vitro using the standard optical PIV technique. We evaluated the repeatability and reproducibility of echo PIV for measuring WSS in the human common carotid artery. We measured WSS in 28 healthy participants (18 males and 10 females, mean age: 56 ± 12 y). Echo PIV was highly repeatable, with an intra-observer variability of 1.0 ± 0.1 dyn/cm2 for peak systolic (maximum), 0.9 dyn/cm2 for mean and 0.5 dyn/cm2 for end-diastolic (minimum) WSS measurements. Likewise, echo PIV was reproducible, with a low inter-observer variability (max: 2.0 ± 0.2 dyn/cm2, mean: 1.3 ± 0.1 dyn/cm2, end-diastolic: 0.7 dyn/cm2) and more variable inter-scan (test-retest) variability (max: 7.1 ± 2.3 dyn/cm2, mean: 2.9 ± 0.4 dyn/cm2, min: 1.5 ± 0.1 dyn/cm2). We compared echo PIV with the reference method, phase-contrast magnetic resonance imaging (PC-MRI); echo PIV-based WSS measurements agreed qualitatively with PC-MRI measurements (r = 0.89, p < 0.05). Significant differences were observed in some WSS measurements (echo PIV vs. PC-MRI): WSS at peak systole: 21 ± 7.0 dyn/cm2 vs. 15 ± 5.0 dyn/cm2; time-averaged WSS: 8.9 ± 3.0 dyn/cm2 vs. 7.1 ± 3.0 dyn/cm2 (p < 0.05); WSS at end diastole: 3.8 ± 2.8 dyn/cm2 vs. 3.9 ± 2 dyn/cm2 (p > 0.05). For the first time, we report that echo PIV can measure WSS with good repeatability and reproducibility in adult humans with a broad age range. Echo PIV is feasible in humans and offers an easy-to-use, ultrasound-based, quantitative technique for measuring WSS in vivo in humans with good repeatability and reproducibility.

Associations between cardiac target organ damage and microvascular dysfunction: the role of blood pressure.

BACKGROUND: Microvascular dysfunction may be an early precursor of cardiovascular disease (CVD). Increased left ventricular mass (LVM), concentric left ventricular remodelling and increased left atrial size are the factors that could predict future CVD. We investigated whether microvascular dysfunction was associated with these cardiac measures. METHODS AND RESULTS: Laser Doppler fluximetry of skin vessels was used to study associations with risk factors and echocardiographic measurements of LVM, relative wall thickness (RWT), and left atrial size in 305 people (aged 40-65 years; 117 with type 2 diabetes). Flow in response to a 3-min arterial occlusion was measured. Postischaemic peak flow responses were categorized into three distinct groups: slow rise to peak (normal), nondominant early peak group (mildly abnormal) and a dominant early peak (abnormal). Those with a dominant early peak had higher blood pressure (P = 0.001), weight (P = 0.001), fasting glucose (P = 0.001) and prevalence of diabetes (P = 0.02). LVM (P = 0.01), RWT (P < 0.001) and left atrial size (P < 0.001) were greater with worsening postischaemic peak flow responses. Differences in LVM between postischaemic response groups were accounted for by blood pressure (BP). However, differences in BP and other CVD risk factors did not account for the greater RWT and left atrial size observed in the more adverse peak response groups [geometric mean of RWT [95% confidence interval (CI)] 0.40 (0.38-0.41) vs. 0.41 (0.40-0.42) vs. 0.43 (0.41-0.45), P = 0.007; left atrial size 36.1 (35.4-36.1) vs. 37.4 (36.8-38.0) vs. 38.7 (37.5-40.0), P = 0.002 for normal vs. mildly abnormal vs. abnormal respectively]. CONCLUSION: An abnormal microcirculatory cutaneous peak flow response following ischaemia is associated with adverse cardiac remodelling, independent of CVD risk factors including blood pressure.

Attenuation of microvascular function in those with cardiovascular disease is similar in patients of Indian Asian and European descent.

BACKGROUND: Indian Asians are at increased risk of cardiovascular death which does not appear to be explained by conventional risk factors. As microvascular disease is also more prevalent in Indian Asians, and as it is thought to play a role in the development of macrovascular disease, we decided to determine whether impaired microcirculation could contribute to this increased cardiovascular risk in Indian Asians. METHODS: Forearm skin laser Doppler fluximetry in response to heating and ischaemia was assessed in 83 Europeans (41 with angiographically confirmed atherosclerotic coronary artery disease (CAD) and 42 from the general population) and 84 Indian Asians (41 with CAD). Explanations for differences in microvascular function were sought using multivariate analysis including conventional cardiovascular risk factors. RESULTS: Compared to ethnically matched control populations both Europeans and Indian Asians with CAD had poorer microvascular responses to heating than those without (117(95% CI 105-131) vs. 142(130-162) arbitrary units, (au) for Europeans and 111(101-122) vs. 141(131-153)au for Indian Asians) and to ischaemia (44(38-50) vs. 57(49-67)au & 39(34-45) vs. 49(43-56)au respectively). These differences were not accounted for by conventional cardiovascular risk factors. There was no ethnic difference in the attenuation of microvascular function associated with CAD. CONCLUSION: Patients of European and Indian Asian descent with symptomatic CAD have poorer microvascular maximal tissue perfusion and reactive hyperaemia in the skin compared to ethnically matched asymptomatic control populations. Despite the increased cardiovascular risk in Indian Asians, the attenuation of microvascular function associated with CAD was equivalent in the ethic groups. This suggests that in Indian Asians microcirculation does not explain the increased susceptibility to CAD.

Ethnic differences in skin microvascular function and their relation to cardiac target-organ damage.

BACKGROUND: People of Black African descent have increased risks of vascular target-organ damage not explained by greater blood pressures. OBJECTIVE: To study ethnic differences in the microvasculature. DESIGN AND METHODS: Flow (flux) in microcirculatory skin vessels was assessed using laser Doppler fluximetry in 181 Afro-Caribbean and European men and women aged 40-65 years from the general population in London, UK. Flux in response to maximal heating (maximal hyperaemic response) was measured and minimum vascular resistance calculated. Peak flux and time to peak after an ischaemic stimulus were also measured. Target-organ damage was assessed using echocardiographic interventricular septal thickness (IVST). RESULTS: In men, maximum hyperaemic response was attenuated in Afro-Caribbeans [109 arbitrary units (au), 25th and 75th percentiles 101, 117] compared with Europeans [165 (155, 179) au; P = 0.008]. Minimum vascular resistance was greater in Afro-Caribbeans, significantly so in men [(1.22 (1.18, 1.28) au/mmHg compared with 0.80 (0.77, 0.83) au/mmHg; P = 0.006]. Peak ischaemic response was attenuated in Afro-Caribbean men and women compared with Europeans (35.6 au compared with 49.5 au; P < 0.001) and time to peak was prolonged (14.1 s compared with 12.5 s; P = 0.07). These ethnic differences could not be accounted for by standard cardiovascular risk factors. IVST was greater in Afro-Caribbeans than in Europeans. Minimum vascular resistance and peak response accounted for a small proportion of this ethnic difference, in addition to conventional factors. CONCLUSIONS: Afro-Caribbeans have poorer microvascular structure and function, unexplained by conventional risk factors, which may contribute to greater rates of vascular target-organ damage.