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Proof-of-Concept Study for an Enhanced Surrogate Marker of Endothelial Function in Diabetes.

ABSTRACT: Diabetes mellitus affects distal small vessels earlier and to a greater extent than proximal vessels. Vascular disease starts from activation of the endothelial cells, which if prolonged may lead to reduced distensibility of the vessel when maximally stimulated. Hence a device which measures distensibility of a distal vessel should be a good biomarker for subclinical disease. We have developed a device capable of measuring reactive hyperaemia induced changes in the radial artery flow, volumetric changes and accompanying effects on the vessel wall. The measurement is based on the magnetic flux disturbance upon haemodynamic modulation as blood flows through a uniformly applied magnetic field, and generates what we have termed the radial artery maximum distensibility index (RA-MDI). In a proof-of-concept study we found significant correlations between RA-MDI and cardiovascular risk factors, scoring systems and carotid artery intima-media thickness. Further large scale prospective studies need to be conducted to ascertain the correlations with cardiovascular events.

SUBMITTER: Dalan R

PROVIDER: S-EPMC5988679 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Proof-of-Concept Study for an Enhanced Surrogate Marker of Endothelial Function in Diabetes.

Dalan R R Goh S S Bing Sun S Seneviratna A A Phua C T CT

Scientific reports 20180605 1

Diabetes mellitus affects distal small vessels earlier and to a greater extent than proximal vessels. Vascular disease starts from activation of the endothelial cells, which if prolonged may lead to reduced distensibility of the vessel when maximally stimulated. Hence a device which measures distensibility of a distal vessel should be a good biomarker for subclinical disease. We have developed a device capable of measuring reactive hyperaemia induced changes in the radial artery flow, volumetric ...[more]

PMID: 29872121

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Project description:STUDY OBJECTIVES:Longitudinal studies support the usage of positive airway pressure (PAP) therapy in treating obstructive sleep apnea (OSA) to improve cardiovascular disease. However, the anticipated benefit is not ubiquitous. In this study, we elucidate whether PAP therapy leads to immediate improvements on endothelial function, a subclinical marker of cardiovascular status, by examining the effect of circulating exosomes, isolated from patients before and after PAP therapy, on naive endothelial cells. METHODS:We isolated plasma-derived circulating exosomes from 12 patients with severe OSA and obesity hypoventilation syndrome (OHS) before and after 6 weeks of PAP therapy, and examined their effect on cultured endothelial cells using several in vitro reporter assays. RESULTS:We found that circulating exosomes contributed to the induction and propagation of OSA/OHS-related endothelial dysfunction (ie, increased permeability and disruption of tight junctions along with increased adhesion molecule expression, and reduced endothelial nitric oxide synthase expression), and promoted increased monocyte adherence. Further, when comparing exosomes isolated before and after PAP therapy, the disturbances in endothelial cell function were attenuated with treatment, including an overall cumulative decrease in endothelial permeability in all 12 subjects by 10.8% (P = .035), as well as detection of a subset of 4 differentially expressed exosomal miRNAs, even in the absence of parallel changes in systemic blood pressure or metabolic function. CONCLUSIONS:Circulating exosomes facilitate important intercellular signals that modify endothelial phenotype, and thus emerge as potential fundamental contributors in the context of OSA/OHS-related endothelial dysfunction. Exosomes may not only provide candidate biomarkers, but are also a likely and plausible mechanism toward OSA/OHS-induced cardiovascular disease. CLINICAL TRIAL REGISTRATION:Registry: ClinicalTrials.gov, Title: AVAPS-AE Efficacy Study, URL: https://clinicaltrials.gov/ct2/show/NCT01368614, Identifier: NCT01368614.

Project description:ObjectivesDevelopment of pharmaceutical agents in transplantation is currently limited by long waits for hard endpoints. We applied a validated integrative risk-prognostication system integrative Box (iBox) as a surrogate endpoint to the TRANSFORM Study, a large randomised controlled trial, to project individual patient long-term kidney allograft survival from 1 year to 11 years after randomisation.DesignPost-hoc analysis of a randomised open-label controlled trial.SettingMulticentre study including 186 centres in 42 countries worldwide.Participants2037 de novo kidney transplant recipients.InterventionParticipants were randomised (1:1) to receive everolimus with reduced-exposure calcineurin inhibitor (EVR+rCNI) or mycophenolic acid with standard-exposure CNI (MPA+sCNI).Primary outcome measureThe iBox scores were computed for each participant at 1 year after randomisation using functional, immunological and histological parameters. Individual long-term death-censored allograft survival over 4, 6 and 11 years after randomisation was projected with the iBox risk-prognostication system.ResultsOverall, 940 patients receiving EVR+rCNI and 932 receiving MPA+sCNI completed the 1-year visit. iBox scores generated at 1 year yielded graft survival prediction rates of 90.9% vs 92.1%, 87.9% vs 89.5%, and 80.0% vs 82.4% in the EVR+rCNI versus MPA+sCNI arms at 4, 6, and 11 years post-randomisation, respectively (all differences below the 10% non-inferiority margin defined by study protocol). Inclusion of immunological and histological Banff diagnoses parameters in iBox scores resulted in comparable and non-inferior predicted graft survival for both treatments.ConclusionsThis proof-of-concept study provides the first application of a validated prognostication system as a surrogate endpoint in the field of transplantation. The iBox system, by projecting kidney allograft survival up to 11 years post-randomisation, confirms the non-inferiority of EVR+rCNI versus MPA+sCNI regimen. Given the current process engaged for surrogate endpoints qualification, this study illustrates the potential to fast track development of pharmaceutical agents.Trial registration numberTRANSFORM trial: NCT01950819.iBox prognostication system: NCT03474003.

Dataset Information

Proof-of-Concept Study for an Enhanced Surrogate Marker of Endothelial Function in Diabetes.

Publications

Proof-of-Concept Study for an Enhanced Surrogate Marker of Endothelial Function in Diabetes.

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