Glycoxidation, Arterial Biomechanics, and Target Organ Damage
NCT ID: NCT06325800
Last Updated: 2024-04-09
Study Results
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Basic Information
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RECRUITING
500 participants
OBSERVATIONAL
2024-01-01
2029-12-31
Brief Summary
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Detailed Description
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Atherosclerotic cardiovascular disease (ASCVD) represents one of the leading causes of morbidity and mortality in the population. Arterial hypertension (AHT), along with other cardiovascular risk (CVR) factors, predisposes to abnormalities in the structure and function of large and small arteries, leading to premature vascular aging and culminating in the development of target organ damage (TOD),which reresents a clear but underdiagnosed precursor of ASCVD. However, not all patients develop TOD, nor do they do so over the same time span or with the same intensity. Additionally, patients who initially present with low to moderate CVR are already considered to be at moderate to high CVR in the presence of TOD, with more stringent therapeutic objectives.
Vascular biomechanics primarily focuses on the study of mechanical properties and behavior of arteries. Unfavorable arterial biomechanics are associated with the development and progression of atherosclerosis and arteriosclerosis. These processes represent a continuum of vascular damage mediated by the accumulation of oxidized lipoproteins in the subendothelial space, activation and amplification of inflammatory pathways, and development of arterial fibrosis and calcification. At the core of these phenomena lies the occurrence of endothelial dysfunction, characterized by increased permeability and loss of the vascular endothelium's filtering capacity for deleterious molecules to the arterial wall.
Oxidative stress, defined as an imbalance between reactive species production and antioxidant systems in favor of the former, plays a crucial role in the development of endothelial dysfunction, deposition of oxidized lipoproteins, and proinflammatory interaction between these and the mononuclear-phagocytic system. The accumulation of reactive oxygen species (ROS) and others induces lipid peroxidation and glycoxidation phenomena culminating in the formation of advanced lipoxidation and glycation end products (ALEs and AGEs, respectively). ALEs and AGEs can bind to proteins, causing functional and structural abnormalities, and also influence cellular signaling by activating, among others, death pathways.
Unfavorable redox status and glycation levels are linked to aging, degenerative diseases, and accumulated vascular damage in certain subpopulations, particularly patients with diabetes mellitus (DM). However, little is known about the influence of antioxidant system glycation and glycoxidation on arterial biomechanics and the development of target organ damage in apparently healthy patients with moderate to high CVR. The investigators aim to study the specific relationship between arterial biomechanical abnormalities and TOD with serum glycation levels, glycoxidation status, and function-structure balance of some antioxidant system elements, highlighting catalase, superoxide dismutase, and glutathione peroxidase.
MATERIALS AND METHODS
Project Design and Setup
This is an observational, ambispective, and multicenter project promoted by the Unit of Hypertension and Cardiovascular risk belonging to the Internal Medicine Department at the University Hospital of Santiago de Compostela. Participants will be individuals belonging to the Organizational Structure of Integrated Management (EOXI) of Santiago de Compostela and Barbanza who seek consultation for CVR diagnosis, management, and follow-up.
Participants. Inclusion and Exclusion Criteria
From the total pool of consulted patients, only individuals over 18 years with a moderate to high CVR profile based on guideline reference scores will be preselected. Exclusion criteria will include the presence of DM according to current clinical practice guidelines, smoking habit (defined as current consumption and within the 6 months prior to recruitment), risky alcohol consumption (defined as consumption exceeding 10 g and 20 g daily for women and men, respectively), and established cardiovascular disease.
Assessment of Arterial Biomechanical Markers and TOD
The investigators will perform bilateral ultrasound exploration of the Common Carotid Artery (CCA), Internal Carotid Artery (ICA) and distal arteries of the lower limbs using a Mindray Z60 device (Mindray®, Guangdong, China) with high-frequency probe. The following measurements and calculations will be extracted:
1. In motion mode (M-mode), concomitant measurement of arterial radius, arterial pressures, and total wall thickness for the calculation of distensibility and tension parameters in the middle segment of the CCA.
2. In two-dimensional mode (B-mode), automated measurement of intima-media thickness (IMT) in the distal region of the CCA, along with detection and characterization of cholesterol plaque.
3. In spectral Doppler mode, morphological description of volume-time (flow) function in terms of flow velocities and vascular resistance indices in the middle segment of the CCA and ICA.
4. In B-mode with elastography module, direct evaluation of local stiffness degree in a middle segment of the CCA.
5. In spectral Doppler mode with ECG synchronization, assessment of carotid-femoral pulse wave velocity (c-f PWV).
6. In spectral Doppler mode, assessment of the ankle-brachial index (ABI).
The investigators will also assess incipient damage in the retinal microvasculature using retinography with a Topcon TRC-NW6S device (Electronics®, Tokyo, Japan).
Assessment of Oxidative Stress markers and Antioxidant System Activity-Structure
To assess the redox status, plasma and urine thiobarbituric acid reactive substances (TBARS) and reduced thiols will be assessed according to the referenced protocols via spectrophotometric quantification. Enzymatic function of glutathione peroxidase, catalase, and superoxide dismutase will be measured as enzymatic activity according to the referenced protocols. These analyses will be conducted using an Asys UVM-340 analyzer (Biochrom®, Cambridge, UK). Structure features of antioxidant enzymes based on glycation and glycoxidation patterns will be assessed using proteomics.
Determination of Glycation, Glycoxidation, and Lipoxidation status
The percentage of glycated hemoglobin will be assessed using high-performance liquid chromatography (HPLC) with the Hemoglobin next analyzer (A. Menarini Diagnostics®, Florence, Italy). Fructosamine levels will be determined by the diazyme glycated serum protein enzymatic method (Diazyme, Kent, UK) on an Advia 2400 analyser (Siemens Healthcare Diagnostics Inc.®, Tarrytown, USA). The percentage of glycated albumin will be estimated from fructosamine and albumin levels. This laboratory assessment will be performed by the Central Hospital Laboratory department.
General levels of glycoxidation and lipoxidation will be estimated through quantification of dicarbonyl levels using the TBARS spectrophotometric approach. Global glycoxidation status will be also estimated through assessment of skin advanced glycation end products (AGEs) using an AGE Reader (DiagnOptics BV®, Groningen, Netherlands). AGEs mainly represent glycated adducts bound to proteins that arise during glycoxidation processes. The AGE Reader has been developed to assess skin autofluorescence (SAF) non-invasively using the fluorescent properties of various AGEs.
Outcomes in Cardiovascular Risk
The investigators will measure the number needed to treat (NNT) of consultations and exploration time to detect abnormalities in arterial biomechanics and target organ damage (TOD), and thus determine an increased CVR warranting therapeutic intensification. Cardiovascular and cerebrovascular events, hospital admissions, consultations, death and disability will be also assessed.
Ethical Considerations and Good Clinical Practice
This study will be conducted in accordance with the ethical principles of the Declaration of Helsinki and the good practice standards in the research of the Galician (Spain) Health Service (SERGAS). Written informed consent will be obtained from all patients who agreed to participate. The protocols were approved by the Research Ethics Committee of Santiago-Lugo (codes 2021/401 and 2023/302).
Work Plan and Project Flow
In a first phase, the investigators plan to include patients meeting the criteria and consenting to participate. Clinical-anthropometric evaluation, arterial biomechanics, TOD detection, and sample collection will be conducted in a single medical act. Biomechanical, oxidative stress, glycation and glycoxidation markers will be quantified in both patients with and without biomechanical abnormalities and arterial TOD. The aim of this phase is to evaluate the differences between patient groups based on biomechanical parameters and arterial TOD. In a subgroup of patients, differences in the structure-function of antioxidant enzymes in terms of glycation and glycoxidation levels, and their relationship with arterial biomechanical abnormalities and TOD will also be evaluated. This phase will include the extraction, collection, processing, and analysis of preliminary data, along with the attainment of the project's initial results.
In a second phase,
1. Patients without biomechanical abnormalities or TOD will undergo a 5-year follow-up, with anual and final evaluations of biomechanical abnormalities, TOD, and cardiovascular outcomes. The aim of this phase is to evaluate differences in the previous markers between patient groups based on biomechanical parameters and arterial TOD. In a subgroup of patients, differences in the structure-function of antioxidant enzymes in terms of glycation and glycoxidation levels, and their relationship with arterial biomechanical abnormalities and TOD will be also assessed. This phase will include the extraction, collection, processing, and analysis of preliminary data, along with the attainment of the project's final results.
2. Patients with biomechanical abnormalities and/or TOD will undergo a 5-year follow-up, with annual and final evaluations of TOD progression and cardiovascular outcomes. The aim of this phase is to evaluate differences in the previous markers between patient groups based arterial TOD and cardiovascular outcomes. In a subgroup of patients, differences in the structure-function of antioxidant enzymes in terms of glycation and glycoxidation levels, and their relationship with TOD and cardiovascular outcomes will be assessed. This phase will include the extraction, collection, processing, and analysis of preliminary data, along with the attainment of the project's final results.
Mathematical analysis and modeling
The SPSS 22.0 statistical software package (SPSS Inc.®, Chicago, IL, EE.UU) will be employed. A descriptive statistic approach will be performed, including assessment of normality for quantitative variables. Univariate statistics will be used to compare groups with specific tests depending on the variable type. If relevant results are found, linear correlation studies will be conducted. After univariate analysis, multivariate models will be constructed, both explanatory for the association of predictors with the outcomes, and predictive for the risk of biomechanical abnormalities, TOD and cardiovascular results. To assess factors that may influence biomechanical parameters, TOD and cardiovascular results over time, specific mathematical procedures related to joint modeling approach and time series analysis will be applied. Sample size calculations will be based on specific statistical tests according to the variable type and distribution, always considering a moderate effect size, 95% confidence interval (95%CI), and at least 80% power.
Conditions
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Study Design
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CASE_CONTROL
OTHER
Study Groups
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Controls
Patients with
Arterial biomechanics values lower than or equal to the 50th percentile of the distribution (measured as carotid stiffness by ultrasound elastography, distensibility and stress, flow velocity and vascular resistance),
AND
Absence of vascular target organ damage (considered as carotid intima-media thickness \>0.9 mm, cholesterol plaque, carotid stenosis, carotid-femoral pulse wave velocity \>10 m/s, pulse pressure \>60 mmHg, ankle-Brachial Index \<0.9 or \>1.3, hypertensive retinopathy)
AND
Absence of cardiovascular disease (cardiovascular events, cerebrovascular events, hospital admissions, consultations, death, disability)
No interventions assigned to this group
Cases
Patients with
Arterial biomechanics values higher than the 50th percentile of the distribution (measured as carotid stiffness by ultrasound elastography, distensibility and stress, flow velocity and vascular resistance),
OR
Presence of vascular target organ damage (considered as carotid intima-media thickness \>0.9 mm, cholesterol plaque, carotid stenosis, carotid-femoral pulse wave velocity \>10 m/s, pulse pressure \>60 mmHg, ankle-Brachial Index \<0.9 or \>1.3, hypertensive retinopathy)
OR
Presence of cardiovascular disease (cardiovascular events, cerebrovascular events, hospital admissions, consultations, death, disability)
No interventions assigned to this group
Eligibility Criteria
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Inclusion Criteria
* Moderate to high Cardiovascular Risk estimated by SCORE2OP.
* Signed written consent for participation in the study.
Exclusion Criteria
* High-risk alcohol consumption (More than 10 and 20 g/day in women and men, respectively).
* Presence of Diabetes mellitus.
* Established cardiovascular disease, including heart failure, ischemic heart disease, valvular heart disease, atrial fibrillation, peripheral artery disease, and cerebrovascular disease.
18 Years
ALL
Yes
Sponsors
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Instituto de Investigación Sanitaria de Santiago de Compostela
UNKNOWN
Instituto de Salud Carlos III
OTHER_GOV
University of Santiago de Compostela
OTHER
Hospital de Barbanza
UNKNOWN
Complejo Hospitalario Universitario de Santiago
OTHER
Responsible Party
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Nestor Vazquez Agra
Principal Investigator
Locations
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Complejo Hospitalario Universitario de Santiago de Compostela
Santiago de Compostela, A Coruña, Spain
Countries
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Central Contacts
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Facility Contacts
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References
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Other Identifiers
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Grant
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
2021401/2023007
Identifier Type: -
Identifier Source: org_study_id
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