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出境医 / 临床实验 / Molecular Mechanisms and Carotid Atherosclerosis

Molecular Mechanisms and Carotid Atherosclerosis

Study Description
Brief Summary:
The role of methylase system in the accelerated atherosclerotic progression of diabetic patients is unclear. Authors will evaluate methylase activity in carotid plaques of asymptomatic diabetic and non diabetic patients, as well as the effect of metformin in diabetic plaques. Plaques will be obtained from 46 type 2 diabetic and 30 non diabetic patients undergoing carotid endarterectomy. Diabetic patients will receive 1000 mg of metformin (n 23) or placebo (n 23) for 4 months before scheduled endarterectomy. Plaques will be analyzed for macrophages (CD68), T-cells (CD3), inflammatory cells (HLADR), methylase activity, nuclear factor (NF)-KB, tumor necrosis factor (TNF)-alpha, nitrotyrosine, matrix metalloproteinase (MMP) and collagen content (immunohistochemistry and enzyme- linked immunosorbent assay. Authors' study hypothesis is that methylase over-activity will be associated with enhanced inflammatory reaction and NF-KB expression in diabetic plaques. Secondly, the inhibition of methylase activity in atherosclerotic lesions of diabetic patients by metformin might be associated with morphological and compositional characteristics of a potential stable plaque phenotype, possibly by down regulating NF-KB-mediated inflammatory pathways.

Condition or disease Intervention/treatment
Diabetes Mellitus, Type 2 Atherosclerosis of Artery Atherosclerotic Plaque Drug: MetFORMIN 1000 Mg Oral Tablet

Detailed Description:
Diabetes Mellitus (DM) leads to increased vulnerability for plaque disruption and mediates increased incidence and severity of clinical events. Inflammation, particularly in diabetes, plays a central role in the cascade of events that result in plaque erosion and fissuring. There is emerging evidence that the methylase system might be involved in both initial stage and progression of atherosclerosis. Moreover, the methylase system might be involved in inflammatory/oxidative stress pathway, involved for activation of nuclear factor kappa B (NF-KB), and other proteins linked to over inflammation/oxidative stress. Although it has been demonstrated that diabetes may up regulate these inflammatory/oxidative pathway, still no evidence exists about the potential role of methylase system in the evolution of atherosclerotic plaques of diabetic patients. Conversely, less data have been reported about the possible modulation of these pathways by hypoglycemic drugs as oral metfromin. However, in the present study authors hypothesized that by increasing methylase activity, diabetes may enhance the inflammatory potential of atherosclerotic plaques favoring instability. Therefore, authors designed this study to identify differences in inflammatory infiltration as well as methylase activity between carotid plaques of asymptomatic diabetic and non diabetic (normoglycemics) patients. Because experimental and pathological studies suggest that activation of methylase system might control inflammation/oxidative stress, the present study also evaluated the effect of the metformin on methylase activity in carotid plaques of diabetic patients.
Study Design
Layout table for study information
Study Type : Observational
Actual Enrollment : 76 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Molecular Mechanisms Implied in Carotid Atherosclerosis and Atherosclerotic Plaque Progression in Patients Normoglycemics vs. Patients With Diabetes Mellitus
Actual Study Start Date : January 1, 2015
Actual Primary Completion Date : January 1, 2017
Actual Study Completion Date : January 1, 2018
Arms and Interventions
Group/Cohort Intervention/treatment
normoglycemics
In this cohort will be enrolled 30 normoglycemics patients affected by carotid artery atherosclerotic and evidence of atherosclerotic plaque causing an endolumninal stenosis > 60%. These patients will receive a surgical intervention to remove the atherosclerotic plaque and to revascularize the obstructed coronary artery vessel.
patients with diabetes mellitus (DM)
In this cohort will be enrolled 23 DM patients affected by carotid artery atherosclerotic and evidence of atherosclerotic plaque causing an endolumninal stenosis > 60%. These patients will receive a surgical intervention to remove the atherosclerotic plaque and to revascularize the obstructed coronary artery vessel.
patients with diabetes mellitus (DM) plus metformin
In this cohort will be enrolled 23 DM patients affected by carotid artery atherosclerotic and evidence of atherosclerotic plaque causing an endolumninal stenosis > 60%. These patients will receive a surgical intervention to remove the atherosclerotic plaque and to revascularize the obstructed coronary artery vessel. These patients were treated before the surgical intervention by metformin 1000 mg daily.
 Drug: MetFORMIN 1000 Mg Oral Tablet
Patients in the third study cohort will receive for 4 months a 1000 mg metformin oral therapy before to practice surgical intervention for carotid artery obstruction.
Outcome Measures
Primary Outcome Measures :
  1. methylase status [ Time Frame: 12 months ]
    to evaluate the activity (over vs. hypo activation) of methylase complex in atherosclerotic carotid plaques of normoglycemics vs. DM patients, and of DM patients vs. DM patients previous treated by metformin.


Biospecimen Retention:   Samples With DNA
samples of atherosclerotic plaques obtained during revascularization of carotid arteries.

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Study population will be divided in 30 normoglycemics patients vs. 46 DM patients. DM patients will be divided in patients without metformin therapy (23 patients) vs. DM patients previous treated by 1000 mg daily of metformin. All patients will be affected by severe obstructive carotid artery atherosclerosis.
Criteria

Inclusion Criteria:

  • evidence of carotid artery atherosclerosis with endoluminal stenosis > 60%;
  • aged >18 years.
  • aged <75 years

Exclusion Criteria:

  • insulin dependent DM;
  • absence of carotid artery atherosclerosis with endoluminal stenosis > 60%;

  • contraindication to receive a carotid artery revascularization treatment;

    --contraindication to receive metformin treatment;

  • neoplastic diseases;
Contacts and Locations

Locations
Layout table for location information
Italy
Raffaele Marfella
Naples, Italy, 80138
Sponsors and Collaborators
University of Campania "Luigi Vanvitelli"
Tracking Information
First Submitted Date May 22, 2019
First Posted Date May 24, 2019
Last Update Posted Date May 24, 2019
Actual Study Start Date January 1, 2015
Actual Primary Completion Date January 1, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: May 22, 2019) 		methylase status [ Time Frame: 12 months ]
to evaluate the activity (over vs. hypo activation) of methylase complex in atherosclerotic carotid plaques of normoglycemics vs. DM patients, and of DM patients vs. DM patients previous treated by metformin.
Original Primary Outcome Measures Same as current
Change History No Changes Posted
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Molecular Mechanisms and Carotid Atherosclerosis
Official Title Molecular Mechanisms Implied in Carotid Atherosclerosis and Atherosclerotic Plaque Progression in Patients Normoglycemics vs. Patients With Diabetes Mellitus
Brief Summary The role of methylase system in the accelerated atherosclerotic progression of diabetic patients is unclear. Authors will evaluate methylase activity in carotid plaques of asymptomatic diabetic and non diabetic patients, as well as the effect of metformin in diabetic plaques. Plaques will be obtained from 46 type 2 diabetic and 30 non diabetic patients undergoing carotid endarterectomy. Diabetic patients will receive 1000 mg of metformin (n 23) or placebo (n 23) for 4 months before scheduled endarterectomy. Plaques will be analyzed for macrophages (CD68), T-cells (CD3), inflammatory cells (HLADR), methylase activity, nuclear factor (NF)-KB, tumor necrosis factor (TNF)-alpha, nitrotyrosine, matrix metalloproteinase (MMP) and collagen content (immunohistochemistry and enzyme- linked immunosorbent assay. Authors' study hypothesis is that methylase over-activity will be associated with enhanced inflammatory reaction and NF-KB expression in diabetic plaques. Secondly, the inhibition of methylase activity in atherosclerotic lesions of diabetic patients by metformin might be associated with morphological and compositional characteristics of a potential stable plaque phenotype, possibly by down regulating NF-KB-mediated inflammatory pathways.
Detailed Description Diabetes Mellitus (DM) leads to increased vulnerability for plaque disruption and mediates increased incidence and severity of clinical events. Inflammation, particularly in diabetes, plays a central role in the cascade of events that result in plaque erosion and fissuring. There is emerging evidence that the methylase system might be involved in both initial stage and progression of atherosclerosis. Moreover, the methylase system might be involved in inflammatory/oxidative stress pathway, involved for activation of nuclear factor kappa B (NF-KB), and other proteins linked to over inflammation/oxidative stress. Although it has been demonstrated that diabetes may up regulate these inflammatory/oxidative pathway, still no evidence exists about the potential role of methylase system in the evolution of atherosclerotic plaques of diabetic patients. Conversely, less data have been reported about the possible modulation of these pathways by hypoglycemic drugs as oral metfromin. However, in the present study authors hypothesized that by increasing methylase activity, diabetes may enhance the inflammatory potential of atherosclerotic plaques favoring instability. Therefore, authors designed this study to identify differences in inflammatory infiltration as well as methylase activity between carotid plaques of asymptomatic diabetic and non diabetic (normoglycemics) patients. Because experimental and pathological studies suggest that activation of methylase system might control inflammation/oxidative stress, the present study also evaluated the effect of the metformin on methylase activity in carotid plaques of diabetic patients.
Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
samples of atherosclerotic plaques obtained during revascularization of carotid arteries.
Sampling Method Non-Probability Sample
Study Population Study population will be divided in 30 normoglycemics patients vs. 46 DM patients. DM patients will be divided in patients without metformin therapy (23 patients) vs. DM patients previous treated by 1000 mg daily of metformin. All patients will be affected by severe obstructive carotid artery atherosclerosis.
Condition
  • Diabetes Mellitus, Type 2
  • Atherosclerosis of Artery
  • Atherosclerotic Plaque
Intervention Drug: MetFORMIN 1000 Mg Oral Tablet
Patients in the third study cohort will receive for 4 months a 1000 mg metformin oral therapy before to practice surgical intervention for carotid artery obstruction.
Study Groups/Cohorts
  • normoglycemics
    In this cohort will be enrolled 30 normoglycemics patients affected by carotid artery atherosclerotic and evidence of atherosclerotic plaque causing an endolumninal stenosis > 60%. These patients will receive a surgical intervention to remove the atherosclerotic plaque and to revascularize the obstructed coronary artery vessel.
  • patients with diabetes mellitus (DM)
    In this cohort will be enrolled 23 DM patients affected by carotid artery atherosclerotic and evidence of atherosclerotic plaque causing an endolumninal stenosis > 60%. These patients will receive a surgical intervention to remove the atherosclerotic plaque and to revascularize the obstructed coronary artery vessel.
  • patients with diabetes mellitus (DM) plus metformin
    In this cohort will be enrolled 23 DM patients affected by carotid artery atherosclerotic and evidence of atherosclerotic plaque causing an endolumninal stenosis > 60%. These patients will receive a surgical intervention to remove the atherosclerotic plaque and to revascularize the obstructed coronary artery vessel. These patients were treated before the surgical intervention by metformin 1000 mg daily.
    Intervention: Drug: MetFORMIN 1000 Mg Oral Tablet
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Completed
Actual Enrollment
 (submitted: May 22, 2019) 		76
Original Actual Enrollment Same as current
Actual Study Completion Date January 1, 2018
Actual Primary Completion Date January 1, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • evidence of carotid artery atherosclerosis with endoluminal stenosis > 60%;
  • aged >18 years.
  • aged <75 years

Exclusion Criteria:

  • insulin dependent DM;
  • absence of carotid artery atherosclerosis with endoluminal stenosis > 60%;

  • contraindication to receive a carotid artery revascularization treatment;

    --contraindication to receive metformin treatment;

  • neoplastic diseases;
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries Italy
Removed Location Countries  
 
Administrative Information
NCT Number NCT03962686
Other Study ID Numbers SecondUNI 22.05.2019
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party Celestino Sardu, University of Campania "Luigi Vanvitelli"
Study Sponsor University of Campania "Luigi Vanvitelli"
Collaborators Not Provided
Investigators Not Provided
PRS Account University of Campania "Luigi Vanvitelli"
Verification Date May 2019

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