Molecular Mechanisms and Carotid Atherosclerosis

NCT ID: NCT03962686

Last Updated: 2022-08-03

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 76 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2015-01-01
• Study Completion Date: 2018-01-01

Brief Summary

The role of methylase system and Proprotein convertase subtilisin/kexin type 9 (PCSK9) in the accelerated atherosclerotic progression of diabetic patients is unclear. Authors will evaluate methylase activity and PCSK9 in carotid plaques of asymptomatic diabetic and non diabetic patients, as well as the effect of statin added to PCSK9 inhibitors (PCSK9i) therapy vs. statin alone in diabetic plaques. Plaques will be obtained from 43 type 2 diabetic and 30 non diabetic patients undergoing carotid endarterectomy. Diabetic patients will receive statin therapy (n 23) or statin plus PCSK9i (140 mg of evolocumab; n 20) 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 and PCSK9 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 plus SLGT2i 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 drugs as PCSK9i. However, in the present study authors hypothesized that by increasing methylase activity, diabetes may enhance the inflammatory potential of atherosclerotic plaques favoring instability, and its relation with the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9). Therefore, authors designed this study to identify differences in inflammatory infiltration as well as methylase activity and PCSK9 expression 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 statin added to PCSK9i (vs. statin alone) on methylase activity and PCSK9 expression in carotid plaques of diabetic patients.

Conditions

Diabetes Mellitus, Type 2; Atherosclerosis of Artery; Atherosclerotic Plaque

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

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.

No interventions assigned to this group

patients with diabetes mellitus (DM) treated with statin

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.

No interventions assigned to this group

patients with diabetes mellitus (DM) treated with statin plus PCSK9i

In this cohort will be enrolled 20 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 statin therapy daily (n 20) added to PCSK9i, 140 mg twice a month (n 30).

statin Oral Tablet plus PCSK9i

Intervention Type: DRUG

Patients in the third study cohort will receive for statin oral therapy plus 140 mg twice a month PCSK9i therapy via subcutaneous injection before to practice surgical intervention for carotid artery obstruction.

Interventions

statin Oral Tablet plus PCSK9i

Patients in the third study cohort will receive for statin oral therapy plus 140 mg twice a month PCSK9i therapy via subcutaneous injection before to practice surgical intervention for carotid artery obstruction.

Intervention Type: DRUG

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;

• controindication to receive PCSK9i treatment;
• neoplastic diseases;

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Campania Luigi Vanvitelli

OTHER

Sponsor Role: lead

Responsible Party

Celestino Sardu

clinical professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Raffaele Marfella

Naples, , Italy

Countries

Italy

Other Identifiers

SecondUNI 22.05.2019

Identifier Type: -

Identifier Source: org_study_id