Molecular Mechanisms and Carotid Atherosclerosis
Condition: Diabetes Mellitus, Type 2; Atherosclerosis of Artery; Atherosclerotic Plaque
MeSH terms: Carotid Artery Diseases; Atherosclerosis; Diabetes Mellitus; Diabetes Mellitus, Type 2; Plaque, Atherosclerotic
Study type: Observational

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.
    

Intervention name(s): statin Oral Tablet plus PCSK9i
Intervention type(s): Drug
Intervention description(s): 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.
Observational model: Case-Control
Time perspective: Prospective
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 previous treated by oral daily statin therapy (23
        patients) vs. DM patients (n 20) previous treated by daily statin therapy plus 140 mg twice
        a month of PCSK9i. All patients will be affected by severe obstructive carotid artery
        atherosclerosis.
      
Biospecimen description: 
      samples of atherosclerotic plaques obtained during revascularization of carotid arteries.