Pleiotropic Effects of Atorvastatin in High Cardiovascular Risk Patients
Condition: Coronary Artery Disease; HMG-CoA Reductase Inhibitor Toxicity; Atherosclerosis; Oxidative Stress; Endothelial Dysfunction
MeSH terms: Coronary Artery Disease; Atherosclerosis
Study type: Interventional
Phase: Phase 4

Summary: 
      The present study constitutes a study examining the effect of atorvastatin on vascular
      function in high cardiovascular risk patients. For this purpose the investigators will record
      atorvastatin effects on statin-naïve patients (patients that start statins treatment for
      first time). More specifically the investigators will study atorvastatin effects on:

        1. Endothelial function

        2. Arterial elastic properties

        3. Systemic Inflammatory/thrombotic mechanisms

        4. Vascular and myocardial redox state
    

Detailed description: 
      In total we will recruit 72 high cardiovascular risk patients such as patients with ischemic
      cardiomyopathy (ischemic heart failure), coronary artery disease and/or patients undergoing
      elective coronary bypass artery grafting (CABG), valve replacement or aortic surgery. The
      whole study will be divided into 2 distinct clinical arms:

      ARM A

      In this arm patients with ischemic heart failure (NYHA II-III) will be recruited. In a
      double-blind crossover design heart failure patients (n=30) naïve to statins treatment will
      be randomized to atorvastatin 10mg/day (n=15) or 40mg/day (n=15) for 4 weeks. At the end of 4
      weeks a 2-week wash out period will follow and then all patients will switch atorvastatin
      dose (e.g all patients that were under atorvastatin 10mg/day will be switched to 40mg/day and
      vice versa).

      Both at baseline and at the end of 4 weeks period patients will undergo

        -  blood sampling

        -  assessment of endothelium-dependent and -independent vasodilatation and

        -  vascular elastic properties study (see below for methods).

      ARM B

      In this arm, patients undergoing cardiac surgery (CABG, valve replacement or aortic surgery)
      that are not under statins treatment will be recruited (n=42). Patients will be randomized in
      a double-blind fashion to atorvastatin 40mg/day or placebo for 3 days before surgery.

      Both at baseline and on surgery day patients will undergo

        -  blood sampling and

        -  assessment of endothelium-dependent and -independent vasodilatation (see below for
           methods) while

        -  during surgery tissue samples (grafts, myocardium and adipose tissue segments) will be
           obtained that will be used for ex-vivo studies (see below).

      Consent form

      Every patient participating in the clinical study will give a written consent form, and will
      be informed in details for the aims of the study by the researchers. During recruitment
      process all participants will fill out a questionnaire with demographic and clinical data.
      All information given by the participants will be held highly classified. All participants
      will give written consent for the programmed biochemical measurements and vascular studies,
      as stated in the study design. Specifically for patients undergoing cardiac surgery (arm B)
      an additional consent form will be filled out that will permit grafts, myocardium and adipose
      tissue segments harvesting during cardiac surgery.

      Methods

      Endothelial-dependent and independent vasodilatation: Brachial Artery Flow-Mediated
      Dilatation (FMD) of the brachial artery will be measured as a quantitative readout of
      NO-mediated conduit vessel endothelial function, as we have done in several previous studies
      and in accordance with international guidelines.Endothelial dependent (hyperaemic flow after
      cuff occlusion) and endothelial independent (GTN) responses of the brachial artery will be
      measured using high-resolution ultrasound imaging with automated vessel diameter measurements
      (Vascular Analyser, MIA Inc. Iowa). FMD and GTN induced dilatation will be measured as
      absolute and proportional changes in arterial diameter.Reproducibility data from our
      laboratory show a coefficient of variation for inter-study measurements of <10% comparable to
      other reports.

      Arterial Stiffness: Measures of central arterial stiffness are independent predictors of
      cardiovascular outcomes in large prospective studies and is inversely correlated with
      measures of endothelial function.Arterial tonometry is a simple, reproducible method to
      measure, non-invasively, arterial stiffness. We have already established measures of central
      aortic stiffness - augmentation index and aortic pulse wave velocity - using the Sphygmocor
      system for applanation tonometry (AtCor Medical, Australia). Mathematical transformation of
      the radial pulse waveform is used to derive the augmentation index.The difference in time for
      the pulse waveform to reach the carotid compared to the femoral artery measures pulse wave
      velocity down the aorta, with faster transit associated with a 'stiffer' aorta.

      Systemic oxidative stress: We will study statins effects on systemic oxidative stress using a
      systemic oxidative stress marker like lipid peroxides. In more details lipid peroxides will
      be quantified in patients' plasma using malondialdehyde assay (ΜDA-TBARS).

      Vascular oxidative stress: ROS generation in the vascular segments obtained during CABG will
      be determined by lucigenin-enhanced chemiluminescence. The same measurements will also be
      performed in myocardium segments obtained during CABG form the site of right atrium incision,
      where extracorporeal circulation cannula is inserted. Our aim is to determine statins effects
      on vascular and myocardial ROS generation.

      Adipose tissue cultures: During cardiac surgery adipose tissue samples will be collected. In
      more details subcutaneous adipose tissue will be collected from the site of sternum incision;
      pericardial adipose tissue will be collected from the site close to right ventricle; and
      femoral adipose tissue will be collected from the area of saphenous vein harvesting (when
      available). Adipose tissue samples obtained during surgery will be cultured ex-vivo using a
      standard adipose tissue protocol.

      Biochemical and inflammatory markers: Apart from the common laboratory screening tests (whole
      blood count, AST, ALT, γGT, ALP, Urea, Creatinine, glucose, total cholesterol, triglycerides,
      LDL, HDL, Na+, K+, Ca2+, CRP), we will determine additional proinflammatory and prothrombotic
      biomarkers in patients' plasma. More specifically, using enzyme-linked immunosorbent assay
      (ELISA) we will quantify interleukin-6 and other adipokines both in patients plasma and
      adipose tissue cultures supernatants. Using high precision liquid chromatography (HPLC) we
      will quantify biopterin plasma and vascular levels (tetrahydrobiopterin, dihydrobiopterin and
      total biopterins).Studies have shown that the abovementioned markers may have a prognostic
      value in high cardiovascular risk patients.

      Statistical Analysis: Statistical analysis of results will be done separately according to
      the clinical group studied. Therefore there will be separate statistical analysis for
      ischemic heart failure patients group (arm A) and for the patients undergoing cardiac surgery
      (arm B). Especially for arm B we will compare reactive oxygen species generation from
      vascular wall and myocardium between patients randomized to placebo or atorvastatin 40mg/day.
    

Intervention name(s): Atorvastatin, high vs low dose; Atorvastatin vs Placebo
Intervention type(s): Drug; Drug
Intervention description(s): In this arm patients with ischemic heart disease will be recruited. In a double-blind crossover design heart failure patients (n=30) naïve to statins treatment will be randomized to receive oral atorvastatin 10mg/day 1x1(n=15) or oral atorvastatin 40mg/day 1x1 (n=15) for 4 weeks. At the end of 4 weeks a 2-week wash out period will follow and then all patients will switch atorvastatin dose and continue treatment for 4 weeks (e.g all patients that were under atorvastatin 10mg/day will be switched to atorvastatin 40mg/day and vice versa).; In this arm, patients undergoing cardiac surgery (CABG, valve replacement or aortic surgery) that are not under statins treatment will be recruited. Patients will be randomized in a double-blind fashion to atorvastatin 40mg/day or placebo for 3 days before surgery date.
Other intervention name(s): Atorvastatin high vs low dose in ischemic heart disease; Atorvastatin in Patients Undergoing Cardiac Surgery
Intervention MeSH terms: Atorvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science