Pleiotropic Effects of Atorvastatin in High Cardiovascular Risk Patients
Information source: Hippocration General Hospital
Information obtained from ClinicalTrials.gov on December 08, 2011
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Coronary Artery Disease; HMG-CoA Reductase Inhibitor Toxicity; Atherosclerosis; Oxidative Stress; Endothelial Dysfunction
Intervention: Atorvastatin, high vs low dose (Drug); Atorvastatin vs Placebo (Drug)
Phase: Phase 4
Sponsored by: Hippocration General Hospital
Official(s) and/or principal investigator(s):
Dimitris Tousoulis, Principal Investigator, Affiliation: Ass. Professor, Athens University Medical School
Dimitris Tousoulis, Ass. Prof., Email: firstname.lastname@example.org
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
Official title: Effects of Atorvastatin on Endothelial Function, Vascular and Myocardial Redox State in High Cardiovascular Risk Patients
Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science
Primary outcome: Vascular Nitric oxide bioavailability (Arm A + B)
Vascular Redox state (Arm B)
Myocardial redox state (Arm B)
Systemic inflammatory, thrombotic and oxidative stress status (Arms A + B)
Vascular elastic properties (Arm A)
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:
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) naÃ¯ve 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).
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
- during surgery tissue samples (grafts, myocardium and adipose tissue segments) will be
obtained that will be used for ex-vivo studies (see below).
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.
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 (ÎœDA-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, Î³GT, 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
Minimum age: 30 Years.
Maximum age: 80 Years.
- Patients with coronary artery disease confirmed by coronary angiography.
- Patients undergoing cardiac surgery such as elective coronary bypass artery grafting
(CABG), valve replacement or aortic surgery.
- All patients will not be under statins treatment for at least 6 months before their
inclusion to the study.
- Acute coronary syndrome during the last 2 months
- Renal failure (creatinine > 2,2 mg/dl)
- Severe liver disease. Prospective follow-up of liver enzymes will be performed by the
physicians in charge, as indicated by the relative guidelines regarding statins use
and according to the current clinical practice.
- Any chronic/acute inflammatory disease, autoimmune disease and/or cancer
- Use of anti-inflammatory drugs or vitamins supplements
Locations and Contacts
Dimitris Tousoulis, Ass. Prof., Email: email@example.com
Hippocration Hospital, Athens University Medical School, Athens, Attiki 115 28, Greece; Recruiting
Andreas Paschalis, PhD Student, Sub-Investigator
Evaggelos Ekonomou, PhD Student, Sub-Investigator
Starting date: October 2007
Last updated: August 4, 2011