Aleskiren Effect on Plaque Progression Using 3-dimensional Magnetic Resonance Imaging (3D MRI)

Epidemiologic and experimental data suggest that activation of renin-angiotensin system
(RAS) has an important role in pathogenesis of atherosclerosis. Although ACE inhibitors and
AT1R blockers have been used for more than a decade, their benefit in terms of absolute risk
reduction is modest. Many patients with established atherosclerosis continue to suffer from
recurrent events related to ongoing disease, despite inclusion of other evidence based
approaches such as ASA and statin therapy. Tekturna is a new direct renin inhibitor that
decreases plasma activity of AngII, which causes depression of the negative feedback of
renin secretion from the kidney and results in no compensatory increase in plasma renin
concentrations and prevents the formation of both AngI and AngII. This in turn results in
effective antihypertensive effect in high blood pressure subjects. Moreover, there is direct
experimental animal evidence to support aliskiren therapy as a mean to reduce
atherosclerotic plaque progression in thoracic aorta.

This protocol is a pilot study exploring the effectiveness of direct renin inhibitor
Aliskiren to reduce atherosclerotic plaque evolution as shown by 3D MRI quantification. The
secondary objectives are to assess the change in % plaque volume; change in resting clinical
systolic, diastolic and mean blood pressures and change in monocyte global gene expression.

Inclusion Criteria:

- 45 years or older

- females: post-menopausal for 1 year OR surgically sterile OR non-oral contraceptive

- established heart or vascular disease including previous heart attack or stroke
and/or peripheral arterial disease with history of intervention or surgery and/or
cardiac bypass surgery or stent placement

- normal LDL cholesterol (may be on drugs for this)

Exclusion Criteria:

- uncontrolled hypertension (high blood pressure)

- creatinine > 1.5 x upper limit of normal

- new: statin/ACE inhibitor/Angiotensin receptor blocker (ARB)/anti-oxidant/ calcium
channel blocker/diuretic/beta-blocker

- contraindication for MRI (pacemaker, metallic implants or severe claustrophobia

- transient ischemic attack in past 6 months

- secondary form of hypertension such as coarctation of the aorta, hyperaldosteronism,
pheochromocytoma

- dyslipidemia due to other causes including alcoholism, auto-immune disease nephrotic
syndrome, hepatitis clinically active in past 12 months, obstructive biliary or
hepatic disease, macroglobulinemia, multiple myeloma, glycogen storage disease,
uncontrolled hypothyroidism or hyperthyroidism, chronic pancreatitis

- diabetes controlled with insulin or oral medications (may be diet controlled)

- any surgical or medical condition which might alter the absorption, distribution,
metabolism or excretion of the drug

- history of drug abuse in the last 2 years