Vascular Effects of Statins

by

ACKNOWLEDGEMENT

I would take this opportunity to thank my research supervisor, family and friends for their support and guidance without which this research would not have been possible.

DECLARATION

I, [type your full first names and surname here], declare that the contents of this dissertation/thesis represent my own unaided work, and that the dissertation/thesis has not previously been submitted for academic examination towards any qualification. Furthermore, it represents my own opinions and not necessarily those of the University.

Signed __________________ Date _________________

ABSTRACT

The research explores the various aspects of Statins. It provides detail about how statin has been used in order to reduce the incidences of coronary diseases and endothelial dysfunctioning. Furthermore, the study provides detail about how different types of statisn affect and work in different clinical situations. The study also gives details about the impact of statins and various clinical researches carried analyzing the impact of statin on patients having cardiovascular diseases.

TABLE OF CONTENTS

ACKNOWLEDGEMENTii

DECLARATIONiii

ABSTRACTiv

TABLE OF CONTENTSv

INTRODUCTION1

Cardiovascular Disease1

A.1 Statins1

A.1.1 Definitions1

A.1.2 Structures (Lipophilic vs. Hydrophilic)3

A. 2 Pharmacodynamic Properties-indirect vascular effects4

A.2.1 Lipid-lowering Effects of Statins4

A.2.1.1 Cholesterol Synthesis5

A.2.1.2 Effect on Lipoprotein Metabolism6

A.2.2 Pleiotropic Effects7

A.2.2.1 Anti-inflammatory Effects of Statins8

A.2.2.2 Antioxidant Effects of Statins8

A.2.2.3 Anti-platelet effect and effect on coagulation/fibrinolytic system9

A2.2.4 Effect on myocardial hypertrophy & fibrosis10

A.2.2.5 Effect on Ischaemic Reperfusion11

A.3 Pharmacodynamic Properties-Direct Vascular Effects12

A.3.1 Endothelium13

A.3.1.1 Importance of the endothelium14

A.3.1.2 Endothelial derived relaxing & constricting factors15

A.3.2 Nitric Oxide16

A.3.2.1 Nitric Oxide Physiology17

A.3.2.2 Effect of Statins on Nitric Oxide Pathway17

A.3.3 Endothelin19

A.3.3.1 Endothelin-1 Physiology20

A.3.3.2 Effect of Statins on Endothelin-1 Pathway23

A.3.4 Vascular Smooth Muscle Cell24

A.3.4.1 VSMC Physiology24

A.3.4.2 Calcium Channels25

A.3.4.3 Rho kinase25

A.3.4.4 Synthetic Properties28

A.3.5 Effect of Statin on VSMC Physiology28

A.3.6 Angiogenesis29

A.4 Pharmacokinetic Properties29

A.4.1 Absorption29

A.4.2 Distribution & Plasma Therapeutic Levels30

A.4.3 Metabolism & Excretion31

A.5 Clinical Efficacy in Cardiovascular Disease32

A.5.1 Importance of Atherosclerosis in Cardiovascular Disorders33

A.5.1.1 Coronary Heart Disease33

A.5.1.2 Cerebrovascular Disease34

A.5.1.3 Peripheral Arterial Disease35

A.5.2 Effect on Lipids & Lipoproteins35

A.5.3 Effect on Atherosclerotic Regression36

A.5.3.1 Carotid IMT Reduction37

A5.3.2 Coronary Intravascular Ultrasound38

A.5.4 Effect on Endothelial Function38

A.5.4.1 Peripheral Studies - forearm blood flow, brachial artery40

A.5.4.2 Coronary Studies41

A.5.5 Effect on Resistance Vessels43

A.5.5.1 Anti-hypertensive Effects45

A.5.5.2 Coronary Microvascular Dysfunction46

A.5.6 Effect on Cardiovascular Events47

A.5.6.1 Coronary Heart Disease48

A.5.6.2 Stroke51

A.5.6.3 Peripheral Arterial Disease56

A.6 Research Aim56

REFERENCES58

INTRODUCTION

Cardiovascular Disease

Cardiovascular disease (CVD) describes a range of diseases involving the heart and blood vessels. Most commonly (and for the purposes of this thesis) it is considered as disorders involving atherosclerosis including cerebo-vascular disease, peripheral artery disease and coronary disease. Together, these conditions remain the leading cause of death in most regions of the world {Wang, et al, 2008; Reeve, 2005}. Moreover, the Australian Department of Health Services (DHS), indicate that CVD kills more people than any other disease in Australia, and places a heavy burden on the health system as a result of patient disabilities resulting from stroke, by contributing to increased running costs. The DHS has identified coronary artery diseases (CAD) as the leading cause of mortality burden in years of life lost for both men and women. CAD is strongly associated with high blood cholesterol concentrations {Castelli, 1984} and modern treatments used to manage CAD progression involve treatment of CAD patients with a class of cholesterol lowering ...