Investigation of the Effect of Dietary Nitrate Treatment on Endothelial Function and Platelet Reactivity in Hypercholesterolemics.

Inclusion Criteria:

1. Participants will be between 18-80 years of age.
2. They will be largely newly diagnosed patients with hypercholesterolemia (total serum cholesterol>6.0mmol/L or any elevation of total cholesterol, LDL cholesterol or triglycerides with a QRISK 2 score >15%).
3. We will include patients with familial hypercholesterolemia. These patients in general will either be managed in primary care alone or will attend the clinic following referral from general practitioners for further investigation following routine health tests.
4. In addition, patients who have been referred due to inability to tolerate statin treatment will be included.
5. They will be recruited into the study if they are interested in taking part in research, do not have any exclusion criteria on screening and give their written informed consent.

Hypercholesterolemics will be screened by taking a medical history and physical examination, blood pressure measurement and urine sample taken to check for diabetes. The subject will continue his/her usual diet and exercise regime prior to diagnosis of hypercholesterolemia for purposes of this study. They will not be taking any additional vitamin or food supplements for the duration of the study.

Exclusion criteria

1. A history of symptomatic ischemic heart disease (angina, previous myocardial infarction, acute coronary syndrome) or other known atherosclerosis.
2. A history of heart failure NYHA class 2-4 or severe LV dysfunction LVEF<30% regardless of symptom status.
3. Use of statins within 2 months of screening visit.
4. A history of diabetes.
5. Systemic autoimmune disease such as rheumatoid arthritis, connective tissue disease, or other conditions known to be associated with chronic inflammation such as inflammatory bowel disease.
6. Any use of non steroidal anti-Inflammatory drugs, antiplatelet agents or steroids within two months of commencing study or likely future use required during the study.
7. Subjects with any acute infection, or significant trauma (burns, fractures).
8. Subjects who have donated > 500mls blood within 56 days prior to study medication administration.
9. Anaemia with Hb <10g/dl, or any other known blood disorder or significant illness that may affect platelet function, and coagulation. Known essential hypertension on antihypertensive medication is not a contraindication.
10. History of malignancy within the past 5 years other than non-melanoma skin cancer.
11. Any current life threatening condition including severe chronic obstructive airways disease, HIV infection, life threatening arrhythmia that may prevent subject completing the study.
12. Alcohol/drug abuse within the past 6 months of screening visit.
13. Excess alcohol consumption as defined as regular weekly consumption of >28 units male and >21 units female. (Department of Health Guidelines)
14. Use of an investigational device or investigational drug within 30 days or 5 half lives (whichever is longer) preceding the first dose of study medication.
15. Any non stable dosing of ongoing medication regimens throughout the study trial.
16. A history of chronic viral hepatitis (including presence of hepatitis B surface antigen or hepatitis C antibody or other chronic hepatic disorder.)
17. Abnormal liver function due to acute or chronic liver conditions 3 x upper limit of normal at screening.
18. Renal impairment with creatinine clearance (eGFR) of <50ml/min at screening.
19. Pregnancy at time of screening or intention of getting pregnant during course of study.
20. Current smokers or ex smokers who stopped smoking <3 months prior to administration of study medication.
21. BMI <18.5 or > or = 40kg/m2.