Table 1.

Major studies investigating the association between vitamin C and cardiovascular disease (CVD).

Clinical Study	Study Population	Vitamin C Concentration Range	Fasting Blood Sample (Assay Used)	Adjustments	Outcome	Ref.
EPIC-Norfolk	19,496 healthy men and women from Norfolk (US)	25.9–79.2 μmol/L	Non-fasting venous blood (fluorometric assay)	Age, systolic BP, cholesterol, smoking, diabetes, and supplement use	A mean follow-up of 4 years showed that 20 μmol/L rising in plasma Vitamin C concentration was associated with ~20% reduced risk of all-cause mortality	[121,139]
EPIC-Norfolk	20,299 healthy men and women from Norfolk (US)	41–66 μmol/L	Non-fasting venous blood (fluorometric assay)	Age, sex, smoking, BMI, physical activity, systolic BP, diabetes, cholesterol, MI, social class, alcohol, and supplement used	A mean follow-up of 12.8 years showed that every 20 μmol/L increase in plasma Vitamin C was associated with a 9% relative reduction in the risk of HF.	[140]
HPFS—Health Professionals Follow-up Study	39,910 healthy US male, health professionals	95–116 mg/dL	Not reported	Age, season, smoking, energy intake, alcohol, hypertension, history of MI, profession, BMI, and physical activity	After a mean follow-up of 8 years, Vitamin C intake was not associated with a lower risk of CHD and stroke	[141]
NHS I—Nurses’ Health Study 1	85,118 healthy US female nurses	70–704 mg/dL	Not reported	Age, energy intake, supplements use, alcohol, smoking status, and diabetes	Data from 16 years of follow-up indicate that Vitamin C supplement is associated with a significantly lower risk of CHD	[138]
ASAP—Antioxidant Supplementation in Atherosclerosis Prevention	520 men and post-menopausal women, with hyper-cholesterolemia	Not specified	Not specified (HPLC assay)	Sex, baseline HDL cholesterol	A 6–year follow-up indicated that Vitamin C supplementation reduced the slope of the mean carotid artery intima-media thickness progression	[142]
Women’s Antioxidant Cardiovascular Study	8171 female health professionals with CVD, or 3 or more CVD risk factors	Not specified	Not reported	Compliance-adjusted analyses	After a follow-up of 9.4 years, no overall effects of Vitamin C (500 mg/day) on all major cardiovascular events and stroke	[143]
NHANES II	8417 US men and women	17–79.5 μmol/L	Non-fasting venous blood (colorimetric assay)	Age, sex, race, education, physical activity, dietary energy and fat intake, cholesterol, BMI, alcohol, smoking, diabetes, hypertension, CHD, stroke, cancer, use of aspirin, Vitamin E intake	Decreased risk of all-cause mortality	[144]
NHANES III	6624 US men and women	17–85.2 μmol/L	Non-fasting venous blood (colorimetric assay)	Age, sex, race, education, physical activity, smoking, alcohol, cholesterol, BMI, diabetes, hypertension, use of aspirin, Vitamin E intake	Top Vitamin C group had a 27% lower CVD risk compared to bottom group	[145]
SU.VI.MAX study	13,017 French adults	Not specified	Fasting venous blood (continuous flow segmented by air bubbles)	Bonferroni adjustment for multiple mean comparisons	After a follow-up of 7.5 years, no effect of Vitamin C supplementation (120 mg/d) on CVD; lower all-cause mortality in men	[146]
PHS II—Physicians Health Study II	14,641 healthy US male physicians	Not specified	Not reported	Age, PHS cohort, randomized β–carotene, Vitamin E or Vitamin C, and multivitamin assignments	A mean follow-up of ~8 years showed that Vitamin C supplementation (500 mg/day) had no significant effect on the incidence of CVD, stroke, or mortality for cardiovascular events	[147]
Heart Protection Study	20,536 British men and women with CHD, occlusive arterial disease, or diabetes	Not specified	Non-fasting venous blood	Not specified	After a follow-up of 5 years, Vitamin C supplementation (250 mg/d) had no significant effects on CVD	[148]
CARDIA	2884 healthy US men and women	24–70 μmol/L	Fasting venous blood (HPLC assay)	Age, sex, race, center, education, smoking, alcohol, physical activity, a priori diet quality score and food consumption, BMI, waist circumference, history of diabetes, systolic BP	Higher plasma Vitamin C, due to better diet quality, is inversely related to high BP.	[149]
Iowa Women’s Health Study	1923 post-menopausal diabetic women from U.S. (55 to 69 years)	82–≥679 mg/day	Not reported	Age, total energy intake, history of hypertension, BMI, waist-hip ratio, smoking status and amount smoked, alcohol consumption, physical activity score, hormone replacement therapy, main type and duration of diabetes, medications	After a follow-up of 11 years, an association between increased mortality for CVD or CHD and Vitamin C ≥ 300 mg/day was reported. Vitamin C intake was unrelated to CVD and stroke mortality in nondiabetic women.	[150]
Italian section of the EPIC Study	41,620 Italians previously diagnosed with stroke or myocardial infarction (44 to 61 years)	83–201 mg/day	Not reported	Age, sex, hypertension, smoking, alcohol, education, energy intake, waist circumference, obesity, and physical activity	After 7.9 years of follow-up, Vitamin C was associated with a lower risk of ischemic stroke	[151]