Statins is a widely known medication which is used to reduce serum lipids. These medications are used to lower the production of endogenous cholesterol via reducing the activation of hydroxymethylglutaryl CoA reductase enzyme. This represents the rate-limiting step in cholesterol synthesis by the liver. ¹ This results in decreased low-density lipoprotein (LDL) deposition in the vascular walls by upregulation of hepatic LDL-C receptors, an essential event in the pathogenesis of atherosclerosis. ²

Atorvastatin is a widely used statin which augment nitric oxide (NO) activity and production through several ways, which eventually lead to increase expression and activity of endothelial NO synthase enzyme (eNOS). A previous study revealed a significant rise in eNOS levels following atorvastatin therapy in mice model. ³ In addition, atorvastatin can reduce NO elimination through its effects on reactive oxygen species (ROS). ⁴

The benefits above exert several clinical implications. Especially considering the essential activity of NO as vasodilator, inhibiting platelet aggregation, and it promote endothelial function. ⁵ Increased NO production by endothelium could furthermore offer protection against stroke. ⁶

Clopidogrel is a known platelet inhibitor, which has been widely used for the prevention of major complications of heart disease following percutaneous coronary intervention (PCI). ⁶ Previous studies have shown that there was some inter-individual difference in clopidogrel response ^{6 , 7} and resistance to clopidogrel is related with an augmented risk of major adverse cardiac events (MACE). ^{6 , 7} Among the several risk factors that affect the response of platelet to clopidogrel therapy, smoking is linked with enhanced clopidogrel responsiveness. ⁸ Although various processes have been proposed (including those regarding cytochrome P450 enzyme system), the exact mechanism is still unclear. ⁸

Antiplatelet therapy is the backbone for the management and prevention of heart disease, including coronary heart disease, transient ischemic attack or minor stroke, and acute coronary syndrome (ACS). Clopidogrel which is P2Y ₁₂ inhibitors was the first medication in this category, play an essential role in antiplatelet therapy and consequently in the treatment and prevention of CVD. ⁹ However, there are several factors which may alter personal response to clopidogrel therapy. This is in addition to drugs. ¹⁰

The main objective of the following project is to measure the efficacy of 2 known doses of atorvastatin (daily intake of 20 mg, and 40 mg oral supplementation for 16 weeks) on serum nitric oxide level and lipid profile in patients with heart disease, with and without clopidogrel resistance.

This is the first clinical study of its type to be conducted in Iraq and Middle East to highlight the therapeutic impacts of atorvastatin on nitric oxide levels and serum lipids and correlate the data with clopidogrel resistance. The study intended to evaluate the dose-response effects of two doses of atorvastatin (20 mg and 40 mg supplementation per a day for 16 weeks) on serum nitric oxide level and serum lipids in CAD patients, with variable clopidogrel resistance. All non-modifiable and modifiable risk factors were considered, including age, gender, obesity, family history of chronic illnesses (hyperglycemia & hypertension) and lifestyle factors. No significant differences between these factors and both doses of atorvastatin in resistant and non-resistant groups were found in exception to diabetes ^{12 , 13} and inconsistent with findings from others. ¹⁴ Incidence of diabetes mellitus was significantly associated with both doses of atorvastatin in the clopidogrel resistant and non-resistant groups, ¹⁵ but contract with the findings of Pandey et al. ¹⁶

We could not find a statistical difference in nitric oxide levels between the clopidogrel resistant and clopidogrel non-resistant groups using 20 mg/day atorvastatin. Similarly, there was no significant difference with 40 mg/day atorvastatin use in both the clopidogrel resistant and non-resistant groups. However, the levels of nitric oxide were significantly elevated by increasing atorvastatin to 40 mg/day in both clopidogrel resistant and non-resistant groups, Table 2. Having said that, we noted a significant adverse correlation between serum levels of nitric oxide and the percentage of platelet aggregation in this cohort. These data are in accordance with the findings from previous studies. ¹⁷

Moreover, increasing the dose of atorvastatin to 40 mg/day significantly decreased the level of total cholesterol and HDL-C, but not triglycerides and HDL-C in both study groups ( Table 3). ¹⁴ There is no clear understanding of the mechanism behind this. One explanation may be related to the link between levels of nitric oxide and its effects on CVD. The elevation in production nitric oxide might be caused by a compensatory mechanism towards CAD, which can produce more nitric oxide from the vascular endothelium. ^{18 , 19} This contradict the previous knowledge which hypothesized that a) the increased level of nitric oxide is not necessarily reflecting differences in nitric oxide activity, and b) racial differences between our current study participants (Iraqi Nationality) and other nationalities. ²⁰ The variation in the outcomes of previous studies may be related to confounding factors which may include inclusion/exclusion criteria, sample size, racial, geographical, and environmental factors. ^{20 – 22} Hence, it is worth considering all these factors when assessing the effectiveness of atorvastatin therapy in CAD.

In conclusion, atorvastatin supplementation improves the serum levels of nitric oxide and serum lipids (TC and LDL-C) in patients with CAD with and without clopidogrel resistance.

Conceptualization, A.A., A.R., B.M., and H.A.; methodology, A.A., D.J., B.M., and A.R.; investigation, H.A., A.R., A.A., and B.M.; writing—original draft preparation, A.A., B.M., and A.R.; review and editing, H.A., and D.J.; supervision, B. M., and A.R. Authors have read and agreed to the final version of the manuscript.