English abstract
Statins (HMG-CoA reductase inhibitors) are a class of drugs used to treat dyslipidemia in both familial hypercholesterolemia (FH) and non-familial hypercholesterolemia (NFH). However, these drugs also mediate a plethora of non-lipid lowering functions. These cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, augmenting the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Additionally, statins have beneficial extra-hepatic effects on the immune system, CNS, and bone. One of the recent studies indicate that statins up regulate the transcription of carnitine acylcarnitine carrier protein (CAC) at the molecular level, indicating towards the plausibility of their modulatory effect on the process of B oxidation of fatty acids. However, biochemical evidence supporting this pleiotropic effect of statin is currently unavailable. In order to address this deficiency, the present study was designed to appraise the levels of acylcarnitines in the blood of FH and NFH subjects before and after the initiation of statin therapy. Additionally, we also wanted to investigate if statins have an effect on the size of the LDL particle (small LDL particles are more atherogenic than large LDL particles due to more facile penetration into the arterial wall, stronger attachments to arterial wall proteoglycans, enhanced susceptibility to oxidative modification, and more ardent binding to the scavenger receptor) by evaluating its effect on different lipoprotein subclasses.
Aim: Our study aimed to: Appraise the effect of statins in both FH and NFH subjects
on: B-oxidation • Lipoprotein subclasses in both FH and NFH subjects
Method: Two different techniques were used in this study to appraise the effect of statins in FH (n=18) and NFH (n=14). The first technique was tandem mass spectrometry (MS/MS) which was involved in the analysis of acylcarnitines from dried blood spot. The second technique was non-denaturing, linear polyacrylamide gel
electrophoresis for the analysis of LDL-subclasses in serum.
Results: For (n=18 FH subjects), statin therapy indicated a significant decrease in the levels of medium chain decanoyl-L-carnitine. Prior to the initiation of statin therapy the mean level of (C10-carnitine) detected in the blood was (0.1075 + 0.0481 umol/L), whereas post statins therapy the mean level was (0.0881 +0.0328 umol/L; P= 0.035), indicating an approximate of 18% decrease in the levels of medium chain acylcarnitine. Although statins also modulated the levels of the other acylcarnitines, we did not observe statistical significance in this modulatory. On the other hand, for (n=14 NFH subjects) statins showed a significant increase in short chain acylcarnitines in particular the hydroxyl-butyryl-L-carnitine (C4-OH) in post statins treatment as compared with pre statins treatment with (0.0579 + 0.0239pmol/L)
and (0.0689 +0.0245 umol/L; P= 0.016) respectively with approximate 19% increase, In addition, statins also showed a significant impact (P<0.05) on lipoprotein subclasses (LDL-S) such as intermediate density lipoprotein (IDL) (A,B&C) and large low density lipoprotein (LDL-1) in FH subjects in post statins treatment as compared to pre treatment with (9.9 +2.2%), (9.1 + 1.1%), (6.3 +1.3%) and (13.9 + 4.5%) in pre statins treatment and with (8.1 1.1%), (7.7 + 0.9%), (4.8 + 1.5%) and (12.3 + 4.5%) in post statins treatment respectively. The case was different for NFH subjects, as there was no significant difference in different LDL-S. IS
Conclusion: With regard to the effect of statin therapy observed in FH subjects, it can be concluded that statins offer by decreasing the levels of decanoyl-L-carnitine (CIO) mediate a cardioprotective effect as in a recent study, long chain and medium chain acylcarnitines have been indicative of CAD. In NFH patients the elevation d-3 hydroxybutyrate-carnitine (C4-OH) post-statin therapy is indicative that statins may have a role in decreasing insulin sensitivity, which is in line with the findings of several trials where the association of statin therapy with the increase in the risk of T2DM has been appraised. Case in point in the metabolic syndrome in men (METSIM) trial, statin therapy appears to increase the risk for type 2 diabetes by 46%, even after adjustment for confounding. However, reflecting on the other studies, statin therapy has been shown to have inconsistent effects on changing LDL size. This is because most studies have included a small number of subjects familial combined hyperlipidemia without consideration of baseline differences in the LDL size.
