Open access

Resistance of Statin Therapy, and Methods for its Influence

Written By

Lyudmila Georgieva Vladimirova-Kitova and Spas Ivanov Kitov

Submitted: May 4th, 2014 Published: September 17th, 2015

DOI: 10.5772/60004

Chapter metrics overview

1,633 Chapter Downloads

View Full Metrics

1. Introduction

Resistance happens when an individual has an incorrect response to the effectiveness of a drug as stated in the National Library of Medicine. It is difficult to give an accurate definition of statin resistance. Patients who fail to reach LDL-C target levels despite undergoing the best available therapy of the most highly tolerated dose of a more potent statin, are considered to be statin-resistant. Many individuals do not reach LDL-C target levels, even when compliance is taken into consideration. The reduction of LDL-C in response to statin therapy can vary from 5-70 %. This can be influenced by many factors. For instance,racial andestry, with attenuated responses in blacks compared to whites. A study comparing statin resistance patients to patients who show no resistance to statin has yet to appear.

The resistance to statins can be related to differences in drug absorption, drug transport, intrahepatic drug metabolism, drug metabolism within other organs, and drug excretion mechanisms. The same can occur due to differences in the level of the various target pathways that are unrelated to pharmacokinetics, including HMG-CoA reductase, as well as various points along the cholesterol biosynthesis and lipoprotein metabolic pathways.


2. Possible causes of statin resistance

According to Herman and Moncada the process of atherogenesis includes 28 stages. [48] Key points in this process are two - oxygenated LDL-cholesterol and endogenous nitric oxide synthase. Statin reistance may exist in both directions:

2.1. Failed targeting LDL cholesterol

It seems that not only genetic but environmental factors can influence the LDL-C response to statins. Studies have found that patients with hypertension have a smaller decrease than those without hypertension. Furthermore, smokers have smaller statin-induced LDL-C decrease compared with nonsmokers[47]. It also seems that inflammation might cause statin resistance. Namely, it has been shown that inflammatory cytokines, in particular IL-1b which affects sterol regulatory element binding protein cleavage-activating protein, cause statin resistance due to the disruption of LDL-R feedback regulation. Therefore, it has been suggested that in inflammatory states, higher concentrations of statin may be required to achieve the appropriate LDL-C lowering [107]. Particularly interesting are observations concerning certain subpopulations of patients who might be resistant to statin treatment. Some studies have shown statins to be less effective in individuals with HIV infection. [22]. Other studies have a contraversal perspective. [55]. The role of concomitant amiodarone treatment in statin resistance was also suspected. Both amiodarone and amiodarone induced hypothyroidism influence the synthesis of LDLR, which may explain the lack of statin effect. Thyroid hormone is one of several hormones that control gene expression of the LDLR and hypothyroidism is a wellknown cause of secondary dyslipidemia characterized by elevated LDL-C levels. Similar to hypothyroidism, administration of amiodarone also increases LDL-C levels, which is the result of a decreased expression of the LDLR gene [1].

More recently, an approach was published which used metabolomics to identify markers indicative of mechanisms that contribute to differences in LDL-C response to statin. Metabolic changes were shown to be more comprehensive in responders to statin treatment than those seen in nonresponders. The baseline cholesterol ester and phospholipid metabolites correlated with LDL-C response to treatment [56]. It has also been suggested that clusters of metabolites involved in multiple pathways not directly connected with cholesterol metabolism might as well play a role in modulating the response to statin therapy - influence statin resistance [90].

Insufficient LDL-C response to statin treatment is probably the result of pseudo-resistance, which could be caused by nonadherence or nonpersistence in real life circumstances. [68].


3. Lack of effect on the endothelium-dependent vasodilation after targeting LDL-C

There is a lot of evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. [39; 40, 41; 38; 5; 51; 9]. One of the major endothelium-derived vasoactive mediators was shown to be nitric oxide (NO). [38; 74; 51; 67]. Multifactional are the mechanism by which NO activity is reduced: reduced NO release, NO inactivation by superoxide anion, or reduced NO production by NO synthase (NOS). [91] Decrease in NOS expression by oxidized low-density lipoprotein (LDL) can cause impaired NO production [77; 91], or by the presence of asymmetric dimethylarginine (ADMA). [72; 16 ;29]

According to Herman and Moncada the basis of atherogenesis remain oxygenated LDL and eNOS. Lipid-regulating effects of statins in terms of LDL-cholesterol are undeniable, but the pleiotropic discussioncy is a particularly relevant issue of resistance of statin therapy in patients with high levels of ADMA - endogenous inhibitor of eNOS. Research of statin influence on flow-mediated vasodilation (FMD) reveals controversial results. Some studies indicate that there is an effect, whereas others document the opposite tendency [18]. There is a number of studies on simvastatin and likewise they demonstrate controversial findings. These controversies can be dismissed by studing ADMA levels.(18 ;16;6). It has been suggested that ADMA could modify the effect of statins on myocardial blood flow and on FMD% (53).

In our subsequent studies found in a logical sequence following facts. This facts determinate ADMA as a basic factor for statin`s resistans.

International recommendations underline the importance of diagnosis and treatment of asymptomatic individuals with high absolute cardiovascular risk [10; 37; 8], as individuals with severe hypercholesterolemia. [47; 45; 58] the levels of ADMA in patients with severe hypercholesterolemia in our study are higher than those cited in the literature in the same population patients. [13].

1. A good marker of endothelial dysfunction is considered to be ADMA, as indicated by recent publications. [16]. Subjects with cardiovascular risk – hypercholesterolemia, hyperhomocysteinemia, diabetes mellitus, hypertension, smoking, erectile dysfunction having increased ADMA levels. [67; 11; 16,17]. Plasma levels of ADMA have been shown to be elevated in hypercholesterolemic rabbits [108]. The elevation of ADMA is associated with reduced activity of NOS in animal models, as well as in young asymptomatic hypercholesterolemic adults [13]. The mechanism of increased ADMA in hypercholesterolemia is not very clear - LDL cholesterol increases the expression of ADMA precursor protein and reduces the activity of the enzyme dimethyl arginine dimethyl amino hydrolase. [52; 15] Increased ADMA are associated with reduced NO synthesis and this assessed by impaired endothelium-dependent vasodilatation. Flow-mediated dilatation (FMD) - shear stress during hyperemia activates receptors on the endothelial cell surface and causes influx of intracellular calcium, which activates eNOS and NO release [54; 24; 80; 60]. The main effect that dilatation has in respons to shear stress during FMD is influenced by NO and to a smaller extent on prostaglandins and endothelial-dependent hyperpolarizing factors [78; 54; 31; 30; 73]. Ultrasound determination of flow-mediated dilatation of the brachial artery as a method has many advantages – it is non-invasive, with good reproducibility and reliable. [3; 28; 31; 36; 61]. There is convincing evidence that reduced percentage of FMD (FMD%) is a marker of coronary endothelial dysfunction [3].

Several studies have associated hypercholesterolemia with reduced FMD% and this effect can be reversed by L-arginine [34; 26; 32; 33]. However, L-arginine does not lead to the improvement of endothelial dependent vasodilatation in normocholesterolemic individuals. In this condition indicate the main role of endogenous ADMA. [11; 44] Furthermore, a recent publication demonstrated that improvement of FMD% under statin treatment depends on the ADMA levels [53; 12]. Little is know about the relationship between ADMA, and FMD%. In a small number of hypercholesterolemic patients ADMA was shown to be positively correlated with FMD% in mild hypercholesterolemia [13]. A recent paper demonstrated that low cardiovascular risk subjects have increased ADMA level. [6]. No data exist about the relationship between ADMA and FMD% in severe hypercholesterolemia patients. In our study "Relationship of asymmetric dimethylarginine with flow-mediated dilatation in subjects with newly detected severe hypercholesterolemia" was the evaluation of the relationship between ADMA and FMD, also that of ADMA and lipid parameters as well as other endothelial dysfunction in newly detected subjects with severe hypercholesterolemia. The major findings of the present study are that: (1) plasma levels of ADMA, are increased in severe hypercholesterolemia; (2) there is a significant link between ADMA and age, Apo-B, Apo-B ⁄ Apo-A1 and tHcy; (3) newly detected severe hypercholesterolemia has reduced flow-mediated endothelial dependent vasodilatation, there is a correlation between plasma levels of FMD% and age, Apo-B, Apo-B ⁄ Apo-A1 and tHcy; and (4) homocystein levels has no contribution to the atherogenic risk in the patients.

Newly detected severe hypercholesterolemia is associated with elevated ADMA, and to the proportional increase in total cholesterol. The ADMA correlates with age, Apolipoprotein-B, Apo-B ⁄ Apo-A1 and tHcy. Apo-B was found to indicate elevated ADMA in these patients. FMD% correlates most strongly with age, Apolipoprotein-B, index Apo-B ⁄ Apo-A1 and tHcy. In multiple regression analysis, ADMA is the strongest predictor for FMD%. ADMA is the main modulator of FMD% - among the investigated biomarkers in newly detected severe hypercholesterolemia. Serious functional changes in the vascular wall are cause by increased level of ADMA. At the same time, ADMA is found to be a predictor of flow-modulated vasodilation of the brachial artery which also makes a probable marker for endothelial dysfunction. Therefore, measuring ADMA levels in newly detected severe hypercholesterolemia is of great importance when FMD% changes need to be clarified.

2. In the next study we investigated intima-media complex of carotid artery. The intima-media thickness (IMT) of the CCA is one of the validated measurements of subclinical atherosclerosis, as early as structural vascular abnormalities [85]. Intima-media thickening of the CCA correlates with the coronary risk factors [80] and with associated with the degree of coronary atherosclerosis. It serves as a predictor of coronary and vascular events in different patients' populations. Intima-media thickening reflects both intimal atherosclerosis and medial hypertrophy. It is used to evaluate the luminal and wall characteristics of the carotid artery. In the literature, hypercholesterolemia has an important role in early-onset IMT changes in the CCA However, there is not a lot of data about asymptomatic subjects with newly detected severe hypercholesterolemia.[72]. In the literature, data on the IMT of CCA predictors is controversial. There are a few studies of the endothelium-related biomarkers (ADMA, tHcy, soluble cell adhesion molecules), especially in asymptomatic subjects with newly detected severe hypercholesterolemia [72].

The research "Predictors of the intima-media thickness of carotid artery in asymptomatic newly detected severe hypercholesterolemic patients" age and Apo-B were established as the most important statistically significant factors related to IMT mean of CCA. This fact illustrates that they determine the slow progressive structural changes in the vascular wall. The Apo-B is a better biomarker of the total number of atherogenic particles. It might be concluded that Apo-B is a better factor for assessment of risk, as LDL cholesterol underestimates the risk in asymptomatic subjects with newly detected severe hypercholesterolemia.

In the study "Intima-Media Thickness and Flow-Mediated Vasodilation in Asymptomatic Subjects with Newly Detected Severe Hypercholesterolemia", our results show a significant correlation between IMT mean and FMD%. The correlation is still present when separating IMT on the basis of the level of thickening. This supports the idea that the two noninvasive methods complete each other. It is important with regard to building a diagnostic algorithm. These methods show early subclinical atherosclerosis but by different trigger mechanisms.

3. After establishing who is a predictor of FMV - ADMA, the next study proved that ADMA is the main determinant of the effect of simvastatin on FMV in severe hypercholesterolemia - "Asymmetric dimewthylarginine determines the effect of simvastatin on endothelium-dependent vasodilation in severe hypercholesterolemia" Future Medicine Clinical Lipidology 2010. With respect to their total cholesterol, LDL-cholesterol and FMD% the two groups of hypercholesterolemic patients (according to the plasma ADMA levels) differ significantly. ADMA, cell adhesion molecules or total homocysteine levels are not affected by Simvastatin in moderate dose [40 mg). Higher baseline levels of ADMA affect the ability of statins to improve endothelium-dependent vasodilation by diminishing it. Subjects from the same population, but with lower baseline levels of ADMA experience the same effect of simvastatin. Therefore, ADMA seems to be a pathophysiologycal modulator of the statin therapeutic response. The present study has been confirm by studies that there is a connection between ADMA and FMD% response to statins found by Böger et al. The different is that in our study is in the larger group of the patients.

In terms of non-randmized study "Effect of Moderate and High-Dose Simvastatin on Asymmetric-Homocysteine Metabolic Pathways in Patients with Newly Detected Severe Hypercholesterolemia" was demonstrated dose-dependent effect of simvastatin on the levels of ADMA.The 40 mg simvastatin has no effect on ADMA and homocysteine level in contrast to 80 mg, after target LDL-levels are reached ≤2.6 mmol/L. It is likely that statin-pleiotropic effects on ADMA-homocysteine metabolic pathways are independent of their lipid-regulating properties.

In another of our observation "Asymmetric dimethylarginine-a determinant of the effect of the high dose Simvastatin confirmed this dose-dependent effect". The two groups of patients (according to the plasma ADMA levels) differ significantly with respect to their total cholesterol, LDL-cholesterol and FMD%. Simvastatin in moderate dose (40 mg) does no affect ADMA, cell adhesion molecules and total homocysteine levels. The higher levels of ADMA change the ability of statins to improve the endothelium-dependent vasodilatation, by diminishing it. This shows that ADMA is a pathophysiological modulator of the statin therapeutic response. This study confirms that, for the first time, there is a correlation between ADMA levels and FMD% response to statins, found by Böger et al., but in the larger group of patients with severe hypercholesterolemia and with higher dose simvastatin. Obviously, these mechanisms require further investigation

To give a more precise answer to the question of dose-dependent manner for avoidable statin resistance subsequently conducted a randomized, placebo-controlled study "The effect of simvastatin on asymmetric dimethylarginine and flow-mediated vasodilation after optimizing the LDL level — A randomized, placebo-controlled study" The major findings of the present study are 1. Significantly higher ADMA and tHcy were seen in patients with severe hypercholesterolemia compared to the control group. 2. Administration of 40 mg simvastatin for one month results in no variation in ADMA, tHcy plasma levels and FMD%, following optimizing of the LDL. 3. Administration of 80 mg simvastatin for a month leads to a variation of ADMA and tHcy plasma levels and FMD% after optimizing the LDL. FMD%-changes can be predicted with ADMA levels and ApoB%-changes is a predictor of LDL-changes% in patients on 80 mg simvastatin (for one month) following the optimization of the LDL-C.

This study gives evidence that in experimental models and in humans (59), higher ADMA levels have a harmful effect on the coronary endothelium. On the other hand, the experimental model shows that statins have no protective effect against that harmful effect of ADMA on the endothelium. This provokes a discussion as to whether ADMA is the pathophysiological modulator of the therapeutic response of statins in hypercholesterolemia.

The ADMA in severe hypercholesterolemia are higher compared to those in patients in similar research protocols (13), and are similar to those in our previous research studies. Applying various laboratory methods(ELISA in the present study, high-pressure liquid chromatography in other studies) does not allow for the mean levels of ADMA to be compared directly. Using ELISA to differentiate the sample groups is less reliable than LC-MS.This is caused by the fac that the higher coefficient of variation and to the fact that the matrix dependence is likely to cloud or mimic the differences The ADMA ELISA method can be used for clinical investigations in which groups of samples are compared and the result is the shift of the ADMA concentration in response to an intervention. The application of ELISA analysis in our study is the likely ex- planation of the higher levels of ADMA, in comparison with other studies (13). On the other hand, this is likely due to the higher levels of total cholesterol > 7.5 mmol/l and LDL-C > 4.9 mmol/l. The difference in L-arginine substitution in hypercholesterolic patients and normo-cholesterolic patients is explained by the higher levels of ADMA in hypercholesterolic petients in comparison with controls with controls (11; 44).

The mechanism of an increased ADMA level in hypercholesterolemia is not clear enough. An association between ADMA and hypercholesterolemia has been previously observed [13]. Laufs et al. (1998) demonstrated that simvastatin reverse, in a dose-dependent manner, the inhibitory effect of oxidized LDL on NO production. It has been suggested that LDL- cholesterol increases the expression of ADMA precursor protein. This reduces the activity of the enzyme dimethylarginine dimethylaminohydrolase, which breaks down ADMA [52]. This is why, by decreasing cholesterol levels with statin therapy, ADMA plasma levels will decrease as well. The therapeutic hypothesis that the decrease of circulating ADMA levels can be achieved by lowering plasma cholesterol levels is the main idea in this publication.

In randomized, placebo-controlled research, a statistically significant reduction of ADMA plasma levels has been established following a one-month therapy with 80 mg simvastatin, yet the 40 mg simvastatin dose does not result in achieving the LDL target levels. The study showed that a 40 mg simvastatin therapy for 3 months does not produce the desired effect. Therefore, it is likely that the pleiotropic effect of the statins (respectively ADMA and tHcy) is independent from the lipid-regulation in a short-term and long-term plan. The lack of effect on 40 mg simvastatin coincides with the results presented in other studies but there is no optimizing of LDL-C level. The research in similar articles regarding the effect of 80 mg simvastatin on ADMA levels is scant. Most research works have documented a negative effect in hypercholesterolemia. However, these studies have tested a considerably smaller number of patients (64). The present study comprises 85 patients and LDL target levels have been optimized regarding the risk category. The established statistically significant therapeutic effect of 80 mg simvastatin on ADMA is comparable to the results from a recently published study — an experimental model of the effect of simvastatin on ADMA tissue levels (64). This recent experimental data shows that simvastatin regulates dimethylarginine dimethylaminohydrolase transcription via the transcription factor Sterol Regulatory Element Binding Protein. The latter is activated by statins due to a reduction of plasma membrane cholesterol. These experimental models suggest that the level of asymmetric dimethylarginine will be decreased by stаtin therapy. Almost all other clinical studies (of smaller sample size and shorter duration) showed no effect of statins on ADMA (positive effect only 10 mg rosuvastatin and 80 mg fluvastatin). It is unclear whether the higher plasma levels of ADMA in human disease states correlate with a higher intracellular level. Studies testing the statin effect in vivo have reported endothelial protection without overly affecting plasma ADMA levels, however in these studies the tissue levels of ADMA have not been taken into consideration. It is likely that in the present study achieving the LDL-C target level substitutes for the LDL-cholesterol tissue levels. Similar titrations have not been carried out in any other related articles so far. The results of the present study provide further clinical evidence to the experimental model of the Ivashchenko et al., that simvastatin regulates dimethylarginine dimethylaminohydrolase transcription via the transcription factor Sterol Regulatory Element Binding Protein.

The present study shows a statistically significant increase in FMD% in patients on 80 mg simvastatin therapy for one month in the presence of controversial results in related materials on this issue. The mechanism of this improvement is proved to be related to the enhancement of gene expression of eNOS (64). On the other hand, the FMD%-changes correlate (correlations with all biomarkers at a baseline level and the %-changes have been tested) significantly only with the baseline level of ApoB, ADMA, and tHcy. Interestingly enough,patients with ADMA levels greater than 1 μmol/l, following statin therapy, appear to have only small or no FMD% changes. A likely explanation of this finding is that in patients with ADMA greater than 1 μmol/l, competes with L-arginine as a substrate for eNOS and thus decreases the production and availability of endothelium-derived NO. For this reason, in such patients, there are no FMD% changes following statin therapy. In patients with documented small FMD% changes, the most likely explanation is the action of other mediators (endothelium-derived hyperpolarizing factor or prostaglandins) that lead to vasodilation through calcium-activated potassium channels simvastatin (80 mg daily).

The high simvastatin doses should be done with caution. According to the Food and Drug Administration monitoring are also important every 3 and 6 months during the course of therapy.

In the multifactor regressive analysis only the initial ADMA levels remain predictors of an FMD%-change. For the first time, in 2007 Böger GI et al. established that ADMA determines FMD%- changes in a small hypercholesterolemic patients group (treated with a smaller simvastatin dose — 40 mg (12). Further clinical studies can be based off of this study, in order to achieve LDL-target levels and to optimize the effect of different doses statins on ADMA. Other statins are better tolerated at a high dose (atorvastatin, pravastatin, fluvastatin, lovastatin). There is only one study testing the effect of 80 mg fluvastatin treatment in hypercholesteromic patients with metabolic syndrome, which demonstrated decrease in plasma ADMA level at 6 weeks.

What is interesting is that the established fact that the Apo-B%-change (not the LDL%-change) is a predictor of the changes in the plasma levels of ADMA (ADMA%-change) in the linear regression model. It’s very likely that this is due to the level of the smallest atherogenic and dense particles are reflected my ApoB. The fact that ApoB is a predictor of the ADMA%-change presumably is due to the higher proportion of patients with family Apo B defect (previously reported in patients with hypercholesterolemia in our previous studies.

Statins vary in their pharmacokinetics and pharmacodynamics. There is a difference in their lipid regulating and pleiotropic effect. Therefore, the data on simvastatin could not be referred to other statins. There is no other therapeutic option in cases with high ADMA levels in hypersholesterolic ptients,apart from 80 mg simvastatin. The clinical significance of our study is that high-risk patients with severe hypercholesterolemia, a family history of premature atherosclerosis and a high level of plasma ADMA, the high dose of Simvastatin is a possible therapeutic option. Substituting with L-arginine is another possible approach (11; 44; 92). These two hypotheses complete one another.

A number of factors are the cause of controversial results on the effects of statins on the endothelial-dependent vasolidation. 1. The clinical studies, testing the effect of statins on ADMA and FMD% involve only a small number of patients for a short period of time. 2. LDL levels are not optimized in accordance with the risk category of hypercholesterolemic patients (the pleiotropic effects of statins are partly connected to lipid regulating ones). 3. The improvement of FMD% via increasing the activity of NO with the statin therapy is connected additionally to the effect on other inhibitors of eNOS apart from ADMA. 4. In most studies there is no testing of ADMA tissue levels.

The present study established patients with severe hypercholesterolemia have high ADMA levels in comparison with the control group. One-month treatment with 80 mg simvastatin, aimed at achieving LDL target levels of ≤ 2.6 mmol/l in high-risk contingents with severe hypercholesterolemia leads to a statistically significant reduction of ADMA and an increase of FMD% in contrast with 40 mg simvastatin therapy. The FMD%-changes correlate in a statistically significant way with the initial ApoB, ADMA and tHcy levels. The baseline ADMA levels are a predictor of FMD% changes and Apo-B%-changes is a predictor of ADMA%-changes at baseline and post one-month therapy with 80 mg simvastatin. In case of optimized LDL target levels it appears that ADMA is a major modulator of FMD%-change.


4. The impact of genetic factors on statin resistance

The same dose of the same statin in different individuals produces different LDLC decreases. The time to reach maximum LDL-C decrease differs significantly between individuals. [81; 82] Such a wide interindividual variation as the response to statins is more and more attributed, at least partly, to the polymorphisms in genes affecting statin pharmacodynamics and pharmacokinetics. The resistance to statins has been associated with polymorphisms in the HMG-CoA-R, ABCB1, ABCG2, ABCC1, ABCC2, OATP1B1, OATP2B1, RHOA, NPC1L1, FXR, CYP7A1, ApoE, PCSK9, LDLR, LPA, CETP, and TNF-a genes. However, currently, there is still not enough evidence to advocate pharmacogenetic testing before initiating therapy with statins.

Pharmacogenetics seeks to determine the role of genetic factors in variation of statin response. However, today the origins of the notable interindividual variation in response to statins are still poorly understood. In a number of studies, genetic variability has been shown to affect statin responsiveness thus influencing statin resistance. These studies have identified numerous candidate genes (>50) and dozens of single-nucleotide polymorphisms (SNPs). It have been reported to be associated with differing aspects of statin response - pharmacokinetics and pharmacodynamics of statins being potential determinants of drug responsiveness in terms of LDL-C lowering. Although genes are supposed to be associated with statin cholesterol-lowering efficacy, the magnitude of variation in statin response that could be explained by these associations is still questionable. [62; 89; 35; 79; 71]

The association between SNPs in genes involved in lipid metabolism and total cholesterol and LDL-C response to statin therapy is of particular interest. The 3-hydroxyl-3- methylglutaryl coenzyme A reductase (HMG-CoA-R) gene encoding the enzyme HMG-CoA-R, which is the principal target of statins, because the foremost pharmacological action of these drugs is exactly the competitive inhibition of HMG-CoA-R. The last one might be one of the candidate genes when analyzing the SNPs as a possible cause of diminished statin responsiveness. When SNPs and the common haplotypes inferred from them were tested for association with plasma LDL-C levels and LDL-C response to statin treatment, it has been shown that HMG-CoA-R gene polymorphisms are associated with reduced plasma LDL-C levels and LDL-C response to simvastatin. [104; 42; 75; 84; 88; 49; 50]

Therefore, although it was considered that genome-wide association studies may yield a more comprehensive set of markers for predicting statin efficacy and/or resistance, this has not been proven so far and the results of these studies cannot be translated into clinical practice yet. We need future pharmacogenetic research [93].


5. Conclusion

It is difficult to give an accurate definition of statin resistance. The patients who fail to reach LDL-C target values despite the best available therapy, mostly a highest tolerable dose of a more potent statin, are considered to be statin-resistant. Resistance to statins can be related to differences in drug absorption, transport, intrahepatic drug metabolism, drug metabolism within other organs, and drug excretion mechanisms. Possible causes of statin resistance: 1.Failed targeting LDL cholesterol - smokers have smaller statin-induced LDL-C decrease compared with nonsmokers and the patients with hypertension have smaller decrease than those without hypertension, inflammation might cause statin resistance. The role of concomitant amiodarone treatment in statin resistance was also suspected. It has also been suggested that clusters of metabolites involved in multiple pathways not directly connected with cholesterol metabolism might as well play a role in modulating the response to statin therapy and therefore influence statin resistance. 2.Lack of effect on the endothelium-dependent vasodilation after targeting LDL-C. There is much evidence that improvement of endothelium-dependent vasodilation under statin treatment depends on the ADMA levels. At this stage of knowledge, there are two options for the management of this type of statin resistance - the use of a high dose of a statin, or the addition of L-Arginine to the statin. These two strategies are not contradictory, but complementary. 3. The impact of genetic factors on statin resistance. The resistance to statins has been associated with polymorphisms in the HMG-CoA-R, ABCB1, ABCG2, ABCC1, ABCC2, OATP1B1, OATP2B1, RHOA, NPC1L1, FXR, CYP7A1, ApoE, PCSK9, LDLR, LPA, CETP, and TNF-a genes. However, currently, there is still not enough evidence to advocate pharmacogenetic testing before initiating therapy with statins.


  1. 1. Al-Sarraf A, Li M, Frohlich J. Statin resistant dyslipidemia in a patient treated with amiodarone. BMJ Case Rep 2011.
  2. 2. Andel M. Hyperlipoproteinemia impairs endothelium-dependent vasodilatation. Physiol Res [2004]; 53: 471–480
  3. 3. Anderson TJ. Assessment and treatment of endothelial dysfunction humans. J Am Coll Cardiol [1999]; 34: 631–638
  4. 4. Anderson TJ, Mark AL. Flow-mediated and reflex changes in large peripherial artery tone in humans. Circulation [1989]; 79: 93–100
  5. 5. Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Lieberman EH, Ganz P, Creager MA, Yeung AC, Selwyn AP. Close relation of endothelial function in the human coronary and peripheral circulation. J Am Coll Cardiol [1995]; 26: 1235–1241
  6. 6. Ardigo D, Stüehlinger M, Franzini L, Valtueña S, Piatti PM, Pachinger O, Reaven GM, Zavaroni I. ADMA is independently related to flow- mediated vasodilation in subjects at low cardiovascular risk. Eur J Clin Invest [2007]; 37: 263–269
  7. 7. Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE. Serum total homocysteine and coronary heart disease. Int J Epidemiol [1995]; 24: 704–709
  8. 8. Ballantyne CM. Changing lipid-lowering guidelines: whom to treat and how low to go. Eur Heart J [2005]; 7(Suppl. A): A12–A19
  9. 9. Behrendt D, Ganz P. Endothelial function: from vascular biology to clinical applications. Am J Cardiol [2002]; 90(Suppl. 3]: 40L–48L
  10. 10. Betteridge DJ, Morrell JM. Clinicans’ Guide to Lipids and Coronary Heart Disease, 2nd edn [2003]. A Hodder Arnold Publication, London, UK, pp. 275–278. Bhagat K, Hingorani A, Vallance P. Flow-associated or flow-mediated?More than just semantics. BMJ [1997]; 78: 7–8.
  11. 11. Böger GI, Maas R, Schwedhelm E, Bierend A, Benndorf R, Kastner M, Steenpaß A, Böger RH. Improvement of endothelium-dependent vasodilation by simvastatin is potentiated by combination with L-arginine in patients with elevated asymmetric dimethylarginine levels. J Am Coll Cardiol [2004]; 43(Suppl.): 525A
  12. 12. Böger GI, Rudolf TK, Renke M, Schwedhelm E, Dumbadze E, Bierend A, Benndorf RA, Böger RH. Asymmetric dimethylarginine determines the improvement of endothelium-dependent vasodilatation by Sim- vastatin. J Am Coll Cardiol [2007]; 49: 2274–2282
  13. 13. Böger RH, Bode-Böger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP. Asymmetric dimethylagrinine (ADMA): a novel risk factor for endothelial dysfunction. It's role in hypercho- lesterolemia. Circulation [1998]; 98: 1842–1847
  14. 14. Böger RH, Bode-Böger SM. The clinical pharmacology of L-arginine. Annu Rev Pharmacol Toxicol [2001]; 41: 79–99
  15. 15. Böger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Böger SM. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells. Circ Res [2000]; 87: 99–105.
  16. 16. Böger RH, Vallance P, Cooke JP. Asymmetric dimethylarginine (ADMA):a key regulator of nitric oxide synthase. Atherosclerosis [2003]; 4(Suppl. 4]: 1–3
  17. 17. Böger RH. Association of asymmetric dimethylarginine and endothelial dysfunction. Clin Chem Lab Med [2003a); 41: 1467–1472
  18. 18. Böger RH. Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials. Vasc Med [2005]; 10(Suppl. 1]: S19–S25
  19. 19. Böger RH. Asymmetric dimethylarginine (ADMA) modulates endothelial function-therapeutic implications. Vasc Med [2003b); 8: 149–151
  20. 20. Böger RH. Asymmetric dimethylarginine (ADMA) modulates endothelial function – therapeutic implications. Vasc Med [2003c); 8: 149–151
  21. 21. Böger RH. Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explain the ‘‘L-arginine paradox’’ and acts as a novel cardiovascular risk factor. J Nutr [2004]; 134: 2842S–2847S
  22. 22. Boccara F, Simon T, Lacombe K, Cohen A, Laloux B, Bozec E, et al. Influence of pravastatin on carotid artery structure and function in dyslipidemic HIV-infected patients receiving antiretroviral therapy. AIDS 2006;20:2395e8
  23. 23. Bode-Böger SM, Böger SM, Kienke S, Junker W, Fro°lich JC. Elevated L- arginine ⁄ dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits. Biochem Biophys Res Commun [1996]; 219: 598–603
  24. 24. Celermajer DS. Noninvasive detection of atherosclerosis. N Engl J Med[1998]; 339: 2014–2015
  25. 25. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endo- thelial dysfunction in children and adulst at risk of atherosclerosis. Lancet [1992]; 340: 1111–1115
  26. 26. Chowienczyk PJ, Watts GF, Cockroft JR, Ritter JM. Impaired endothe- lium-dependent vasodilatation of forearm resistans vessels in hypercholesterolemia. Lancet [1992]; 340: 1430–1432
  27. 27. Christen WG, Ajani UA, Glynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual? Arch Intern Med [2000]; 160: 422–434
  28. 28. Cooke JP, Rossitch E Jr, Andon NA, Loscalzo J, Dzau VJ. Flow activates an endothelial potassium channel to release an endogenous nitrovaso- dilatator. J Clin Invest [1991]; 88: 1663–1671
  29. 29. Cooke JP. Asymmetric dimethylarginine The Über marker? Circulation [2004]; 109: 1813–1819
  30. 30. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vogel R. Guidelines for the ultrasound assessment of endothelial- dependent flow-mediated vasodilatation of the brachial artery. J Am Coll Cardiol [2002]; 39: 257–265
  31. 31. Corson MA, James NL, Latta SSE, Nerem RM, Berck BC, Harrison DG. Phosphorylation of endothelial nitric oxide synthase in response to fluid shear stress. Circ Res [1996]; 79: 984–991
  32. 32. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilatation of forearm resistens vessels in hypercholesterolemic humans. J Clin Invest [1990]; 86: 228–234
  33. 33. Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, Dzau VJ, Cooke JP. L-arginine improve endothelium-dependent vasodilatation in hyper- cholesterolemic humans. J Clin Invest [1992]; 90: 1248–1953
  34. 34. Davies PF, Rothblat GH, Wilensky RL, Yun Fang IL, Mohler ER, Hsieh IE, Osman H, Hashemi SM. Endothelium in vitro and in vivo hyper- cholesterolemia suppresses inwardly rectifying K+ channels in aortic. Circ Res [2006]; 98: 1064–1071
  35. 35. Donnelly LA, Doney AS, Dannfald J, Whitley AL, Lang CC, Morris AD, et al. A paucimorphic variant in the HMG-CoA reductase gene is associated with lipid-lowering response to statin treatment in diabetes: a GoDARTS study. Pharmacogenet Genomics 2008;18:1021e6
  36. 36. Faulx MD, Wright AT, Hoit BD. Detection of endothelial dysfunction with brachial artery ultrasound scanning. Am Heart J [2003]; 145: 943–951
  37. 37. Favre A, Monpere C, Voyer C, Mirguetn C, Quilliet-Thebaud N, Vern- ochet P, Brochier M. How to improve primary prevention in asymptomatic high risk subjects. Eur Heart J [2004]; 6(Suppl. J): j59–j63
  38. 38. Furchgott RF. Endothelium-derived relaxing factor: discovery, early studies, and identification as nitric oxide. Biosci Rep [1999]; 19: 235–251. Furchgott RF, Jothianandan D. Endothelium-dependent and -indepen- dent vasodilation involving cyclic GMP: relaxation induced by nitric oxide, carbon monoxide and light. Blood Vessels [1991]; 28: 52–61
  39. 39. Furchgott RF, Zawadzki JV. The obligatory role of the endothelium in the relaxation of arterial smooth muscle by acetylcholine. Nature [1980]; 288: 373–376
  40. 40. Furchgott RF. Role of endothelium in responses of vascular smooth muscle. Circulation Res [1983]; 53: 557–573
  41. 41. Furchgott RF. Studies on Relaxation of Rabbit Aorta by Sodium Nitrite: The Basis for the Proposal that the Acid-Activatable Inhibitory Factor from Retractor Penis is Inorganic Nitrite and the Endothelium-Derived Relaxing Factor is Nitric Oxide. In Vasodilation: Vascular Smooth Muscle, Peptides, and Endothelium. [1988], pp. 401–414. Raven Press, New York.
  42. 42. Generaux GT, Bonomo FM, Johnson M, Doan KM. Impact of SLCO1B1 (OATP1B1] and ABCG2 (BCRP) genetic polymorphisms and inhibition on LDL-C lowering and myopathy of statins. Xenobiotica 2011;41:639e51
  43. 43. Genest JJ, McNamara JR, Upson B, Salem DN, Ordovas JM, Schaefer EJ. Prevalence of familial hyperhomocyst(e)inemia in men with prema- ture coronary disease. Arterioscler Thromb [1991]; 11: 1129–3635
  44. 44. Gornic HL, Creager MA. Arginine and endothelial and vascular health. J Nutr [2004]; 134: 2880S–2887S.
  45. 45. Gotto AM. Management of dyslipidemia. Am J Med [2002]; 112(Suppl. 8A): 10S–18S
  46. 46. Greenland P, Abrams J, Aurigemma GP, Bond MG, Clark LT, Criqui MH, Crouse JR, Friedman L, Fuster V, Herrington DM, Kuller LH, Ridker PM, Roberts WC, Stanford W, Stone N, Swan HJ, Taubert KA, Wexler
  47. 47. Greenland P, Abrams J, Aurigemma GP, et al.Prevention conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: noninvasive tests of atherosclerotic burden: writing group III. Circulation [2000]; 101: e16–e22
  48. 48. Herman AG, Moncada S. Therapeutic potential of nitric oxide donors in the prevention and treatment of atherosclerosis European Heart Journal [2005] 26, 1945–1955
  49. 49. Hu M, Lui SS, Tam LS, Li EK, Tomlinson B. The farnesoid X receptor -1G>T polymorphism influences the lipid response to rosuvastatin. J Lipid Res 2012;53:1384e9
  50. 50. Hubacek JA, Vrablik M. Effect of apolipoprotein E polymorphism on statin-induced decreases in plasma lipids and cardiovascular events. Drug Metabol Drug Interact 2011;26:13e20
  51. 51. Ignarro LJ. Nitric Oxide: Biology and Pathobiology [2000], pp. 547–568. Academic Press, London
  52. 52. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethy- larginine dimethyl amino hydrolase. Circulation [1999]; 99: 3092–3095
  53. 53. Janatuinen T, Laakso J, Laaksonen R, Nuutila P, Lehtimaki T, Raitakari OT, Knuuti J. Plasma asymmetric dimethylarginine modifies the effect of pravastatin on myocardial blood flow in young adults. Vasc Med [2003]; 8: 185–189
  54. 54. Joannides R, Haefeli WE, Linder L, Vincent R, Bakkali EH, Thuillez C, Lu° scher TF. Nitric oxide responsible for flow-dependent dilatation of human peripherial Conduit arteries in vivo. Circulation [1995]; 91: 1314–1319.
  55. 55. Johns KW, Bennett MT, Bondy GP. Are HIV positive patients resistant to statin therapy? Lipids Health Dis 2007;6:27
  56. 56. Kaddurah-Daouk R, Baillie RA, Zhu H, Zeng ZB, Wiest MM, Nguyen UT, et al. Lipidomic analysis of variation in response to simvastatin in the Cholesterol and Pharmacogenetics Study.Metabolomics 2010;6:191e201
  57. 57. Kang SS, Wong PW, Cook HY, Norusis M, Messer JV. Protein-bound- homocyst(e)ine. A possible risk factor for coronary artery disease. J Clin Invest [1986]; 77: 1482–1486
  58. 58. Kastelein JJP. The realities of dyslipidaemia: what do the studies tell us? Eur Heart J [2005]; 7(Suppl. F): F27–F33
  59. 59. Kielstein JT, Cooke JP. Should we measure asymmetric dimethylarginine in patients with coronary artery disease? Clin Chem [2007]; 53: 161– 163
  60. 60. Kitamoto Sh, Egashira K. Endothelial dysfunction and coronary atherosclerosis. Curr Drug Targets Cardiovas Haematol Disord [2004]; 4: 13–22. Knekt P, Reunanen A, Alfthan G, Heliövaara M, Harri Rissanen H,
  61. 61. Kobayashi K, Akishita M, Yu W, Hashimoto M, Ohni M, Toba K. Interrelationship between non-invasive measuments of atherosclero- sis: flow-mediated dilatation of brachial artery, carotid intima-media thickness and pulse wave velocity. Atherosclerosis [2004]; 173: 13–18
  62. 62. Krauss RM, Mangravite LM, Smith JD, Medina MW, Wang D, Guo X, et al. Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Circulation 2008;117:1537e44
  63. 63. Landmesser ULF, Hornig B, Drexler H. Endothelial dysfunction in hypercholesterolemia: mechanism, pathophysiological importans and therapeutic interventions. Semin Thromb Hemost [2000]; 26: 529–537
  64. 64. Laufs U, La F, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation [1998]; 97:1129–1135
  65. 65. Lentz SR, Radionov RN, Dayal S. Hyperhomocysteinemia, endothelial dysfunction, and cardiovascular risk: the potential role of ADMA. Atherosclerosis [2003]; 4(Suppl. 4]: 61–65
  66. 66. Lim S, Seon KM, Soo PK, Ho LJ, Hee AG, Ja YM et al. Correlation of plasma homocysteine and mitochondrial DNAcontent in peripheral blood in healthy women. Atherosclerosis [2001]; 158: 399–405
  67. 67. Lin K, Lin SC. A tale of two molecules: nitric oxide and asymmetric dimethylarginine. Acta Cardiol Sin [2004]; 20: 201–211
  68. 68. Mann DM, Woodward M, Muntner P, Falzon L, Kronish I. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother 2010;44:1410e21
  69. 69. Marniemi J, Aromaa A. Hyperhomocystinemia a risk factor or a consequence of coronary heart disease? Arch Intern Med [2001]; 161: 1589–1594
  70. 70. Medina MW, Theusch E, Naidoo D, Bauzon F, Stevens K, Mangravite LM, et al. RHOA is a modulator of the cholesterollowering effects of statin. PLoS Genet 2012;8:e1003058
  71. 71. Mega JL, Morrow DA, Brown A, Cannon CP, Sabatine MS. Identification of genetic variants associated with response to statin therapy. Arterioscler Thromb Vasc Biol 2009;29:1310e5
  72. 72. Miyazaki H, Matsuoka H, Cooke J, Usui M, Ueda S, Okuda S, Imaizuma T. Endogenous nitric oxide synthase inhibitor. Circulation [1999]; 99: 1141–1146
  73. 73. Moens AL, Goovaerts I, Claeys MJ, Vrints CJ. Flow-mediated vasodila- tion: a diagnostic instrument, or an experimental tool? Chest [2005]; 127: 2254–2263
  74. 74. Murad F. Discovery of some of the biological effects of nitric oxide and its role in cell signaling. Biosci Rep [1999]; 19: 133–154
  75. 75. Niemi M, Schaeffeler E, Lang T, Fromm MF, Neuvonen M, Kyrklund C, et al. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion transporting polypeptide-C (OATP-C, SLCO1B1]. Pharmacogenetics 2004;14:429e40
  76. 76. Nygard O, Vollset SE, Refsum H et al. Total plasma homo-cysteineand cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA [1995]; 274: 1526–1533
  77. 77. Oemar BS, Tschudi MR, Godoy N, Brovkovich V, Malinski T,Lüscher TF. Reduced endothelial nitric oxide synthase expression and production in human atherosclerosis. Circulation [1998]; 97: 2494–2498
  78. 78. Pohl U, Holtz J, Busse R, Bassenge E. Crucial role of the endothelium in the vasodilator response to flow in vivo. Hypertension [1985]; 8: 37–44
  79. 79. Polisecki E, Muallem H, Maeda N, Peter I, Robertson M, McMahon AD, et al. Genetic variation at the LDL receptor and HMG-CoA reductase gene loci, lipid levels, statin response, and cardiovascular disease incidence in PROSPER. Atherosclerosis 2008;200:109e14
  80. 80. Raitakari OT, Celermajer DS. Testing for endothelial function. Ann Med [2000]; 32: 293–304
  81. 81. Reiner Z, De Bacquer D, Kotseva K, Prugger C, De Backer G, Wood D. EUROASPIRE III study group. Treatment potential for dyslipidaemia management in patients with coronary heart disease across Europe: findings from the EUROASPIRE III survey. Atherosclerosis 2013;231:300e7
  82. 82. Reiner Z, Tedeschi-Reiner E. Prevalence and types of persistent dyslipidemia in patients treated with statins. Croat Med J 2013;54:339e45
  83. 83. Ridker PM, Manson JE, Buring JE, Shih J, Matias M, Hennekens H. Homocysteine and risk of cardiovascular disease among postmeno- pausal women. JAMA [1999]; 281: 1817–1821
  84. 84. Rodrigues AC, Perin PM, Purim SG, Silbiger VN, Genvigir FD, Willrich MA, et al. Pharmacogenetics of OATP transporters reveals that SLCO1B1 c.388A>G variant is determinant of increased atorvastatin response. Int J Mol Sci 2011;12:5815e27
  85. 85. Simon JA, Lin F, Hulley SB, Blanche PJ, Waters D, Shiboski S, et al. Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the cholesterol and pharmacogenetics (CAP) Study. Am J Cardiol 2006;97:843e50
  86. 86. Stühlinger M, Stanger Ol. Asymmetric dimethylarginine (ADMA): a possible link between homocystein and endothelial dysfunction. Current Drug Metabolism [2005]; 6: 3–14
  87. 87. Stühlinger M, Tsao Ph, Her J, Kimoto M, Balint R, Cooke J. Homocysteine impairs the nitric oxide synthase pathway:role of asymmetric dimethylarginine. Circulation [2001]; 104: 2569–2575
  88. 88. Takane H, Miyata M, Burioka N, Shigemasa C, Shimizu E, Otsubo K, et al. Pharmacogenetic determinants of variability in lipid-lowering response to pravastatin therapy. J Hum Genet 2006;51:822e6
  89. 89. Thompson JF, Hyde CL, Wood LS, Paciga SA, Hinds DA, Cox DR, et al. Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the treating to new targets (TNT) cohort. Circ Cardiovasc Genet 2009;2:173e81
  90. 90. Trupp M, Zhu H, Wikoff WR, Baillie RA, Zeng ZB, Karp PD, et al.Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment. PLoS One 2012;7:e38386
  91. 91. Tsao Ph, Cooke JP. Endothelial alteration in hypercholesterolemia: more than simply vasodilatator dysfunction. J Cardiovasc Pharmacol [1998]; 32(Suppl. 3]: S48–S53
  92. 92. Tsikas D, Böger RH, Sandmann J, Bode-Böger SM, Flo°lich JC. Endoge- nous nitric oxide synthase inhibitors are responsible for the L-arginine paradox. FEBS Lett [2000]; 478: 1–3
  93. 93. van der Baan FH, Knol MJ, Maitland-van der Zee AH, Regieli JJ, van Iperen EP, Egberts AC, et al. Added value of pharmacogenetic testing in predicting statin response: results from the REGRESS trial. Pharmacogenomics J 2013;13:318e24
  94. 94. Veerkamp MJ, de Graaf J, den Heijer M, Blom HJ, Stalenhoef AFH. Plasma homocystein in subjects with familial combined hyperlipid- emia. Atherosclerosis [2003]; 166: 111–117
  95. 95. Vladimirova-Kitova L, D. Terzieva, F. Nikolov. Asymmetric dimewthylarginine determines the effect of simvastatin on endothelium-dependent vasodilation in severe hypercholesterolemia Future Medicine Clinical Lipidology 2010: 5 [1]; 29-41
  96. 96. Vladimirova-Kitova L, D. Terzieva. Intima-media thickness and flow mediated vasodilation in asymptomatic subjects with newly detected severe hypercholesterolemia Echocardiography 2009; 26 [9]: 1060-1068
  97. 97. Vladimirova-Kitova L, Deneva T, Marinov B. Predictors of the intima-media thickness of carotid artery in asymptomatic newly detected severe hypercholesterolemic patients. Clin Physiol Funct Imaging. 2010; 30 [4]: 250-259
  98. 98. Vladimirova-Kitova L, Deneva-Кoycheva T. Asymmetric dimethylarginine- a determinant of effect of the high dose simvastatin. Clinical biochemistry. 2010 [43]: 843-850
  99. 99. Vladimirova-Kitova LG, Deneva T. I, Marinov B. Effect of Moderate and High-Dose Simvastatin on Asymmetric Dimethylarginine-Homocysteine Metabolic Pathways in Patients with Newly Detected Severe Hypercholesterolemia. Cardiovasc Therapeutics 2011 [29] : 340-348
  100. 100. Vladimirova-Kitova LG, Deneva TI. Simvastatin and asymmetric dimethylarginine-homocysteine metabolic pathways in patients with newly detected severe hypercholesterolemia. Clin Lab. 2010; 56 [7-8]: 291-302
  101. 101. Vladimirova-Kitova LG, Deneva-Koicheva TI Тhe effect of simvastatin on Asymmetric Dimethylarginine after optimizing the LDL – a randomized, placebo-controlled study. Vascular Pharmacology. 2012, 56 [3-4]: 122-130
  102. 102. Vladimirova-Kitova LG, Deneva-Koycheva T.I. Increased intima-media thickness in carriers of the LDL-receptor defective gene versus noncarriers with newly detected asymptomatic severe hypercholesterolemia. Echocardiography. 2011 28, [2], 223–234
  103. 103. Vladimirova-Kitova, L.G., Deneva, T., Angelova E.,. Nikolov, F., Marinov B., Mateva, N. Relationship of asymmetric dimethylarginine with flow-mediated dilation in subjects with newly detected severe hypercholesterolemia. Clinical Physiology and Functional Imaging 2008 28[6], 417-425
  104. 104. Voora D, Shah SH, Reed CR, Zhai J, Crosslin DR, Messer C, et al. Pharmacogenetic predictors of statin-mediated low-density lipoprotein Cholesterol Reduction and Dose Response Circ Cardiovasc Genet. Dec 2008; 1[2]: 100–106
  105. 105. Whinchup PH, Refsum H, Perry IJ. Serum total homocysteine and coronary heart disease: prospective study in middle aged men. Heart [1999]; 82: 448–454
  106. 106. Wu LL, Wu J, Hunt SC, James BC, Vincent GM, Williams RR et al. Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease. Clin Chem [1994]; 40: 552–561
  107. 107. Y1 Chen, Ku H, Zhao L, Wheeler DC, Li LC, Li Q, et al. Inflammatory stress induces statin resistance by disrupting 3-hydroxy-3-methylglutaryl-CoA reductase feedback regulation. Arterioscler Thromb Vasc Biol 2014;34:365e76
  108. 108. Yu X, Li Y, Xiong Y. Increase of a endogenous inhibotor of nitric oxide synthesis in serum of high cholesterol fed rabbits. Life Sci [1994]; 54: 753–758

Written By

Lyudmila Georgieva Vladimirova-Kitova and Spas Ivanov Kitov

Submitted: May 4th, 2014 Published: September 17th, 2015