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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 9  |  Issue : 1  |  Page : 16-21

Statins for endothelial dysfunction in sickle cell disease: A cohort study


1 Department of Physiology, College of Medicine, Al-Nahrain University, Baghdad, Iraq
2 Department of Medicine, College of Medicine, Al-Nahrain University, Baghdad, Iraq

Date of Web Publication22-Mar-2018

Correspondence Address:
Dr. Waseem F Al-Tameemi
Department of Physiology, College of Medicine, Al-Nahrain University, Baghdad
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_60_17

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  Abstract 

Background: The sickling process of sickle cell disease (SCD) has harmful effects on the vascular endothelium manifested as vascular blockade, diminished tissue oxygenation, and consequently reperfusion injury. Statins pleiotropic effects can be demonstrated through improvement of endothelial function. Studies on the role of statins (e.g., atorvastatin) on endothelial dysfunction in SCD are minimal.
Objective: The objective is to assess the possible therapeutic use of atorvastatin in patients with SCD.
Subjects and Methods: Thirty SCD patients (15 female and 15 male) with a mean age of 27.0 ± 8.9 years and 30 healthy controls (18 female and 12 male) with a mean age of 29.7 ± 9.1 years participated in the study. Endothelial function was assessed with flow mediated dilatation (FMD) and endothelial independent dilatation (EID) of the brachial and common carotid arteries at baseline and after 6 weeks therapy with atorvastatin, 20 mg/day.
Results: SCD patients had diminished FMD% and EID% values compared with corresponding values in the controls. The values were improved significantly after atorvastatin treatment (P = 0.002 for FMD%; P = 0.001 for EDI%).
Conclusion: SCD patients have endothelial dysfunction. Atorvastatin, 20 mg daily for 6 weeks, improved the markers of endothelial function, FMD%, and EID%, in these patients.

Keywords: Atorvastatin, brachial artery, common carotid artery, endothelial-independent dilatation, flow-mediated dilatation, sickle cell disease


How to cite this article:
Al-Janabi H, Hamdan FB, Al-Tameemi WF. Statins for endothelial dysfunction in sickle cell disease: A cohort study. J Appl Hematol 2018;9:16-21

How to cite this URL:
Al-Janabi H, Hamdan FB, Al-Tameemi WF. Statins for endothelial dysfunction in sickle cell disease: A cohort study. J Appl Hematol [serial online] 2018 [cited 2018 Jun 17];9:16-21. Available from: http://www.jahjournal.org/text.asp?2018/9/1/16/228333


  Introduction Top


Sickle cell disease (SCD) typically inherited as autosomal recessive hemoglobinopathy and results from genetic alteration in the β-globin chain, in which valine translocate glutamic acid at the sixth amino acid position of hemoglobin and produces hemoglobin S (HbS).[1] Under conditions of hypoxia and dehydration, HbS polymerizes inside the red blood cells (RBC) and gives them the characteristic sickle-shaped.[1],[2]

The polymerization of HbS causes intravascular hemolysis, which releases HbS into the plasma.[3] Repeated polymerization initiates a series of events that results in intermittent vasoocclusion, ischemia-reperfusion injury, vascular endothelial dysfunction, and inflammation.[4]

Vascular endothelium – once believed to be an inert separation between the arterial wall and the blood – is now known to perform an array of homeostatic functions within normal blood vessels, such as sensing pressure, shear stress, hormones, and vasoactive substances. In response to these stimuli, the endothelium produces a wide range of factors that regulate vascular tone, cellular adhesion, thrombus resistance, smooth muscle cell proliferation, and vessel wall inflammation.[5]

Endothelial dysfunction has been observed in murine models and humans with SCD, and it is now classified as a vasculopathic disease.[6],[7] The endothelium in SCD has several abnormal features, including moyamoya-type intracranial blood vessels, abnormal vascular tone,[8] elevated endothelin-1 levels, increased number of circulating endothelial cells, and increased expression of adhesion receptors and procoagulant proteins.[9],[10]

In addition to vasoocclusion, SCD has other abnormal features, such as restricted blood supply and endothelial tissue injury, inflammation, RBC lysis, production of reactive oxygen species, insufficient nitric oxide (NO) production, endothelial activation, abnormal vascular reactivity that disables the adjustments of blood flow and alterations of vessel tone and diameter, and imbalanced sympathetic-parasympathetic activity.[6],[7],[11] Many of these abnormalities influence the development of others. Fifty percent of those patients with SCD develop endothelial dysfunction as a result of diminished endogenous NO, consequent to scavenging by cell-free plasma Hb.[12]

Based on the phenotype of the patient, SCD can be classified into viscosity-vasoocclusion or hemolysis-endothelial dysfunction. The RBC lysis-endothelial dysfunction phenotype reveals to a large extent insufficiency of or resistance to NO.[13]

Statins, the 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, reduce atherosclerosis by their direct action on cholesterol in the liver and lower serum cholesterol.[14] Statins also have powerful pleiotropic effects that are independent of their effects on lipids and lipoproteins.[15] Statins are anti-inflammatory, antiproliferative, immunomodulatory, antithrombotic, antiapoptotic, and improve endothelial dysfunction.[16],[17]

Some studies have shown that statins significantly improve endothelial function within 3 h of administration.[18],[19] Others have shown that the endothelial function is improved over 15 days [16] to 3 months of treatment with 20 mg/day of atorvastatin. One study showed that atorvastatin had no effect on the carotid intima-media thickness (IMT) but had a nonsignificant improvement in the endothelial function of the brachial artery (BA) and significant improvement in the coronary flow reserve.[20]

This study was designed to assess the use of statins (atorvastatin) in improving endothelial dysfunction in patients with SCD.


  Subjects and Methods Top


We enrolled consecutive patients presenting to the Hematology Unit of Al-Imamain Al-Kadhimiyan Medical City, Department of Inherited Blood Diseases in Al-Karama Teaching Hospital, Iraq, and the National Center for Hematology Diseases and Researches, Baghdad, Iraq, between April 1, 2013, and November 1, 2014.

Subjects

Thirty patients with homozygous SCD meeting the eligibility criteria were included in this study. There were 15 males and 15 females, with ages between 15 and 50 years (mean ± standard deviation [SD]: 27.0 ± 8.9 years).

The following kinds of patients were excluded from the study: SCD patients with crises in the past week, severe anemia (Hb <5 g / dL), blood transfusion within the last 4 weeks, significant cardiac disease, electrocardiogram abnormalities, serum creatinine >1.5 mg/dL, or alanine aminotransferase >3 times the upper limit of normal; pregnant patients; those taking tonic supplements, such as L-arginine, fibrates (within the last week), statins (within the last 4 weeks), or drugs with significant interactions with statins (e.g., fluconazole, erythromycin, clarithromycin, cyclosporine, niacin); and patients with conditions that may independently affect endothelial function, such as diabetes, fasting blood glucose >120 mg/dL, cigarette smoking within 1 month, and hypertension (diastolic blood pressure >90 mmHg).

Thirty healthy volunteers (females: 18; males: 12) with ages between 18 and 49 years (mean ± SD = 29.7 ± 9.1 years) served as the control group.

Methods

Endothelial function was assessed by measuring the diameter of the BA and common carotid arteries (CCA) with a high-resolution Doppler probe of 5–13 MHz (Logiq P6 Pro, South Korea). All ultrasonographic measurements were made by a single-blinded experienced sonographer. Ultrasonography was performed in the morning between 8 am and 10 am after an overnight fast.

The resting arterial diameter, flow-mediated dilation (FMD), endothelium-independent dilation (EID), and IMT were measured noninvasively.[21],[22] IMT was defined as the distance between the blood-intima interface and the media-adventitia interface. While imaging, the veins and facial planes were noticed, and the scanned area was marked to measure the same segment of the artery throughout the study. The participants were asked to remain in the supine position for 10 min to allow blood pressure to stabilize.

Flow-mediated vasodilatation

The diameter of the BA was measured 2–5 cm above the antecubital fossa during peak systole with a spectral Doppler. After a rest period of 10 min, a baseline rest diameter was measured for a segment with clear anterior and posterior intimal interfaces between the lumen and the vessel wall. The right forearm was compressed by inflation of a sphygmomanometer cuff at a pressure of 200 mmHg for 5 min. The BA diameter was measured again 15 s and 10 min after deflation of the cuff to ensure that the baseline diameter had been reached.

The percent change in BA diameter was taken as the average of three measurements and recorded as FMD%, according to the equation: FMD = (d2 − d1) × 100/d1, where d1 is the BA diameter at baseline and d2 is the BA diameter 60 s after release of the cuff.

Endothelium-independent vasodilation

Each image was taken after 10 min of rest after reactive hyperemia to allow the re-establishment of baseline conditions. A tablet of 0.4 mg nitroglycerine was given sublingually for 5 min to determine the maximum vasodilation, which is a measure of EID.

Carotid ultrasonography studies

The participants were placed in the supine position with the head rotated 45° to the left or right on a pillow. The CCA-IMT value was defined as the mean of three measurements of the right and left CCAs at a distance of 10 mm proximal to the carotid bifurcation. Longitudinal and cross-sectional views of both CCAs were acquired to visualize ≥10 mm of the IMT complex on the far wall.

The same measurements were made again in patients with SCD after 20 mg/day of atorvastatin for 6 weeks.

Statistical analysis

The data were analyzed with IBM Statistical Package for the Social Sciences (IBM SPSS), version 22 produced by SPSS Inc., and the developer IBM Corporation (Armonk, New York, United States). The means between two groups were compared by the Student's t-test for unpaired observations and by the paired Student's t-test for paired observations. ANOVA was used to compare more than two independent means. Qualitative data were analyzed with the Pearson's Chi-squared test, Yate's correction, and Fisher's exact test, wherever applicable. A P ≤ 0.05 was considered statistically significant.


  Results Top


SCD patients body mass index (BMI) was significantly lower than that of control group (22.9 ± 4 vs. 26 ± 4.7, respectively) (P = 0.006). In SCD patients, the pretreatment FMD% was significantly lower than the posttreatment value (13.02 ± 4.59 vs. 15.30 ± 5.60, respectively; P = 0.002). However, the pre- and post-treatment FMD% was not significantly different from that of the control group. The pretreatment EID% was significantly lower than the posttreatment value (21.71 ± 6.96 vs. 24.72 ± 8.63, respectively; P < 0.05). Moreover, pretreatment EID% was significantly lower than that of the control group (26.81 ± 6.31; P = 0.004), but there was no significant difference between the posttreatment and control group EID%.

Compared with the CCA-IMT in the control group (0.55 ± 0.13 mm), the pretreatment (0.47 ± 0.10 mm) and posttreatment (0.47 ± 0.08 mm) CCA-IMT values in the SCD group were significantly lower (P = 0.032; P = 0.016, respectively) [Table 1].
Table 1: Doppler parameters of sickle cell disease patients and controls

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The pre- and post-treatment FMD% negatively correlated with baseline BA diameter (r = −0.392; P = 0.032 and r = −0.47; P = 0.009, respectively). Similarly, the pre- and post-treatment EID% negatively correlated with baseline BA diameter (r = −0.57; P = 0.001 and r = −0.47; P = 0.009, respectively) [Figure 1]a-d].
Figure 1: (a-d) Relationship of flow-mediated dilatation and brachial artery pretreatment to atorvastatin (a) flow-mediated dilatation and brachial artery posttreatment to atorvastatin (b) endothelium-independent dilatation and brachial artery diameter pretreatment to atorvastatin (c) and endothelium-independent dilatation and brachial artery diameter postatorvastatin treatment (d)

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[Figure 2] shows that FMD% correlated positively with EID% before and after drug administration (r = 0.752; P = 0.0001 and r = 0.75; P = 0.0001, respectively).
Figure 2: (a and b) Relationship of flow-mediated dilatation and endothelium-independent dilatation preatorvastatin treatment (a) and flow-mediated dilatation and endothelium-independent dilatation postatorvastatin treatment (b)

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[Figure 3] shows that the CCA-IMT before and after treatment with atorvastatin (r = 0.533; P = 0.002 and r = 0.59; P = 0.001, respectively) correlated with the age of the patients.
Figure 3: (a and b). Relationship of age and common carotid artery intima-media thickness to preatorvastatin treatment (a) and age and common carotid artery intima-media thickness to postatorvastatin treatment (b)

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Furthermore, CCA-IMT correlated positively with BA-IMT pre- and post-atorvastatin treatment (r = 0.644; P = 0.0001 and r = 0.46; P = 0.01, respectively) [Figure 4].
Figure 4: (a and b) Relationship of common carotid artery intima-media thickness and brachial artery intima-media thickness preatorvastatin treatment (a) and common carotid artery intima-media thickness with brachial artery intima-media thickness postatorvastatin treatment (b)

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  Discussion Top


This study showed that the pretreatment FMD% was lower in SCD patients compared with controls, but this was not statistically significant. Several previous studies have demonstrated a decrease in FMD% in SCD patients.[5],[23] A decline in endothelial function has been observed with increasing duration of symptoms and number of vasoocclusive crises/year. Other studies have shown a decreased FMD% in SCD patients in steady states.[24],[25] One possible explanation for the insignificant difference in FMD% in this study could be the higher BMI of controls compared with that of the SCD patients. FMD% and BMI have a negative relationship,[26] which is also seen in this study.

Another possible explanation is that impaired FMD% indicates failure of muscular arteries to adjust their internal diameter in response to mechanical stimuli. However, the difference between baseline diameters between the patients and controls was not statistically significant. Baseline BA diameter in SCD patients (pre- and post-treatment) was similar to that of the controls, which suggests an inability to adjust the arterial diameter in response to chronic shear stress in SCD patients. Furthermore, an acute increase in the shear stress, in the form of reactive hyperemia, induced a smaller increase in BA diameter in the patients than in the controls. The reduced change in the arterial diameter of patients in response to hyperemia suggests a decrease in vasodilation reserve due to decreased bioavailability of NO.

The mean pretreatment EID% was significantly lower than the posttreatment value, which is in agreement with previous studies.[24],[25] FMD% and nitroglycerin-induced dilation were also impaired in SCD patients compared with controls. The impaired response to a nonendothelium-dependent NO donor suggests reduced bioavailability of NO or reduced response of vascular smooth muscle to NO. In addition, both inflammation and oxidative stress influence EID by reducing bioconversion of GTN to NO and scavenging of NO in smooth muscles.[27]

In this study, FMD% and EID% significantly increased after 6 weeks of treatment with atorvastatin. Previous studies showed significantly improved FMD% and EID% in response to atorvastatin treatment in patients with acute coronary syndrome,[28] atherosclerosis,[29] or smoking.[30]

We found no difference in the BA diameter and IMT between patients and controls, which is in concordance with Eberhardt et al.[24] and Belhassen et al.[31] studies. Those studies did not find any significant difference in BA diameter and IMT between SCD patients and controls. Interestingly, baseline BA diameter was similar in patients and controls, indicating impaired adjustment of arterial diameter in response to shear stress. Sustained wall shear stress induces a NO-dependent increase in arterial diameter that reduces stress regardless of the blood flow. Therefore, failure of vessels to adjust their diameter in response to shear stress reflects impaired basal or stimulated the release of NO.[31]

The CCA diameter was similar between the two groups, which is in agreement with the de Montalembert et al.[32] study. Conversely, the pre- and post-treatment CCA-IMT in SCD patients was significantly lower than that for the controls. Some studies [33] have shown higher CCA-IMT in patients compared with that in the controls. Another study [32] showed no difference in CCA-IMT between SCD patients and controls, which may be explained by a high CCA-IMT in the controls as a result of their higher BMI or unequal age distribution.

This study showed a negative correlation between FMD% and EID% and baseline BA diameter, which is in agreement with Maruhashi et al.[34] Baseline BA diameter may confound the interpretation of FMD.[35] FMD increases in proportion to the hyperemic systolic shear stress during postischemic hyperemia.[36] A possible explanation for the inverse correlation between FMD and baseline BA diameter is that shear stress during reactive hyperemia predominantly affects small arteries because of their dependence on postischemic systolic flow on radius squared.[37]

A previous study showed a positive correlation between the age and CCA-IMT, a finding supported by other studies conducted on patients with diabetes and young children, respectively.[38],[39]

Bereal-Williams et al. did not agree with assumption of pleiotropic effect of low doses of statin in SCA and considered its effect just related to cholesterol-lowering effect without vasodilator effect [40] which is in contrast to Hoppe et al. who demonstrated role of simvastatin in enhancing NO level in both low and moderate doses with its subsequent vasodilation regardless lipid-lowering effect.[41]


  Conclusion Top


Treatment with moderate doses of atorvastatin improves FMD% and EID% in SCD patients, which is evidence of a favorable effect of the statin on the endothelial dysfunction which characterizes the disease. The effects of statins and GTN on vasoocclusive crises in SCD patients should be evaluated in the future studies.

Limitation of the study

The limitations of this study were related to small sample size and short follow-up observation.

Acknowledgment

The authors are grateful to all the participants of this study and the staff of the laboratory in Al-Imamain Al-Kadhimiyan Medical City.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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