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Congenital heart disease
Original article
Effects of atorvastatin on endothelial function and the expression of proinflammatory cytokines and adhesion molecules in young subjects with successfully repaired coarctation of aorta
  1. S Brili,
  2. D Tousoulis,
  3. A S Antonopoulos,
  4. C Antoniades,
  5. G Hatzis,
  6. C Bakogiannis,
  7. N Papageorgiou,
  8. C Stefanadis
  1. 1st Cardiology Department, Hippokration Hospital, Athens University Medical School, Athens Greece
  1. Correspondence to Professor Dimitris Tousoulis, Athens University Medical School, S Karagiorga 69, Glifada, Athens 16675, Greece; tousouli{at}med.uoa.gr

Abstract

Objective To investigate the effects of atorvastatin on endothelial function and low-grade systemic inflammation in subjects with successful surgery for aortic coarctation repair (SCR).

Design Open-label study.

Setting Outpatients visiting the adult congenital heart disease department of our hospital.

Patients 34 young people with SCR.

Interventions Patients with SCR received atorvastatin 10 mg/day (n=17) or no treatment (n=17) for 4 weeks. At baseline and at 4 weeks, endothelial function was assessed by flow-mediated dilatation (FMD) of the right brachial artery, and blood samples were obtained. Serum levels of interleukin (IL) 1b, IL-6 and soluble vascular cell adhesion molecule-1 (sVCAM-1) were determined by ELISA.

Main outcome measures Effects of treatment on FMD and serum levels of IL-1b, IL-6 and sVCAM-1.

Results FMD in the atorvastatin group was significantly improved after 4 weeks (from 6.46±0.95% to 11.24±1.38%, p<0.01), while remaining unchanged in the control group (from 6.74±0.58% to 6.95±0.53%, p=NS). Even though atorvastatin had no effect on serum IL-6 levels (0.62 (0.37–0.88) pg/ml to 0.53 (0.28–0.73) pg/ml, p=NS), it significantly reduced circulating levels of IL-1b (from 1.17 (0.92–1.77) pg/ml to 1.02 (0.75–1.55) pg/ml, p<0.05) and sVCAM-1 (from 883.4 (660.3–1093.1) ng/ml to 801.4 (566.7–1030.2) ng/ml, p<0.05). No changes were seen in serum levels of IL-6, IL-1b and sVCAM-1 in the control group after 4 weeks compared with baseline (p=NS for all).

Conclusions Atorvastatin treatment for 4 weeks in subjects with SCR significantly improved endothelial function and suppressed systemic inflammatory status by decreasing circulating levels of IL-1b and sVCAM-1.

  • Coarctation
  • inflammation
  • endothelium
  • statins
  • nitric oxide
  • oxidative stress
  • coronary physiology
  • congenital heart disease
  • platelet activation
  • atherosclerosis
  • coronary artery disease
  • valvular disease
  • renal disease
  • pharmacology
  • stable angina
  • endothelial function
  • valvuloplasty
  • interventional cardiology
  • acute ischaemic syndromes
  • EBM

https://doi.org/10.1136/heartjnl-2011-300287

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    Despite successful surgery for aortic coarctation repair (SCR), life expectancy of these patients remains dramatically reduced compared with the general population.1 Epidemiological evidence suggests that these subjects are at increased myocardial infarction risk, as systemic hypertension and premature atherosclerosis develop early in life.2 3 Increased cardiovascular risk in these patients is the result of commonly relapsed hypertension (at rest or during exercise), and also of proatherogenic abnormalities that are seen even in the absence of arterial hypertension.4 5

    As we have previously shown,4 6 early functional and structural vascular changes, leading to persisting endothelial dysfunction and abnormal arterial elastic properties, have been documented even in normotensive subjects with SCR. Furthermore, patients with SCR have increased circulating levels of proinflammatory cytokines and adhesion molecules, which have a well-established role in atherogenesis development.4 Increased systemic inflammatory status may be associated with the early vascular changes and impaired global vascular function seen in these subjects.4

    Statins have well-documented anti-atherogenic effects and statin treatment is associated with improved prognosis in primary and secondary prevention of cardiovascular disease.7 8 Statins reduce systemic and vascular wall inflammation9 and improve endothelial function in humans.10 11 Furthermore, as we have recently demonstrated, short-term atorvastatin treatment rapidly improves vascular redox state and nitric oxide (NO) bioavailability, by inhibiting vascular Rac1-mediated activation of NADPH-oxidase in human vessels.12

    Despite these well-characterised pleiotropic effects of statins, it is still unclear whether patients with SCR might benefit from treatment with statins. In this study we investigated whether statins could reverse endothelial dysfunction and improve systemic inflammatory status in patients with SCR.

    Methods

    Study population

    A total of 34 subjects with SCR (resection and end-to-end anastomosis in all) were included in this prospective open-label study. The patients were recruited from our department of adult congenital heart disease (Hippokration Hospital, Athens, Greece). The successful repair of aortic coarctation was confirmed by continuous Doppler gradient at the descending aorta <25 mm Hg, the presence of palpable femoral pulses and the absence of radiofemoral delay. Exclusion criteria were use of lipid-lowering drugs during the past 6 months, uncontrolled hypertension, any acute or chronic inflammatory disease or cancer, hepatic dysfunction (alanine aminotransferase level more than twice the upper limit of the normal range), renal dysfunction (creatinine >2 mg/dl), a creatine kinase level more than three times the upper limit of the normal range, hypothyroidism, use of corticosteroids, immunosuppressant agents or anti-inflammatory drugs and alcohol abuse. No patient had any other cardiovascular malformations or Turner syndrome. Patients' demographic characteristics are presented in table 1.

    View this table:
    Table 1

    Population characteristics

    Study design

    At the baseline visit, all participants underwent endothelial function assessment in the right forearm and blood samples were obtained. Then the patients were allocated into two groups: group A (n=17) received atorvastatin 10 mg/day for 4 weeks while group B (n=17) received no treatment and served as the control group of the study. After 4 weeks all participants again underwent endothelial function assessment and blood sampling. During the treatment period, all patients were monitored for side effects of statin treatment (elevation of liver enzymes, myalgias and/or rhabdomyolysis), but none of the participants required reduction or termination of the drug use for any of these reasons. The patients' compliance with treatment was monitored by counting the remaining treatment tablets at 4 weeks. No patients dropped out during the study period. The study was approved by the institutional ethics committee of Hippokration Hospital and written consent was given by each subject.

    Endothelial function assessment

    We evaluated flow-mediated dilatation (FMD) of postischaemic hyperaemia in the right forearm, which is a widely used index of endothelial function and NO bioavailability in human forearm circulation. Briefly, all measurements were performed in the morning in a dark quiet room at a constant temperature of 22–25°C. All subjects abstained from alcohol for 24 h and from food, tobacco and caffeine-containing drinks for at least 12 h before each vascular study. Before measurements were started, subjects rested in a supine position for 30 min. The brachial artery diameter was recorded at baseline and 60 s after a 5 min forearm blood flow occlusion. FMD was determined as the percentage change of brachial artery diameter from baseline. All measurements were performed by a single, appropriately trained and experienced investigator.

    Biochemical determinations

    Venous blood samples were obtained at the start of each protocol. After centrifugation at 3500 rpm, at 4°C for 10 min, plasma or serum was collected and stored at −80°C until assayed. Total cholesterol, low density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol serum concentrations were determined by a routine biochemical method. C-reactive protein levels were determined by immunonephelometry (N high sensitivity CRP; Dade Behring, Germany). Serum levels of interleukin (IL)-1b, IL-6 and soluble vascular cell adhesion molecule (sVCAM)-1 were determined by ELISA (R&D Systems, Wiesbaden-Nordenstadt, Germany). The selection of proinflammatory molecules was based on our past observation that serum levels of IL-6, IL-1b and sVCAM-1 are increased in young patients with SCR.4

    Statistical analysis

    All variables were tested for normal distribution using the Kolmogorov–Smirnov test. For comparisons of normally distributed, continuous variables between groups an independent samples t test was used. Categorical variables were compared using χ2, where appropriate. For comparison of non-normally distributed variables between groups, the Mann–Whitney U test was used. The effect of treatment on non-normally distributed variables was examined using Wilcoxon matched-pair signed-rank test. All analyses were carried out by using the SPSS V.15.0 statistical package (SPSS Inc).

    Results

    Effects of treatment on cholesterol levels

    As expected, total cholesterol and LDL levels were significantly reduced in the atorvastatin group after 4 weeks of treatment, while there was also a small but significant increase in HDL levels. In the control group there were no significant changes in plasma lipid levels (table 1).

    Effects of treatment on endothelial function

    In the control group no change was seen in endothelial function, as assessed by FMD. However, atorvastatin 10 mg/day for 4 weeks induced a significant improvement in FMD (figure 1), suggesting improved endothelium-dependent vasodilatation and NO bioavailability in the forearm of these patients. Importantly this improvement was irrespective of LDL lowering. In bivariate analysis the change induced by atorvastatin in FMD was not correlated with the changes in LDL cholesterol (p=NS). Furthermore, the change in FMD was not associated with age at operation, systolic blood pressure, diastolic blood pressure or pulse pressure levels at baseline (p=NS for all).

    Figure 1
    Figure 1

    Effects of atorvastatin on endothelial function. Atorvastatin significantly improved flow-mediated dilatation (FMD) of the brachial artery in patients with successfully repaired coarctation of aorta. There was no change in FMD in the control group (p=NS). The percentage change of FMD from baseline in the atorvastatin group (by +185.1±85.7%) was significantly (p<0.05) greater from that in the control group (by +7.1±5.7%). Values are presented as mean±SEM; *p<0.01 versus before treatment.

    Effects of treatment on systemic inflammatory status

    We next examined the effects of treatment on circulating levels of proinflammatory cytokines. There was no significant change of serum IL-6 levels in any of the two groups (figure 2, panel A). Notably however, there was a significant reduction of serum IL-1b in the atorvastatin-treated group, while no change of IL-1b serum levels was seen in the control group (figure 2, panel B). Moreover, a significant reduction of sVCAM-1 was observed in the atorvastatin-treated group, but not in the control group (figure 2, panel C). Age at operation was not associated with baseline circulating proinflammatory cytokines levels or their respective changes after treatment.

    Figure 2
    Figure 2

    Effects of atorvastatin on systemic inflammatory status. Even though there was no significant change of serum interleukin (IL)-6 levels in any of the two groups (A), atorvastatin treatment for 4 weeks significantly reduced circulating levels of serum IL-1b (B) and soluble vascular cell adhesion molecule (sVCAM)-1 (C). There was no change in serum levels of IL-1b and sVCAM-1 in the control group; atorvastatin-induced reductions of IL-1b (by −28.0±49.9%) and sVCAM-1 (by −5.6±6.7%) were significantly greater than the respective changes in the control group (IL-1b: +18.1±16.3%, p<0.01 vs atorvastatin and sVCAM-1: +4.6±5.6%, p<0.05 vs atorvastatin). There was no difference in the change of IL-6 levels from baseline between the two groups (atorvastatin group: +11.5±5.6%, control group: +18.1±16.3%, p= NS). Values in the figures are presented as median (25th to 75th centile); *p<0.05 versus before treatment.

    Overall we demonstrated for the first time in patients with SCR that atorvastatin (10 mg/day) for 4 weeks has favourable effects on both endothelial function and low-grade systemic inflammation.

    Discussion

    It is well established that patients with SCR are at increased risk of cardiovascular events, with endothelial dysfunction and atherosclerosis being developed early in life.3 Given the adverse clinical outcome of these patients, new therapeutic strategies aiming at reducing global cardiovascular risk should be investigated. In this study we examined whether patients with SCR could benefit from treatment with statins. We demonstrated for the first time that atorvastatin treatment reversed endothelial dysfunction and decreased circulating levels of proinflammatory cytokines (IL-1b) and adhesion molecules (sVCAM-1) in subjects with SCR.

    Effects of atorvastatin on endothelial function in subjects with SCR

    We4 and others5 have consistently shown that even after SCR, persistent endothelial dysfunction can be documented in these patients, which is an independent predictor of cardiovascular events.13 Arterial NO bioavailability is significantly reduced in subjects with SCR compared with healthy individuals.4 5 Furthermore, clinical data support the presence of endothelial and also global vascular dysfunction in the upper body of these subjects.4 14

    The mechanisms responsible for the persisting vascular dysfunction after SCR have not been fully elucidated yet. Aortic coarctation is related to structural changes of coronary vessel wall, mainly smooth muscle cell degeneration and collagenous transformation.15 Experimental aortic coarctation in animals leads to endothelial dysfunction in the coronary arteries, associated with intimal and medial thickening, malalignment of endothelial cells, disruption of the internal elastic lamina and increase in the number of smooth muscle cells in the media.16 Whether these structural vascular changes subside after coarctation repair in humans is still unclear. Importantly, the age at operation and left ventricular mass are strongly associated with the degree of postoperative vascular dysfunction.6 17

    Relapse of hypertension, due to an interplay of factors such as residual coarctaction at the site of surgery, arch morphology, structural changes of upper part body vessels and altered baroreceptor function,18 19 is another important factor leading to endothelial dysfunction. However, accumulating evidence suggests that hypertension may not be the cause but rather the result of vascular dysfunction,4 5 since the latter may long precede hypertension development. This hypothesis is supported by previous studies from our group4 and others,5 highlighting that many years after SCR normotensive patients exhibit persistent global vascular dysfunction. Increased renin–angiotensin system activity may have a role in endothelial dysfunction of these patients.20 As we have demonstrated, blockade of the renin–angiotensin system by ramipril (5 mg/day) for 4 weeks results in a significant improvement of endothelial function and systemic inflammatory status in normotensive subjects with SCR.21

    Statins are widely used in the primary and secondary prevention of cardiovascular disease and have overall beneficial vascular effects. Statins upregulate endothelial nitric oxide synthase (eNOS) expression and prolong eNOS mRNA half-life, therefore increasing NO production.9 In experimental studies, atorvastatin improved eNOS coupling by increasing the bioavailability of the critical eNOS cofactor tetrahydrobiopterin (BH4).22 In addition, atorvastatin rapidly improves the redox state of saphenous vein grafts by inhibiting Rac1 and NADPH-oxidase activity, which is a significant source of superoxide radicals in the vascular wall.12 Therefore both by increasing eNOS activity and preventing BH4 oxidation, statins ameliorate net NO vascular bioavailability.9 In clinical studies atorvastatin treatment significantly improves endothelium-dependent vasodilatation in vivo in subjects at high cardiovascular risk.10 11 Reversal of endothelial dysfunction is important since it has been considered as the initial step in atherogenesis. In prospective studies, FMD has been identified as an independent predictor of clinical outcome in patients with cardiovascular disease.13

    In this study we demonstrated that atorvastatin treatment for 4 weeks significantly increased FMD in subjects with SCR, indicating improved NO bioavailability and reversal of endothelial dysfunction, which may be related to the better prognosis of these patients.

    Effects of atorvastatin on inflammatory status in subjects with SCR

    Increased expression of proinflammatory cytokines and adhesion molecules has a strong proatherogenic effect.23 Increased circulating levels of proinflammatory cytokines, such as IL-6, have been independently associated with increased cardiovascular risk.24 As we4 and others25 have shown, subjects with SCR have increased circulating levels of proinflammatory cytokines and the soluble forms of adhesion molecules compared with healthy age- and sex-matched individuals, even in the absence of hypertension or coronary atherosclerosis.4 It has been suggested that the source of these proatherogenic mediators is the dysfunctional vascular wall.25 It has been previously demonstrated that statins downregulate nuclear factor-κ B or activator protein-1 signalling, which are the major redox-sensitive transcriptional pathways responsible for proinflammatory cytokine expression in human endothelium and vascular smooth muscle cells.26 As we have previously demonstrated low-dose atorvastatin treatment (10 mg/day) in patients at high cardiovascular risk significantly improves systemic inflammatory status.10 11 Furthermore, findings from large clinical studies suggest that statins-induced suppression of low-grade inflammation in healthy8 and high-risk subjects7 is associated with improved clinical outcome.

    In this study we showed that treatment with atorvastatin (10 mg/day) for 4 weeks suppresses low-grade systemic inflammation in patients with SCR, by reducing circulating levels of IL-1b and sVCAM-1.

    In conclusion, in this study we showed for the first time that 4 weeks' treatment with atorvastatin in patients with SCR significantly improves endothelial function and decreases serum levels of proatherogenic inflammatory cytokines (IL-1b) and adhesion molecules (sVCAM-1). Taken together, these new findings suggest that statins treatment in patients with SCR could confer anti-atherogenic and anti-inflammatory effects. Further clinical studies are needed to elucidate whether statins might prevent development of premature atherosclerosis and improve clinical outcome of patients with SCR.

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    Footnotes

    • SB and DT contributed equally to this work.

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval This study was conducted with the approval of the institutional ethics committee of Hippokration Hospital.

    • Provenance and peer review Not commissioned; externally peer reviewed.