Asymmetric dimethylarginine and vascular indices of atherosclerosis in patients after coarctation of aorta repair

https://doi.org/10.1016/j.ijcard.2011.01.037Get rights and content

Abstract

Objective

Cardiovascular events are the main cause of premature death after successful repair of aortic coarctation (CoA). The aim of this study was to assess the selected biochemical markers of atherosclerosis in normotensive CoA repaired patients and to establish its relation to ultrasound indexes of vascular pathology.

Methods

62 patients after CoA repair (37 males, age: 34.1 ± 1.4 yrs) and 20 control individuals (10 males, age: 34.8 ± 2.2 yrs) were enrolled in the study. The serum markers: asymmetric dimethylarginine (ADMA), nitrites/nitrates (NOx), high-sensitivity C-reactive protein (hsCRP), and following vascular parameters: flow-mediated dilatation (FMD), intima-media thickness (IMT) and pulse wave velocity (PWV) were analyzed.

Results

33 CoA repaired patients were normotensive, and compared to controls, they presented higher serum ADMA concentrations (0.59 ± 0.04 umol/l vs. 0.46 ± 0.03 umol/l, p = 0.035). An analysis of the vascular parameters revealed decreased FMD (4.75 ± 0.5%), NMD (11.86 ± 0.8%) and increased PWV (6.90 ± 0.2 m/s) values in the normotensive patients as compared with the control group (FMD: 8.6 ± 0.9%, p < 0.001, NMD: 20.94 ± 1.7%, p < 0.001; PWV: 5.49 ± 0.2, p = 0.023). There were no differences in the serum levels of NOx, hsCRP as well as IMT values between normotensive patients and the control group. A multivariate regression analysis revealed that serum ADMA level was a factor independently associated with the FMD value (r = −0.334; p = 0.031) in normotensive CoA repaired group.

Conclusions

Early biochemical and vascular indices of atherosclerosis such as increased serum ADMA concentration as well as impaired vasodilatation and increased arterial stiffness are observed in patients after CoA repair. Serum ADMA is a strong predictor of endothelial dysfunction in patients with CoA repair.

Introduction

Regardless of a successful repair of aortic coarctation (CoA), life expectancy remains reduced in post-repair CoA patients [1]. The most common cause of premature death in this group is myocardial infarction, which is a problem even in young subjects [2]. It is well established that 30–50% of CoA repaired patients exhibit arterial hypertension (AH)[3], [4], which leads to widespread atherosclerosis [2], [5], [6], [7]. However, recently published data suggests early functional and structural atherosclerotic changes even in normotensive patients after CoA repair [8], [9], [10], [11]. In the CoA repaired population impaired endothelium-dependent arterial relaxation as well as increased arterial stiffness and thickening of the intima-media complex were found [8], [9], [10], [11]. The reason for the vascular abnormalities are probably the pathological changes in the precoartaction arteries.

Regardless of the fact that atherosclerosis is an inflammatory disease [12], there are limited data on the role of inflammation in the aforementioned atherosclerotic remodeling in patients after CoA. Isolated papers concerning small groups of patients reported higher serum levels of cytokines and adhesion molecules [13]. Taking into account a crucial role of oxidative stress in the induction of inflammation, it seemed interesting to assess the levels of asymmetric dimethylarginine (ADMA; an endogenous competitive inhibitor of NO synthase) and nitric oxide (NO) in relation to standard inflammation markers such as high-sensitivity C-reactive protein (hsCRP) and vascular indexes in CoA-repaired subjects. Although, it is well known that ADMA concentrations are increased and NO bioavailability is decreased in subjects with atherosclerosis [14], we have not found any study concerning assessment of ADMA nor NO in patients after CoA surgical correction. Moreover, ADMA may have a causative role in atherogenesis and constitutes one of the strongest risk predictors of cardiovascular events [15], [16]. Recognition of these processes is of great clinical importance and having knowledge of this topic may improve the prognosis for CoA-repaired patients.

Thus the aim of the presented study was to assess the role of selected biochemical markers of atherosclerosis: ADMA, nitrite/nitrate (NOx) — a stable end product of NO, and hsCRP in the development of early functional and structural atherosclerotic vascular pathology in patients after CoA repair.

Section snippets

Patients and method

Sixty two patients after CoA repair (37 males) aged 19–64 years (mean age: 34.1 ± 1.4 years) who had undergone an operation at the age of 0.5 to 34 years (11.1 ± 1.1 years) were enrolled in the study. All of them were attending our adult congenital heart disease outpatient clinic. Only the normotensive subjects after CoA repair (group CoA-AH(−): n = 33, 17 males, mean age: 33.9 ± 1.6 years) were involved in the analysis. The control group (group C) consisted of 20 healthy individuals (10 males) aged 24–48 

Clinical characteristic

Clinical characteristic of the examined groups is presented in Table 1. The group CoA-AH(−) and the group C were compared as to the age, weight, height, serum glucose and lipids’ levels. Mean value of DBP was significantly higher in the CoA-AH(−) group. Mean heart rate (HR) was comparable between the groups.

Serum concentrations of ADMA, NOx, hsCRP

The serum level of ADMA in the CoA-AH() group (0.59 ± 0.04) was higher as compared with group C (0.46 ± 0.03 umol/l; p = 0.035) (Fig. 1). No significant differences were found between those groups

Discussion

In the study presented above, we have focused on the problem whether biochemical markers of atherosclerosis may provide any new information for the vascular parameters and the mechanism of vascular abnormalities in patients after CoA repair. In order to distinguish “pure” CoA-related abnormalities from hypertension-induced vascular remodeling we have analyzed the normotensive patients only.

The results indicate the novel aspects of the vascular pathology observed in patients after CoA repair.

Acknowledgement

The authors of this manuscript have certified that they comply with the Principles of the Ethical Publishing in the International Journal of Cardiology [41].

References (41)

  • D.A. Celermajer et al.

    Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis

    Lancet

    (1992)
  • J.J. Bobby et al.

    Operative survival and 40 year follow up surgical repair of aortic coarctation

    Br Heart J

    (1991)
  • M. Cohen et al.

    McGoon DC. Coarctation of the aorta. Long term follow-up and prediction of outcome after surgical correction

    Circulation

    (1989)
  • J.J. O'Sullivan et al.

    Prevalence of hypertension in children after early repair of coarctation of the aorta: a cohort study using casual and 24 hour blood pressure measurement

    Heart

    (2002)
  • A.F. Corno et al.

    Surgery for aortic coarctation: a 30 years experience

    Eur J Cardiothorac Surg

    (2001)
  • O.H. Toro-Salazar et al.

    Long-term follow-up of patients after coarctation of the aorta repair

    Am J Cardiol

    (2002)
  • D.S. Celermajer et al.

    Survivors of coarctation repair: fixed but not cured

    Heart

    (2002)
  • A.A. Meyer et al.

    Predicting the risk of early atherosclerotic disease development in children after repair of aortic coarctation

    Eur Heart J

    (2005)
  • S. Brilli et al.

    Aortic elastic properties in patients with repaired coarctation of aorta

    Am J Cardiol

    (1998)
  • R. Ross

    Atherosclerosis: an inflammatory disease

    N Engl J Med

    (1999)
  • Cited by (13)

    • Arterial stiffness and pulsatile hemodynamics in congenital heart disease

      2022, Textbook of Arterial Stiffness and Pulsatile Hemodynamics in Health and Disease
    • Low plasma renalase concentration in hypertensive patients after surgical repair of coarctation of aorta

      2014, Journal of the American Society of Hypertension
      Citation Excerpt :

      The cornerstone of coarctation of aorta consists in a systemic vasculopathy, not only related with the narrowing of the aortic isthmus itself but also related with widespread remodeling of arterial vascular bed.3 Large body of evidence suggests that complex cytokine interactions, involving members of transforming growth factor beta (TGF-β) superfamily,4 lead to profibrotic and antiapoptotic propensity inside the arterial wall, which, in turn, results in stiffening of arteries3,5–8 in addition to endothelial5 and baroreceptor dysfunction.9 The effect of long-term renal ischemia in coarctation of aorta on patients' health status after successful repair is poorly recognized.

    • Aortic stiffness and left ventricular diastolic function in children following early repair of aortic coarctation

      2013, American Journal of Cardiology
      Citation Excerpt :

      In young patients with repaired CoA, bicuspid aortic valves, or Marfan syndrome, increased aortic stiffness is thought to be due to primarily abnormal aortic wall structure.1,2,21 However, chronic inflammation and endothelial dysfunction appear to play a role as well in patients with repaired CoA.18,22,23 With increased vascular stiffness, the PW velocity is increased and, thus, the reflected wave returns to the heart early (i.e., in late systole).

    View all citing articles on Scopus
    View full text