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Table of Contents    
Year : 2019  |  Volume : 67  |  Issue : 4  |  Page : 1013-1014

eNOS: A Passing Fad or the Crux of the Panacea?

Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication10-Sep-2019

Correspondence Address:
Dr. Sivashanmugam Dhandapani
Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.266243

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How to cite this article:
Dhandapani S. eNOS: A Passing Fad or the Crux of the Panacea?. Neurol India 2019;67:1013-4

How to cite this URL:
Dhandapani S. eNOS: A Passing Fad or the Crux of the Panacea?. Neurol India [serial online] 2019 [cited 2021 Jan 27];67:1013-4. Available from:

I congratulate Konar SK, Ramesh S, Christopher R, Prasanthi A, Bhat DI, Shukla D, et al. The correlation of endothelial nitric oxide synthase (eNOS) polymorphism and other risk factors with aneurysmal subarachnoid hemorrhage: A case-control study. Neurol India 2019;67:1006-12.[1]

Nitric oxide (NO), a vascular signaling molecule and immune effector has garnered much attention since 1998 when it was recognized with a Nobel prize in physiology or medicine. Endothelial nitric oxide synthase (eNOS) is one of the three isoforms of the enzyme responsible for the generation of NO in the vascular endothelium. eNOS polymorphisms have been implicated in a wide spectrum of pathology, ranging from vascular disorders such as stroke and aneurysmal subarachnoid hemorrhage (aSAH); lifestyle disease combinations such as metabolic syndrome; immune-inflammatory processes such as systemic lupus erythematosus; and, even multifactorial ailments such as cancer and schizophrenia.[2],[3],[4] The NIMHANS study identifies polymorphisms in the eNOS gene to be similar among patients of aSAH and controls, with 4AA of 24VNTR and CC of T786C polymorphisms having a significant association with Glasgow Outcome Scale. However, the effect of these gene polymorphisms were not independent of other factors. Moreover, TT of G894T polymorphism was most associated with vasospasm.[1]

The molecular substrates responsible for an unfavorable neurological outcome after aSAH, though similar in nature to head injury, have in addition, vasospasm, a condition puzzling not merely in its pathophysiology but also in terminology as well as in its proportional burden on the outcome.[5],[6] We had previously reported on MTHFR polymorphisms and a complex interplay of metabolic aberrations, inflammation and nutritional load in aSAH leading to a 'reverse epidemiology paradox'.[7],[8] Many parameters in aSAH have been noted in various studies to have a significant association with either of the factors including angiographic vasospasm, delayed cerebral ischemia (DCI), neurological outcome or cognitive deficits, but this association is seldom in congruity.[9],[10],[11] It is still not lucid why there is a disparity between the impact of radiologic and clinical vasospasm on the overall clinical outcome. Unless the prognostic link between a substrate, clinico-radiological phenomena and outcome is complete with coherent reasoning, the association remains controversial.

The role of NO and eNOS polymorphisms in aSAH is as intriguing as its plethora of disease associations.[3],[12],[13] Studies have even shown the T786C polymorphism to be associated with the development of aneurysms,[12] in contrast to the similarity with the control group in the NIMHANS study.[1] While other studies on aSAH have noted a significant association of 4AA of 24VNTR and CC of T786C polymorphisms with DCI and cardiac instability, none have shown an independent association with the neurological outcome.[13] This may probably be due to a combination of the following reasons:First, eNOS polymorphisms may be associated with more serious early brain injury induced by aSAH, thereby decreasing the threshold of vasospasm, leading to a poorer outcome. Second, it may have a role in shared biochemical mechanisms of cytotoxicity common to many other diseases. Third, it may be a mere bystander of the confounding metabolic derangements which worsen outcome after aSAH.

Although the direct causality or specificity of eNOS polymorphisms on the outcome after aSAH is not known, we may still utilize these polymorphisms in clinical practice, by identifying high-risk patients who may benefit from proactive management. Thus, an unfavorable outcome may be preventable. As the pharmacogenetic studies focusing on eNOS polymorphisms have shown promise in predicting the therapeutic response of medications such as statins and phosphodiesterase inhibitors, it is even possible that supportive and definitive management of aneurysms in the future may be tailored according to the eNOS genomics. We need collaboration between neurosurgeons, radiologists, geneticists, epidemiologists, and statisticians to design good multicenter trials to bring out evidence whether eNOS polymorphism is merely a passing fad in the management of aSAH or is the crux of the panacea, the beneficial effects of which may be extending to other diseases as well.

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There are no conflicts of interest.

  References Top

Konar SK, Ramesh S, Christopher R, Prasanthi A, Bhat DI, Shukla D, et al. The correlation of endothelial nitric oxide synthase (eNOS) polymorphism and other risk factors with aneurysmal subarachnoid hemorrhage: A case-control study. Neurol India 2019;67:1006-12.  Back to cited text no. 1
  [Full text]  
Kumar A, Misra S, Kumar P, Prasad K, Pandit AK, Chakravarty K, et al. Association between endothelial nitric oxide synthase gene polymorphisms and risk of ischemic stroke: A meta-analysis. Neurol India 2017;65:22-34.  Back to cited text no. 2
[PUBMED]  [Full text]  
Stepanova EI, Skvarskaia EA. Role of polymorphism NO-synthase gene in the pathogenesis of multifactorial diseases. Lik Sprava 2014;5-6:47-55.  Back to cited text no. 3
Zhang L, Chen LM, Wang MN, Chen XJ, Li N, Huang YD, et al. The G894t, T-786c and 4b/a polymorphisms in Enos gene and cancer risk: A meta-analysis. J Evid Based Med 2014;7:263-9.  Back to cited text no. 4
Aggarwal A, Dhandapani S, Praneeth K, Sodhi HB, Pal SS, Gaudihalli S, et al. Comparative evaluation of H&H and WFNS grading scales with modified H&H (sans systemic disease): A study on 1000 patients with subarachnoid hemorrhage. Neurosurg Rev 2018;41:241-7.  Back to cited text no. 5
Dhandapani SS, Manju D, Vivekanandhan S, Agarwal M, Mahapatra AK. Prospective longitudinal study of biochemical changes in critically ill patients with severe traumatic brain injury: Factors associated and outcome at 6 months. Indian J Neurotrauma 2010;7:23-7.  Back to cited text no. 6
Dhandapani S, Goudihalli S, Mukherjee KK, Singh H, Srinivasan A, Danish M, et al. Prospective study of the correlation between admission plasma homocysteine levels and neurological outcome following subarachnoid hemorrhage: A case for the reverse epidemiology paradox? Acta neurochirurgica 2015;157:399-407.  Back to cited text no. 7
Kumar M, Goudihalli S, Mukherjee K, Dhandapani S, Sandhir R. Methylenetetrahydrofolate reductase C677T variant and hyperhomocysteinemia in subarachnoid hemorrhage patients from India. Metabolic brain disease. 2018 Jun 21. [Epub ahead of print].  Back to cited text no. 8
Dhandapani S, Singh A, Singla N, Praneeth K, Aggarwal A, Sodhi HB, et al. Has Outcome of Subarachnoid Hemorrhage Changed With Improvements in Neurosurgical Services? Study of 2000 Patients Over 2 Decades From India. Stroke 2018;49:2890-5.  Back to cited text no. 9
Kapoor A, Dhandapani S, Gaudihalli S, Dhandapani M, Singh H, Mukherjee KK. Serum albumin level in spontaneous subarachnoid haemorrhage: More than a mere nutritional marker! Br J Neurosurg 2018;32:47-52.  Back to cited text no. 10
Mohanty M, Dhandapani S, Gupta SK, Shahid AH, Patra DP, Sharma A, Mathuriya SN. Cognitive Impairments After Clipping of Ruptured Anterior Circulation Aneurysms. World Neurosurg. 2018 Jun 18. [Epub ahead of print].  Back to cited text no. 11
Paschoal EHA, Yamaki VN, Teixeira RK, Paschoal Junior FM, Jong-A-Liem GS, Teixeira MJ, et al. Relationship between endothelial nitric oxide synthase (eNOS) and natural history of intracranial aneurysms: Meta-analysis. Neurosurg Rev 2018;41:87-94.  Back to cited text no. 12
Rosalind Lai PM, Du R. Role of genetic polymorphisms in predicting delayed cerebral ischemia and radiographic vasospasm after aneurysmal subarachnoid hemorrhage: A meta-analysis. World Neurosurg 2015;84:933-41.  Back to cited text no. 13


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