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Thromb Haemost 2015; 113(03): 617-624
DOI: 10.1160/TH14-07-0571
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Serum NOX2 and urinary isoprostanes predict vascular events in patients with atrial fibrillation

Pasquale Pignatelli   *
1   I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Umberto I Policlinico of Rome, Italy
,
Daniele Pastori   *
1   I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Umberto I Policlinico of Rome, Italy
,
Roberto Carnevale
1   I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Umberto I Policlinico of Rome, Italy
,
Alessio Farcomeni
3   Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
,
Roberto Cangemi
1   I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Umberto I Policlinico of Rome, Italy
,
Cristina Nocella
1   I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Umberto I Policlinico of Rome, Italy
,
Simona Bartimoccia
1   I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Umberto I Policlinico of Rome, Italy
,
Tommasa Vicario
1   I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Umberto I Policlinico of Rome, Italy
,
Mirella Saliola
1   I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Umberto I Policlinico of Rome, Italy
,
Gregory Y. H. Lip   **
2   University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK
,
Francesco Violi   **
1   I Clinica Medica, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Umberto I Policlinico of Rome, Italy
› Author Affiliations
Further Information

Publication History

Received: 24 July 2014

Accepted after minor revision: 03 October 2014

Publication Date:
29 November 2017 (online)

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Summary

There are limited prospective data evaluating the role of urinary F2-IsoP and NOX2 as predictive markers in atrial fibrillation (AF). The aim of this study was to analyse the role of urinary prostaglandin PGF2alpha (8-iso-PGF2α) and NOX2, markers of systemic oxidative stress, in predicting cardiovascular (CV) events and mortality in anticoagulated non-valvular AF patients. This was a prospective study including 1,002 anticoagulated AF patients, followed for a median time of 25.7 months (interquartile range: 14.8–50.9). All major CV events, CV deaths and all-cause deaths were considered as primary outcomes of the study. CV events included fatal/nonfatal ischaemic stroke, fatal/ nonfatal myocardial infarction (MI), cardiac revascularisation and transient ischaemic attack (TIA). Oxidative stress biomarkers, such as urinary 8-iso-PGF2α and serum sNOX2-dp, a marker of NOX2 activation, were measured. A CV event occurred in 125 patients (12.5 %); 78 CV deaths and 31 non-CV deaths were registered. 8-iso-PGF2α and sNOX2-dp were correlated (Rs=0.765 p> 0.001). A significant increased cumulative incidence of CV events and CV deaths was observed across tertiles for 8-iso-PGF2α and sNOX2-dp. An increased rate of all-cause death was observed across tertiles of urinary 8-iso-PGF2α.In Cox or Fine and Gray models, 8-iso-PGF2α predicted CV events and CV and non-CV deaths. The addition of tertiles of 8-iso-PGF2α to CHA2DS2-VASc score improved ROC curves for each outcome and NRI for CV events (0.24 [0.06–0.53] p=0.0067). The study shows that in AF patients 8-iso-PGF2α and NOX2 levels are predictive of CV events and total mortality. F2-IsoP may complement conventional risk factors in prediction of CV events.

Note: The review process for this manuscript was fully handled by Christian Weber, Editor in Chief. Clinical Trial Registration: ClinicalTrials.gov NCT01882114.

Keywords

Arrhythmia - atrial fibrillation - urinary isoprostanes - NOX2 - cardiovascular events

* equal contribution


** joint senior authors


 

  • References

  • 1 Benjamin EJ, Wolf PA, D’Agostino RB. et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98: 946-952.
    CrossrefPubMedGoogle Scholar
  • 2 Soliman EZ, Safford MM, Muntner P. et al. Atrial fibrillation and the risk of myocardial infarction. J Am Med Assoc Intern Med 2014; 174: 107-114.
    PubMedGoogle Scholar
  • 3 Violi F, Loffredo L. Thromboembolism or atherothromboembolism in atrial fibrillation?. Circulation Arrhythm Electrophysiol 2012; 5: 1053-1055.
    CrossrefPubMedGoogle Scholar
  • 4 Van Wagoner DR. Oxidative stress and inflammation in atrial fibrillation: role in pathogenesis and potential as a therapeutic target. J Cardiovasc Pharmacol 2008; 52: 306-313.
    CrossrefPubMedGoogle Scholar
  • 5 Kim YM, Guzik TJ, Zhang YH. et al. A myocardial Nox2 containing NAD (P)H oxidase contributes to oxidative stress in human atrial fibrillation. Circ Res 2005; 97: 629-636.
    CrossrefPubMedGoogle Scholar
  • 6 Cangemi R, Celestini A, Calvieri C. et al. Different behaviour of NOX2 activation in patients with paroxysmal/persistent or permanent atrial fibrillation. Heart 2012; 98: 1063-1066.
    CrossrefPubMedGoogle Scholar
  • 7 Kvietys PR, Granger DN. Role of reactive oxygen and nitrogen species in the vascular responses to inflammation. Free Rad Biol Med 2012; 52: 556-592.
    CrossrefPubMedGoogle Scholar
  • 8 Sigala F, Kotsinas A, Savari P. et al. Oxidized LDL in human carotid plaques is related to symptomatic carotid disease and lesion instability. J Vasc Surg 2010; 52: 704-713.
    CrossrefPubMedGoogle Scholar
  • 9 Gorlach A. Redox regulation of the coagulation cascade. Antiox Redox Signal 2005; 7: 1398-1404.
    CrossrefPubMedGoogle Scholar
  • 10 Leopold JA, Loscalzo J. Oxidative risk for atherothrombotic cardiovascular disease. Free Rad Biol Med 2009; 47: 1673-1706.
    CrossrefPubMedGoogle Scholar
  • 11 Herkert O, Gorlach A. Redox control of tissue factor expression in smooth muscle cells and other vascular cells. Meth Enzymol 2002; 352: 220-231.
    PubMedGoogle Scholar
  • 12 Golino P, Ragni M, Cirillo P. et al. Effects of tissue factor induced by oxygen free radicals on coronary flow during reperfusion. Nature Med 1996; 2: 35-40.
    CrossrefPubMedGoogle Scholar
  • 13 Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscl Thromb Vasc Biol 2007; 27: 1687-1693.
    CrossrefPubMedGoogle Scholar
  • 14 Freedman JE. Oxidative stress and platelets. Arterioscl Thromb Vasc Biol 2008; 28: s11-16.
    CrossrefPubMedGoogle Scholar
  • 15 Violi F, Pignatelli P. Platelet NOX a novel target for antithrombotic treatment. Thromb Haemost 2014; 111: 817-823.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Fam SS, Morrow JD. The isoprostanes: unique products of arachidonic acid oxidation-a review. Curr Med Chem 2003; 10: 1723-1740.
    CrossrefPubMedGoogle Scholar
  • 17 Carnevale R, Iuliano L, Nocella C. et al. Relationship Between Platelet and Urinary 8-Iso-PGF2alpha Levels in Subjects With Different Degrees of NOX2 Regulation. J Am Heart Assoc 2013; 2: e000198.
    PubMedGoogle Scholar
  • 18 Violi F, Pignatelli P, Pignata C. et al. Reduced atherosclerotic burden in subjects with genetically determined low oxidative stress. Arterioscl Thromb Vasc Biol 2013; 33: 406-412.
    CrossrefPubMedGoogle Scholar
  • 19 Hummel SL, Seymour EM, Brook RD. et al. Low-sodium dietary approaches to stop hypertension diet reduces blood pressure, arterial stiffness, and oxidative stress in hypertensive heart failure with preserved ejection fraction. Hypertension 2012; 60: 1200-1206.
    CrossrefPubMedGoogle Scholar
  • 20 Loffredo L, Martino F, Carnevale R. et al. Obesity and hypercholesterolemia are associated with NOX2 generated oxidative stress and arterial dysfunction. J Pediatr 2012; 161: 1004-1009.
    CrossrefPubMedGoogle Scholar
  • 21 Davi G, Chiarelli F, Santilli F. et al. Enhanced lipid peroxidation and platelet activation in the early phase of type 1 diabetes mellitus: role of interleukin-6 and disease duration. Circulation 2003; 107: 3199-3203.
    CrossrefPubMedGoogle Scholar
  • 22 Angelico F, Loffredo L, Pignatelli P. et al. Weight loss is associated with improved endothelial dysfunction via NOX2-generated oxidative stress down-regulation in patients with the metabolic syndrome. Int Emerg Med 2012; 7: 219-227.
    CrossrefPubMedGoogle Scholar
  • 23 Loffredo L, Carnevale R, Perri L. et al. NOX2-mediated arterial dysfunction in smokers: acute effect of dark chocolate. Heart 2011; 97: 1776-1781.
    CrossrefPubMedGoogle Scholar
  • 24 LeLeiko RM, Vaccari CS, Sola S. et al. Usefulness of elevations in serum choline and free F2)-isoprostane to predict 30-day cardiovascular outcomes in patients with acute coronary syndrome. Am J Cardiol 2009; 104: 638-643.
    CrossrefPubMedGoogle Scholar
  • 25 Woodward M, Croft KD, Mori TA. et al. Association between both lipid and protein oxidation and the risk of fatal or non-fatal coronary heart disease in a human population. Clin Sci 2009; 116: 53-60.
    CrossrefPubMedGoogle Scholar
  • 26 Gage BF, Waterman AD, Shannon W. et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. J Am Med Assoc 2001; 285: 2864-2870.
    CrossrefPubMedGoogle Scholar
  • 27 European Heart Rhythm A. European Association for Cardio-Thoracic S Camm AJ et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369-2429.
    CrossrefPubMedGoogle Scholar
  • 28 Mancia G, De Backer G, Dominiczak A. et al. 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007; 28: 1462-1536.
    PubMedGoogle Scholar
  • 29 Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic Med 1998; 15: 539-553.
    CrossrefPubMedGoogle Scholar
  • 30 Dickstein K, Cohen-Solal A, Filippatos G. et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008; 29: 2388-2442.
    CrossrefPubMedGoogle Scholar
  • 31 Thygesen K, Alpert JS, White HD. et al. Universal definition of myocardial infarction. Circulation 2007; 116: 2634-2653.
    CrossrefPubMedGoogle Scholar
  • 32 Special report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III. Stroke 1990; 21: 637-676.
    CrossrefPubMedGoogle Scholar
  • 33 World Medical A. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Bull WHO 2001; 79: 373-374.
    PubMedGoogle Scholar
  • 34 Pignatelli P, Carnevale R, Cangemi R. et al. Atorvastatin inhibits gp91phox circulating levels in patients with hypercholesterolemia. Arterioscl Thromb Vasc Biol 2010; 30: 360-367.
    CrossrefPubMedGoogle Scholar
  • 35 Pencina MJ, D‘Agostino RB, Pencina KM. et al. Interpreting incremental value of markers added to risk prediction models. Am J Epidemiol 2012; 176: 473-481.
    CrossrefPubMedGoogle Scholar
  • 36 French B, Saha-Chaudhuri P, Ky B. et al. Development and evaluation of multi-marker risk scores for clinical prognosis. Stat Methods Med Res. 2012 Epub ahead of print.
    PubMedGoogle Scholar
  • 37 Davies SS, Roberts 2 LJ. F2-isoprostanes as an indicator and risk factor for coronary heart disease. Free Rad Biol Med 2011; 50: 559-566.
    CrossrefPubMedGoogle Scholar
  • 38 Puccetti L, Santilli F, Pasqui AL. et al. Effects of atorvastatin and rosuvastatin on thromboxane-dependent platelet activation and oxidative stress in hypercholesterolemia. Atherosclerosis 2011; 214: 122-128.
    CrossrefPubMedGoogle Scholar
  • 39 Shishehbor MH, Zhang R, Medina H. et al. Systemic elevations of free radical oxidation products of arachidonic acid are associated with angiographic evidence of coronary artery disease. Free Rad Biol Med 2006; 41: 1678-1683.
    CrossrefPubMedGoogle Scholar
  • 40 Wang B, Pan J, Wang L. et al. Associations of plasma 8-isoprostane levels with the presence and extent of coronary stenosis in patients with coronary artery disease. Atherosclerosis 2006; 184: 425-430.
    CrossrefPubMedGoogle Scholar
  • 41 Kim JY, Hyun YJ, Jang Y. et al. Lipoprotein-associated phospholipase A2 activity is associated with coronary artery disease and markers of oxidative stress: a case-control study. Am J Clin Nutr 2008; 88: 630-637.
    CrossrefPubMedGoogle Scholar
  • 42 Violi F, Sanguigni V, Carnevale R. et al. Hereditary deficiency of gp91 (phox) is associated with enhanced arterial dilatation: results of a multicentre study. Circulation 2009; 120: 1616-1622.
    CrossrefPubMedGoogle Scholar
  • 43 Violi F, Sanguigni V, Loffredo L. et al. Nox2 is determinant for ischaemia-induced oxidative stress and arterial vasodilatation: a pilot study in patients with hereditary Nox2 deficiency. Arterioscl Thromb Vasc Biol 2006; 26: e131-132.
    CrossrefPubMedGoogle Scholar
  • 44 Hirase T, Node K. Endothelial dysfunction as a cellular mechanism for vascular failure. Am J Physiol Heart Circ Physiol 2012; 302: H499-505.
    CrossrefPubMedGoogle Scholar
  • 45 Pignatelli P, Carnevale R, Di Santo S. et al. Inherited human gp91phox deficiency is associated with impaired isoprostane formation and platelet dysfunction. Arterioscl Thromb Vasc Biol 2011; 31: 423-434.
    CrossrefPubMedGoogle Scholar
  • 46 Saha P, Modarai B, Humphries J. et al. The monocyte/macrophage as a therapeutic target in atherosclerosis. Curr Opin Pharmacol 2009; 9: 109-118.
    CrossrefPubMedGoogle Scholar
  • 47 Morrow JD. Quantification of isoprostanes as indices of oxidant stress and the risk of atherosclerosis in humans. Arterioscl Thromb Vasc Biol 2005; 25: 279-286.
    PubMedGoogle Scholar
  • 48 Maghzal GJ, Krause KH, Stocker R. et al. Detection of reactive oxygen species derived from the family of NOX NADPH oxidases. Free Rad Biol Med 2012; 53: 1903-1918.
    CrossrefPubMedGoogle Scholar
  • 49 Ward WF, Qi W, Van Remmen H. et al. Effects of age and caloric restriction on lipid peroxidation: measurement of oxidative stress by F2-isoprostane levels. J Gerontol Series A Biol Sci Med Sci 2005; 60: 847-851.
    CrossrefPubMedGoogle Scholar
  • 50 Montine TJ, Neely MD, Quinn JF. et al. Lipid peroxidation in aging brain and Alzheimer’s disease. Free Rad Biol Med 2002; 33: 620-626.
    CrossrefPubMedGoogle Scholar
  • 51 Reilly SN, Jayaram R, Nahar K. et al. Atrial sources of reactive oxygen species vary with the duration and substrate of atrial fibrillation: implications for the antiarrhythmic effect of statins. Circulation 2011; 124: 1107-1117.
    CrossrefPubMedGoogle Scholar
  • 52 Pignatelli P, Carnevale R, Pastori D. et al. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation 2012; 126: 92-103.
    CrossrefPubMedGoogle Scholar
  • 53 Pignatelli P, Carnevale R, Di Santo S. et al. Rosuvastatin reduces platelet recruitment by inhibiting NADPH oxidase activation. Biochem Pharmacol 2012; 84: 1635-1642.
    CrossrefPubMedGoogle Scholar
  • 54 Bang CN, Gislason GH, Greve AM. et al. Statins reduce new-onset atrial fibrillation in a first-time myocardial infarction population: a nationwide propensity score-matched study. Eur J Prevent Cardiol 2014; 21: 330-338
    PubMedGoogle Scholar