- Email: [email protected]
Adropin levels and target organ damage secondary to high blood pressure in the ED
YAJEM-55737; No of Pages 4 American Journal of Emergency Medicine xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
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Article history: Received 7 March 2016 Received in revised form 8 April 2016 Accepted 10 April 2016 Available online xxxx
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Bedia Gulen, MD a,⁎, Cenker Eken, MD b, Okkes Taha Kucukdagli, MD c, Mustafa Serinken, MD d, Abdurrahim Kocyigit, MD e, Elif Kılıc, MD e, Hüseyin Uyarel, MD f Bezmialem Vakif University, Department of Emergency Medicine, Istanbul, Turkey Akdeniz University, Department of EmergencyMedicine, Antalya, Turkey Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey d Pamukkale University, Department of Emergency Medicine, Denizli, Turkey e Bezmialem Vakif University, Department of Biochemistry, Istanbul, Turkey f Bezmialem Vakif University, Department of Cardiology, Istanbul, Turkey b
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Adropin levels and target organ damage secondary to high blood pressure in the ED
a b s t r a c t
Background: High blood pressure is still a challenge for emergency physicians to discern the patients that require further analysis to establish the existence of acute hypertensive target organ damage (TOD). The present study aimed to reveal that adropin levels are useful for detecting TOD in patients presenting with high blood pressure. Methods: Patients presenting with a blood pressure of more than 180/110 mm Hg were enrolled into the study. After a resting period of 15 minutes, patients' blood pressures were measured thrice at 5-minute intervals while the patients were sitting on a chair, and the average of these measurements was accepted as the baseline value. Blood samples were obtained for either adropin levels or possible TOD during the emergency department admission. Results: A total of 119 patients were included in the study. The mean systolic and diastolic blood pressures of study patients were 204.8 ±23.2 and 108.3 ± 10.3, respectively, and 42% (n = 50) of the patients had TOD. Although the adropin levels were similar between the patients with or without TOD (TOD group = 195 pg/mL, interquartile range [IQR]: 178-201; no-TOD group = 196 pg/mL, IQR: 176-204 [P = .982]), it is significantly higher in normotensive patients (normotensive group = 289 pg/mL, IQR: 193-403) compared with the hypertensive ones (P b .001). Conclusions: Despite the significantly higher levels of adropin in normotensive patients compared with hypertensive ones, adropin could not be used as a decision tool for detecting TOD in patients presenting with high blood pressure to the emergency department. © 2016 Published by Elsevier Inc.
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1. Introduction
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Hypertension (HT) is the most important risk factor for cardiovascular diseases and ranks fourth among the most frequently seen medical conditions. Nearly 75% of the US hypertensive population cannot maintain their blood pressures at 140/90 mm Hg, and consequently, many patients present to the emergency department (ED) because of high blood pressure. The scariest complication of hypertension is hypertensive emergency, which is defined as large elevations in systolic or diastolic blood pressure (N 180 or N120 mm Hg, respectively) associated with impending or progressive OD, such as major neurological changes, hypertensive encephalopathy, cerebral infarction, intracranial
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⁎ Corresponding author. E-mail addresses: [email protected] (B. Gulen), [email protected] (C. Eken), [email protected] (O.T. Kucukdagli), [email protected] (M. Serinken), [email protected] (A. Kocyigit), [email protected] (E. Kılıc).
hemorrhage, acute left ventricular failure, acute pulmonary edema, aortic dissection, renal failure, or eclampsia [1]. (See Figure.) Adropin was discovered by Kumar and colleagues. Adropin has various effects such as metabolic homeostasis and has been shown to be released in many tissues in rats [2]. Adropin is also released by vascular endothelial cells and plays a role in the neovascularization via activation of vascular endothelial growth factor 2 and endothelial nitric oxide synthase. One study demonstrated that adropin had an endothelial protective effect via upregulation of endothelial nitric oxide synthase expression [3]. In recent years, the association between adropin and endothelial dysfunction has been reported, and there is also growing evidence that adropin is a potential regulator of cardiovascular functions and plays a protective role in the pathogenesis and development of cardiovascular disease [2]. Decreased levels of plasma adropin are related to high blood pressure [3]. Although a drop in plasma adropin levels has been determined in patients with HT, its role in the detection of target organ damage
http://dx.doi.org/10.1016/j.ajem.2016.04.014 0735-6757/© 2016 Published by Elsevier Inc.
Please cite this article as: Gulen B, et al, Adropin levels and target organ damage secondary to high blood pressure in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2016.04.014
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
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computed tomography, magnetic resonance imaging, electrocardiography, renal function tests, and measurement of cardiac markers. An ophthalmologist examined and evaluated ocular fundus of each study participant.
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2.4. Sample collection and measurement of adropin levels
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Blood samples were collected in tubes containing heparin by cardiac puncture. Plasma samples were removed by centrifugation for 10 minutes at 3000 rpm. The samples were maintained at − 80°C until analysis. Samples were thawed, and Adropin ELISA kit (Sunred Biotechnology Company, Shangai) was used for the quantitative measurement of adropin in serum samples. Samples and standards were added to appropriate wells, which were precoated with anti-human monoclonal antibody before incubation. Biotin was added to all wells and combined with streptavidin–horseradish peroxidase to form immune complex; incubation was carried out again, and then cells were washed to remove the uncombined enzyme. Chromogen solutions A and B were added for the color of the liquid changes into the blue. Finally added stop solution was changed of the color becomes yellow. Optical density was read on a standard automated plate reader at 450 nm (ThermoScientific Microplate Reader). The detection range of the kit was between 5 and 1000 pg/mL.
107 108
2.5. Outcome
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Figure. TOD of the relation between serum adropin levels and blood pressure.
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2. Materials and methods
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2.1. Study setting
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This prospective cross-sectional study was performed in the ED of Bezmialem Foundation University Hospital between March 2015 and August 2015. The local ethical committee approved the study. Inform consent was obtained from each study patient.
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2.2. Patients and methods
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This study enrolled patients whose blood pressures were ≥ 180/ 110 mm Hg at their presentations to the ED. The control group consisted of healthy relatives of the patients who consulted to the ED. Individuals who were under drug therapy for any other indication (including oral contraceptives) and those with a history of smoking or substance use were not included in the control group. The patient group was classified based on the presence of a TOD. Patients younger than 18 years; those who are pregnant; and those with a previously known renal disease, heart failure or stroke, malignant disease, hepatic dysfunction, hematologic disease, or acute and chronic infection were excluded from the study. TOD was defined as acute heart failure, acute pulmonary edema, cerebrovascular events (ischemic, hemorrhagic, or transient ischemic attack), hypertensive encephalopathy, aortic dissection, grade 3-4 retinopathy, or acute renal failure by mainly referring to the 2013 European Society of Hypertension/European Society of Cardiology guidelines. The presence of high blood pressure accompanying an acute coronary syndrome (myocardial infarction [MI] with or without ST elevation) was also accepted as TOD.
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2.3. Measurement of blood pressure
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Blood pressures of the patients were measured in the ED from the right arm using a mercury sphygmomanometer. After a resting period of 15 minutes, patients' blood pressures were measured thrice at 5minute intervals by a nurse while the patients were sitting on a chair, and the average of these measurements was accepted as the baseline value. However, only the initial blood pressure value was used for STelevation MI patients. The presence of a TOD was checked with
83 84 85 86 87 88 89 90 91 92
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The primary outcome was the TOD detected in the ED. The secondary outcome was the adverse outcome such as death, MI, stroke, or aortic dissection that occurred at the end of 30 days. The data on the adverse outcome of the study patients were obtained by telephone follow-up.
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(TOD) is not known. The present study aimed to investigate the relation between adropin levels and TOD secondary to high blood pressure in the ED.
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Abbreviations: TOD: target organ disease
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2.6. Statistical analysis
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The study data were analyzed in MedCalc and SPSS software. The numeric variables were presented as mean ± standard deviation or median (interquartile range [IQR]); and categorical data, as percentages. Two-independent-groups comparison was performed by Mann-Whitney U test, and Kolmogorov-Smirnov test was used for normality analysis. Three-independent-groups comparison was carried out by Kruskal-Wallis test, and Bonferroni correction was used for post hoc analysis. Logistic regression analysis was performed to reveal the independent variables that predict the adverse outcome in the study patients. Spearman correlation coefficient was used for detecting the correlation between adropin levels and blood pressure of study patients (excluding the healthy controls). All hypotheses were constructed as 2 tailed, and an α critical value of .05 was accepted as significant.
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3. Results
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A total of 119 patients were included in the study. The mean age of study subjects was 62.8 ± 13.3 years, and 45.4% (n = 54) of them were male. The mean systolic and diastolic blood pressures of study patients were 204.8 ± 23.2 and 108.3 ± 10.3, respectively, and 42% (n = 50) of patients had TOD. The most common TODs were stroke in 17 (14.2%) patients, MI in 12 (10.1%) patients, and retinopathy in 11 (9.2%) patients. The baseline features of study patients are displayed in Table. Thirty-nine (32.8%) patients were admitted to the hospital, whereas 80 (67.2%) were discharged from the ED. Sixty-six of 69 patients without TOD were discharged from ED, and 65 of them were reached by telephone follow-up at the end of 30 days. The mean systolic and diastolic blood pressures of patients without TOD during the discharge were 146 ± 13 and 81 ± 6 mm Hg, respectively. Three patients had adverse outcomes, 2 deaths and 1 MI, among these 65 patients. There
145 146
Please cite this article as: Gulen B, et al, Adropin levels and target organ damage secondary to high blood pressure in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2016.04.014
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Table Baseline characteristics of the 119 patients Characteristics
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Age (mean ± SD) Male sex, n (%) Baseline systolic blood pressure (mm Hg) (mean ± SD) • TOD group • No-TOD group Baseline diastolic blood pressure (mm Hg) (mean ± SD) • TOD group • No-TOD group Target organ disease, n (%) • Stroke • MI • Retinopathy • Cardiac failure • Acute renal failure • Stroke and retinopathy • No TOD ED treatment, n (%) • ACE inhibitor (1) • Calcium channel blocker (2) • Nitroglycerin (3) • Furosemide (4) • Combination therapy (1 and 2) • Combination therapy (1 and 3) • Combination therapy ((3 and 4) • Combination therapy (1, 2, and 3) • Combination therapy (1, 2, 3, 4) Comorbid disease, n (%) • Diabetes mellitus • Hyperlipidemia • Smoking
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ACE, angiotensin-converting enzyme.
62.8 ± 13.3 54 (45.4) 204.8 ± 23.2 208 ± 19 202 ± 25 108.3 ± 10.3 108 ± 10 108 ± 10 16 (13.4) 12 (10.1) 11 (9.2) 9 (7.6) 1 (0.8) 1 (0.8) 69 (58) 33 (27.7) 2 (1.7) 39 (32.8) 0 (0) 12 (10.1) 13 (10.9) 1 (0.8) 7 (5.9) 12 (10.1) 44 (37) 57 (47.9) 31 (26.1)
5. Study limitations
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Our study has been performed with a small number of patients and in a single center. Further studies should be conducted with larger group of patients. These studies may not reflect all populations with different ethnicities in the world. Treatment alternatives may be very diverse based on facilities and capabilities of the institutions. Another limitation to this study is that postponing of the blood pressure– lowering therapy might not be correct in patients with possible endorgan damage secondary to hypertension.
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6. Conclusions
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As a conclusion, despite the significantly higher levels of adropin in normotensive patients compared with hypertensive ones, adropin could not be used as a decision tool for detecting TOD in patients presenting with high blood pressure to the ED.
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References
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Hypertensive emergency is defined as the presence of TOD in the presence of remarkably higher blood pressure. In clinical practice, discrimination between hypertensive emergency and urgency carries utmost importance. Indeed, hypertensive emergency is a condition which requires closer patient monitoring and emergency parenteral antihypertensive treatment [4,5]. For these patients, treatment approach in emergency service should be to limit the extent of damage in the presence of TOD or prevent development of TOD [1,6]. A biomarker which will predict TOD before its development in patients who present to the emergency service with remarkably high blood pressure
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levels is not available so far. The data of this study support the assertion that adropin is not associated with target organ disease, but it is directly correlated with blood pressure levels. Pathophysiology of HT is associated with endothelial dysfunction. At first peak of blood pressure, endothelium increases release of endothelial vasodilators (such as nitric oxide) in an attempt to break vascular resistance. However, when HT persists at very high levels, this endothelial compensation mechanism fails, leading to endothelial decompensation. In this condition, blood pressure rises further, and endothelial damage emerges. However, the mechanism leading to acute hypertensive endothelial failure is much more complex and has not been fully understood up to now [7,8]. Various studies have provided evidence supporting the potential role of adropin in the regulation of cardiovascular functions and asserting its protective role in the pathogenesis and development of cardiovascular functions [1,9]. In another study, negative effects of adropin on blood pressure and its regulation by way of its impact on endothelial function have been also reported [8]. Recent studies have demonstrated the presence of a close relationship between lower serum adropin levels, acute MI, and coronary atherosclerosis [10,11]. In our study, we investigated whether adropin has a role in the evaluation of patients who presented to the ED with remarkably high blood pressure and also in the prediction of TOD. Within this context, we investigated whether the adropin levels could discriminate hypertensive emergency and urgency at the early stage of the disease. Adropin levels were similar between hypertensive patients who had TOD and no TOD. However, in consistence with the previous literature, a significant difference was detected between adropin levels in normo- and hypertensive patients. Adropin levels in hypertensive patients were significantly lower when compared with the normotensive group. Endothelial dysfunction not only is related to HT but also is associated with aging, heart and renal failure, preeclampsia, type I and II diabetes mellitus, atherosclerosis, and others. Persistent exposure of intima to higher blood pressure for a long time will cause aging of intima.
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were 7 patients who could not be reached at the end of the 30 days. There were 14 deaths, 9 MIs, and 1 stroke among all the study patients. The adropin levels were similar between the patients with or without TOD (TOD group = 195 pg/mL, IQR: 178-201; no-TOD group = 196 pg/mL, IQR: 176-204 [P = .982]). Although there is no difference between the patients with or without TOD, 3-group comparison including 60 patients without hypertension revealed a significant difference between the normotensive patients and patients with hypertension either with or without TOD (normotensive group = 289 pg/mL, IQR: 193-403; TOD group = 195 pg/mL, IQR: 178-201; no-TOD group = 196 pg/mL, IQR: 176-204 [P b .001]). Post hoc analysis revealed that adropin levels were significantly higher in normotensive patients than the hypertensive patients either with or without TOD. There was no correlation between adropin levels and systolic blood pressure (r = −0.06, P = .45) or diastolic blood pressure (r = −0.07, P = .39). The logistic regression analysis including age, systolic and diastolic blood pressures, body mass index, presence of diabetes, creatinine and troponin levels, adropin, and TOD in the ED as the independent variables and adverse outcome at the end of the 30 days as the dependent variable showed diabetes (odds ratio, 5.2; 95% confidence interval, 1.6-17) and TOD (odds ratio, 24.5; 95% confidence interval, 5-110) in the ED as the independent risk factors.
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[1] Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC 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). J Hypertens 2013;31(7):1281–357. [2] Li L, Xie W, Zheng XL, Yin WD, Tang CK. A novel peptide adropin in cardiovascular diseases. Clin Chim Acta 2016;453:107–13. [3] Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M. Adropin is a novel regulator of endothelial function. Circulation 2010;122(11 Suppl.):S185–92. [4] Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure [the JNC 7 report]. JAMA 2003;289:2560–72. [5] Centers for Disease Control and Prevention. Vital signs: prevalence, treatment, and control of hypertension United States, 1999-2002 and 2005-2008. MMWR Morb Mortal Wkly Rep 2011;60(4):103–8.
Please cite this article as: Gulen B, et al, Adropin levels and target organ damage secondary to high blood pressure in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2016.04.014
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[9] Celik A, Balin M, Kobat MA, Erdem K, Baydas A, Bulut M, et al. Deficiency of anew protein associated with cardiac syndrome X; called adropin. Cardiovasc Ther 2013;31:174–8. [10] Zhao LP, Xu WT, Wang L, You T, Chan SP, Zhao X, et al. Serum adropin level in patients with stable coronary artery disease. Heart Lung Circ 2015;24(10):975–9. [11] Yu HY, Zhao P, Wu MC, Liu J, Yin W. Serum adropin levels are decreased in patients with acute myocardial infarction. Regul Pept 2014;190-191:46–9.
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[6] Van den Born BJ, Beutler JJ, Gaillard CA. Dutch guideline for the management of hypertensive crisis – 2010 revision. Neth J Med 2011;69:248–55. [7] Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet 2000;356(9227):411–7. [8] Gu X, Li H, Zhu X, Gu H, Chen J, Wang L, et al. Inverse correlation between plasma adropin and ET-1 levels in essential hypertension: a cross-sectional study. Medicine (Baltimore) 2015;94(40), e1712.
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Please cite this article as: Gulen B, et al, Adropin levels and target organ damage secondary to high blood pressure in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2016.04.014
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Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
F
6 7 8 9 10 11
a
1 2
a r t i c l e
13 14 15 16 17
Article history: Received 7 March 2016 Received in revised form 8 April 2016 Accepted 10 April 2016 Available online xxxx
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Bedia Gulen, MD a,⁎, Cenker Eken, MD b, Okkes Taha Kucukdagli, MD c, Mustafa Serinken, MD d, Abdurrahim Kocyigit, MD e, Elif Kılıc, MD e, Hüseyin Uyarel, MD f Bezmialem Vakif University, Department of Emergency Medicine, Istanbul, Turkey Akdeniz University, Department of EmergencyMedicine, Antalya, Turkey Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey d Pamukkale University, Department of Emergency Medicine, Denizli, Turkey e Bezmialem Vakif University, Department of Biochemistry, Istanbul, Turkey f Bezmialem Vakif University, Department of Cardiology, Istanbul, Turkey b
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Adropin levels and target organ damage secondary to high blood pressure in the ED
a b s t r a c t
Background: High blood pressure is still a challenge for emergency physicians to discern the patients that require further analysis to establish the existence of acute hypertensive target organ damage (TOD). The present study aimed to reveal that adropin levels are useful for detecting TOD in patients presenting with high blood pressure. Methods: Patients presenting with a blood pressure of more than 180/110 mm Hg were enrolled into the study. After a resting period of 15 minutes, patients' blood pressures were measured thrice at 5-minute intervals while the patients were sitting on a chair, and the average of these measurements was accepted as the baseline value. Blood samples were obtained for either adropin levels or possible TOD during the emergency department admission. Results: A total of 119 patients were included in the study. The mean systolic and diastolic blood pressures of study patients were 204.8 ±23.2 and 108.3 ± 10.3, respectively, and 42% (n = 50) of the patients had TOD. Although the adropin levels were similar between the patients with or without TOD (TOD group = 195 pg/mL, interquartile range [IQR]: 178-201; no-TOD group = 196 pg/mL, IQR: 176-204 [P = .982]), it is significantly higher in normotensive patients (normotensive group = 289 pg/mL, IQR: 193-403) compared with the hypertensive ones (P b .001). Conclusions: Despite the significantly higher levels of adropin in normotensive patients compared with hypertensive ones, adropin could not be used as a decision tool for detecting TOD in patients presenting with high blood pressure to the emergency department. © 2016 Published by Elsevier Inc.
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1. Introduction
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Hypertension (HT) is the most important risk factor for cardiovascular diseases and ranks fourth among the most frequently seen medical conditions. Nearly 75% of the US hypertensive population cannot maintain their blood pressures at 140/90 mm Hg, and consequently, many patients present to the emergency department (ED) because of high blood pressure. The scariest complication of hypertension is hypertensive emergency, which is defined as large elevations in systolic or diastolic blood pressure (N 180 or N120 mm Hg, respectively) associated with impending or progressive OD, such as major neurological changes, hypertensive encephalopathy, cerebral infarction, intracranial
39 40 41 42 43 44 45 46 Q3 47
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⁎ Corresponding author. E-mail addresses: [email protected] (B. Gulen), [email protected] (C. Eken), [email protected] (O.T. Kucukdagli), [email protected] (M. Serinken), [email protected] (A. Kocyigit), [email protected] (E. Kılıc).
hemorrhage, acute left ventricular failure, acute pulmonary edema, aortic dissection, renal failure, or eclampsia [1]. (See Figure.) Adropin was discovered by Kumar and colleagues. Adropin has various effects such as metabolic homeostasis and has been shown to be released in many tissues in rats [2]. Adropin is also released by vascular endothelial cells and plays a role in the neovascularization via activation of vascular endothelial growth factor 2 and endothelial nitric oxide synthase. One study demonstrated that adropin had an endothelial protective effect via upregulation of endothelial nitric oxide synthase expression [3]. In recent years, the association between adropin and endothelial dysfunction has been reported, and there is also growing evidence that adropin is a potential regulator of cardiovascular functions and plays a protective role in the pathogenesis and development of cardiovascular disease [2]. Decreased levels of plasma adropin are related to high blood pressure [3]. Although a drop in plasma adropin levels has been determined in patients with HT, its role in the detection of target organ damage
http://dx.doi.org/10.1016/j.ajem.2016.04.014 0735-6757/© 2016 Published by Elsevier Inc.
Please cite this article as: Gulen B, et al, Adropin levels and target organ damage secondary to high blood pressure in the ED, Am J Emerg Med (2016), http://dx.doi.org/10.1016/j.ajem.2016.04.014
19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
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computed tomography, magnetic resonance imaging, electrocardiography, renal function tests, and measurement of cardiac markers. An ophthalmologist examined and evaluated ocular fundus of each study participant.
102
2.4. Sample collection and measurement of adropin levels
106
Blood samples were collected in tubes containing heparin by cardiac puncture. Plasma samples were removed by centrifugation for 10 minutes at 3000 rpm. The samples were maintained at − 80°C until analysis. Samples were thawed, and Adropin ELISA kit (Sunred Biotechnology Company, Shangai) was used for the quantitative measurement of adropin in serum samples. Samples and standards were added to appropriate wells, which were precoated with anti-human monoclonal antibody before incubation. Biotin was added to all wells and combined with streptavidin–horseradish peroxidase to form immune complex; incubation was carried out again, and then cells were washed to remove the uncombined enzyme. Chromogen solutions A and B were added for the color of the liquid changes into the blue. Finally added stop solution was changed of the color becomes yellow. Optical density was read on a standard automated plate reader at 450 nm (ThermoScientific Microplate Reader). The detection range of the kit was between 5 and 1000 pg/mL.
107 108
2.5. Outcome
124
65
Figure. TOD of the relation between serum adropin levels and blood pressure.
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2. Materials and methods
69
2.1. Study setting
70 71 72 73
This prospective cross-sectional study was performed in the ED of Bezmialem Foundation University Hospital between March 2015 and August 2015. The local ethical committee approved the study. Inform consent was obtained from each study patient.
74
2.2. Patients and methods
75
93
This study enrolled patients whose blood pressures were ≥ 180/ 110 mm Hg at their presentations to the ED. The control group consisted of healthy relatives of the patients who consulted to the ED. Individuals who were under drug therapy for any other indication (including oral contraceptives) and those with a history of smoking or substance use were not included in the control group. The patient group was classified based on the presence of a TOD. Patients younger than 18 years; those who are pregnant; and those with a previously known renal disease, heart failure or stroke, malignant disease, hepatic dysfunction, hematologic disease, or acute and chronic infection were excluded from the study. TOD was defined as acute heart failure, acute pulmonary edema, cerebrovascular events (ischemic, hemorrhagic, or transient ischemic attack), hypertensive encephalopathy, aortic dissection, grade 3-4 retinopathy, or acute renal failure by mainly referring to the 2013 European Society of Hypertension/European Society of Cardiology guidelines. The presence of high blood pressure accompanying an acute coronary syndrome (myocardial infarction [MI] with or without ST elevation) was also accepted as TOD.
94
2.3. Measurement of blood pressure
95 96
Blood pressures of the patients were measured in the ED from the right arm using a mercury sphygmomanometer. After a resting period of 15 minutes, patients' blood pressures were measured thrice at 5minute intervals by a nurse while the patients were sitting on a chair, and the average of these measurements was accepted as the baseline value. However, only the initial blood pressure value was used for STelevation MI patients. The presence of a TOD was checked with
83 84 85 86 87 88 89 90 91 92
97 98 99 100 101
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The primary outcome was the TOD detected in the ED. The secondary outcome was the adverse outcome such as death, MI, stroke, or aortic dissection that occurred at the end of 30 days. The data on the adverse outcome of the study patients were obtained by telephone follow-up.
D
66 67
(TOD) is not known. The present study aimed to investigate the relation between adropin levels and TOD secondary to high blood pressure in the ED.
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Abbreviations: TOD: target organ disease
R O
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103 104 105
109 110 111 112 113 114 115 116 117 118 119 Q5 120 Q6 121 122 123
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2.6. Statistical analysis
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The study data were analyzed in MedCalc and SPSS software. The numeric variables were presented as mean ± standard deviation or median (interquartile range [IQR]); and categorical data, as percentages. Two-independent-groups comparison was performed by Mann-Whitney U test, and Kolmogorov-Smirnov test was used for normality analysis. Three-independent-groups comparison was carried out by Kruskal-Wallis test, and Bonferroni correction was used for post hoc analysis. Logistic regression analysis was performed to reveal the independent variables that predict the adverse outcome in the study patients. Spearman correlation coefficient was used for detecting the correlation between adropin levels and blood pressure of study patients (excluding the healthy controls). All hypotheses were constructed as 2 tailed, and an α critical value of .05 was accepted as significant.
131
3. Results
144
A total of 119 patients were included in the study. The mean age of study subjects was 62.8 ± 13.3 years, and 45.4% (n = 54) of them were male. The mean systolic and diastolic blood pressures of study patients were 204.8 ± 23.2 and 108.3 ± 10.3, respectively, and 42% (n = 50) of patients had TOD. The most common TODs were stroke in 17 (14.2%) patients, MI in 12 (10.1%) patients, and retinopathy in 11 (9.2%) patients. The baseline features of study patients are displayed in Table. Thirty-nine (32.8%) patients were admitted to the hospital, whereas 80 (67.2%) were discharged from the ED. Sixty-six of 69 patients without TOD were discharged from ED, and 65 of them were reached by telephone follow-up at the end of 30 days. The mean systolic and diastolic blood pressures of patients without TOD during the discharge were 146 ± 13 and 81 ± 6 mm Hg, respectively. Three patients had adverse outcomes, 2 deaths and 1 MI, among these 65 patients. There
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Table Baseline characteristics of the 119 patients Characteristics
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Age (mean ± SD) Male sex, n (%) Baseline systolic blood pressure (mm Hg) (mean ± SD) • TOD group • No-TOD group Baseline diastolic blood pressure (mm Hg) (mean ± SD) • TOD group • No-TOD group Target organ disease, n (%) • Stroke • MI • Retinopathy • Cardiac failure • Acute renal failure • Stroke and retinopathy • No TOD ED treatment, n (%) • ACE inhibitor (1) • Calcium channel blocker (2) • Nitroglycerin (3) • Furosemide (4) • Combination therapy (1 and 2) • Combination therapy (1 and 3) • Combination therapy ((3 and 4) • Combination therapy (1, 2, and 3) • Combination therapy (1, 2, 3, 4) Comorbid disease, n (%) • Diabetes mellitus • Hyperlipidemia • Smoking
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ACE, angiotensin-converting enzyme.
62.8 ± 13.3 54 (45.4) 204.8 ± 23.2 208 ± 19 202 ± 25 108.3 ± 10.3 108 ± 10 108 ± 10 16 (13.4) 12 (10.1) 11 (9.2) 9 (7.6) 1 (0.8) 1 (0.8) 69 (58) 33 (27.7) 2 (1.7) 39 (32.8) 0 (0) 12 (10.1) 13 (10.9) 1 (0.8) 7 (5.9) 12 (10.1) 44 (37) 57 (47.9) 31 (26.1)
5. Study limitations
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Our study has been performed with a small number of patients and in a single center. Further studies should be conducted with larger group of patients. These studies may not reflect all populations with different ethnicities in the world. Treatment alternatives may be very diverse based on facilities and capabilities of the institutions. Another limitation to this study is that postponing of the blood pressure– lowering therapy might not be correct in patients with possible endorgan damage secondary to hypertension.
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6. Conclusions
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As a conclusion, despite the significantly higher levels of adropin in normotensive patients compared with hypertensive ones, adropin could not be used as a decision tool for detecting TOD in patients presenting with high blood pressure to the ED.
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References
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Hypertensive emergency is defined as the presence of TOD in the presence of remarkably higher blood pressure. In clinical practice, discrimination between hypertensive emergency and urgency carries utmost importance. Indeed, hypertensive emergency is a condition which requires closer patient monitoring and emergency parenteral antihypertensive treatment [4,5]. For these patients, treatment approach in emergency service should be to limit the extent of damage in the presence of TOD or prevent development of TOD [1,6]. A biomarker which will predict TOD before its development in patients who present to the emergency service with remarkably high blood pressure
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levels is not available so far. The data of this study support the assertion that adropin is not associated with target organ disease, but it is directly correlated with blood pressure levels. Pathophysiology of HT is associated with endothelial dysfunction. At first peak of blood pressure, endothelium increases release of endothelial vasodilators (such as nitric oxide) in an attempt to break vascular resistance. However, when HT persists at very high levels, this endothelial compensation mechanism fails, leading to endothelial decompensation. In this condition, blood pressure rises further, and endothelial damage emerges. However, the mechanism leading to acute hypertensive endothelial failure is much more complex and has not been fully understood up to now [7,8]. Various studies have provided evidence supporting the potential role of adropin in the regulation of cardiovascular functions and asserting its protective role in the pathogenesis and development of cardiovascular functions [1,9]. In another study, negative effects of adropin on blood pressure and its regulation by way of its impact on endothelial function have been also reported [8]. Recent studies have demonstrated the presence of a close relationship between lower serum adropin levels, acute MI, and coronary atherosclerosis [10,11]. In our study, we investigated whether adropin has a role in the evaluation of patients who presented to the ED with remarkably high blood pressure and also in the prediction of TOD. Within this context, we investigated whether the adropin levels could discriminate hypertensive emergency and urgency at the early stage of the disease. Adropin levels were similar between hypertensive patients who had TOD and no TOD. However, in consistence with the previous literature, a significant difference was detected between adropin levels in normo- and hypertensive patients. Adropin levels in hypertensive patients were significantly lower when compared with the normotensive group. Endothelial dysfunction not only is related to HT but also is associated with aging, heart and renal failure, preeclampsia, type I and II diabetes mellitus, atherosclerosis, and others. Persistent exposure of intima to higher blood pressure for a long time will cause aging of intima.
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were 7 patients who could not be reached at the end of the 30 days. There were 14 deaths, 9 MIs, and 1 stroke among all the study patients. The adropin levels were similar between the patients with or without TOD (TOD group = 195 pg/mL, IQR: 178-201; no-TOD group = 196 pg/mL, IQR: 176-204 [P = .982]). Although there is no difference between the patients with or without TOD, 3-group comparison including 60 patients without hypertension revealed a significant difference between the normotensive patients and patients with hypertension either with or without TOD (normotensive group = 289 pg/mL, IQR: 193-403; TOD group = 195 pg/mL, IQR: 178-201; no-TOD group = 196 pg/mL, IQR: 176-204 [P b .001]). Post hoc analysis revealed that adropin levels were significantly higher in normotensive patients than the hypertensive patients either with or without TOD. There was no correlation between adropin levels and systolic blood pressure (r = −0.06, P = .45) or diastolic blood pressure (r = −0.07, P = .39). The logistic regression analysis including age, systolic and diastolic blood pressures, body mass index, presence of diabetes, creatinine and troponin levels, adropin, and TOD in the ED as the independent variables and adverse outcome at the end of the 30 days as the dependent variable showed diabetes (odds ratio, 5.2; 95% confidence interval, 1.6-17) and TOD (odds ratio, 24.5; 95% confidence interval, 5-110) in the ED as the independent risk factors.
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