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Copeptin levels in patients with vasovagal syncope
IJCA-24379; No of Pages 4 International Journal of Cardiology xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Copeptin levels in patients with vasovagal syncope Panayota Flevari a,⁎,1, Dionyssios Leftheriotis a,1, Christos Kroupis b,1, George Antonakos b,1, John Lekakis a,1, Kleanthi Dima b,1 a b
2nd Department of Cardiology, Attikon University Hospital, Athens, Greece Department of Biochemistry, Attikon University Hospital, Athens, Greece
a r t i c l e
i n f o
Article history: Received 4 September 2016 Received in revised form 31 December 2016 Accepted 3 January 2017 Available online xxxx Keywords: Copeptin Arginine-vasopressin Vasoconstriction Syncope
a b s t r a c t Background and purpose: Vasovagal syncope (VVS) is linked to more than one pathophysiologic mechanisms. Copeptin, an emerging cardiovascular marker, is a surrogate for arginine-vasopressin, which increases following VVS. We aimed to assess the dynamic pattern of copeptin levels in typical VVS, categorized by the degree of vasoconstriction during orthostasis, and healthy controls. Methods: The following groups were studied: Group A (n = 21), with adequate limb vasoconstriction during the first min. of tilt, assessed by limb plethysmography (at least 30% flow reduction); Group B (n = 15), showing impaired vasoconstriction during orthostasis (b10% reduction); Group C (n = 18), history of VVS and negative tilt test result; Group D (n = 18), healthy controls. Copeptin plasma levels were assessed before and 5 min following tilt test positivity or termination. Results: Baseline copeptin values were similar in all groups (8.3 ± 6.4 in Group A, 5.7 ± 2.3 pmol/l in B, 6.0 ± 1.9 in C, and 6.9 ± 2.6 in D, p: 0.41). Significant increases in copeptin during tilt were observed in all Groups of VVS patients (A, B, C), including those with negative tilt (Group C: from 6.0 ± 1.9 to 27.7 ± 12.6 pmol/l, p: 0.001), but not in controls. Following tilt termination, a greater increase was observed in copeptin values in Group B vs all other Groups A, C, and D (111.6 ± 63.5 vs 29.5 ± 51.3, 27.7 ± 12.6, and 8.3 ± 2.9, respectively). Conclusions: Copeptin increases following tilt not only in VVS with a positive response, but also in typical history patients with a negative test. Increased copeptin levels following orthostasis may be useful for diagnosing VVS. © 2016 Published by Elsevier Ireland Ltd.
1. Introduction Copeptin, a stable cleavage product of vasopressin formation, is an emerging cardiovascular biomarker [1], easier to measure than vasopressin. Vasopressin increases during orthostasis leading to vasovagal syncope VVS, [2]. Copeptin has also been proposed for diagnosing VVS [3], but the pathophysiological significance of such a finding is still unclear. The presence of different patterns of vascular and blood pressure regulation during orthostasis has previously been described in VVS [4–7]. In order to better characterize mechanisms leading to syncope, we monitored forearm vasoconstriction, which has shown to be i) either less than that normally observed, i.e. ‘impaired’ (b 10% reduction in forearm blood flow – FBF-relative to supine values), or ii) similar to that of controls, who show a ‘sufficient’ reduction in forearm blood flow during orthostasis (at least by 30% reductions relative to supine, ⁎ Corresponding author at: 2nd Department of Cardiology, Attikon University Hospital, 12462, Haidari, Athens, Greece E-mail address: pfl[email protected] (P. Flevari). 1 These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
pre-test values) [6]. This degree of vasoconstriction is also observed in healthy controls. In an attempt to better understand the role of copeptin in VVS, we assessed copeptin levels during head-up tilt test (HUT) in i) three groups of patients with typical VVS, and ii) healthy asymptomatic controls. Patients were divided into different groups taking into account i) the degree of vasoconstriction during orthostasis, prior to presyncope or syncope, and ii) tilt test positivity or negativity. 2. Methods 2.1. Study population We studied 54 successive patients assessed in our center from September 2013 to September 2015, all with typical history of recurrent VVS (at least 2 episodes during the preceding 6 months), without underlying cardiovascular disease or renal dysfunction. Patients with any type of cardiovascular cause of potential orthostatic dysregulation were not studied (i.e. hypertension, diabetes, anemia, cardiomyopathy, carotid artery disease, prior stroke, valve disease, vasoactive medications, neurological diseases affecting cardiovascular status, such as Parkinson's disease). ‘Typical’ history of VVS was defined according
http://dx.doi.org/10.1016/j.ijcard.2017.01.014 0167-5273/© 2016 Published by Elsevier Ireland Ltd.
Please cite this article as: P. Flevari, et al., Copeptin levels in patients with vasovagal syncope, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2017.01.014
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P. Flevari et al. / International Journal of Cardiology xxx (2016) xxx–xxx
to current guidelines for syncope [8], as mediated by emotion or orthostatic stress, usually preceded by prodromal symptoms of autonomic activation (sweating, pallor, nausea). All underwent a diagnostic, positive tilt test, discontinued at the presyncopal phase of the reflex, so that a possible increase in copeptin levels may not represent a result of the syncopal event. Patients with syncope during tilt were not included, in an attempt to have copeptin values not being the result of a syncopal event, but – instead – values as much aetiologic as possible of an imminent (though aborted) syncope. Patients with orthostatic hypotension during the initial minutes of tilt we not included, either. Group A comprised patients with a positive tilt test and sufficient limb vasoconstriction during the first 10 min of HUT, as assessed by forearm blood flow by means of venous occlusion plethysmography (at least 30% flow reduction); Group B, with positive tilt test and impaired vasoconstriction during orthostasis (b10% flow reduction). A similar group of patients with typical VVS history and a negative tilt test result were also studied (Group C). A fourth group of age and sex-matched healthy, asymptomatic controls underwent the same testing (Group D). Recruited volunteers without history of syncope were defined as ‘healthy’ if they had no history of syncope, presyncope or any other symptomatology. They also had to be free of any other known disease and not to take any medications.
2.5. Statistical analysis Continuous data are presented as mean ± SD, whereas absolute proportions and percentages were used to describe categorical data. Normality of variables was tested by the Shapiro-Wilks W test, and, since some variables did not fit to a normal distribution, nonparametric tests were used: non-parametric ANOVA was used to compare continuous variables, where appropriate. Yates corrected Chi-square test was used to compare frequency data. Spearman Rank Order Correlation test was used for correlations. A p value b0.05 was considered statistically significant. STATISTICA software package, version 10, was used for analysis. 3. Results 3.1. Patient characteristics Clinical characteristics of all subjects are listed in Table 1. There were no significant differences in sex, age, or ejection fraction between study groups. None of the patients or control subjects participated in competitive athletics. None of the control subjects gave a history of syncope or presyncope. 3.2. Copeptin levels and vasoconstrictive response types
2.2. Head-up tilt protocol HUT was performed by means of an electrically controlled tilt table test with a footboard for weight bearing. Blood pressure, heart rate, heart rhythm, and right forearm blood flow were closely monitored and recorded. Blood pressure was automatically assessed every 1 min. The test was performed after an initial observation with the patient in the supine position for 10 min. It comprised 2 stages: in stage 1, patients were tilted at 60° for up to 20 min without drug provocation. If presyncope with arterial hypotension (systolic blood pressure b 80 mm Hg) did not develop, patients entered stage 2, in which they received 0.4 mg of sublingual glyceryl trinitrate and continued to be tilted for a further 10-min period. If presyncope with hypotension occurred during the test, the tilt table was rapidly lowered to return the patient to the supine position, and the study was terminated.
2.3. Limb plethysmography Forearm blood flow was initially assessed in the supine position, every 15 s during the immediate 3-min period prior to upright position initiation, and, subsequently, during the initial 10 min of 60° head-up tilting. Forearm blood flow was assessed as previously described [6]. In brief, venous occlusion plethysmography was performed using mercury in silastic strain gauges connected to a plethysmograph. The venous cuff was connected to a rapid cuff inflator, filled from a compressor, allowing inflation of the cuff to a preset pressure (50 mm Hg) in b 0.3 s. Limb blood flow was derived from the rate of increase in limb circumference during venous occlusion using an electronic calibration signal and expressed in milliliters per 100 ml/min.
Baseline copeptin values were similar in the 2 positive patient groups (Group A and B), patients with negative tilt (Group C), and controls (Group C). The respective copeptin values were 8.3 ± 6.4 pmol/l in Group A, 5.7 ± 2.3 in B, 6.0 ± 1.9 in C, and 6.9 ± 2.6 in D, p: 0.41. As shown in Fig. 1, significant increases were observed in all 3 Groups of VVS patients (Groups A, B, and C) relative to baseline, including those with negative HUT (Group C: from 6.0 ± 1.9 to 27.7 ± 12.6 pmol/l, p: 0.001). No increase was observed in healthy controls during tilt test (Group D: from 6.9 ± 2.6 to 8.3 ± 2.9 pmol/l, p: 0.1). Following tilt termination, greater copeptin values were observed in the positive tilt patients with initially adequate limb vasoconstriction (Group B) vs positive patients with impaired vasoconstrictive response (Group A), negative tilt patients (Group C), and healthy controls (Group D) (111.6 ± 63.5 vs 29.5 ± 51.3, 27.7 ± 12.6, and 8.3 ± 2.9 respectively, p: 0.001). Twenty-four out of the total 36 patients with a positive tilt (67%) had increased copeptin values following tilt. Among the 24 positive patients with increased copeptin levels following tilt, 19 (79%) belonged to Group A (impaired vasoconstriction, positive HUT), while the remaining 5 (21%) to Group B (sufficient vasoconstriction, positive HUT). 3.3. Copeptin levels in vasovagal patients tolerant to HUT All patients of this group had sufficient vasoconstriction during HUT. In these patients, copeptin levels increased from 6.0 ± 1.9 to 27.7 ± 12.6 pmol/l. Levels following orthostasis were above 14 pmol/l (the upper limit of normality) in 15/18 (83%) vasovagal patients with a negative HUT. A significant relation was observed between copeptin plasma values following the negative test and the total number of syncopal events among tilt-negative vasovagal patients (R = 0.75, p: 0.0004, Fig. 2). 3.4. Positive HUT and copeptin levels
2.4. Blood collection and measurement Copeptin plasma levels were assessed prior to and 5 min following tilt test positivity or termination. Blood samples were stored at −80 °C. Assessment of copeptin was blinded. Levels of copeptin were measured using the B-R-A-H-M-S Copeptin KRYPTOR Assay (Thermo Scientific, Hennigsdorf, Germany). Values N14 pmol/l were considered abnormal.
Baseline copeptin values were similar between tilt-positive patients (Groups A and B as a whole), tilt-negative patients (Group C), and controls (Group D): 7.2 ± 5.4 pmol/l vs 6.0 ± 1.9 vs 6.9 ± 2.6 pmol/l respectively, p: 0.41. Copeptin levels increased with tilt test in positive vasovagal patients (to 77.4 ± 75, p: 0.0001), exceeding the upper limit of normality (14 pmol/l) in 24/36 (67%) patients, but in only 4/18 (22%) controls (p: 0.005). A significant difference was
Please cite this article as: P. Flevari, et al., Copeptin levels in patients with vasovagal syncope, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2017.01.014
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Table 1 Clinical characteristics of study groups and baseline copeptin values across groups.
Age (years) Sex (male/female) Syncopal episodes during the last 6 months Presyncopal episodes during the last 6 months Emotional distress preceding clinical episodes Orthostatic stress preceding clinical episodes Typical prodrome preceding clinical episodes Supine heart rate (bpm) Supine systolic blood pressure (mm Hg) Baseline copeptin values (pmol/l)
Positive tilt Positive history Adequate initial vasoconstriction (Group A, n = 21)
Positive tilt Negative tilt Negative tilt p value Positive history Positive history Negative history between Impaired initial vasoconstriction (Group C, n = 18) (Group D, n = 18) assessed groups (Group B, n = 15)
48.1 ± 19 9/12 2.9 ± 5 5.0 ± 9 10/21 (48%) 19/21 (90%) 20/21 (95%) 69 ± 14 121 ± 27 8.3 ± 6.4
52.4 ± 22 7/8 2.8 ± 4 6 ± 12 6/15 (40%) 14/15 (93%) 15/15 (100%) 72 ± 15 119 ± 19 5.7 ± 2.3
observed in copeptin values between vasovagal patients (combined Groups A, B, C) and controls (Group D) following tilt test termination, irrespective of tilt test result (47.6 ± 52.5 vs 8.3 ± 2.9, p: 0.0001), between positive patients and controls (77.4 ± 75 vs 8.3 ± 2.9, p: 0.0001), as well as between negative vasovagal patients and controls (27.7 ± 12.6 vs 8.3 ± 2.9, p: 0.0003). In the positive tilt test groups (A and B, separately, and as a whole Group), no relation was observed between copeptin levels following tilt and the number of syncopal events in each patient's history (respective p values: 0.52, 0.64, and 0.45). No relation was observed, either, between copeptin levels and time to positive response to HUT (p: 0.8).
4. Discussion The main findings of this study are: i) copeptin levels - surrogate for arginine-vasopressin secretion – increase in patients with VVS following a positive HUT, ii) copeptin values also increase in similar vasovagal patients during a subsequently negative tilt test, iii) in this negative patient group, copeptin levels following orthostasis are related to symptomatic burden, as assessed by previous syncopal events, iv) a marked elevation in copeptin levels is especially observed in patients with adequate forearm vasoconstrictive response during initial orthostasis.
Fig. 1. Copeptin plasma levels prior to and following HUT in patients with a positive tilt test and adequate forearm vasoconstriction during initial tilt (Group A, n = 21, closed rectangles), patients with a positive test and impaired forearm vasoconstriction during initial tilt (Group B, n = 15, open circles), patients with typical history of VVS and a negative test (Group C, n = 18, open rectangles), and healthy controls (Group D, n = 18, closed circles). Significant differences within groups relative to baseline are depicted by asterisks.
49.3 ± 13 8/10 2.8 ± 3 5.2 ± 6 7/18 (39%) 17/18 (94%) 18/18 (100%) 69 ± 10 122 ± 16 6.0 ± 1.9
49.5 ± 13 8/10 – – – – – 67 ± 13 119 ± 13 6.9 ± 2.6
0.82 N0.90 0.32 0.54 0.44 0.82 0.84 0.34 0.84 0.41
This is to our knowledge the first time that copeptin, a stable and sensitive marker of arginine-vasopressin release, is systematically assessed in VVS, taking into account the different patterns of limb vasoconstriction that are observed in this syndrome. Arginine-vasopressin is a vasoconstrictive substance. As previously shown, the principal stimulus for its secretion is arterial hypotension. This is mediated via arterial baroreceptors located in the aortic arch and the carotid sinus, while osmotic stimuli also play a role [9–11]. Arginine-vasopressin causes mainly splanchnic vasoconstriction, which plays a significant role in the pathophysiology of VVS [12]. In agreement with recent investigations regarding baseline copeptin levels in patients with syncope and healthy controls [13], we have shown that all studied groups had normal copeptin values at baseline. To our knowledge this is the first time that copeptin levels are assessed during orthostasis. We have also confirmed previous observations that arginine-vasopressin plasma levels do not increase during orthostasis in normal subjects [14]. This increase implies that VVS is characterized by activation of the arginine-vasopressin/copeptin axis during orthostasis, possibly in a physiological (or pathological) attempt to counterbalance potential vasodilative factors, previously described in VVS, such as: i) active secretion of circulating vasoactive substances [15,16], ii) differential autonomic control between various vascular beds, causing inhomogeneous fall in peripheral resistance [17,18], iii) transient, sympathetically mediated, cholinergic vasodilation [19], iv) increased or altered central nervous system centers sensitivity and centrally mediated baroreflex uncoupling [20,21]. Further studies would further elucidate whether one or more of these possible vasodilating pathways is directly related to the increase
Fig. 2. Copeptin plasma levels and total number of syncopal events among tilt-negative vasovagal patients.
Please cite this article as: P. Flevari, et al., Copeptin levels in patients with vasovagal syncope, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2017.01.014
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in copeptin plasma levels in vasovagal patients during orthostasis. Moreover, it would be interesting to understand why the subset of patients with sufficient limb vasoconstriction prior to a vasovagal event show significantly higher copeptin levels than the - also increased -levels of the impaired vasoconstriction group of patients. A putative explanation is that the group with sufficient limb vasoconstriction exhibits markedly impaired splanchnic vasoconstriction, which indeed is more directly linked to copeptin/vasopressin release [22]. An interesting finding of our study was that 83% of patients with negative tilt test and typical history of vasovagal syncope had increased levels of copeptin following HUT. This implies that copeptin levels are linked to vasovagal physiology and not necessarily to hypotension or syncope, and that copeptin assessment during HUT could be a useful means to improve tilt test positivity. Tilt test is one of the best examinations for diagnosing the etiology of syncope, however, its sensitivity needs improvement, while, not infrequently, the diagnosis of vasovagal syncope remains difficult. In this respect, increased copeptin levels following orthostasis, without arterial hypotension, might be used as markers of vasovagal physiology, not necessarily of syncope, as previously proposed [4]. The importance of this finding is underlined by the fact that these levels have been directly related to the symptomatic severity of VVS in our patient population with a negative tilt. In the present study we have assessed only patients with typical history of VVS, which is diagnostic for vasovagal etiology, and have observed the close relationship between copeptin and vasovagal phenotype. A next step would be to assess copeptin in patients with syncope of unknown etiology, where copeptin may be more useful clinically. The need to assess copeptin immediately following an orthostatic challenge could explain the apparently conflicting results regarding the usefulness of copeptin for diagnosing syncope [3,13]. Since copeptin is an emerging biomarker in Cardiology, this reason of copeptin plasma increase should also be taken into account, when copeptin assessment is considered in acute heart conditions, such as precordial pain or heart failure [23,24]. 4.1. Limitations of the study The small number of patients is a clear limitation of the study, a possible cause of undetectable differences between groups. Another limitation of our study is that we were not able to study splanchnic vasoconstriction, too, in relation to copeptin release. However, the presently assessed limb vasoconstriction, that is available in our laboratory, enabled us to get important and possibly clinically useful information regarding copeptin in VVS. 5. Conclusions An increase in copeptin levels is observed following HUT, not only in VVS with a positive test response (presyncope with hypotension), but also in vasovagal patients with a negative response. Increased copeptin levels may be a marker of vasovagal physiology, not necessarily a marker of systematic hypotension. Copeptin assessment during HUT could be a useful means to improve tilt test positivity and may discern different pathophysiological VVS subtypes. A next step would be to assess copeptin in patients with syncope of unknown etiology, where copeptin may be even more useful.
Conflict of interest None.
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Please cite this article as: P. Flevari, et al., Copeptin levels in patients with vasovagal syncope, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2017.01.014
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Copeptin levels in patients with vasovagal syncope Panayota Flevari a,⁎,1, Dionyssios Leftheriotis a,1, Christos Kroupis b,1, George Antonakos b,1, John Lekakis a,1, Kleanthi Dima b,1 a b
2nd Department of Cardiology, Attikon University Hospital, Athens, Greece Department of Biochemistry, Attikon University Hospital, Athens, Greece
a r t i c l e
i n f o
Article history: Received 4 September 2016 Received in revised form 31 December 2016 Accepted 3 January 2017 Available online xxxx Keywords: Copeptin Arginine-vasopressin Vasoconstriction Syncope
a b s t r a c t Background and purpose: Vasovagal syncope (VVS) is linked to more than one pathophysiologic mechanisms. Copeptin, an emerging cardiovascular marker, is a surrogate for arginine-vasopressin, which increases following VVS. We aimed to assess the dynamic pattern of copeptin levels in typical VVS, categorized by the degree of vasoconstriction during orthostasis, and healthy controls. Methods: The following groups were studied: Group A (n = 21), with adequate limb vasoconstriction during the first min. of tilt, assessed by limb plethysmography (at least 30% flow reduction); Group B (n = 15), showing impaired vasoconstriction during orthostasis (b10% reduction); Group C (n = 18), history of VVS and negative tilt test result; Group D (n = 18), healthy controls. Copeptin plasma levels were assessed before and 5 min following tilt test positivity or termination. Results: Baseline copeptin values were similar in all groups (8.3 ± 6.4 in Group A, 5.7 ± 2.3 pmol/l in B, 6.0 ± 1.9 in C, and 6.9 ± 2.6 in D, p: 0.41). Significant increases in copeptin during tilt were observed in all Groups of VVS patients (A, B, C), including those with negative tilt (Group C: from 6.0 ± 1.9 to 27.7 ± 12.6 pmol/l, p: 0.001), but not in controls. Following tilt termination, a greater increase was observed in copeptin values in Group B vs all other Groups A, C, and D (111.6 ± 63.5 vs 29.5 ± 51.3, 27.7 ± 12.6, and 8.3 ± 2.9, respectively). Conclusions: Copeptin increases following tilt not only in VVS with a positive response, but also in typical history patients with a negative test. Increased copeptin levels following orthostasis may be useful for diagnosing VVS. © 2016 Published by Elsevier Ireland Ltd.
1. Introduction Copeptin, a stable cleavage product of vasopressin formation, is an emerging cardiovascular biomarker [1], easier to measure than vasopressin. Vasopressin increases during orthostasis leading to vasovagal syncope VVS, [2]. Copeptin has also been proposed for diagnosing VVS [3], but the pathophysiological significance of such a finding is still unclear. The presence of different patterns of vascular and blood pressure regulation during orthostasis has previously been described in VVS [4–7]. In order to better characterize mechanisms leading to syncope, we monitored forearm vasoconstriction, which has shown to be i) either less than that normally observed, i.e. ‘impaired’ (b 10% reduction in forearm blood flow – FBF-relative to supine values), or ii) similar to that of controls, who show a ‘sufficient’ reduction in forearm blood flow during orthostasis (at least by 30% reductions relative to supine, ⁎ Corresponding author at: 2nd Department of Cardiology, Attikon University Hospital, 12462, Haidari, Athens, Greece E-mail address: pfl[email protected] (P. Flevari). 1 These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
pre-test values) [6]. This degree of vasoconstriction is also observed in healthy controls. In an attempt to better understand the role of copeptin in VVS, we assessed copeptin levels during head-up tilt test (HUT) in i) three groups of patients with typical VVS, and ii) healthy asymptomatic controls. Patients were divided into different groups taking into account i) the degree of vasoconstriction during orthostasis, prior to presyncope or syncope, and ii) tilt test positivity or negativity. 2. Methods 2.1. Study population We studied 54 successive patients assessed in our center from September 2013 to September 2015, all with typical history of recurrent VVS (at least 2 episodes during the preceding 6 months), without underlying cardiovascular disease or renal dysfunction. Patients with any type of cardiovascular cause of potential orthostatic dysregulation were not studied (i.e. hypertension, diabetes, anemia, cardiomyopathy, carotid artery disease, prior stroke, valve disease, vasoactive medications, neurological diseases affecting cardiovascular status, such as Parkinson's disease). ‘Typical’ history of VVS was defined according
http://dx.doi.org/10.1016/j.ijcard.2017.01.014 0167-5273/© 2016 Published by Elsevier Ireland Ltd.
Please cite this article as: P. Flevari, et al., Copeptin levels in patients with vasovagal syncope, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2017.01.014
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to current guidelines for syncope [8], as mediated by emotion or orthostatic stress, usually preceded by prodromal symptoms of autonomic activation (sweating, pallor, nausea). All underwent a diagnostic, positive tilt test, discontinued at the presyncopal phase of the reflex, so that a possible increase in copeptin levels may not represent a result of the syncopal event. Patients with syncope during tilt were not included, in an attempt to have copeptin values not being the result of a syncopal event, but – instead – values as much aetiologic as possible of an imminent (though aborted) syncope. Patients with orthostatic hypotension during the initial minutes of tilt we not included, either. Group A comprised patients with a positive tilt test and sufficient limb vasoconstriction during the first 10 min of HUT, as assessed by forearm blood flow by means of venous occlusion plethysmography (at least 30% flow reduction); Group B, with positive tilt test and impaired vasoconstriction during orthostasis (b10% flow reduction). A similar group of patients with typical VVS history and a negative tilt test result were also studied (Group C). A fourth group of age and sex-matched healthy, asymptomatic controls underwent the same testing (Group D). Recruited volunteers without history of syncope were defined as ‘healthy’ if they had no history of syncope, presyncope or any other symptomatology. They also had to be free of any other known disease and not to take any medications.
2.5. Statistical analysis Continuous data are presented as mean ± SD, whereas absolute proportions and percentages were used to describe categorical data. Normality of variables was tested by the Shapiro-Wilks W test, and, since some variables did not fit to a normal distribution, nonparametric tests were used: non-parametric ANOVA was used to compare continuous variables, where appropriate. Yates corrected Chi-square test was used to compare frequency data. Spearman Rank Order Correlation test was used for correlations. A p value b0.05 was considered statistically significant. STATISTICA software package, version 10, was used for analysis. 3. Results 3.1. Patient characteristics Clinical characteristics of all subjects are listed in Table 1. There were no significant differences in sex, age, or ejection fraction between study groups. None of the patients or control subjects participated in competitive athletics. None of the control subjects gave a history of syncope or presyncope. 3.2. Copeptin levels and vasoconstrictive response types
2.2. Head-up tilt protocol HUT was performed by means of an electrically controlled tilt table test with a footboard for weight bearing. Blood pressure, heart rate, heart rhythm, and right forearm blood flow were closely monitored and recorded. Blood pressure was automatically assessed every 1 min. The test was performed after an initial observation with the patient in the supine position for 10 min. It comprised 2 stages: in stage 1, patients were tilted at 60° for up to 20 min without drug provocation. If presyncope with arterial hypotension (systolic blood pressure b 80 mm Hg) did not develop, patients entered stage 2, in which they received 0.4 mg of sublingual glyceryl trinitrate and continued to be tilted for a further 10-min period. If presyncope with hypotension occurred during the test, the tilt table was rapidly lowered to return the patient to the supine position, and the study was terminated.
2.3. Limb plethysmography Forearm blood flow was initially assessed in the supine position, every 15 s during the immediate 3-min period prior to upright position initiation, and, subsequently, during the initial 10 min of 60° head-up tilting. Forearm blood flow was assessed as previously described [6]. In brief, venous occlusion plethysmography was performed using mercury in silastic strain gauges connected to a plethysmograph. The venous cuff was connected to a rapid cuff inflator, filled from a compressor, allowing inflation of the cuff to a preset pressure (50 mm Hg) in b 0.3 s. Limb blood flow was derived from the rate of increase in limb circumference during venous occlusion using an electronic calibration signal and expressed in milliliters per 100 ml/min.
Baseline copeptin values were similar in the 2 positive patient groups (Group A and B), patients with negative tilt (Group C), and controls (Group C). The respective copeptin values were 8.3 ± 6.4 pmol/l in Group A, 5.7 ± 2.3 in B, 6.0 ± 1.9 in C, and 6.9 ± 2.6 in D, p: 0.41. As shown in Fig. 1, significant increases were observed in all 3 Groups of VVS patients (Groups A, B, and C) relative to baseline, including those with negative HUT (Group C: from 6.0 ± 1.9 to 27.7 ± 12.6 pmol/l, p: 0.001). No increase was observed in healthy controls during tilt test (Group D: from 6.9 ± 2.6 to 8.3 ± 2.9 pmol/l, p: 0.1). Following tilt termination, greater copeptin values were observed in the positive tilt patients with initially adequate limb vasoconstriction (Group B) vs positive patients with impaired vasoconstrictive response (Group A), negative tilt patients (Group C), and healthy controls (Group D) (111.6 ± 63.5 vs 29.5 ± 51.3, 27.7 ± 12.6, and 8.3 ± 2.9 respectively, p: 0.001). Twenty-four out of the total 36 patients with a positive tilt (67%) had increased copeptin values following tilt. Among the 24 positive patients with increased copeptin levels following tilt, 19 (79%) belonged to Group A (impaired vasoconstriction, positive HUT), while the remaining 5 (21%) to Group B (sufficient vasoconstriction, positive HUT). 3.3. Copeptin levels in vasovagal patients tolerant to HUT All patients of this group had sufficient vasoconstriction during HUT. In these patients, copeptin levels increased from 6.0 ± 1.9 to 27.7 ± 12.6 pmol/l. Levels following orthostasis were above 14 pmol/l (the upper limit of normality) in 15/18 (83%) vasovagal patients with a negative HUT. A significant relation was observed between copeptin plasma values following the negative test and the total number of syncopal events among tilt-negative vasovagal patients (R = 0.75, p: 0.0004, Fig. 2). 3.4. Positive HUT and copeptin levels
2.4. Blood collection and measurement Copeptin plasma levels were assessed prior to and 5 min following tilt test positivity or termination. Blood samples were stored at −80 °C. Assessment of copeptin was blinded. Levels of copeptin were measured using the B-R-A-H-M-S Copeptin KRYPTOR Assay (Thermo Scientific, Hennigsdorf, Germany). Values N14 pmol/l were considered abnormal.
Baseline copeptin values were similar between tilt-positive patients (Groups A and B as a whole), tilt-negative patients (Group C), and controls (Group D): 7.2 ± 5.4 pmol/l vs 6.0 ± 1.9 vs 6.9 ± 2.6 pmol/l respectively, p: 0.41. Copeptin levels increased with tilt test in positive vasovagal patients (to 77.4 ± 75, p: 0.0001), exceeding the upper limit of normality (14 pmol/l) in 24/36 (67%) patients, but in only 4/18 (22%) controls (p: 0.005). A significant difference was
Please cite this article as: P. Flevari, et al., Copeptin levels in patients with vasovagal syncope, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2017.01.014
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Table 1 Clinical characteristics of study groups and baseline copeptin values across groups.
Age (years) Sex (male/female) Syncopal episodes during the last 6 months Presyncopal episodes during the last 6 months Emotional distress preceding clinical episodes Orthostatic stress preceding clinical episodes Typical prodrome preceding clinical episodes Supine heart rate (bpm) Supine systolic blood pressure (mm Hg) Baseline copeptin values (pmol/l)
Positive tilt Positive history Adequate initial vasoconstriction (Group A, n = 21)
Positive tilt Negative tilt Negative tilt p value Positive history Positive history Negative history between Impaired initial vasoconstriction (Group C, n = 18) (Group D, n = 18) assessed groups (Group B, n = 15)
48.1 ± 19 9/12 2.9 ± 5 5.0 ± 9 10/21 (48%) 19/21 (90%) 20/21 (95%) 69 ± 14 121 ± 27 8.3 ± 6.4
52.4 ± 22 7/8 2.8 ± 4 6 ± 12 6/15 (40%) 14/15 (93%) 15/15 (100%) 72 ± 15 119 ± 19 5.7 ± 2.3
observed in copeptin values between vasovagal patients (combined Groups A, B, C) and controls (Group D) following tilt test termination, irrespective of tilt test result (47.6 ± 52.5 vs 8.3 ± 2.9, p: 0.0001), between positive patients and controls (77.4 ± 75 vs 8.3 ± 2.9, p: 0.0001), as well as between negative vasovagal patients and controls (27.7 ± 12.6 vs 8.3 ± 2.9, p: 0.0003). In the positive tilt test groups (A and B, separately, and as a whole Group), no relation was observed between copeptin levels following tilt and the number of syncopal events in each patient's history (respective p values: 0.52, 0.64, and 0.45). No relation was observed, either, between copeptin levels and time to positive response to HUT (p: 0.8).
4. Discussion The main findings of this study are: i) copeptin levels - surrogate for arginine-vasopressin secretion – increase in patients with VVS following a positive HUT, ii) copeptin values also increase in similar vasovagal patients during a subsequently negative tilt test, iii) in this negative patient group, copeptin levels following orthostasis are related to symptomatic burden, as assessed by previous syncopal events, iv) a marked elevation in copeptin levels is especially observed in patients with adequate forearm vasoconstrictive response during initial orthostasis.
Fig. 1. Copeptin plasma levels prior to and following HUT in patients with a positive tilt test and adequate forearm vasoconstriction during initial tilt (Group A, n = 21, closed rectangles), patients with a positive test and impaired forearm vasoconstriction during initial tilt (Group B, n = 15, open circles), patients with typical history of VVS and a negative test (Group C, n = 18, open rectangles), and healthy controls (Group D, n = 18, closed circles). Significant differences within groups relative to baseline are depicted by asterisks.
49.3 ± 13 8/10 2.8 ± 3 5.2 ± 6 7/18 (39%) 17/18 (94%) 18/18 (100%) 69 ± 10 122 ± 16 6.0 ± 1.9
49.5 ± 13 8/10 – – – – – 67 ± 13 119 ± 13 6.9 ± 2.6
0.82 N0.90 0.32 0.54 0.44 0.82 0.84 0.34 0.84 0.41
This is to our knowledge the first time that copeptin, a stable and sensitive marker of arginine-vasopressin release, is systematically assessed in VVS, taking into account the different patterns of limb vasoconstriction that are observed in this syndrome. Arginine-vasopressin is a vasoconstrictive substance. As previously shown, the principal stimulus for its secretion is arterial hypotension. This is mediated via arterial baroreceptors located in the aortic arch and the carotid sinus, while osmotic stimuli also play a role [9–11]. Arginine-vasopressin causes mainly splanchnic vasoconstriction, which plays a significant role in the pathophysiology of VVS [12]. In agreement with recent investigations regarding baseline copeptin levels in patients with syncope and healthy controls [13], we have shown that all studied groups had normal copeptin values at baseline. To our knowledge this is the first time that copeptin levels are assessed during orthostasis. We have also confirmed previous observations that arginine-vasopressin plasma levels do not increase during orthostasis in normal subjects [14]. This increase implies that VVS is characterized by activation of the arginine-vasopressin/copeptin axis during orthostasis, possibly in a physiological (or pathological) attempt to counterbalance potential vasodilative factors, previously described in VVS, such as: i) active secretion of circulating vasoactive substances [15,16], ii) differential autonomic control between various vascular beds, causing inhomogeneous fall in peripheral resistance [17,18], iii) transient, sympathetically mediated, cholinergic vasodilation [19], iv) increased or altered central nervous system centers sensitivity and centrally mediated baroreflex uncoupling [20,21]. Further studies would further elucidate whether one or more of these possible vasodilating pathways is directly related to the increase
Fig. 2. Copeptin plasma levels and total number of syncopal events among tilt-negative vasovagal patients.
Please cite this article as: P. Flevari, et al., Copeptin levels in patients with vasovagal syncope, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2017.01.014
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in copeptin plasma levels in vasovagal patients during orthostasis. Moreover, it would be interesting to understand why the subset of patients with sufficient limb vasoconstriction prior to a vasovagal event show significantly higher copeptin levels than the - also increased -levels of the impaired vasoconstriction group of patients. A putative explanation is that the group with sufficient limb vasoconstriction exhibits markedly impaired splanchnic vasoconstriction, which indeed is more directly linked to copeptin/vasopressin release [22]. An interesting finding of our study was that 83% of patients with negative tilt test and typical history of vasovagal syncope had increased levels of copeptin following HUT. This implies that copeptin levels are linked to vasovagal physiology and not necessarily to hypotension or syncope, and that copeptin assessment during HUT could be a useful means to improve tilt test positivity. Tilt test is one of the best examinations for diagnosing the etiology of syncope, however, its sensitivity needs improvement, while, not infrequently, the diagnosis of vasovagal syncope remains difficult. In this respect, increased copeptin levels following orthostasis, without arterial hypotension, might be used as markers of vasovagal physiology, not necessarily of syncope, as previously proposed [4]. The importance of this finding is underlined by the fact that these levels have been directly related to the symptomatic severity of VVS in our patient population with a negative tilt. In the present study we have assessed only patients with typical history of VVS, which is diagnostic for vasovagal etiology, and have observed the close relationship between copeptin and vasovagal phenotype. A next step would be to assess copeptin in patients with syncope of unknown etiology, where copeptin may be more useful clinically. The need to assess copeptin immediately following an orthostatic challenge could explain the apparently conflicting results regarding the usefulness of copeptin for diagnosing syncope [3,13]. Since copeptin is an emerging biomarker in Cardiology, this reason of copeptin plasma increase should also be taken into account, when copeptin assessment is considered in acute heart conditions, such as precordial pain or heart failure [23,24]. 4.1. Limitations of the study The small number of patients is a clear limitation of the study, a possible cause of undetectable differences between groups. Another limitation of our study is that we were not able to study splanchnic vasoconstriction, too, in relation to copeptin release. However, the presently assessed limb vasoconstriction, that is available in our laboratory, enabled us to get important and possibly clinically useful information regarding copeptin in VVS. 5. Conclusions An increase in copeptin levels is observed following HUT, not only in VVS with a positive test response (presyncope with hypotension), but also in vasovagal patients with a negative response. Increased copeptin levels may be a marker of vasovagal physiology, not necessarily a marker of systematic hypotension. Copeptin assessment during HUT could be a useful means to improve tilt test positivity and may discern different pathophysiological VVS subtypes. A next step would be to assess copeptin in patients with syncope of unknown etiology, where copeptin may be even more useful.
Conflict of interest None.
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Please cite this article as: P. Flevari, et al., Copeptin levels in patients with vasovagal syncope, Int J Cardiol (2016), http://dx.doi.org/10.1016/ j.ijcard.2017.01.014