Patients with Atrioventricular Block During Tilt Test-Induced Vasovagal Syncope

original papers Adv Clin Exp Med 2011, 20, 3, 305 312 ISSN 1230-025X Copyright by Wroclaw Medical University Jacek Gajek 1, Dorota Zyśko 2, Anil K. Agrawal 3, Jerzy Rudnicki 4 Patients with Atrioventricular Block During Tilt Test-Induced Vasovagal Syncope Pacjenci z blokiem przedsionkowo-komorowym podczas testu pochyleniowego 1 Department of Cardiology, Wroclaw Medical University, Wrocław, Poland 2 Department of Emergency Medicine, Wroclaw Medical University, Wrocław, Poland 3 2nd Department and Clinic of General and Oncological Surgery, Wroclaw Medical University, Wrocław, Poland 4 Department of Minimally Invasive Surgery and Proctology, Wroclaw Medical University, Wrocław, Poland Abstract Background. Sinus bradycardia or sinus arrest are the most prevalent rhythms during a cardioinhibitory type of neurocardiogenic reaction, while atrioventricular block (AVB) occurs rarely. Objectives. The aim of the study was to compare the medical histories and tilt test (TT) findings among patients with and without AVB during a positive TT. Material and Methods. The study group consisted of 578 vasovagal patients with positive TTs. Among them there were 34 patients with AVB, which constituted 5.9% of the total study group. The medical histories and TT data were analyzed. The TTs were performed according to the Italian protocol. Results. The medical histories of patients with AVB showed a significantly higher incidence of syncope-related traumatic injuries requiring hospitalization. AVB occurrence was found to be independently related to a history of instrumentation-injection-blood (IIB) phobia and to the duration of the PR interval on a baseline electrocardiogram. Receiver operating characteristic (ROC) analysis revealed that a PR interval 177 ms in duration differentiates patients without and with AVB during a neurocardiogenic reaction. It was also shown that other factors related to AVB occurrence include a shorter duration of the slowing of the heart rate and syncope as a TT outcome. Conclusions. Patients with AVB during TT differ from those without AVB. Sudden onset of a syncopal event, particularly in women or in patients of either gender with instrumentation-injection-blood (IIB) phobia, can be an indicator for AVB during vasovagal syncope. The population of subjects with AVB during TT is not homogenous; it consists of a younger subgroup with IIB phobia, and an older subgroup with a concealed organic AV node dysfunction (Adv Clin Exp Med 2011, 20, 3, 305 312). Key words: vasovagal syncope, tilt test, atrioventricular block. Streszczenie Wprowadzenie. Bradykardia zatokowa i/lub zahamowanie zatokowe są najczęstszymi rytmami podczas reakcji neurokardiogennej typu kardiodepresyjnego. Bloki przedsionkowo-komorowe wyższych stopni są obserwowane rzadko. Cel pracy. Porównanie danych z wywiadu oraz parametrów testu pochyleniowego u pacjentów, u których podczas reakcji neurokardiogennej wystąpił lub nie blok przedsionkowo-komorowy. Materiał i metody. Badana grupa obejmowała 578 pacjentów z omdleniami wazowagalnymi, u których wykonano dodatni test pochyleniowy. Wśród badanych stwierdzono występowanie kardiodepresyjnego typu reakcji neurokardiogennej w mechanizmie bloku przedsionkowo-komorowego u 34 pacjentów, co stanowiło 5,9% wszystkich badanych. Analizie poddano dane z wywiadu od pacjentów oraz parametry testu pochyleniowego. Testy pochyleniowe wykonywano zmodyfikowanym protokołem włoskim z prowokacją NTG w razie potrzeby. Wyniki. Wywiad chorobowy u pacjentów z blokiem przedsionkowo-komorowym wskazywał na statystycznie istotną większą częstość występowania urazów związanych z omdleniami, które wymagały hospitalizacji. Wystąpienie bloku przedsionkowo-komorowego było niezależnie powiązane z wywiadem w kierunku omdleń na widok krwi i instrumentację wraz z czasem trwania odstępu PR w spoczynkowym elektrokardiogramie. Analiza krzywych ROC wykazała, że czas trwania odstępu PR 177 ms pozwalał na wyodrębnienie pacjentów z blokiem przedsionkowo- -komorowym podczas reakcji neurokardiogennej. Wykazano ponadto, że innymi czynnikami wystąpienia bloku

306 J. Gajek et al. przedsionkowo-komorowego są krótszy czas trwania fazy zwalniania rytmu zatokowego oraz wystąpienie pełnego omdlenia jako wyniku testu pochyleniowego. Wnioski. Pacjenci z blokiem przedsionkowo-komorowym podczas testu pochyleniowego różnią się od osób bez bloku. Nagły początek omdlenia, zwłaszcza u kobiet i pacjentów z omdleniami na widok krwi i instrumentację mogą wskazywać na blok przedsionkowo-komorowy podczas omdlenia wazowagalnego. Populacja pacjentów z blokiem przedsionkowo-komorowym podczas testu pochyleniowego nie jest jednorodna. Obejmuje osoby młodsze z omdleniami na widok krwi i instrumentację oraz starsze, najprawdopodobniej z utajonym organicznym zaburzeniem funkcji węzła przedsionkowo-komorowego (Adv Clin Exp Med 2011, 20, 3, 305 312). Słowa kluczowe: omdlenie wazowagalne, test pochyleniowy, blok przedsionkowo-komorowy. Sinus bradycardia or sinus arrest are the most prevalent rhythms during a cardioinhibitory type of neurocardiogenic reaction, and atrioventricular block (AVB) occurs in 5% of tilt test-induced neurocardiogenic reactions [1]. Vasovagal reflexes vary from patient to patient, and may last from a few seconds to several minutes [2]. Progressive sinus bradycardia followed by AVB with a concomitant decrease in the sinus rate is a feature of vagally induced AVB, in contrast to a sudden onset of AVB with a concomitant increase in the sinus rate, which is presumed to have an intrinsic origin [3]. The slowing of the heart rate during a neurocardiogenic reaction is usually preceded by a decrease in blood pressure, but differences in the dynamics of the slowing of the heart rate may also reflect differences in the course of the neurocardiogenic reflex and lead to differences in its clinical consequences. Prodromal signs and symptoms warn fainting subjects of impending syncope, which enables them to change their body position to prevent falls and injuries [4, 5]. Objectives The aim of the study was to compare the medical histories and tilt test (TT) findings among patients with and without AVB during a positive TT, and to analyze whether patients with AVB during a neurocardiogenic reaction are a homogenous or heterogeneous population. Material and Methods The study group consisted of vasovagal patients with positive TTs. Their medical histories were collected, focussing on the number of syncopal episodes, traumatic injuries related to syncope, hospitalization due to such injuries, instrumentation-injections-blood (IIB) phobia, autonomic features during events and jerking movements during spontaneous syncope. The TT was performed according to the Italian protocol with a 20-minute passive phase (60 degrees of tilt), nitroglycerine (NTG) provocation if necessary, and continuation of the test for a further 15 minutes. Throughout the entire procedure the subject s ECG was recorded with the ECG Holter monitoring system. The procedure was carried out on an electrically controlled tilt table with a footboard for weight bearing. Blood pressure was measured automatically using an oscillometric method. Patients were asked to report any perception of sweating before and after TT termination. The following TT data were collected: the need for NTG provocation, the duration of the slowing of the heart rate during the neurocardiogenic reaction and the outcome of TT assessed as a total loss of consciousness (TLOC) or presyncope. The duration of TLOC was dichotomized and assessed as long when it lasted at least 32 seconds, or as short when it lasted no more than 31 seconds. The duration of the slowing of the heart rate was established by analyzing the heart rate trend line of the ECG recordings. The patients were divided into four groups on the basis of their TT outcomes and the cardiac rhythm during the neurocardiogenic reaction: Group 1 had presyncope and no AVB, Group 2 had short syncope and no AVB, Group 3 had long syncope and no AVB and Group 4 had AVB during a TT-induced neurocardiogenic reaction. Statistical Analysis Continuous variables are presented as means ± SD, and categorical variables as percentages and counts. Continuous variables were compared using a one-way ANOVA with Tukey HSD post hoc test. Frequencies were compared with a χ 2 test. A univariate logistic regression analysis was performed to identify possible predictors for AVB occurrence. Receiver operating characteristic (ROC) analysis was performed to determine the cut-off points of continuous variables that allow patients with and without AVB to be distinguished with the highest sensitivity and specificity. Classification and regression tree (CART) analysis was performed to identify factors associated with AVB occurrence during the TT-induced neurocardiogenic reaction.

Patients with Atrioventricular Block 307 CART is a non-parametric method of identifying predictor variables, described by Breiman et al. [6], using binary recursive partitioning: CART generates a classification rule that can be visualized as a classification tree. A k-means cluster analysis assigned AVB patients to two subgroups of similar age. The parameters studied were compared in these subgroups. All analyses were performed using Statistica and MedCalc software; and p values < 0.05 were considered significant. Results A total of 578 patients were included in the study. There were 34 patients with AVB (Group 4), which constituted 5.9% of the total study population. The clinical characteristics of the patient population are shown in Table 1 and their TT data in Table 2. Group 4 had a significantly higher incidence of syncope-related traumatic injuries requiring hospitalization in their medical histories than Group 1. Predicting AVB Using Data From Medical Histories as Independent Variables The results of the univariate analysis indicating predictors of AVB occurrence during TT are shown in Table 3. The multiple logistic regression analysis revealed that AVB occurrence was independently related to a history of IIB phobia and to the duration of the PR interval on the baseline electrocardiogram. ROC analysis revealed that patients without AVB during the neurocardiogenic reaction had PR intervals 177 ms in duration, while those with AVB had longer baseline PR intervals. CART analysis revealed an increased risk of AVB occurrence among women with IIB phobia and among those without IIB phobia whose PR interval at baseline was longer than 177 ms. The sensitivity of this parameter was 74% and the specificity was 70%. The results of this analysis are depicted in Fig. 1. Table 1. Demographics, clinical and electrocardiographic data Tabela 1. Charakterystyka demograficzna, kliniczna oraz wskaźniki elektrokardiograficzne badanych pacjentów Overall without AVB n = 535 (Wszyscy pacjenci bez bloku) Group 1 n = 146 Group 2 n = 212 Group 3 n = 177 Group 4 n = 34 Control group n = 47 (Grupa kontrolna) Age years ± SD (Wiek lata ± odchylenie standardowe) 42.3 ± 17.9 42.3 ± 22.3 37.1 ± 13.9 48.6 ± 17.4 40.7 ± 18.8 38.6 ± 13.9 Male gender % (Płeć męska) Syncope number median IQ (Liczba omdleń mediana) 36 38 34 38 24 45 3 (1 6) 2 (0 5) 2 (1 5) 4 (2 10) 3 (1 7) 0 Traumatic injuries % (Urazy) 30 25 26 40 32 0 Hospitalization due to trauma (Hospitalizacja z powodu urazów) IIB phobia % (Omdlewanie na widok krwi i instrumentację) 6 3 7 8 12 0 20 14 22 23 44 0 Jerks % (Ruchy drgawkopodobne) 5 4 4 7 15 0 Sweating % (Pocenie się) 29 27 33 27 24 0 PR interval at baseline ms (Odstęp PR w spoczynku) RR interval at baseline ms (Odstęp RR w spoczynku) 159 ± 28 157 ± 29 155 ± 27 167 ± 29 179 ± 38 151 ± 25 952 ± 160 942 ± 154 934 ± 134 980 ± 158 922 ± 149 944 ± 153 # p < 0.01 vs. control group. # p < 0.01 vs grupa kontrolna.

308 J. Gajek et al. Table 2. Tilt testing data Tabela 2. Test pochyleniowy Overall without AVB n = 535 Group 1 n = 146 Group 2 n = 212 Group 3 n = 177 Group 4 n = 34 Control group n = 47 NTG use % (Prowokacja NTG) 77 66 80 82 88 100 Syncope % (Omdlenie) 72 0 100 100 94 0 Sweating before TT termination (Pocenie się przed zakończeniem testu Sweating after TT termination (Pocenie się po zakończeniu testu Duration of heart rate slowing s (Czas trwania spadku częstotliwości rytmu serca) 18 26 18 11 3 0 23 13 21 33 32 0 104 ± 60 128 ± 63 96 ± 54 81 ± 56 70 ± 34 100 ± 43 Table 3. Predictors of AVB occurrence during TT in univariate analysis Tabela 3. Czynniki predykcyjne wystąpienia bloku AV podczas testu pochyleniowego w analizie jednoczynnikowej Odds ratio (Iloraz szans) 95% confidence interval (95% przedział ufności) P-value (Istotność statystyczna) Age years (Wiek lata) 0.69 0.17 2.79 ns. Male gender (Płeć męska) 0.54 0.24 1.22 ns. Syncope number (Liczba omdleń) 0.11 0.00004 318 ns. Trauma related to syncope (Uraz związany z omdleniem) Hospitalisation due to trauma (Hospitalizacja z powodu urazów) IIB phobia (Omdlewanie na widok krwi i instrumentację) PR interval at baseline ms (Odstęp PR w spoczynku) 0.11 0.53 2.34 ns. 1.96 0.65 5.91 ns. 3.12 1.53 6.35 < 0.002 48.3 6.0 389 < 0.001 NTG use (Prowokacja NTG) 2.29 0.79 6.63 ns. Jerks (Ruchy drgawkopodobne) 3.12 1.12 8.70 < 0.05 Syncope at TT (Omdlenie podczas testu Sweating before TT termination (Pocenie się przed zakończeniem testu Sweating after TT termination (Pocenie się po zakończeniu testu Duration of heart rate slowing s (Czas trwania spadku częstotliwości rytmu serca) Heart rate slowing less than 72 s (Spadek częstotliwości rytmu serca 72 s) 6.18 1.46 26.18 < 0.02 0.14 0.02 1.04 ns. 1.62 0.77 3.42 ns. 0.003 0.0001 0.11 < 0.002 2.89 1.42 5.87 < 0.005

Patients with Atrioventricular Block 309 Fig. 1. The results of CART analysis, factors associated with AV block occurrence during neurocardiogenic reflex, the number 1 in the right upper corner depicts increased risk for AVB occurrence Ryc. 1. Wyniki analizy CART, czynniki powiązane z wystąpieniem bloku AV podczas testu pochyleniowego, jedynka w prawym górnym rogu oznacza zwiększenie ryzyka bloku Fig. 2. The results of CART analysis, factors associated with AV block occurrence during neurocardiogenic reflex, the number 1 in the right upper corner depicts increased risk for AVB occurrence. Ryc. 2. Wyniki analizy CART, czynniki powiązane z wystąpieniem bloku AV podczas testu pochyleniowego, jedynka w prawym górnym rogu oznacza zwiększenie ryzyka bloku Predicting AVB Using TT Data as Independent Variables The multiple logistic regression analysis revealed that a shorter duration of the slowing of the heart rate and syncope as a TT outcome are factors independently related to AVB occurrence. ROC analysis revealed that in patients with AVB during the neurocardiogenic reaction the slowing of the heart rate lasted under 72 seconds, which distinguished them from those without AVB. CART analysis revealed that AVB in female subjects with a short duration of the slowing of the heart rate was related to a lack of sweating before TT termination. The sensitivity of this parameter was 50% and the specificity was 94%. The results of this analysis are depicted in Fig. 2. Patients with AVB during TT The k-means clustering analysis revealed that the subjects with AVB constituted a heterogeneous population. Two clusters can be distinguished: The first cluster consisted of 20 subjects aged 27.4 ± 7.9 years and the second one consisted of 14 subjects aged 59.6 ± 12.0 years. A comparison of these groups is shown in Table 4.

310 J. Gajek et al. Table 4. Comparison of AVB patients subgroups Tabela 4. Porównanie podgrup pacjentów z blokiem AV Group 4 a Group 4 b P-value (Istotność statystyczna) Age years ± SD (Wiek lata ± odchylenie standardowe) Male sex % (Płeć męska) 27.4 ± 7.9 59.6 ± 12.0 < 0.001 10 43 < 0.001 Hypertension % (Nadciśnienie) 0 57 < 0.001 Syncope number median IQ (Liczba omdleń mediana) 5 (2 12) 2 (1 6) ns. Traumatic injuries % (Urazy) 25 42 ns. Hospitalization due to trauma (Hospitalizacja z powodu urazów) IIB phobia % (Omdlewanie na widok krwi i instrumentację) 5 21 ns. 65 14 < 0.005 Jerking movements % (Ruchy drgawkopodobne) 20 7 ns. Sweating % (Pocenie się) 20 29 ns. PR interval at baseline ms (Odstęp PR w spoczynku) 164 ± 24 200 ± 45 < 0.01 RR interval at baseline ms (Odstęp RR w spoczynku) 897 ± 147 957 ± 149 ns. NTG provocation % (Prowokacja NTG) 80 100 ns. Syncope % (Omdlenie) 100 86 ns. Sweating before TT termination (Pocenie się przed zakończeniem testu Sweating after TT termination (Pocenie się po zakończeniu testu Duration of heart rate slowing s (Czas trwania spadku częstotliwości rytmu serca) 5 0 ns. 25 43 ns. 65 ± 29 76 ± 40 NS Discussion The main finding of our study is the fact that the clinical predictors for AVB during tilt test-induced neurocardiogenic reaction are IIB phobia in the medical history, a longer baseline PR duration and a shorter duration of the slowing of the heart rate. These predictors have a high sensitivity but a low specificity. The shorter duration of the slowing of the heart rate during neurocardiogenic reaction in the AVB group, as in the group with a long syncope, may be associated with a significant decrease in the duration of prodromal symptoms, in comparison with the groups with presyncope and a short syncope. Assuming that this pattern during neurocardiogenic reaction persists in spontaneous events, the clinical consequences of the shorter prodromal phase could include an association between AVB occurrences during TT-induced neurocardiogenic reactions and a history of severe traumatic injuries during spontaneous syncopal spells. A longer prodromal phase allows the subject to find a safe place to lie down and facilitates the prevention of severe traumatic injuries. Our study confirmed a disparity among neurocardiogenic reactions in terms of the slowing of the heart rate and the correlation with the clinical courses of vasovagal reflexes assessed as presyncope, short syncope and long syncope. The frequency of sweating (an autonomic feature) also varied: sweating was more frequent among patients whose TT was terminated during presyncope. This finding indicates the importance of sympathetic activation in the initiation of the

Patients with Atrioventricular Block 311 neurocardiogenic reaction as well as in the prolongation of the slowing of the heart rate. The pathophysiological meaning of abrupt slowing of the heart rate is not fully understood, but its fundamental purpose in patients with IIB phobia can be speculated upon: Human beings have a natural fear of blood and injury. In the normal population exposure to blood or injury often results in disgust, discomfort, light-headedness or even syncope. This kind of emotional fainting is a reflex which is thought to be an evolutionary safety feature. According to Bracha et al., the primary function of fear-induced faint ing may have been to non-verbally communicate to equally preverbal adversaries that one was not an immediate threat and could be safely ignored [7]. According to that hypothesis, syncope related to IIB phobia should occur rapidly as a way to prevent injury. The longer duration of the PR interval on the baseline electrocardiogram is related to AVB during the neurocardiogenic reaction. That observation suggests that the vagal innervations of a cardiac conduction system may be enhanced in vasovagal patients with AVB during TT-induced syncope, or that there is a subclinical intrinsic abnormality of an atrioventricular node in these patients. The significance of the type of neurocardiogenic reaction occurring during TT is usually overlooked because it is presumed to have low reproducibility during spontaneous syncope [8, 9]. However, neurocardiogenic reactions are deemed to have a stable electrocardiographic pattern during spontaneous syncope. It is puzzling that neurocardiogenic reactions of a given subject are similar except when induced by TT. The reason may be a tendency to terminate TT at an earlier point than the subject breaks the reflex in environmental circumstances by finding a suitable place to lie down. In a previously published paper the authors of the current study reported that the cardiodepressive type of neurocardiogenic reaction has the highest reproducibility [8, 9]. This type of neurocardiogenic reaction is very common during carotid sinus massage, and it has been reported that those patients had a similar type of the neurocardiogenic reaction during spontaneous syncopal spells [10]. If the termination of TT occurs too early, the vasodepressive type of neurocardiogenic reaction predominates, similarly as in daily life circumstances an immediate assumption of a supine position, during the initial phase of vasovagal reflex can terminate the reaction. This can lead to presyncope with tachycardia and without the heart rate slowing and syncope [11, 12]. The differences observed between clinical and electrocardiographic parameters within the groups of patients presenting with and without AVB indicate the non-random nature of the groups differentiation. The presence of AVB during tilt testinduced neurocardiogenic reaction should alert the physician performing the test to the possibility that the patient could experience such sudden reflex reactions in everyday life due to emotional factors. The k-means cluster analysis that was performed to assess the homogeneity of the group of patients with AVB showed two populations of different ages. In the younger subgroup there were more women, IIB phobia reactions were more frequent and the mean PR interval was much shorter. The duration of the slowing of the heart rate did not differ between the two subgroups. CART analysis permits the identification of previously unrecognized patient subgroups and is a useful method for dissecting complex clinical situations and identifying heterogeneous patient populations. In the current study, the CART analysis basically separated the vasovagal patients into those who experienced neurocardiogenic reaction in response to the sight of blood, instrumentation or injection, and in those who did not do so. This finding is in line with the theory that AVB during neurocardiogenic reaction could be a mechanism for enabling a fast and total loss of consciousness. The presence of neurocardiogenic reactions in response to IIB in daily life circumstances predicts the increased probability of AVB occurrence during TT-induced vasovagal syncope. In the group with IIB phobia, female gender is the second factor related to the AVB occurrence: women are more prone than men to have syncope in response to IIB [7]. In the group without IIB phobia, the branching of the CART analysis is caused by the duration of the PR interval, the duration of the slowing of the heart rate during the neurocardiogenic reaction and by gender. The authors concluded that patients with AVB during TT differ from those without AVB, a sudden onset of a syncopal event, particularly in women or in patients of either gender with instrumentation-injection-blood phobia, can indicate AVB during vasovagal syncope. The population of subjects with AVB during TT is not homogenous; it consists of a younger subgroup with IIB phobia, and an older subgroup with a concealed organic AV node dysfunction.

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