The relationship between carotid sinus hypersensitivity, orthostatic hypotension, and vasovagal syncope: a case control study

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1 Europace (2008) 10, doi: /europace/eun278 The relationship between carotid sinus hypersensitivity, orthostatic hypotension, and vasovagal syncope: a case control study Maw Pin Tan 1,2, Julia L. Newton 1,2, Tom J. Chadwick 3, and Steve W. Parry 1,2 * 1 Institute for Ageing and Health, Wolfson Centre, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK; 2 Falls and Syncope Service, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK; and 3 Institute of Health and Society, Newcastle University, 21 Claremont Place, Newcastle upon Tyne NE2 4AA, UK Received 4 July 2008; accepted after revision 16 September 2008; online publish-ahead-of-print 5 November 2008 KEYWORDS Syncope; Carotid sinus hypersensitivity; Vasovagal; Orthostatic hypotension; Carotid sinus massage; Tilt-table test Aims Previous uncontrolled studies reported an overlap between carotid sinus hypersensitivity (CSH), vasovagal syncope (VVS), and orthostatic hypotension (OH). We conducted a case control study evaluating this relationship in a large patient cohort. Methods and results The electronically stored continuous electrocardiograph and blood pressure (BP) measurements for active stand and head-up tilt-table (HUT) tests of 302 consecutive patients investigated with carotid sinus massage (CSM) were analysed. Carotid sinus hypersensitivity was defined as 3 s asystole and/or systolic BP (SBP) drop of 50 mmhg during CSM. Orthostatic hypotension was defined as BP reductions of 20 mmhg systolic or of 10 mmhg diastolic, whereas VVS was diagnosed with a positive HUT test. There was no significant difference in the number of subjects with OH (57 vs. 55%; P ¼ 0.778) or HUT-positive VVS (45 vs. 47%; P ¼ 0.828) between cases with CSH and controls without CSH. Carotid sinus hypersensitivity subjects had significantly larger SBP reduction (P ¼ 0.039) and longer time to nadir (P ¼ 0.007) during active stand, and trends to vasodepressor (P ¼ 0.071) and dysautonomic responses to HUT (P ¼ 0.151). Conclusion Carotid sinus hypersensitivity, OH, and VVS are common conditions affecting patients with syncope and falls which are likely to co-exist in such individuals. The differences in haemodynamic response patterns to active stand and HUT in CSH subjects could be the result of an age-associated delay in sympathetic responses. Introduction Syncope accounts for 1 3% of admissions to the emergency room 1 3 and up to 6% of acute hospital admissions. 4 Vasovagal syncope (VVS) is most common in the younger age group, whereas arrhythmias, cardiac structural causes, orthostatic hypotension (OH), and carotid sinus hypersensitivity (CSH) become more common in the older age group. However, VVS is now being diagnosed with increasing frequency in older patients since the use of head-up tilt-table (HUT) test in ,6 An overlap is said to occur for VVS, CSH, and OH. McIntosh et al. 7 reported that 14 of 26 (60%) patients with vasodepressor carotid sinus syndrome had OH or vasodepressor VVS, now classified as type 3 response according to the Vasovagal Syncope International Study (VASIS) classification. 7,8 * Corresponding author.tel: þ ; fax: þ address: swparry@hotmail.com Alboni et al. 9 described a complex neurally mediated syncope (NMS) in a group of subjects with a positive HUT and a positive response to carotid sinus massage (CSM). Subjects with complex NMS comprised 31 of 280 (11%) patients diagnosed with NMS or reflex syncope following a systematic evaluation for unexplained syncope. 9 The above studies were uncontrolled observational studies. The relationship between VVS, OH, and CSH has never been evaluated in a case control fashion. We conducted a retrospective case control study to investigate the overlap between VVS, OH, and CSH in patients investigated with CSM for syncope, drop attacks, and unexplained falls. Methods Subjects and investigative procedures All consecutive patients investigated with CSM from 1 January 2004 to 31 March 2007 at our tertiary referral falls and syncope facility Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oxfordjournals.org.

2 Relationship between CSH, OH, and VVS 1401 were included in the study. Patients were referred from a variety of sources, including the accident and emergency department, general practitioners, or other hospital departments. A detailed history, clinical examination, and electrocardiogram (ECG) had been obtained from each patient. Lying and standing blood pressure (BP) (active stand) measurements were obtained during beat-to-beat BP monitoring with a vascular unloading device (Taskforce TM, CNsystems, Austria) and a continuous ECG monitoring, following a period of 10 min supine rest. Patients who had negative investigations for cardiac syncope, suspected NMS, or recurrent unexplained syncope were then investigated using CSM and HUT tests according to the European Society of Cardiology Guidelines. 10 Bilateral CSM was performed by longitudinal massage at the carotid sinus, at the position of maximum pulsation of the carotid artery, approximately two fingers breadth below the angle of the mandible, for 5 s, beginning on the right side. The procedure was first conducted supine, then erect at 708 upright tilt on a tilt-table with a foot plate. 11 Head-up tilt tests were performed at a 708 tilt-angle following at least 10 min supine rest in a dim, quiet environment. The usual protocol involved a 20 min passive, unmedicated, phase followed by a further 15 min of HUTafter the administration of 400 mg of glyceryl trinitrate (GTN) sublingually (20:15 HUT). 12 A front-loaded HUT 13 following 800 mg of GTN at the start of the tilt followed by 20 min of HUTwas performed as a second-line investigation, if the clinical suspicion of VVS remained high following a negative 20:15 HUT, or if the patient was unable to tolerate prolonged HUT. Additional HUT protocols using incremental doses of intravenous isoprenaline 14 or lower body negative pressure 15,16 were also used, if initial HUT tests were inconclusive with continuing clinical suspicion, according to clinicians preference. All beat-to-beat BP and continuous ECG data were stored electronically within a secure computer server. A delayed analysis of the haemodynamic responses to CSM, active stand, and HUT investigations were performed for each individual investigated with CSM within the specified period. Definitions Carotid sinus hypersensitivity was defined as asystole of at least 3 s (cardioinhibitory CSH) and/or systolic BP (SBP) reduction of 50 mmhg or greater (vasodepressor CSH) in response to CSM. 10,11 Orthostatic hypotension was defined as a BP reduction of 20 mmhg systolic or of 10 mmhg diastolic within 2 min of assuming the upright position. 17,18 The heart rate response to active stand (30:15) was determined by calculating the ratio between the minimal heart rate around 30 beats after standing and the maximal heart rate at around 15 beats. 19 The time (in seconds) of the lowest SBP after assumption of the upright posture (time to nadir) was also recorded. A HUT test was deemed positive, if characteristic haemodynamic responses occurred during a HUT test in association with reproduction of presenting symptoms. 11 The haemodynamic response to HUT was then classified according to the VASIS classifications. 8 (i) Type 1 or mixed: BP fall precedes bradycardia and heart rate falls but not below 40 bpm or,40 bpm for,10 s with or without asystole of,3 s at the time of syncope. (ii) Type 2A: cardioinhibition of,40 bpm for more than 10 s without asystole of more than 3 s. Blood pressure falls before heart rate falls. (iii) Type 2B: cardioinhibition with asystole of more than 3 s, and BP fall coincides with or occurs after the fall in heart rate. (iv) Type 3: vasodepressor. Heart rate does not fall more than 10% below baseline. The exceptions to this classification are: (i) chronotropic incompetence whereby the heart rate rise during upright tilt is,10%; (ii) postural tachycardia syndrome, where there is an excessive heart rate rise to,130 bpm at the beginning of upright tilt and through its duration before syncope. The haemodynamic responses to HUT were also classified according to the proposed new classification by Brignole et al. 20 This alternative classification differentiates the haemodynamic patterns in response to HUT tests to classical vasovagal response, dysautonomic vasovagal response, and orthostatic intolerance. The classical vasovagal response is characterized by an initial increase in heart rate on assumption of the upright tilt, which stabilizes within the first few minutes, with a sudden catastrophic drop in heart rate and/ or BP. With the dysautonomic response, the BP fails to stabilize with upright posture, and the BP reduces gradually before the onset of symptoms. 20 Data analysis and statistics Summary statistics for continuous variables was expressed as mean + standard deviation for normally distributed variables and median with inter-quartile range (IQR) for non-normally distributed variables. Normally distributed continuous variables were compared using Student s t-test, and non-normally distributed variables were compared with the Mann Whitney U-test. The statistical significance of comparisons of nominal variables was expressed as odds ratios with 95% confidence intervals, and tested with the x 2 test. Analysis of covariance (ANCOVA) was then employed to adjust for the potential confounders of age and sex for interval outcomes. The variables of time to nadir and 30:15 ratio for active stand were non-normally distributed and therefore natural logarithmically transformed to form normal distributions before performing an ANCOVA. For categorical outcomes such as the presence of OH and positive HUT, multivariate logistic regression was used to control for age differences by dividing age into five categories by decades. All statistical analysis was conducted using the SPSS TM 15.0 software package. Results Three hundred and two patients, aged (range 38 98) years, were investigated with CSM during the specified period. Subjects with CSH were significantly older and more likely to be male (Table 1). Clinical characteristics including symptoms at presentation, co-morbidities (with the exception of atrial fibrillation and hypertension), and medication use were similar in both groups (Table 1). Seventy-four patients (25%) had a positive response to CSM (Figure 1). Thirty-seven (50%) developed asystole of at least 3 s (cardioinhibitory), and 37 (50%) had a BP drop of 50 mmhg or greater without a significant bradycardiac response (vasodepressor) to CSM. The remaining 228 patients had no significant response to CSM. Orthostatic hypotension and CSH The electronic files containing the continuous ECG and lying and standing BP measurements of 281 (93%) patients could be retrieved from the server. Subjects with OH were more likely to be males [52 vs. 35%; OR ¼ 2.06, 95% CI ( ); P ¼ 0.003], and to be taking psychoactive medications (32 vs. 22%; P ¼ 0.047). There was no difference in age ( vs years; P ¼ 0.847) between subjects with and without OH. There was no difference between the proportion of CSH subjects who had OH and the proportion of subjects in the non-csh group with OH (57 vs. 55%; P ¼ 0.778) (Table 2). The mean reduction in BP following active stand was statistically different for SBP ( vs mmhg; P ¼ 0.039)

3 1402 M.P. Tan et al. Table 1 Table of characteristics of subjects with and without CSH Characteristics CSH (%) (n ¼ 74) No CSH (%) (n ¼ 228) Odds ratio (95% CI) P-value Age (years), mean + SD ,0.001 Male sex, n (%) 43 (58) 91 (40) 1.74 ( ) Syncope, n (%) 45 (61) 116 (51) 1.57 ( ) Unexplained falls, n (%) 26 (35) 81 (36) 1.01 ( ) 0.97 Atrial fibrillation, n (%) 9 (12) 10 (4) 3.02 ( ) Hypertension, n (%) 3 (4) 30 (13) 0.28 ( ) All occlusive vascular disease a, n (%) 6 (8) 17 (8) 1.1 ( ) Diabetes, n (%) 1 (1) 6 (3) 0.51 ( ) Psychoactive medications, n (%) 17 (30) 65 (28) 1.25 ( ) Antidepressants 12 (16) 57 (25) 0.58 ( ) Antipsychotics 4 (5) 6 (3) 2.11 ( ) Benzodiazepines 5 (7) 19 (8) 0.78 ( ) Cardioactive medications, n (%) 36 (49) 91 (40) 1.43 ( ) Beta-blockers 11 (15%) 34 (15%) 1.00 ( ) ACE-inhibitors 18 (24) 33 (14) 1.90 ( ) Calcium-channel blockers 12 (16) 29 (13) 1.33 ( ) Diuretics 21 (28) 60 (26) 1.11 ( ) Nitrates 11 (15) 18 (8) 2.04 ( ) Heart rate, mean + SD Systolic blood pressure, mean + SD Diastolic blood pressure, mean + SD CSH, carotid sinus hypersensitivity; CI, confidence interval; SD, standard deviation. a Includes myocardial infarction, ischaemic heart disease, cerebrovascular disease, and peripheral vascular disease. Figure 1 Subjects investigated with head-up tilt test and active stand. CSM, carotid sinus massage; CSH, carotid sinus hypersensitivity; BP, blood pressure; HUT, head up tilt-table test. but not diastolic BP (DBP) ( vs mmhg; P ¼ 0.109) between CSH and non-csh subjects. The mean difference in SBP drop was no longer statistically significant after adjustment for age and sex (P ¼ 0.062). The 30:15 heart rate ratio was similar for both CSH and non-csh subjects (P ¼ 0.249). The time to nadir was significantly longer for subjects with CSH [17.8 ( ) s] than subjects without CSH [11.8 ( ) s; P ¼ 0.007]. However, when adjustments were made for age and sex using ANCOVA, the relationship between time to nadir and CSH was no longer statistically significant (P ¼ 0.135). Orthostatic hypotension was present in 63% of subjects with cardioinhibitory CSH and 51% of subjects with vasodepressor CSH (P ¼ 0.345). Vasovagal syncope and CSH One hundred and seventy-nine (59%) patients who had CSM were also investigated with HUT. Overall, 83 of 179 (46%) subjects had a bradycardiac and/or hypotensive response to HUT test. There were no age or sex differences between subjects with and without HUT-positive VVS ( vs ; P ¼ and male sex ¼ 39 vs. 43%, P ¼ 0.573, respectively). There were also no significant differences in clinical characteristics or medication use between subjects with and without VVS. Forty-seven (57%) subjects with VVS also had OH. Seven (8%) subjects had all three conditions. There was again no significant difference in the proportion of subjects with a positive HUT in the CSH group compared with the non-csh group (P ¼ 0.828) (Table 3). Four (33%) out of the 12 CSH subjects with positive HUT tests had a cardioinhibitory response (VASIS 1 or 2) compared with 45 of 71 (63%) subjects without CSH. Six (50%) subjects with positive HUT tests in the CSH group had pure vasodepressor (VASIS 3) responses to HUT compared with 20 (38%) subjects in the non-csh group. The percentage of subjects with the classical haemodynamic HUT response was smaller in the CSH group than in the non-csh group (17 vs. 39%), whereas the proportion with the dysautonomic responses was larger in the CSH group than in the non-csh group (67 vs. 52%). The above differences in VASIS classification and haemodynamic patterns were not statistically significant (P ¼ and 0.151, respectively). Discussion Our case control study revealed that patients with CSH were no more likely than elderly patients without CSH to have OH and VVS. Among our subjects who were investigated with both CSM and active stand, 57% of subjects with CSH and 55% of subjects without CSH had a positive active stand. Similarly, 44% of CSH subjects who were investigated with HUT tests had a positive HUT compared with 47% of non-csh subjects. Our findings, therefore, reinforce

4 Relationship between CSH, OH, and VVS 1403 Table 2 Table of active stand characteristics of subjects with and without CSH Characteristics CSH No CSH OR (95% CI) P-value Adjusted OR (95% CI) a Adjusted P-value No. of subjects DSBP (mmhg), mean + SD DDBP (mmhg), mean + SD :15 ratio, median (IQR) 1.12 ( ) 1.12 ( ) Time to nadir (s), median (IQR) 17.8 ( ) 11.8 ( ) DSBP 20 mmhg, n (%) 32 (47) 93 (44) 1.14 ( ) ( ) DDBP 10 mmhg, n (%) 36 (51) 102 (49) 1.20 ( ) ( ) OH, n (%) 39 (57) 118 (55) 1.08 ( ) ( ) No OH, n (%) 29 (43) 95 (45) CSH, carotid sinus hypersensitivity; OR, odds ratio; CI, confidence interval; SBP, systolic blood pressure; DBP, diastolic blood pressure; OH, orthostatic hypotension. a Adjusted for age and sex using multiple logistic regression; age was divided into five categories. Table 3 Table of HUT characteristics CSH (n ¼ 27) No CSH (n ¼ 152) Odds ratio (95% CI) P-value Adjusted OR (95% CI) a P-value HUT results Positive, n (%) 12 (44) 71 (47) 0.91 ( ) ( ) Negative, n (%) 15 (56) 81 (53) VASIS classification VASIS 1, n (%) 4 (33) 35 (49) VASIS 2a, n (%) 0 5 (7) VASIS 2b, n (%) 0 5 (7) VASIS 3, n (%) 6 (50) 20 (28) 3.38 ( ) b b 2.79 ( ) b b Chronotropic incompetence, n (%) 2 (17) 6 (8) HUT pattern Classical, n (%) 2 (17) 29 (39) Dysautonomic, n (%) 8 (67) 37 (52) 3.13 ( ) c c 2.68 ( ) c c Orthostatic intolerance, n (%) 1 (8) 2 (3) Indistinguishable, n (%) 1 (8) 3 (4) CSH, carotid sinus hypersensitivity; HUT, head-up tilt-table test; CI, confidence interval. a Adjusted for age and sex differences; age was divided into five categories by decades. b Odds ratio and P-value for VASIS 3 vs. VASIS 1 or 2 for CSH vs. non-csh subjects. c Odds ratio and P-value for dysautonomic vs. classical haemodynamic patterns for CSH vs. non-csh subjects. McIntosh et al. 7 and Alboni et al. s 9 findings that the diagnoses of OH and VVS commonly co-exist in subjects with CSH. However, our study also shows that these diagnoses are present in similar proportions of control subjects who were investigated for falls, drop attacks, and syncope, but did not have CSH. A much smaller study involving 65 subjects using lying and standing BP with a standard mercury sphygmomanometer, and prolonged passive HUT, showed that 11 out of the 26 (42%) subjects with pure vasodepressor or mixed CSH also have OH and 5 of 26 (19%) subjects have VVS. 7 Our diagnostic rates of OH and VVS were higher in both the CSH and the non-csh groups. The lying and standing BP measurement was conducted in our study during beat-to-beat BP monitoring, which would have increased the sensitivity of the test. Our HUT test protocols also included the use of GTN or other provocative agents known to enhance the positivity rates, partially accounting for the higher percentage of positive tests in our study ,21 In their study involving 280 subjects with neurally mediated reflex syncope, Alboni et al. 9 reported that 65 of 207 (31.4%) subjects evaluated with CSM and HUT tests have positive responses to CSM, and 31 of the 65 (48%) subjects with CSH also have positive HUT tests. Their diagnostic rate for tilt-positive VVS for subjects with CSH was therefore similar to our diagnostic rate of 44%. Neurally mediated syncope is the umbrella term for VVS, situational syncope, and CSH, 10 which does not include OH. Orthostatic hypotension was therefore not considered in this study. The conclusions on the association between CSH and VVS for these previous studies 7,9 are drawn without comparison with a control group. Our study suggests that CSH, OH, and VVS are common conditions affecting individuals with syncope, drop attacks, and unexplained falls, and are likely to co-exist as a result. The only population study of CSH published so far revealed that 39% of community dwellers over the age of 65 have CSH, 22 whereas OH has been reported in 5 30% of the older population. 23,24 Carotid sinus hypersensitivity and OH are also known to exist in asymptomatic subjects. 22,24 In Kerr et al. s 22 study, CSH was present in 35% participants with no history of falls, dizziness, or syncope.

5 1404 M.P. Tan et al. Asymptomatic OH was present in 16% of 4931 noninstitutionalized older people aged 65 or over. 24 These data and our current findings suggest that CSH and OH can often be clinical signs rather than distinct pathological entities that need to be interpreted according to the clinical context in association with symptoms. The prevalence of VVS in older individuals is unknown. 6 However, VVS is the most common cause of syncope across all age groups, accounting for 40% of all syncopal episodes presenting to the emergency room. 25 The clarification of the relationship between CSH, VVS, and OH has major implications for future efforts to unravel the underlying pathophysiology of these conditions, which at present remains elusive. On the basis of their findings that 15% of subjects investigated with CSM and HUT had a diagnosis of CSH and VVS, Alboni et al. 9 alluded to a common, central abnormality to the spectrum of neurally mediated disorders. However, our study suggests that the overlap observed by previous studies signifies the co-existence of three common disorders. Therefore, although our study does not exclude the possibility of a common pathophysiological process for the three conditions, our findings do not support the above theory. The mean age of subjects with CSH in our study was significantly higher than the mean age of subjects without CSH. The relationship between CSH and ageing is well established, with previous studies demonstrating sharp rises in the prevalence of CSH with increasing age. 26,27 Carotid sinus hypersensitivity was also more common in male subjects in our cohort. The original article describing the different haemodynamic patterns in response to HUT mentioned a higher number of subjects with CSH in the group of subjects with a dysautonomic HUT response. 20 Subjects in the dysautonomic group were also significantly older than subjects with a classical response in the above study. A subgroup analysis of our subjects with positive CSH and HUT revealed that a larger percentage of our CSH subjects did appear to have a dysautonomic tilt response pattern. Our subjects with CSH also appeared to have a predominantly vasodepressor response (VASIS type 3) whereas subjects without CSH tended to display bradycardiac responses (VASIS type 1 or 2). Although a clear trend could be observed, the differences above did not achieve statistical significance due to the small numbers involved. The SBP drop during active stand was significantly larger and time to nadir significantly longer in subjects with CSH, with no difference in heart rate response with standing (30:15). The maintenance of BP with standing and HUT is reliant on peripheral vascular tone regulated by the sympathetic nervous system. The exaggerated reduction in BP seen in our subjects during both active stand and HUT indicate that individuals with CSH have a reduction in peripheral alpha-adrenergic responsiveness supporting the findings of Mangoni et al., 28 who assessed forearm vascular resistance during lower body negative pressure. There were significant age and sex differences between their eight elderly controls and eight subjects with vasodepressor CSH, which were not statistically controlled for. The differences in SBP drop and time to nadir between CSH and non-csh subjects in our cohort were no longer statistically significant once adjusted for age and sex differences. The impairment in sympathetically mediated vasoconstriction in CSH subjects could, therefore, be an age-related phenomenon. 29,30 This will be a subject for future studies. The main limitations of our study were its retrospective case selection and the use of HUT testing per clinical need rather than in all subjects. Nearly, all our subjects were investigated with both active stand and CSM. Our study involved an unselected group of patients and is, hence, a true reflection of clinical practice. Twenty-five per cent of our subjects fell within the extreme elderly age of years, many of whom were frail with multiple co-morbidities. A number of our subjects were not able to tolerate 35 min of HUT due to physical disabilities. Furthermore, although HUT tests are deemed relatively safe, it is our practice to avoid exposing frail elderly patients to prolonged periods of hypotension unnecessarily. 11 Conclusion The prevalence of OH and HUT-positive VVS in subjects investigated with CSM was similar for subjects with and without CSH. Orthostatic hypotension, VVS, and CSH are, therefore, common conditions that are likely to co-exist in older patients with syncope, unexplained falls, and drop attacks. Orthostatic hypotension and CSH should also be considered physical signs that should be interpreted in association with symptoms. The absence of true associations between OH and VVS with CSH does not support the theory of an association leading to a common mechanism between the three conditions. The haemodynamic responses to active stand and HUT indicated a reduction in sympathetic responsiveness in CSH subjects which were attributable to age and sex differences. Our study, therefore, emphasizes the clinical importance of investigating for multiple potential causes in this group of older patients. It also has important implications for the direction of future research efforts to unravel the mechanisms underlying OH, VVS, and CSH. Acknowledgements Our thanks to Ann Harrison and Dawn Jungerius for providing database support. Conflict of interest: none declared. Funding This work was supported by a Royal College of Physicians/ Dunhill Medical Trust joint research fellowship grant. References 1. Brignole M, Menozzi C, Bartoletti A, Giada F, Lagi A, Ungar A et al. A new management of syncope: prospective systematic guideline-based evaluation of patients referred urgently to general hospitals. Eur Heart J 2006;27: Day SC, Cook EF, Funkenstein H, Goldman L. Evaluation and outcome of emergency room patients with transient loss of consciousness. Am J Med 1982;73: Disertori M, Brignole M, Menozzi C, Raviele A, Rizzon P, Santini M et al. Management of patients with syncope referred urgently to general hospitals. Europace 2003;5: Parry SW, Newton JL, Frearson R, Tryambake P, Steen N, Kenny RA. Evidence-based algorithms and the management of falls and syncope in the acute medical setting. Clin Med 2008;8: Kenny RA, Ingram A, Bayliss J, Sutton R. Head-up tilt: a useful test for investigating unexplained syncope. Lancet 1986;1:

6 Relationship between CSH, OH, and VVS Tan MP, Parry SW. Vasovagal syncope in the older patient. JAmColl Cardiol 2008;51: McIntosh S, Da Costa D, Kenny RA. Outcome of an integrated approach to the investigation of dizziness, falls and syncope in elderly patients referred to a syncope clinic. Age Ageing 1993;22: Sutton R, Peterson M, Brignole M, Raviele A, Menozzi C, Giani P. Proposed classification for tilt induced vasovagal syncope. Eur J Card Pacing Electrophysiol 1992;2: Alboni P, Brignole M, Menozzi C, Raviele A, Del Rosso A, Dinelli M et al. Clinical spectrum of neurally mediated reflex syncopes. Europace 2004; 6: Brignole M, Alboni P, Benditt DG, Bergfeldt L, Blanc JJ, Bloch Thomsen PE et al. Guidelines on management (diagnosis and treatment) of syncope update Europace 2004;6: Parry SW, Reeve P, Lawson J, Shaw FE, Davison J, Norton M et al. The Newcastle Protocols 2008: an update on head-up tilt table testing and the management of vasovagal syncope and related disorders. Heart 2008; Epub ahead of print 13 August 2008, doi: /hrt Bartoletti A, Alboni P, Ammirati F, Brignole M, Del Rosso A, Foglia Manzillo G et al. The Italian Protocol : a simplified head-up tilt testing potentiated with oral nitroglycerin to assess patients with unexplained syncope. Europace 2000;2: Parry SW, Gray JC, Baptist M, O Shea D, Newton JL, Kenny RA. Front-loaded glyceryl trinitrate-head-up tilt table testing: validation of a rapid first line tilt protocol for the diagnosis of vasovagal syncope. Age Ageing 2008;37: Almquist A, Goldenberg IF, Milstein S, Chen MY, Chen XC, Hansen R et al. Provocation of bradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Engl J Med 1989;320: el-bedawi KM, Hainsworth R. Combined head-up tilt and lower body suction: a test of orthostatic tolerance. Clin Auton Res 1994;4: Hainsworth R, el-bedawi KM. Orthostatic tolerance in patients with unexplained syncope. Clin Auton Res 1994;4: Anonymous. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. J Neurol Sci 1996;144: Ward C, Kenny RA. Reproducibility of orthostatic hypotension in symptomatic elderly. Am J Med 1996;100: Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 1996;93: Brignole M, Menozzi C, Del Rosso A, Costa S, Gaggioli G, Bottoni N et al. New classification of haemodynamics of vasovagal syncope: beyond the VASIS classification. Europace 2000;2: Raviele A, Gasparini G, Di Pede F, Menozzi C, Brignole M, Dinelli M et al. Nitroglycerin infusion during upright tilt: a new test for the diagnosis of vasovagal syncope. Am Heart J 1994;127: Kerr SR, Pearce MS, Brayne C, Davis RJ, Kenny RA. Carotid sinus hypersensitivity in asymptomatic older persons: implications for diagnosis of syncope and falls. Arch Intern Med 2006;166: Low PA. Prevalence of orthostatic hypotension. Clin Auton Res 2008;18: Rutan GH, Hermanson B, Bild DE, Kittner SJ, LaBaw F, Tell GS. Orthostatic hypotension in older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. Hypertension 1992;19: Brignole M, Disertori M, Menozzi C, Raviele A, Alboni P, Pitzalis MV et al. Management of syncope referred urgently to general hospitals with and without syncope units. Europace 2003;5: Humm AM, Mathias CJ. Unexplained syncope is screening for carotid sinus hypersensitivity indicated in all patients aged.40 years? J Neurol Neurosurg Psychiatry 2006;77: Puggioni E, Guiducci V, Brignole M, Menozzi C, Oddone D, Donateo P et al. Results and complications of the carotid sinus massage performed according to the method of symptoms. Am J Cardiol 2002;89: Mangoni AA, Ouldred E, Allain TJ, Close JC, Hilton D, Swift CG et al. Paradoxical vasodilation during lower body negative pressure in patients with vasodepressor carotid sinus syndrome. J Am Geriatr Soc 2003;51: Ramsey MW, Behnke BJ, Prisby RD, Delp MD. Effects of aging on adipose resistance artery vasoconstriction: possible implications for orthostatic blood pressure regulation. J Appl Physiol 2007;103: Smith EG, Voyles WF, Kirby BS, Markwald RR, Dinenno FA. Ageing and leg postjunctional alpha-adrenergic vasoconstrictor responsiveness in healthy men. J Physiol (Lond) 2007;582:63 71.