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Postural symptoms and vasovagal syncope (VVS) syncope are recognised chronic complications of severe weight loss, greater than 40kg; following bariatric surgery.[[1,2]] The relationship of syncope symptoms within months of moderate weight loss, between 5kg and 40kg, has not been reported. Additionally, moderate weight loss is usually achieved by lifestyle changes, for example dieting and exercise, rather than bariatric surgery. At our syncope clinic we had noted an apparent increase in the number of patients presenting for assessment with recent VVS apparently triggered by moderate weight loss.
The benefits of weight loss include decreased blood pressure and blood volume, both of which are probably secondary to a fall in sympathetic activity.[[3]] This activity is controlled by diverse mechanisms including the renin-angiotensin system, insulin levels, leptin, and the baroreflexes.[[3,4]] We postulated that weight loss and decreased central blood volume may predispose some patients to posture-triggered vasovagal syncope. With 10kg of weight loss, total blood volume falls by about 500ml, representing 10% of circulating volume, and approximately half of this is central blood volume.[[5,6]] Central blood volume is the major determinant of stroke volume and both are observed to fall immediately when the human body is tilted head-up.[[7,8]] If tilt is continued, a progressive fall in stroke volume is the key mechanism leading to syncope.[[9]] Despite the importance of central blood volume to maintenance of mean arterial pressure in the upright position, weight loss is not listed as a risk factor for posture-triggered VVS in review articles and guidelines.[[10–13]] Based on the complex mechanisms controlling sympathetic nerve activity, the relationship between weight loss and the onset of vasovagal syncope is unlikely to be simple. For example, the sigmoid nature of baroreflex responses might prevent BP from falling until blood volume falls below a certain threshold. To clarify, the association between weight loss and the onset of VVS in our clinic population, we examined the association between weight loss and other possible confounding demographic characteristics, or medical conditions, which can also cause syncope. Secondly, we wanted to explore the temporal relationship between recent weight loss and the onset of syncope symptoms. If weight loss is an important predisposing factor to VVS then: (a) it should precede the onset of fainting; (b) it might dictate a relatively short fainting history; (c) there might be an association between the duration of fainting symptoms and the length of time over which weight loss occurs; and (d) it might trigger VVS in patients who have never fainted before. Finally, we explored non-invasive haemodynamic data from head-up tilt to see if weight loss was associated with an exaggerated fall in stroke volume, which may be a possible mechanism for VVS in these patients.
Methods
This was a retrospective case-control study comparing demographic and other characteristics, in relation to syncope histories of VVS patients, with and without weight loss. Head-up tilt responses were also compared for two weight loss groups, with those of a control group without syncope symptoms. All patients were selected from our syncope clinic and the majority were referred by general practitioners. All patients in this study were assessed in syncope clinic by the same doctor (DLJ) over a six-year study period between January 2014 and December 2019.
Clinic procedures
A week before attending clinic, patients were sent a syncope questionnaire (see Appendix) which detailed the onset, severity and duration of syncope symptoms, as well as predisposing factors, for example drug treatment, background medical conditions and syncope in childhood. There was a specific question about syncope in childhood, as life-long susceptibility might be less prevalent in patients fainting in response to recent physiological changes such as pregnancy, anaemia, or weight loss. The questionnaire was reviewed with the doctor during the first part of the clinic assessment. In clinic patients were specifically asked about weight loss, including magnitude, duration and possible aetiology. The duration of weight loss was then collated with the syncope history so that patients could confirm or refute a temporal association. The practice of a pre-clinic questionnaire was to allow patients sufficient time to remember and document syncope symptoms before being asked about weight loss. If patients were uncertain about current weight and height, these measurements were made in clinic and additionally past measurements from the electronic record were reviewed. Therefore, although quantification of recent weight loss was by self-report, these estimates were validated against other clinical records. Posture-triggered VVS was diagnosed on the basis of an expert history, a normal ECG, and the exclusion of other possibilities using an abbreviated tilt test.[[14,15]] A positive 40 minute tilt test is not sensitive for VVS and, although clinically useful in some patients, is generally not be used as an inclusion criterion for studies of this nature.[[10,16]] On the other hand, a limited tilt test is useful to exclude diagnoses such as postural tachycardia syndrome (POTS), drug-related postural hypotension (DRPH), and neurogenic orthostatic hypotension.[[15]] The clinic review included a focussed cardiovascular examination and a 12-lead ECG, followed by an abbreviated head-up tilt test, (supervised by David L Jardine). All these occurred during the same clinic session. For the tilt test patients initially rested in the horizontal position on a hydraulic tilt table and a cuff was placed around the right index finger for continuous plethysmographic blood pressure recordings (FINAPRES, The Netherlands).[[17]] When blood pressure and heart rate were stable, usually after 10 minutes, patients were tilted to the head-up 70-degree position with foot support. No provocative manoeuvres were used.[[15]] The time taken to get from horizontal to tilt angle was 20s. All patients were tilted for a maximum of ten minutes if symptoms permitted, and then returned to the horizontal position for a further five minutes. A diagnosis of VVS required all of the following:
1. a typical history, based on the questionnaire and expert review in clinic, consisting recurrent episodes of transient loss of consciousness occurring when upright in certain situations and following the usual stimuli e.g., prolonged standing, standing up too quickly, blood phobia,[[10-14]]
2. no features in the history to suggest other conditions e.g., cardiac syncope, epilepsy, orthostatic hypotension, DRPH or POTS,[[15]]
3. a normal or vasovagal response to abbreviated tilt.
Patient groups
Data on all patients attending the syncope clinic during the study period were reviewed.
Patients were not used in the study if there was: a history of bariatric surgery; weight loss exceeding 40kg; or weight loss starting more than five years before assessment in clinic.
The weight loss group (WL) were selected based on: a clinical diagnosis of VVS; and moderate, and sustained weight loss of between 5kg and 40kg within five years of the syncope clinic assessment. Weight-stable group (WS) were randomly selected from clinic patients based on: a clinical diagnosis of VVS without moderate weight loss as defined above. Control group (C) were randomly from clinic patients during the study period did not have syncope or weight loss.
Calculated blood volume was estimated using the Nadler equations.[[18]]
Men: Total blood volume = 0.3669 (Height)[[3]] + 0.03219 (Weight) + 0.604
Women: Total blood volume = 0.3561 (Height)[[3]] + 0.03308 (Weight) + 0.1833
The accuracy of the Nadler equation for estimating blood volume may vary, depending on the magnitude and the aetiology of the weight loss.[[19]]
Hemodynamic measurements included blood pressure as the mean arterial pressure (MAP), heart rate (HR), and stroke volume (SV)—all averaged over one-minute periods. Stroke volume was derived from the blood pressure waveform using the MODELFLOW algorithm and expressed as % baseline.[[17]] Baseline values were measured in the horizontal position, in the last minute before head-up tilt; early tilt included the third minute of tilt; end of tilt included the tenth minute of tilt, and this was immediately before tilt-back to the horizontal position.
Statistical methods
The three groups were compared using one-way ANOVA, for scale variables, and Chi-squared tests, for categorical variables; and as appropriate and t-tests were used to clarify differences between the groups. Linear regression and product moment correlation coefficients were used to assess associations between continuous variables.
SPPS statistics software version 26 (IBM Corp, Armonk, NY, USA) was used.
After consultation, we were advised by our local ethics committee that formal approval was not required. This study was therefore undertaken under the auspices of the Research Office (University of Otago) and our hospital Quality Control committee.
Results
Over the six-year study period, 480/1,209 (40%) of patients seen in the syncope clinic had VVS. Of these patients 57/480 (11.9%) reported a history of moderate weight loss, between 5kg and 40 kg within five years of the clinic assessment: designated the weight loss (WL) group (Figure 1). From the remaining VVS patients, n=423, a random selection was made of unmatched patients without weight loss, designated the weight stable (WS) group, n=73. Additionally, a control (C) group was selected of patients with neither of weight loss nor syncope, n=24.
The demographic and other clinical characteristics of the patients are summarised in Table 1. There was no evidence of a difference between groups in weight, gender, body mass index, or calculated blood volume. Mechanisms for weight loss in the WL group included lifestyle (n=25), unknown (n=17), anxiety or depression (n=9) and medical conditions (n=6). Medical conditions contributing to weight loss included Crohn's disease, hyperthyroidism, and dysphagia. Both syncope groups had other treated medical conditions not thought to be related to weight loss. The most frequent medications used were serotonin-specific reuptake inhibitors, proton pump inhibitors, thyroxine, and statins. Very few patients in the VVS groups were using blood pressure lowering medication; one in the WS group and two in the WL group. This was, however, likely an artefact of the clinical assessment, because patients with syncope onset coinciding with starting of medications usually had an abnormal early response to tilt and were classified as having DRPH rather than VVS.
In the WL group, mean (SD) weight loss and calculated change in blood volume were 11.5 (7) kg and 0.4 (0.2) L respectively, occurring over 18.7 (13) months. The distribution of weight loss is shown in Figure 1. Weight loss preceded the onset of syncope in 80% of patients. The duration of syncope symptoms was shorter in the WL group compared to the WS group: mean (SD) 13.5 (15) versus 32.9 (44) months, p=0.002. The distribution of syncope symptoms over time was skewed with a long right tail. Although, in the majority of both groups symptoms started within 24 months of presentation, the distribution was more skewed in the WS group: 22/75 (29%) of the WS group had prolonged symptoms versus only 8/57 (14%) in the WL group. In the WL group there was evidence of an association between the duration of symptoms and time over which weight loss occurred, product moment correlation coefficient 0.45, p=0.001; with a slope (95% CI) of 0.48 (0.22 to 0.75) (see Figure 2). There was no evidence of an association between symptom duration and the magnitude of weight loss; product moment correlation coefficient -0.03, p=0.85. The proportion of patients with a history of syncope in childhood and teenage years was lower in the WL group, 23/57 (37%) compared to the WS group, 39/73 (53%).
No patients had syncope during the tilt-test. Haemodynamic variables before tilt (baseline) and at the two measurement times are summarised in Table 2. The baseline values of the haemodynamic variables were similar in all groups. There was strong evidence of a difference in mean arterial blood pressure in the two VVS groups compared to control, there was no evidence of a difference in heart rate, and although there was no evidence of a difference in stroke volume after three minutes; the control group had a lower stroke volume after 10 minutes of tilt.
View Supplementary Material.
Discussion
We found that recent moderate weight loss was rather common in patients presenting to our clinic with vasovagal syncope. Weight loss in most patients was intentional, through dieting and exercise; however, many patients were uncertain as to the cause. Apart from weight loss, the demographic characteristics, background medical histories and medications of this group were no different to other VVS patients. VVS onset usually followed or coincided with the onset of weight loss resulting in a shorter duration of syncope symptoms before clinic assessment. The duration of VVS symptoms was associated with the time interval over which weight loss occurred. Furthermore, fewer patients with weight loss reported syncope in earlier life, suggesting that onset of syncope was secondary to a physiological change, not a life-long predisposition. In the absence of other possible confounders it seems likely that weight loss, and the associated fall in blood volume, were the most likely physiological explanations for the synchrony between the onset of weight loss and postural VVS. We further hypothesised that patients with weight loss and decreased central blood volume might have an exaggerated fall in stroke volume during head-up tilt. However, we found that even though blood pressure was lower in both syncope groups during early tilt, stroke volume changes were less than in controls. Although adipose tissue is relatively low in blood volume, studies in dieting patients report reductions of both total and central blood volume within months.[[6,20]] We calculated that moderate weight loss, on average 12kg, would include 0.4L of blood volume, half of which is centrally distributed and the main determinant of stroke volume.[[18]] During tilt SV fell by approximately 30% in all of our patients. This occurred mainly in the first three minutes, consistent with previous studies on VVS.[[9]] We did not study tilt responses beyond ten minutes and so cannot comment on how weight loss might have affected the later changes preceding syncope. Crucially, our methods did not allow direct measurements of central blood volume or absolute SV levels immediately before tilt. Instead, we compared only changes in SV after tilt which has an uncertain relationship with absolute baseline levels. Furthermore, because of the retrospective nature of this study, we cannot determine how stroke volume and blood pressure may have fallen during the months over which weight loss occurred. Presumably the blood pressure level was similar in the two syncope groups because in the WL group it had fallen from higher levels. Therefore, most of the important changes in MAP and SV probably occurred during the months before clinic assessment and it is not surprising that our tilt data was not helpful. This in no way refutes our important finding of the association between weight loss and VVS.
It is possible that the fall in blood pressure, consistently observed after weight loss predisposes some patients to recurrent vasovagal syncope.[[1,5]] New-onset syncope has been observed in other situations when blood pressure is lowered, e.g., following the introduction of antihypertensive medication and during pregnancy.[[10]] Normally, arterial baroreflexes buffer acute falls in stroke volume and blood pressure in response to postural changes. After weight loss, although the baroreflexes become more sensitive, they reset and modulate heart rate and sympathetic nerve activity at lower MAP levels.[[3,21]] However, the absolute MAP at which syncope occurs remains the same (approximately 60mmHg), therefore the lower the MAP levels at which the baroreflex curve operates, the more likely the patient is to develop syncope.[[22]] Other studies have used head-down bed rest (over three weeks) to lower blood volume and reported no changes in arterial baroreflex function despite clear demonstration of orthostatic intolerance.[[23]] We emphasise that in our study (and other weight loss studies) the weight change was greater and over a much longer time interval, therefore a major “left” shift of the baroreflex curves towards lower MAP levels is likely.[[3,21]] Re-setting is complicated and involves not only arterial but also cardiopulmonary baroreflexes which control renin, vasopressin and endothelin secretion.[[24,27]] Furthermore, cardiopulmonary baroreflexes also modulate sympathetic activity and augment arterial baroreflex function when central blood volume is decreased.[[28,29]] In view of these interactions and the nature of baroreflex responses, it is not surprising that we were unable to demonstrate a strong linear correlation between the recent duration of weight loss and syncope symptoms.
Limitations
In this study, the estimation of duration of syncope symptoms and weight loss depended on patient recall. Onset of syncope after weight loss may have biased how some patients remembered their symptoms. We think this was partly mitigated by sending the patients a written questionnaire and checking their reported weight data with the electronic record as described in the methods. We were unable to directly measure central blood volume or compare absolute stroke volume levels at baseline. Sample size and statistical power were limited by the numbers of controls and patients presenting with weight loss. Multiple comparisons between these groups may have increased the risk of a type I error. An ideal future study would prospectively measure weight loss, tilt responses, and symptoms before and after dietary intervention.
Conclusion
In the majority of patients presenting to our clinic with recurrent blackouts occurring in a standing or sitting position, the diagnosis is vasovagal syncope.[[15]] It is usually made by taking a careful history.[[10,12,14]] When the history is unclear, other less common causes can be excluded by the appropriate investigations, for example long-term cardiac monitoring for arrhythmia or tilt testing for postural hypotension.[[10,12]] If these results are normal, patients can be reassured that the diagnosis is still most likely to be VVS because it is so prevalent in all age groups. In some, the diagnosis is supported by a satisfactory response to treating predisposing factors e.g., anaemia, dehydration, prolonged bedrest, drugs, pregnancy, or fever; but in others there are no associated changes other than weight loss. The results of this study are consistent with that in a subset of patients with recent onset VVS, there may be an association with simultaneous moderate weight loss. This association is generally not recognised by patients and has not previously been reported. This may be because the temporal association between duration of weight loss and onset of syncope is not simple. We suspect that when weight stabilises at a lower level and the baroreflex mechanisms re-set, the time interval during which the patient remains symptomatic is variable. We plan a follow-up study to examine the length of this time interval and what baroreflex changes occur. In the meantime, we reassure our patients that the symptoms will improve (without any form of medication), and they are discouraged from putting the weight back on.
Summary
Abstract
Aim
In adults, the onset of vasovagal syncope is often unexplained. We wished to explore if moderate weight loss triggers the onset of vasovagal syncope (VVS).
Method
A retrospective case-control study comparing demographic characteristic, syncope symptoms, and tilt-table results of patients who had recently lost weight (n=57), with randomly selected weight-stable patients (n=73), and controls, patients without syncope (n=24).
Results
VVS was diagnosed in 480 out of 1,209 clinic patients of whom 57 (11.9%) reported moderate weight loss. The mean (SD) reported weight loss was 11.5 (7) kg over 18.7 (13) months. Age and gender did not differ between groups: in the weight loss, weight stable, and control groups the mean age was 44.8, 45.2, and 44 years respectively; and proportion female 60%, 64%, and 54%. Body weight, mass index and calculated blood volume at presentation were also similar in the different groups. Weight loss preceded or coincided the onset of syncope in 80% of patients; the length of time over which weight loss occurred was associated with the length of time of syncope symptoms, product moment correlation coefficient 0.45, p=0.001. Syncope in childhood and teenage years was less frequent in the weight loss group compared to the weight stable group: 37% vs 53%. After 10 minutes of head-up tilt, stroke volume was preserved in both syncope groups compared to controls; percentage of baseline mean (SD) in the weight loss, weight stable, and control groups: 71(18), 69(10), and 61 (11) respectively; despite lower blood pressure in the weight loss groups with mean (SD) 90 (14) mmHg, 93 (13) and 103 (14) respectively.
Conclusion
Some patients have onset of VVS within a few months of weight loss resulting in earlier presentation to clinic. The physiological mechanism for this is uncertain.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
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2) Ponnusamy V, Owens AP, Purkayastha S, et al. Orthostatic intolerance and autonomic dysfunction following bariatric surgery: a retrospective study and review of the literature. Autonom Neurosci 2016;198:1-7.
3) Grassi G, Seravalle G, Columbo M et al. Weight reduction, sympathetic nerve traffic and arterial baroreflex in obese normotensive humans.Circulation. 1998;97:2037-2042.
4) Lambert E, Esler MD, Schlaich MP et al. Obesity-Associated Organ Damage and Sympathetic Nervous Activity. Hypertension 2019;73:1150-1159.
5) Messerli FH, Christie B, DeCarvalho JG et al. Obesity and essential hypertension: hemodynamics, intravascular volume, sodium excretion and plasma renin activity. Arch Intern Med. 1981;141:81-85.
6) Reisin E, Frohlich ED, Messerli FH et al. Cardiovascular changes after weight reduction surgery. Ann Intern Med. 1983;98:315-319.
7) Stewart JM, McLeod KJ, Sanyal S et al. Relation of postural vasovagal syncope to splanchnic hypervolemia in adolescents. Circulation. 2004; 110:2575-2581.
8) van Lieshout JJ, Harms MP, Pott F et al. Stroke volume of the heart and thoracic fluid volume during head-up and head-down tilt in humans. Acta Anaesthesiol Scand. 2005;49:1287-1292.
9) Verheyden B, Liu J, van Dijk N et al.. Steep fall in cardiac output is the main determinant of hypotension in drug-free and nitroglycerin-induced orthostatic vasovagal syncope. Heart Rhythm. 2008;5:1695-1701.
10) Brignole M, Moya A, de Lange FJ et al. Guidelines for the diagnosis and management of vasovagal syncope. Eur Heart J 2018; 39:1883-1948.
11) Colman N, Nahm K, Ganzeboom KS et al. Epidemiology of reflex syncope. Clin Autonom Res 2004; 14 Suppl 1:9-17.
12) Shen WK, Sheldon RS. ACC/AHA/HRS guidelines for the evaluation and management of patients with syncope. J Am Coll Cardiol 2017;70:e41-e109.
13) van Dijk GG, Thijs RD, Benditt DG and Wouter Wieling. A guide to disorders causing transient loss of consciousness: focus on syncope. Nat Rev Neurol 2009;5:438-448.
14) Wieling W, Kaufmann H. What is the best method to diagnose vasovagal syncope? Clin Autonom Res 2021;3:335-337.
15) Al-Busaidi IS, Jardine DL. Different types of syncope presenting to clinic: do we miss cardiac syncope? Heart Lung Circ. 2019:S1443-9506(19)31454-4. doi: 10.1016/j.hlc.2019.09.008.
16) Moya A. Tilt testing and neurally-mediated syncope: too many protocols for one condition or specific protocols for different situations? Eur Heart J 2009;30:2174-2176.
17) Bogert LW, van Lieshout JJ. Non-invasive pulsatile arterial pressure and stroke volume changes from the human finger. Exp Physiol. 2005;90:437-446.
18) Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery. 1962;51:224-232.
19) Funkhouser RK, Pritchard WH, Little AS. Change in relationship of blood volume to weight in congestive heart failure. Circulation 1957;16:548-557.
20) Alexander JK, Peterson KL. Cardiovascular effects of weight reduction. Circulation 1972;45:310-318.
21) Alvarez GE, Davy BM, Ballard TP et al. Weight loss increases cardiovagal baroreflex function in obese young and older men. Am J Physiol Endocrinol Metab. 2005;289:E665-E669.
22) Wieling W, Thijs RD, van Dijk N et al. Symptoms and signs of syncope: a review of the link between physiology and clinical clues. Brain 2009; 132: 2630-2642.
23) Kamiya A, Michikami D, Fu Q et al. Pathophysiology of orthostatic hypotension after bedrest: paradoxical sympathetic withdrawal. Am J Physiol Heart Circ Physiol 2003;285:H1158-H1167.
24) Grassi G, Giannattasio C, Cuspidi C et al. Cardiopulmonary receptor regulation of renin release. Am J Med. 1988;84 (Suppl 3A):97-104.
25) Hainsworth R. Cardiovascular control from cardiac and pulmonary vascular receptors. Exp Physiol 2014;99:312-319.
26) Jacobsen T, Morgan B, Scherrer U et al. Relative contributions of cardiopulmonary and sinoaortic baroreflexes in causing sympathetic activation in human skeletal muscle circulation during orthostatic stress. Circ Res. 1993;73:367-378.
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29) Ogoh S, Brothers RM, Barnes Q et al. Effects of changes in central blood volume on carotid-vasomotor baroreflex sensitivity at rest and during exercise. J Appl Physiol 2006;101:68-75.
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Postural symptoms and vasovagal syncope (VVS) syncope are recognised chronic complications of severe weight loss, greater than 40kg; following bariatric surgery.[[1,2]] The relationship of syncope symptoms within months of moderate weight loss, between 5kg and 40kg, has not been reported. Additionally, moderate weight loss is usually achieved by lifestyle changes, for example dieting and exercise, rather than bariatric surgery. At our syncope clinic we had noted an apparent increase in the number of patients presenting for assessment with recent VVS apparently triggered by moderate weight loss.
The benefits of weight loss include decreased blood pressure and blood volume, both of which are probably secondary to a fall in sympathetic activity.[[3]] This activity is controlled by diverse mechanisms including the renin-angiotensin system, insulin levels, leptin, and the baroreflexes.[[3,4]] We postulated that weight loss and decreased central blood volume may predispose some patients to posture-triggered vasovagal syncope. With 10kg of weight loss, total blood volume falls by about 500ml, representing 10% of circulating volume, and approximately half of this is central blood volume.[[5,6]] Central blood volume is the major determinant of stroke volume and both are observed to fall immediately when the human body is tilted head-up.[[7,8]] If tilt is continued, a progressive fall in stroke volume is the key mechanism leading to syncope.[[9]] Despite the importance of central blood volume to maintenance of mean arterial pressure in the upright position, weight loss is not listed as a risk factor for posture-triggered VVS in review articles and guidelines.[[10–13]] Based on the complex mechanisms controlling sympathetic nerve activity, the relationship between weight loss and the onset of vasovagal syncope is unlikely to be simple. For example, the sigmoid nature of baroreflex responses might prevent BP from falling until blood volume falls below a certain threshold. To clarify, the association between weight loss and the onset of VVS in our clinic population, we examined the association between weight loss and other possible confounding demographic characteristics, or medical conditions, which can also cause syncope. Secondly, we wanted to explore the temporal relationship between recent weight loss and the onset of syncope symptoms. If weight loss is an important predisposing factor to VVS then: (a) it should precede the onset of fainting; (b) it might dictate a relatively short fainting history; (c) there might be an association between the duration of fainting symptoms and the length of time over which weight loss occurs; and (d) it might trigger VVS in patients who have never fainted before. Finally, we explored non-invasive haemodynamic data from head-up tilt to see if weight loss was associated with an exaggerated fall in stroke volume, which may be a possible mechanism for VVS in these patients.
Methods
This was a retrospective case-control study comparing demographic and other characteristics, in relation to syncope histories of VVS patients, with and without weight loss. Head-up tilt responses were also compared for two weight loss groups, with those of a control group without syncope symptoms. All patients were selected from our syncope clinic and the majority were referred by general practitioners. All patients in this study were assessed in syncope clinic by the same doctor (DLJ) over a six-year study period between January 2014 and December 2019.
Clinic procedures
A week before attending clinic, patients were sent a syncope questionnaire (see Appendix) which detailed the onset, severity and duration of syncope symptoms, as well as predisposing factors, for example drug treatment, background medical conditions and syncope in childhood. There was a specific question about syncope in childhood, as life-long susceptibility might be less prevalent in patients fainting in response to recent physiological changes such as pregnancy, anaemia, or weight loss. The questionnaire was reviewed with the doctor during the first part of the clinic assessment. In clinic patients were specifically asked about weight loss, including magnitude, duration and possible aetiology. The duration of weight loss was then collated with the syncope history so that patients could confirm or refute a temporal association. The practice of a pre-clinic questionnaire was to allow patients sufficient time to remember and document syncope symptoms before being asked about weight loss. If patients were uncertain about current weight and height, these measurements were made in clinic and additionally past measurements from the electronic record were reviewed. Therefore, although quantification of recent weight loss was by self-report, these estimates were validated against other clinical records. Posture-triggered VVS was diagnosed on the basis of an expert history, a normal ECG, and the exclusion of other possibilities using an abbreviated tilt test.[[14,15]] A positive 40 minute tilt test is not sensitive for VVS and, although clinically useful in some patients, is generally not be used as an inclusion criterion for studies of this nature.[[10,16]] On the other hand, a limited tilt test is useful to exclude diagnoses such as postural tachycardia syndrome (POTS), drug-related postural hypotension (DRPH), and neurogenic orthostatic hypotension.[[15]] The clinic review included a focussed cardiovascular examination and a 12-lead ECG, followed by an abbreviated head-up tilt test, (supervised by David L Jardine). All these occurred during the same clinic session. For the tilt test patients initially rested in the horizontal position on a hydraulic tilt table and a cuff was placed around the right index finger for continuous plethysmographic blood pressure recordings (FINAPRES, The Netherlands).[[17]] When blood pressure and heart rate were stable, usually after 10 minutes, patients were tilted to the head-up 70-degree position with foot support. No provocative manoeuvres were used.[[15]] The time taken to get from horizontal to tilt angle was 20s. All patients were tilted for a maximum of ten minutes if symptoms permitted, and then returned to the horizontal position for a further five minutes. A diagnosis of VVS required all of the following:
1. a typical history, based on the questionnaire and expert review in clinic, consisting recurrent episodes of transient loss of consciousness occurring when upright in certain situations and following the usual stimuli e.g., prolonged standing, standing up too quickly, blood phobia,[[10-14]]
2. no features in the history to suggest other conditions e.g., cardiac syncope, epilepsy, orthostatic hypotension, DRPH or POTS,[[15]]
3. a normal or vasovagal response to abbreviated tilt.
Patient groups
Data on all patients attending the syncope clinic during the study period were reviewed.
Patients were not used in the study if there was: a history of bariatric surgery; weight loss exceeding 40kg; or weight loss starting more than five years before assessment in clinic.
The weight loss group (WL) were selected based on: a clinical diagnosis of VVS; and moderate, and sustained weight loss of between 5kg and 40kg within five years of the syncope clinic assessment. Weight-stable group (WS) were randomly selected from clinic patients based on: a clinical diagnosis of VVS without moderate weight loss as defined above. Control group (C) were randomly from clinic patients during the study period did not have syncope or weight loss.
Calculated blood volume was estimated using the Nadler equations.[[18]]
Men: Total blood volume = 0.3669 (Height)[[3]] + 0.03219 (Weight) + 0.604
Women: Total blood volume = 0.3561 (Height)[[3]] + 0.03308 (Weight) + 0.1833
The accuracy of the Nadler equation for estimating blood volume may vary, depending on the magnitude and the aetiology of the weight loss.[[19]]
Hemodynamic measurements included blood pressure as the mean arterial pressure (MAP), heart rate (HR), and stroke volume (SV)—all averaged over one-minute periods. Stroke volume was derived from the blood pressure waveform using the MODELFLOW algorithm and expressed as % baseline.[[17]] Baseline values were measured in the horizontal position, in the last minute before head-up tilt; early tilt included the third minute of tilt; end of tilt included the tenth minute of tilt, and this was immediately before tilt-back to the horizontal position.
Statistical methods
The three groups were compared using one-way ANOVA, for scale variables, and Chi-squared tests, for categorical variables; and as appropriate and t-tests were used to clarify differences between the groups. Linear regression and product moment correlation coefficients were used to assess associations between continuous variables.
SPPS statistics software version 26 (IBM Corp, Armonk, NY, USA) was used.
After consultation, we were advised by our local ethics committee that formal approval was not required. This study was therefore undertaken under the auspices of the Research Office (University of Otago) and our hospital Quality Control committee.
Results
Over the six-year study period, 480/1,209 (40%) of patients seen in the syncope clinic had VVS. Of these patients 57/480 (11.9%) reported a history of moderate weight loss, between 5kg and 40 kg within five years of the clinic assessment: designated the weight loss (WL) group (Figure 1). From the remaining VVS patients, n=423, a random selection was made of unmatched patients without weight loss, designated the weight stable (WS) group, n=73. Additionally, a control (C) group was selected of patients with neither of weight loss nor syncope, n=24.
The demographic and other clinical characteristics of the patients are summarised in Table 1. There was no evidence of a difference between groups in weight, gender, body mass index, or calculated blood volume. Mechanisms for weight loss in the WL group included lifestyle (n=25), unknown (n=17), anxiety or depression (n=9) and medical conditions (n=6). Medical conditions contributing to weight loss included Crohn's disease, hyperthyroidism, and dysphagia. Both syncope groups had other treated medical conditions not thought to be related to weight loss. The most frequent medications used were serotonin-specific reuptake inhibitors, proton pump inhibitors, thyroxine, and statins. Very few patients in the VVS groups were using blood pressure lowering medication; one in the WS group and two in the WL group. This was, however, likely an artefact of the clinical assessment, because patients with syncope onset coinciding with starting of medications usually had an abnormal early response to tilt and were classified as having DRPH rather than VVS.
In the WL group, mean (SD) weight loss and calculated change in blood volume were 11.5 (7) kg and 0.4 (0.2) L respectively, occurring over 18.7 (13) months. The distribution of weight loss is shown in Figure 1. Weight loss preceded the onset of syncope in 80% of patients. The duration of syncope symptoms was shorter in the WL group compared to the WS group: mean (SD) 13.5 (15) versus 32.9 (44) months, p=0.002. The distribution of syncope symptoms over time was skewed with a long right tail. Although, in the majority of both groups symptoms started within 24 months of presentation, the distribution was more skewed in the WS group: 22/75 (29%) of the WS group had prolonged symptoms versus only 8/57 (14%) in the WL group. In the WL group there was evidence of an association between the duration of symptoms and time over which weight loss occurred, product moment correlation coefficient 0.45, p=0.001; with a slope (95% CI) of 0.48 (0.22 to 0.75) (see Figure 2). There was no evidence of an association between symptom duration and the magnitude of weight loss; product moment correlation coefficient -0.03, p=0.85. The proportion of patients with a history of syncope in childhood and teenage years was lower in the WL group, 23/57 (37%) compared to the WS group, 39/73 (53%).
No patients had syncope during the tilt-test. Haemodynamic variables before tilt (baseline) and at the two measurement times are summarised in Table 2. The baseline values of the haemodynamic variables were similar in all groups. There was strong evidence of a difference in mean arterial blood pressure in the two VVS groups compared to control, there was no evidence of a difference in heart rate, and although there was no evidence of a difference in stroke volume after three minutes; the control group had a lower stroke volume after 10 minutes of tilt.
View Supplementary Material.
Discussion
We found that recent moderate weight loss was rather common in patients presenting to our clinic with vasovagal syncope. Weight loss in most patients was intentional, through dieting and exercise; however, many patients were uncertain as to the cause. Apart from weight loss, the demographic characteristics, background medical histories and medications of this group were no different to other VVS patients. VVS onset usually followed or coincided with the onset of weight loss resulting in a shorter duration of syncope symptoms before clinic assessment. The duration of VVS symptoms was associated with the time interval over which weight loss occurred. Furthermore, fewer patients with weight loss reported syncope in earlier life, suggesting that onset of syncope was secondary to a physiological change, not a life-long predisposition. In the absence of other possible confounders it seems likely that weight loss, and the associated fall in blood volume, were the most likely physiological explanations for the synchrony between the onset of weight loss and postural VVS. We further hypothesised that patients with weight loss and decreased central blood volume might have an exaggerated fall in stroke volume during head-up tilt. However, we found that even though blood pressure was lower in both syncope groups during early tilt, stroke volume changes were less than in controls. Although adipose tissue is relatively low in blood volume, studies in dieting patients report reductions of both total and central blood volume within months.[[6,20]] We calculated that moderate weight loss, on average 12kg, would include 0.4L of blood volume, half of which is centrally distributed and the main determinant of stroke volume.[[18]] During tilt SV fell by approximately 30% in all of our patients. This occurred mainly in the first three minutes, consistent with previous studies on VVS.[[9]] We did not study tilt responses beyond ten minutes and so cannot comment on how weight loss might have affected the later changes preceding syncope. Crucially, our methods did not allow direct measurements of central blood volume or absolute SV levels immediately before tilt. Instead, we compared only changes in SV after tilt which has an uncertain relationship with absolute baseline levels. Furthermore, because of the retrospective nature of this study, we cannot determine how stroke volume and blood pressure may have fallen during the months over which weight loss occurred. Presumably the blood pressure level was similar in the two syncope groups because in the WL group it had fallen from higher levels. Therefore, most of the important changes in MAP and SV probably occurred during the months before clinic assessment and it is not surprising that our tilt data was not helpful. This in no way refutes our important finding of the association between weight loss and VVS.
It is possible that the fall in blood pressure, consistently observed after weight loss predisposes some patients to recurrent vasovagal syncope.[[1,5]] New-onset syncope has been observed in other situations when blood pressure is lowered, e.g., following the introduction of antihypertensive medication and during pregnancy.[[10]] Normally, arterial baroreflexes buffer acute falls in stroke volume and blood pressure in response to postural changes. After weight loss, although the baroreflexes become more sensitive, they reset and modulate heart rate and sympathetic nerve activity at lower MAP levels.[[3,21]] However, the absolute MAP at which syncope occurs remains the same (approximately 60mmHg), therefore the lower the MAP levels at which the baroreflex curve operates, the more likely the patient is to develop syncope.[[22]] Other studies have used head-down bed rest (over three weeks) to lower blood volume and reported no changes in arterial baroreflex function despite clear demonstration of orthostatic intolerance.[[23]] We emphasise that in our study (and other weight loss studies) the weight change was greater and over a much longer time interval, therefore a major “left” shift of the baroreflex curves towards lower MAP levels is likely.[[3,21]] Re-setting is complicated and involves not only arterial but also cardiopulmonary baroreflexes which control renin, vasopressin and endothelin secretion.[[24,27]] Furthermore, cardiopulmonary baroreflexes also modulate sympathetic activity and augment arterial baroreflex function when central blood volume is decreased.[[28,29]] In view of these interactions and the nature of baroreflex responses, it is not surprising that we were unable to demonstrate a strong linear correlation between the recent duration of weight loss and syncope symptoms.
Limitations
In this study, the estimation of duration of syncope symptoms and weight loss depended on patient recall. Onset of syncope after weight loss may have biased how some patients remembered their symptoms. We think this was partly mitigated by sending the patients a written questionnaire and checking their reported weight data with the electronic record as described in the methods. We were unable to directly measure central blood volume or compare absolute stroke volume levels at baseline. Sample size and statistical power were limited by the numbers of controls and patients presenting with weight loss. Multiple comparisons between these groups may have increased the risk of a type I error. An ideal future study would prospectively measure weight loss, tilt responses, and symptoms before and after dietary intervention.
Conclusion
In the majority of patients presenting to our clinic with recurrent blackouts occurring in a standing or sitting position, the diagnosis is vasovagal syncope.[[15]] It is usually made by taking a careful history.[[10,12,14]] When the history is unclear, other less common causes can be excluded by the appropriate investigations, for example long-term cardiac monitoring for arrhythmia or tilt testing for postural hypotension.[[10,12]] If these results are normal, patients can be reassured that the diagnosis is still most likely to be VVS because it is so prevalent in all age groups. In some, the diagnosis is supported by a satisfactory response to treating predisposing factors e.g., anaemia, dehydration, prolonged bedrest, drugs, pregnancy, or fever; but in others there are no associated changes other than weight loss. The results of this study are consistent with that in a subset of patients with recent onset VVS, there may be an association with simultaneous moderate weight loss. This association is generally not recognised by patients and has not previously been reported. This may be because the temporal association between duration of weight loss and onset of syncope is not simple. We suspect that when weight stabilises at a lower level and the baroreflex mechanisms re-set, the time interval during which the patient remains symptomatic is variable. We plan a follow-up study to examine the length of this time interval and what baroreflex changes occur. In the meantime, we reassure our patients that the symptoms will improve (without any form of medication), and they are discouraged from putting the weight back on.
Summary
Abstract
Aim
In adults, the onset of vasovagal syncope is often unexplained. We wished to explore if moderate weight loss triggers the onset of vasovagal syncope (VVS).
Method
A retrospective case-control study comparing demographic characteristic, syncope symptoms, and tilt-table results of patients who had recently lost weight (n=57), with randomly selected weight-stable patients (n=73), and controls, patients without syncope (n=24).
Results
VVS was diagnosed in 480 out of 1,209 clinic patients of whom 57 (11.9%) reported moderate weight loss. The mean (SD) reported weight loss was 11.5 (7) kg over 18.7 (13) months. Age and gender did not differ between groups: in the weight loss, weight stable, and control groups the mean age was 44.8, 45.2, and 44 years respectively; and proportion female 60%, 64%, and 54%. Body weight, mass index and calculated blood volume at presentation were also similar in the different groups. Weight loss preceded or coincided the onset of syncope in 80% of patients; the length of time over which weight loss occurred was associated with the length of time of syncope symptoms, product moment correlation coefficient 0.45, p=0.001. Syncope in childhood and teenage years was less frequent in the weight loss group compared to the weight stable group: 37% vs 53%. After 10 minutes of head-up tilt, stroke volume was preserved in both syncope groups compared to controls; percentage of baseline mean (SD) in the weight loss, weight stable, and control groups: 71(18), 69(10), and 61 (11) respectively; despite lower blood pressure in the weight loss groups with mean (SD) 90 (14) mmHg, 93 (13) and 103 (14) respectively.
Conclusion
Some patients have onset of VVS within a few months of weight loss resulting in earlier presentation to clinic. The physiological mechanism for this is uncertain.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
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4) Lambert E, Esler MD, Schlaich MP et al. Obesity-Associated Organ Damage and Sympathetic Nervous Activity. Hypertension 2019;73:1150-1159.
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6) Reisin E, Frohlich ED, Messerli FH et al. Cardiovascular changes after weight reduction surgery. Ann Intern Med. 1983;98:315-319.
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8) van Lieshout JJ, Harms MP, Pott F et al. Stroke volume of the heart and thoracic fluid volume during head-up and head-down tilt in humans. Acta Anaesthesiol Scand. 2005;49:1287-1292.
9) Verheyden B, Liu J, van Dijk N et al.. Steep fall in cardiac output is the main determinant of hypotension in drug-free and nitroglycerin-induced orthostatic vasovagal syncope. Heart Rhythm. 2008;5:1695-1701.
10) Brignole M, Moya A, de Lange FJ et al. Guidelines for the diagnosis and management of vasovagal syncope. Eur Heart J 2018; 39:1883-1948.
11) Colman N, Nahm K, Ganzeboom KS et al. Epidemiology of reflex syncope. Clin Autonom Res 2004; 14 Suppl 1:9-17.
12) Shen WK, Sheldon RS. ACC/AHA/HRS guidelines for the evaluation and management of patients with syncope. J Am Coll Cardiol 2017;70:e41-e109.
13) van Dijk GG, Thijs RD, Benditt DG and Wouter Wieling. A guide to disorders causing transient loss of consciousness: focus on syncope. Nat Rev Neurol 2009;5:438-448.
14) Wieling W, Kaufmann H. What is the best method to diagnose vasovagal syncope? Clin Autonom Res 2021;3:335-337.
15) Al-Busaidi IS, Jardine DL. Different types of syncope presenting to clinic: do we miss cardiac syncope? Heart Lung Circ. 2019:S1443-9506(19)31454-4. doi: 10.1016/j.hlc.2019.09.008.
16) Moya A. Tilt testing and neurally-mediated syncope: too many protocols for one condition or specific protocols for different situations? Eur Heart J 2009;30:2174-2176.
17) Bogert LW, van Lieshout JJ. Non-invasive pulsatile arterial pressure and stroke volume changes from the human finger. Exp Physiol. 2005;90:437-446.
18) Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery. 1962;51:224-232.
19) Funkhouser RK, Pritchard WH, Little AS. Change in relationship of blood volume to weight in congestive heart failure. Circulation 1957;16:548-557.
20) Alexander JK, Peterson KL. Cardiovascular effects of weight reduction. Circulation 1972;45:310-318.
21) Alvarez GE, Davy BM, Ballard TP et al. Weight loss increases cardiovagal baroreflex function in obese young and older men. Am J Physiol Endocrinol Metab. 2005;289:E665-E669.
22) Wieling W, Thijs RD, van Dijk N et al. Symptoms and signs of syncope: a review of the link between physiology and clinical clues. Brain 2009; 132: 2630-2642.
23) Kamiya A, Michikami D, Fu Q et al. Pathophysiology of orthostatic hypotension after bedrest: paradoxical sympathetic withdrawal. Am J Physiol Heart Circ Physiol 2003;285:H1158-H1167.
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Postural symptoms and vasovagal syncope (VVS) syncope are recognised chronic complications of severe weight loss, greater than 40kg; following bariatric surgery.[[1,2]] The relationship of syncope symptoms within months of moderate weight loss, between 5kg and 40kg, has not been reported. Additionally, moderate weight loss is usually achieved by lifestyle changes, for example dieting and exercise, rather than bariatric surgery. At our syncope clinic we had noted an apparent increase in the number of patients presenting for assessment with recent VVS apparently triggered by moderate weight loss.
The benefits of weight loss include decreased blood pressure and blood volume, both of which are probably secondary to a fall in sympathetic activity.[[3]] This activity is controlled by diverse mechanisms including the renin-angiotensin system, insulin levels, leptin, and the baroreflexes.[[3,4]] We postulated that weight loss and decreased central blood volume may predispose some patients to posture-triggered vasovagal syncope. With 10kg of weight loss, total blood volume falls by about 500ml, representing 10% of circulating volume, and approximately half of this is central blood volume.[[5,6]] Central blood volume is the major determinant of stroke volume and both are observed to fall immediately when the human body is tilted head-up.[[7,8]] If tilt is continued, a progressive fall in stroke volume is the key mechanism leading to syncope.[[9]] Despite the importance of central blood volume to maintenance of mean arterial pressure in the upright position, weight loss is not listed as a risk factor for posture-triggered VVS in review articles and guidelines.[[10–13]] Based on the complex mechanisms controlling sympathetic nerve activity, the relationship between weight loss and the onset of vasovagal syncope is unlikely to be simple. For example, the sigmoid nature of baroreflex responses might prevent BP from falling until blood volume falls below a certain threshold. To clarify, the association between weight loss and the onset of VVS in our clinic population, we examined the association between weight loss and other possible confounding demographic characteristics, or medical conditions, which can also cause syncope. Secondly, we wanted to explore the temporal relationship between recent weight loss and the onset of syncope symptoms. If weight loss is an important predisposing factor to VVS then: (a) it should precede the onset of fainting; (b) it might dictate a relatively short fainting history; (c) there might be an association between the duration of fainting symptoms and the length of time over which weight loss occurs; and (d) it might trigger VVS in patients who have never fainted before. Finally, we explored non-invasive haemodynamic data from head-up tilt to see if weight loss was associated with an exaggerated fall in stroke volume, which may be a possible mechanism for VVS in these patients.
Methods
This was a retrospective case-control study comparing demographic and other characteristics, in relation to syncope histories of VVS patients, with and without weight loss. Head-up tilt responses were also compared for two weight loss groups, with those of a control group without syncope symptoms. All patients were selected from our syncope clinic and the majority were referred by general practitioners. All patients in this study were assessed in syncope clinic by the same doctor (DLJ) over a six-year study period between January 2014 and December 2019.
Clinic procedures
A week before attending clinic, patients were sent a syncope questionnaire (see Appendix) which detailed the onset, severity and duration of syncope symptoms, as well as predisposing factors, for example drug treatment, background medical conditions and syncope in childhood. There was a specific question about syncope in childhood, as life-long susceptibility might be less prevalent in patients fainting in response to recent physiological changes such as pregnancy, anaemia, or weight loss. The questionnaire was reviewed with the doctor during the first part of the clinic assessment. In clinic patients were specifically asked about weight loss, including magnitude, duration and possible aetiology. The duration of weight loss was then collated with the syncope history so that patients could confirm or refute a temporal association. The practice of a pre-clinic questionnaire was to allow patients sufficient time to remember and document syncope symptoms before being asked about weight loss. If patients were uncertain about current weight and height, these measurements were made in clinic and additionally past measurements from the electronic record were reviewed. Therefore, although quantification of recent weight loss was by self-report, these estimates were validated against other clinical records. Posture-triggered VVS was diagnosed on the basis of an expert history, a normal ECG, and the exclusion of other possibilities using an abbreviated tilt test.[[14,15]] A positive 40 minute tilt test is not sensitive for VVS and, although clinically useful in some patients, is generally not be used as an inclusion criterion for studies of this nature.[[10,16]] On the other hand, a limited tilt test is useful to exclude diagnoses such as postural tachycardia syndrome (POTS), drug-related postural hypotension (DRPH), and neurogenic orthostatic hypotension.[[15]] The clinic review included a focussed cardiovascular examination and a 12-lead ECG, followed by an abbreviated head-up tilt test, (supervised by David L Jardine). All these occurred during the same clinic session. For the tilt test patients initially rested in the horizontal position on a hydraulic tilt table and a cuff was placed around the right index finger for continuous plethysmographic blood pressure recordings (FINAPRES, The Netherlands).[[17]] When blood pressure and heart rate were stable, usually after 10 minutes, patients were tilted to the head-up 70-degree position with foot support. No provocative manoeuvres were used.[[15]] The time taken to get from horizontal to tilt angle was 20s. All patients were tilted for a maximum of ten minutes if symptoms permitted, and then returned to the horizontal position for a further five minutes. A diagnosis of VVS required all of the following:
1. a typical history, based on the questionnaire and expert review in clinic, consisting recurrent episodes of transient loss of consciousness occurring when upright in certain situations and following the usual stimuli e.g., prolonged standing, standing up too quickly, blood phobia,[[10-14]]
2. no features in the history to suggest other conditions e.g., cardiac syncope, epilepsy, orthostatic hypotension, DRPH or POTS,[[15]]
3. a normal or vasovagal response to abbreviated tilt.
Patient groups
Data on all patients attending the syncope clinic during the study period were reviewed.
Patients were not used in the study if there was: a history of bariatric surgery; weight loss exceeding 40kg; or weight loss starting more than five years before assessment in clinic.
The weight loss group (WL) were selected based on: a clinical diagnosis of VVS; and moderate, and sustained weight loss of between 5kg and 40kg within five years of the syncope clinic assessment. Weight-stable group (WS) were randomly selected from clinic patients based on: a clinical diagnosis of VVS without moderate weight loss as defined above. Control group (C) were randomly from clinic patients during the study period did not have syncope or weight loss.
Calculated blood volume was estimated using the Nadler equations.[[18]]
Men: Total blood volume = 0.3669 (Height)[[3]] + 0.03219 (Weight) + 0.604
Women: Total blood volume = 0.3561 (Height)[[3]] + 0.03308 (Weight) + 0.1833
The accuracy of the Nadler equation for estimating blood volume may vary, depending on the magnitude and the aetiology of the weight loss.[[19]]
Hemodynamic measurements included blood pressure as the mean arterial pressure (MAP), heart rate (HR), and stroke volume (SV)—all averaged over one-minute periods. Stroke volume was derived from the blood pressure waveform using the MODELFLOW algorithm and expressed as % baseline.[[17]] Baseline values were measured in the horizontal position, in the last minute before head-up tilt; early tilt included the third minute of tilt; end of tilt included the tenth minute of tilt, and this was immediately before tilt-back to the horizontal position.
Statistical methods
The three groups were compared using one-way ANOVA, for scale variables, and Chi-squared tests, for categorical variables; and as appropriate and t-tests were used to clarify differences between the groups. Linear regression and product moment correlation coefficients were used to assess associations between continuous variables.
SPPS statistics software version 26 (IBM Corp, Armonk, NY, USA) was used.
After consultation, we were advised by our local ethics committee that formal approval was not required. This study was therefore undertaken under the auspices of the Research Office (University of Otago) and our hospital Quality Control committee.
Results
Over the six-year study period, 480/1,209 (40%) of patients seen in the syncope clinic had VVS. Of these patients 57/480 (11.9%) reported a history of moderate weight loss, between 5kg and 40 kg within five years of the clinic assessment: designated the weight loss (WL) group (Figure 1). From the remaining VVS patients, n=423, a random selection was made of unmatched patients without weight loss, designated the weight stable (WS) group, n=73. Additionally, a control (C) group was selected of patients with neither of weight loss nor syncope, n=24.
The demographic and other clinical characteristics of the patients are summarised in Table 1. There was no evidence of a difference between groups in weight, gender, body mass index, or calculated blood volume. Mechanisms for weight loss in the WL group included lifestyle (n=25), unknown (n=17), anxiety or depression (n=9) and medical conditions (n=6). Medical conditions contributing to weight loss included Crohn's disease, hyperthyroidism, and dysphagia. Both syncope groups had other treated medical conditions not thought to be related to weight loss. The most frequent medications used were serotonin-specific reuptake inhibitors, proton pump inhibitors, thyroxine, and statins. Very few patients in the VVS groups were using blood pressure lowering medication; one in the WS group and two in the WL group. This was, however, likely an artefact of the clinical assessment, because patients with syncope onset coinciding with starting of medications usually had an abnormal early response to tilt and were classified as having DRPH rather than VVS.
In the WL group, mean (SD) weight loss and calculated change in blood volume were 11.5 (7) kg and 0.4 (0.2) L respectively, occurring over 18.7 (13) months. The distribution of weight loss is shown in Figure 1. Weight loss preceded the onset of syncope in 80% of patients. The duration of syncope symptoms was shorter in the WL group compared to the WS group: mean (SD) 13.5 (15) versus 32.9 (44) months, p=0.002. The distribution of syncope symptoms over time was skewed with a long right tail. Although, in the majority of both groups symptoms started within 24 months of presentation, the distribution was more skewed in the WS group: 22/75 (29%) of the WS group had prolonged symptoms versus only 8/57 (14%) in the WL group. In the WL group there was evidence of an association between the duration of symptoms and time over which weight loss occurred, product moment correlation coefficient 0.45, p=0.001; with a slope (95% CI) of 0.48 (0.22 to 0.75) (see Figure 2). There was no evidence of an association between symptom duration and the magnitude of weight loss; product moment correlation coefficient -0.03, p=0.85. The proportion of patients with a history of syncope in childhood and teenage years was lower in the WL group, 23/57 (37%) compared to the WS group, 39/73 (53%).
No patients had syncope during the tilt-test. Haemodynamic variables before tilt (baseline) and at the two measurement times are summarised in Table 2. The baseline values of the haemodynamic variables were similar in all groups. There was strong evidence of a difference in mean arterial blood pressure in the two VVS groups compared to control, there was no evidence of a difference in heart rate, and although there was no evidence of a difference in stroke volume after three minutes; the control group had a lower stroke volume after 10 minutes of tilt.
View Supplementary Material.
Discussion
We found that recent moderate weight loss was rather common in patients presenting to our clinic with vasovagal syncope. Weight loss in most patients was intentional, through dieting and exercise; however, many patients were uncertain as to the cause. Apart from weight loss, the demographic characteristics, background medical histories and medications of this group were no different to other VVS patients. VVS onset usually followed or coincided with the onset of weight loss resulting in a shorter duration of syncope symptoms before clinic assessment. The duration of VVS symptoms was associated with the time interval over which weight loss occurred. Furthermore, fewer patients with weight loss reported syncope in earlier life, suggesting that onset of syncope was secondary to a physiological change, not a life-long predisposition. In the absence of other possible confounders it seems likely that weight loss, and the associated fall in blood volume, were the most likely physiological explanations for the synchrony between the onset of weight loss and postural VVS. We further hypothesised that patients with weight loss and decreased central blood volume might have an exaggerated fall in stroke volume during head-up tilt. However, we found that even though blood pressure was lower in both syncope groups during early tilt, stroke volume changes were less than in controls. Although adipose tissue is relatively low in blood volume, studies in dieting patients report reductions of both total and central blood volume within months.[[6,20]] We calculated that moderate weight loss, on average 12kg, would include 0.4L of blood volume, half of which is centrally distributed and the main determinant of stroke volume.[[18]] During tilt SV fell by approximately 30% in all of our patients. This occurred mainly in the first three minutes, consistent with previous studies on VVS.[[9]] We did not study tilt responses beyond ten minutes and so cannot comment on how weight loss might have affected the later changes preceding syncope. Crucially, our methods did not allow direct measurements of central blood volume or absolute SV levels immediately before tilt. Instead, we compared only changes in SV after tilt which has an uncertain relationship with absolute baseline levels. Furthermore, because of the retrospective nature of this study, we cannot determine how stroke volume and blood pressure may have fallen during the months over which weight loss occurred. Presumably the blood pressure level was similar in the two syncope groups because in the WL group it had fallen from higher levels. Therefore, most of the important changes in MAP and SV probably occurred during the months before clinic assessment and it is not surprising that our tilt data was not helpful. This in no way refutes our important finding of the association between weight loss and VVS.
It is possible that the fall in blood pressure, consistently observed after weight loss predisposes some patients to recurrent vasovagal syncope.[[1,5]] New-onset syncope has been observed in other situations when blood pressure is lowered, e.g., following the introduction of antihypertensive medication and during pregnancy.[[10]] Normally, arterial baroreflexes buffer acute falls in stroke volume and blood pressure in response to postural changes. After weight loss, although the baroreflexes become more sensitive, they reset and modulate heart rate and sympathetic nerve activity at lower MAP levels.[[3,21]] However, the absolute MAP at which syncope occurs remains the same (approximately 60mmHg), therefore the lower the MAP levels at which the baroreflex curve operates, the more likely the patient is to develop syncope.[[22]] Other studies have used head-down bed rest (over three weeks) to lower blood volume and reported no changes in arterial baroreflex function despite clear demonstration of orthostatic intolerance.[[23]] We emphasise that in our study (and other weight loss studies) the weight change was greater and over a much longer time interval, therefore a major “left” shift of the baroreflex curves towards lower MAP levels is likely.[[3,21]] Re-setting is complicated and involves not only arterial but also cardiopulmonary baroreflexes which control renin, vasopressin and endothelin secretion.[[24,27]] Furthermore, cardiopulmonary baroreflexes also modulate sympathetic activity and augment arterial baroreflex function when central blood volume is decreased.[[28,29]] In view of these interactions and the nature of baroreflex responses, it is not surprising that we were unable to demonstrate a strong linear correlation between the recent duration of weight loss and syncope symptoms.
Limitations
In this study, the estimation of duration of syncope symptoms and weight loss depended on patient recall. Onset of syncope after weight loss may have biased how some patients remembered their symptoms. We think this was partly mitigated by sending the patients a written questionnaire and checking their reported weight data with the electronic record as described in the methods. We were unable to directly measure central blood volume or compare absolute stroke volume levels at baseline. Sample size and statistical power were limited by the numbers of controls and patients presenting with weight loss. Multiple comparisons between these groups may have increased the risk of a type I error. An ideal future study would prospectively measure weight loss, tilt responses, and symptoms before and after dietary intervention.
Conclusion
In the majority of patients presenting to our clinic with recurrent blackouts occurring in a standing or sitting position, the diagnosis is vasovagal syncope.[[15]] It is usually made by taking a careful history.[[10,12,14]] When the history is unclear, other less common causes can be excluded by the appropriate investigations, for example long-term cardiac monitoring for arrhythmia or tilt testing for postural hypotension.[[10,12]] If these results are normal, patients can be reassured that the diagnosis is still most likely to be VVS because it is so prevalent in all age groups. In some, the diagnosis is supported by a satisfactory response to treating predisposing factors e.g., anaemia, dehydration, prolonged bedrest, drugs, pregnancy, or fever; but in others there are no associated changes other than weight loss. The results of this study are consistent with that in a subset of patients with recent onset VVS, there may be an association with simultaneous moderate weight loss. This association is generally not recognised by patients and has not previously been reported. This may be because the temporal association between duration of weight loss and onset of syncope is not simple. We suspect that when weight stabilises at a lower level and the baroreflex mechanisms re-set, the time interval during which the patient remains symptomatic is variable. We plan a follow-up study to examine the length of this time interval and what baroreflex changes occur. In the meantime, we reassure our patients that the symptoms will improve (without any form of medication), and they are discouraged from putting the weight back on.
Summary
Abstract
Aim
In adults, the onset of vasovagal syncope is often unexplained. We wished to explore if moderate weight loss triggers the onset of vasovagal syncope (VVS).
Method
A retrospective case-control study comparing demographic characteristic, syncope symptoms, and tilt-table results of patients who had recently lost weight (n=57), with randomly selected weight-stable patients (n=73), and controls, patients without syncope (n=24).
Results
VVS was diagnosed in 480 out of 1,209 clinic patients of whom 57 (11.9%) reported moderate weight loss. The mean (SD) reported weight loss was 11.5 (7) kg over 18.7 (13) months. Age and gender did not differ between groups: in the weight loss, weight stable, and control groups the mean age was 44.8, 45.2, and 44 years respectively; and proportion female 60%, 64%, and 54%. Body weight, mass index and calculated blood volume at presentation were also similar in the different groups. Weight loss preceded or coincided the onset of syncope in 80% of patients; the length of time over which weight loss occurred was associated with the length of time of syncope symptoms, product moment correlation coefficient 0.45, p=0.001. Syncope in childhood and teenage years was less frequent in the weight loss group compared to the weight stable group: 37% vs 53%. After 10 minutes of head-up tilt, stroke volume was preserved in both syncope groups compared to controls; percentage of baseline mean (SD) in the weight loss, weight stable, and control groups: 71(18), 69(10), and 61 (11) respectively; despite lower blood pressure in the weight loss groups with mean (SD) 90 (14) mmHg, 93 (13) and 103 (14) respectively.
Conclusion
Some patients have onset of VVS within a few months of weight loss resulting in earlier presentation to clinic. The physiological mechanism for this is uncertain.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1) Billakanty SR, Kigman MD, Kanjwal YM et al. New onset orthostatic intolerance following bariatric surgery. Pacing Clin Electrophysiol 2008;31:884-888.
2) Ponnusamy V, Owens AP, Purkayastha S, et al. Orthostatic intolerance and autonomic dysfunction following bariatric surgery: a retrospective study and review of the literature. Autonom Neurosci 2016;198:1-7.
3) Grassi G, Seravalle G, Columbo M et al. Weight reduction, sympathetic nerve traffic and arterial baroreflex in obese normotensive humans.Circulation. 1998;97:2037-2042.
4) Lambert E, Esler MD, Schlaich MP et al. Obesity-Associated Organ Damage and Sympathetic Nervous Activity. Hypertension 2019;73:1150-1159.
5) Messerli FH, Christie B, DeCarvalho JG et al. Obesity and essential hypertension: hemodynamics, intravascular volume, sodium excretion and plasma renin activity. Arch Intern Med. 1981;141:81-85.
6) Reisin E, Frohlich ED, Messerli FH et al. Cardiovascular changes after weight reduction surgery. Ann Intern Med. 1983;98:315-319.
7) Stewart JM, McLeod KJ, Sanyal S et al. Relation of postural vasovagal syncope to splanchnic hypervolemia in adolescents. Circulation. 2004; 110:2575-2581.
8) van Lieshout JJ, Harms MP, Pott F et al. Stroke volume of the heart and thoracic fluid volume during head-up and head-down tilt in humans. Acta Anaesthesiol Scand. 2005;49:1287-1292.
9) Verheyden B, Liu J, van Dijk N et al.. Steep fall in cardiac output is the main determinant of hypotension in drug-free and nitroglycerin-induced orthostatic vasovagal syncope. Heart Rhythm. 2008;5:1695-1701.
10) Brignole M, Moya A, de Lange FJ et al. Guidelines for the diagnosis and management of vasovagal syncope. Eur Heart J 2018; 39:1883-1948.
11) Colman N, Nahm K, Ganzeboom KS et al. Epidemiology of reflex syncope. Clin Autonom Res 2004; 14 Suppl 1:9-17.
12) Shen WK, Sheldon RS. ACC/AHA/HRS guidelines for the evaluation and management of patients with syncope. J Am Coll Cardiol 2017;70:e41-e109.
13) van Dijk GG, Thijs RD, Benditt DG and Wouter Wieling. A guide to disorders causing transient loss of consciousness: focus on syncope. Nat Rev Neurol 2009;5:438-448.
14) Wieling W, Kaufmann H. What is the best method to diagnose vasovagal syncope? Clin Autonom Res 2021;3:335-337.
15) Al-Busaidi IS, Jardine DL. Different types of syncope presenting to clinic: do we miss cardiac syncope? Heart Lung Circ. 2019:S1443-9506(19)31454-4. doi: 10.1016/j.hlc.2019.09.008.
16) Moya A. Tilt testing and neurally-mediated syncope: too many protocols for one condition or specific protocols for different situations? Eur Heart J 2009;30:2174-2176.
17) Bogert LW, van Lieshout JJ. Non-invasive pulsatile arterial pressure and stroke volume changes from the human finger. Exp Physiol. 2005;90:437-446.
18) Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery. 1962;51:224-232.
19) Funkhouser RK, Pritchard WH, Little AS. Change in relationship of blood volume to weight in congestive heart failure. Circulation 1957;16:548-557.
20) Alexander JK, Peterson KL. Cardiovascular effects of weight reduction. Circulation 1972;45:310-318.
21) Alvarez GE, Davy BM, Ballard TP et al. Weight loss increases cardiovagal baroreflex function in obese young and older men. Am J Physiol Endocrinol Metab. 2005;289:E665-E669.
22) Wieling W, Thijs RD, van Dijk N et al. Symptoms and signs of syncope: a review of the link between physiology and clinical clues. Brain 2009; 132: 2630-2642.
23) Kamiya A, Michikami D, Fu Q et al. Pathophysiology of orthostatic hypotension after bedrest: paradoxical sympathetic withdrawal. Am J Physiol Heart Circ Physiol 2003;285:H1158-H1167.
24) Grassi G, Giannattasio C, Cuspidi C et al. Cardiopulmonary receptor regulation of renin release. Am J Med. 1988;84 (Suppl 3A):97-104.
25) Hainsworth R. Cardiovascular control from cardiac and pulmonary vascular receptors. Exp Physiol 2014;99:312-319.
26) Jacobsen T, Morgan B, Scherrer U et al. Relative contributions of cardiopulmonary and sinoaortic baroreflexes in causing sympathetic activation in human skeletal muscle circulation during orthostatic stress. Circ Res. 1993;73:367-378.
27) Vissing SF, Scherrer U, Victor RG. Relation Between Sympathetic Outflow and Vascular Resistance in the Calf During Perturbations in Central Venous Pressure. Evidence for Cardiopulmonary Afferent Regulation of Calf Vascular Resistance in Humans. Circ Res 1989;65:1710-1717.
28) Ichinose M, Saito M, Kitano A et al. Modulation of arterial baroreflex dynamic response during mild orthostastic stress in humans. J Physiol 2004;557:321-330.
29) Ogoh S, Brothers RM, Barnes Q et al. Effects of changes in central blood volume on carotid-vasomotor baroreflex sensitivity at rest and during exercise. J Appl Physiol 2006;101:68-75.
Contact diana@nzma.org.nz
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Postural symptoms and vasovagal syncope (VVS) syncope are recognised chronic complications of severe weight loss, greater than 40kg; following bariatric surgery.[[1,2]] The relationship of syncope symptoms within months of moderate weight loss, between 5kg and 40kg, has not been reported. Additionally, moderate weight loss is usually achieved by lifestyle changes, for example dieting and exercise, rather than bariatric surgery. At our syncope clinic we had noted an apparent increase in the number of patients presenting for assessment with recent VVS apparently triggered by moderate weight loss.
The benefits of weight loss include decreased blood pressure and blood volume, both of which are probably secondary to a fall in sympathetic activity.[[3]] This activity is controlled by diverse mechanisms including the renin-angiotensin system, insulin levels, leptin, and the baroreflexes.[[3,4]] We postulated that weight loss and decreased central blood volume may predispose some patients to posture-triggered vasovagal syncope. With 10kg of weight loss, total blood volume falls by about 500ml, representing 10% of circulating volume, and approximately half of this is central blood volume.[[5,6]] Central blood volume is the major determinant of stroke volume and both are observed to fall immediately when the human body is tilted head-up.[[7,8]] If tilt is continued, a progressive fall in stroke volume is the key mechanism leading to syncope.[[9]] Despite the importance of central blood volume to maintenance of mean arterial pressure in the upright position, weight loss is not listed as a risk factor for posture-triggered VVS in review articles and guidelines.[[10–13]] Based on the complex mechanisms controlling sympathetic nerve activity, the relationship between weight loss and the onset of vasovagal syncope is unlikely to be simple. For example, the sigmoid nature of baroreflex responses might prevent BP from falling until blood volume falls below a certain threshold. To clarify, the association between weight loss and the onset of VVS in our clinic population, we examined the association between weight loss and other possible confounding demographic characteristics, or medical conditions, which can also cause syncope. Secondly, we wanted to explore the temporal relationship between recent weight loss and the onset of syncope symptoms. If weight loss is an important predisposing factor to VVS then: (a) it should precede the onset of fainting; (b) it might dictate a relatively short fainting history; (c) there might be an association between the duration of fainting symptoms and the length of time over which weight loss occurs; and (d) it might trigger VVS in patients who have never fainted before. Finally, we explored non-invasive haemodynamic data from head-up tilt to see if weight loss was associated with an exaggerated fall in stroke volume, which may be a possible mechanism for VVS in these patients.
Methods
This was a retrospective case-control study comparing demographic and other characteristics, in relation to syncope histories of VVS patients, with and without weight loss. Head-up tilt responses were also compared for two weight loss groups, with those of a control group without syncope symptoms. All patients were selected from our syncope clinic and the majority were referred by general practitioners. All patients in this study were assessed in syncope clinic by the same doctor (DLJ) over a six-year study period between January 2014 and December 2019.
Clinic procedures
A week before attending clinic, patients were sent a syncope questionnaire (see Appendix) which detailed the onset, severity and duration of syncope symptoms, as well as predisposing factors, for example drug treatment, background medical conditions and syncope in childhood. There was a specific question about syncope in childhood, as life-long susceptibility might be less prevalent in patients fainting in response to recent physiological changes such as pregnancy, anaemia, or weight loss. The questionnaire was reviewed with the doctor during the first part of the clinic assessment. In clinic patients were specifically asked about weight loss, including magnitude, duration and possible aetiology. The duration of weight loss was then collated with the syncope history so that patients could confirm or refute a temporal association. The practice of a pre-clinic questionnaire was to allow patients sufficient time to remember and document syncope symptoms before being asked about weight loss. If patients were uncertain about current weight and height, these measurements were made in clinic and additionally past measurements from the electronic record were reviewed. Therefore, although quantification of recent weight loss was by self-report, these estimates were validated against other clinical records. Posture-triggered VVS was diagnosed on the basis of an expert history, a normal ECG, and the exclusion of other possibilities using an abbreviated tilt test.[[14,15]] A positive 40 minute tilt test is not sensitive for VVS and, although clinically useful in some patients, is generally not be used as an inclusion criterion for studies of this nature.[[10,16]] On the other hand, a limited tilt test is useful to exclude diagnoses such as postural tachycardia syndrome (POTS), drug-related postural hypotension (DRPH), and neurogenic orthostatic hypotension.[[15]] The clinic review included a focussed cardiovascular examination and a 12-lead ECG, followed by an abbreviated head-up tilt test, (supervised by David L Jardine). All these occurred during the same clinic session. For the tilt test patients initially rested in the horizontal position on a hydraulic tilt table and a cuff was placed around the right index finger for continuous plethysmographic blood pressure recordings (FINAPRES, The Netherlands).[[17]] When blood pressure and heart rate were stable, usually after 10 minutes, patients were tilted to the head-up 70-degree position with foot support. No provocative manoeuvres were used.[[15]] The time taken to get from horizontal to tilt angle was 20s. All patients were tilted for a maximum of ten minutes if symptoms permitted, and then returned to the horizontal position for a further five minutes. A diagnosis of VVS required all of the following:
1. a typical history, based on the questionnaire and expert review in clinic, consisting recurrent episodes of transient loss of consciousness occurring when upright in certain situations and following the usual stimuli e.g., prolonged standing, standing up too quickly, blood phobia,[[10-14]]
2. no features in the history to suggest other conditions e.g., cardiac syncope, epilepsy, orthostatic hypotension, DRPH or POTS,[[15]]
3. a normal or vasovagal response to abbreviated tilt.
Patient groups
Data on all patients attending the syncope clinic during the study period were reviewed.
Patients were not used in the study if there was: a history of bariatric surgery; weight loss exceeding 40kg; or weight loss starting more than five years before assessment in clinic.
The weight loss group (WL) were selected based on: a clinical diagnosis of VVS; and moderate, and sustained weight loss of between 5kg and 40kg within five years of the syncope clinic assessment. Weight-stable group (WS) were randomly selected from clinic patients based on: a clinical diagnosis of VVS without moderate weight loss as defined above. Control group (C) were randomly from clinic patients during the study period did not have syncope or weight loss.
Calculated blood volume was estimated using the Nadler equations.[[18]]
Men: Total blood volume = 0.3669 (Height)[[3]] + 0.03219 (Weight) + 0.604
Women: Total blood volume = 0.3561 (Height)[[3]] + 0.03308 (Weight) + 0.1833
The accuracy of the Nadler equation for estimating blood volume may vary, depending on the magnitude and the aetiology of the weight loss.[[19]]
Hemodynamic measurements included blood pressure as the mean arterial pressure (MAP), heart rate (HR), and stroke volume (SV)—all averaged over one-minute periods. Stroke volume was derived from the blood pressure waveform using the MODELFLOW algorithm and expressed as % baseline.[[17]] Baseline values were measured in the horizontal position, in the last minute before head-up tilt; early tilt included the third minute of tilt; end of tilt included the tenth minute of tilt, and this was immediately before tilt-back to the horizontal position.
Statistical methods
The three groups were compared using one-way ANOVA, for scale variables, and Chi-squared tests, for categorical variables; and as appropriate and t-tests were used to clarify differences between the groups. Linear regression and product moment correlation coefficients were used to assess associations between continuous variables.
SPPS statistics software version 26 (IBM Corp, Armonk, NY, USA) was used.
After consultation, we were advised by our local ethics committee that formal approval was not required. This study was therefore undertaken under the auspices of the Research Office (University of Otago) and our hospital Quality Control committee.
Results
Over the six-year study period, 480/1,209 (40%) of patients seen in the syncope clinic had VVS. Of these patients 57/480 (11.9%) reported a history of moderate weight loss, between 5kg and 40 kg within five years of the clinic assessment: designated the weight loss (WL) group (Figure 1). From the remaining VVS patients, n=423, a random selection was made of unmatched patients without weight loss, designated the weight stable (WS) group, n=73. Additionally, a control (C) group was selected of patients with neither of weight loss nor syncope, n=24.
The demographic and other clinical characteristics of the patients are summarised in Table 1. There was no evidence of a difference between groups in weight, gender, body mass index, or calculated blood volume. Mechanisms for weight loss in the WL group included lifestyle (n=25), unknown (n=17), anxiety or depression (n=9) and medical conditions (n=6). Medical conditions contributing to weight loss included Crohn's disease, hyperthyroidism, and dysphagia. Both syncope groups had other treated medical conditions not thought to be related to weight loss. The most frequent medications used were serotonin-specific reuptake inhibitors, proton pump inhibitors, thyroxine, and statins. Very few patients in the VVS groups were using blood pressure lowering medication; one in the WS group and two in the WL group. This was, however, likely an artefact of the clinical assessment, because patients with syncope onset coinciding with starting of medications usually had an abnormal early response to tilt and were classified as having DRPH rather than VVS.
In the WL group, mean (SD) weight loss and calculated change in blood volume were 11.5 (7) kg and 0.4 (0.2) L respectively, occurring over 18.7 (13) months. The distribution of weight loss is shown in Figure 1. Weight loss preceded the onset of syncope in 80% of patients. The duration of syncope symptoms was shorter in the WL group compared to the WS group: mean (SD) 13.5 (15) versus 32.9 (44) months, p=0.002. The distribution of syncope symptoms over time was skewed with a long right tail. Although, in the majority of both groups symptoms started within 24 months of presentation, the distribution was more skewed in the WS group: 22/75 (29%) of the WS group had prolonged symptoms versus only 8/57 (14%) in the WL group. In the WL group there was evidence of an association between the duration of symptoms and time over which weight loss occurred, product moment correlation coefficient 0.45, p=0.001; with a slope (95% CI) of 0.48 (0.22 to 0.75) (see Figure 2). There was no evidence of an association between symptom duration and the magnitude of weight loss; product moment correlation coefficient -0.03, p=0.85. The proportion of patients with a history of syncope in childhood and teenage years was lower in the WL group, 23/57 (37%) compared to the WS group, 39/73 (53%).
No patients had syncope during the tilt-test. Haemodynamic variables before tilt (baseline) and at the two measurement times are summarised in Table 2. The baseline values of the haemodynamic variables were similar in all groups. There was strong evidence of a difference in mean arterial blood pressure in the two VVS groups compared to control, there was no evidence of a difference in heart rate, and although there was no evidence of a difference in stroke volume after three minutes; the control group had a lower stroke volume after 10 minutes of tilt.
View Supplementary Material.
Discussion
We found that recent moderate weight loss was rather common in patients presenting to our clinic with vasovagal syncope. Weight loss in most patients was intentional, through dieting and exercise; however, many patients were uncertain as to the cause. Apart from weight loss, the demographic characteristics, background medical histories and medications of this group were no different to other VVS patients. VVS onset usually followed or coincided with the onset of weight loss resulting in a shorter duration of syncope symptoms before clinic assessment. The duration of VVS symptoms was associated with the time interval over which weight loss occurred. Furthermore, fewer patients with weight loss reported syncope in earlier life, suggesting that onset of syncope was secondary to a physiological change, not a life-long predisposition. In the absence of other possible confounders it seems likely that weight loss, and the associated fall in blood volume, were the most likely physiological explanations for the synchrony between the onset of weight loss and postural VVS. We further hypothesised that patients with weight loss and decreased central blood volume might have an exaggerated fall in stroke volume during head-up tilt. However, we found that even though blood pressure was lower in both syncope groups during early tilt, stroke volume changes were less than in controls. Although adipose tissue is relatively low in blood volume, studies in dieting patients report reductions of both total and central blood volume within months.[[6,20]] We calculated that moderate weight loss, on average 12kg, would include 0.4L of blood volume, half of which is centrally distributed and the main determinant of stroke volume.[[18]] During tilt SV fell by approximately 30% in all of our patients. This occurred mainly in the first three minutes, consistent with previous studies on VVS.[[9]] We did not study tilt responses beyond ten minutes and so cannot comment on how weight loss might have affected the later changes preceding syncope. Crucially, our methods did not allow direct measurements of central blood volume or absolute SV levels immediately before tilt. Instead, we compared only changes in SV after tilt which has an uncertain relationship with absolute baseline levels. Furthermore, because of the retrospective nature of this study, we cannot determine how stroke volume and blood pressure may have fallen during the months over which weight loss occurred. Presumably the blood pressure level was similar in the two syncope groups because in the WL group it had fallen from higher levels. Therefore, most of the important changes in MAP and SV probably occurred during the months before clinic assessment and it is not surprising that our tilt data was not helpful. This in no way refutes our important finding of the association between weight loss and VVS.
It is possible that the fall in blood pressure, consistently observed after weight loss predisposes some patients to recurrent vasovagal syncope.[[1,5]] New-onset syncope has been observed in other situations when blood pressure is lowered, e.g., following the introduction of antihypertensive medication and during pregnancy.[[10]] Normally, arterial baroreflexes buffer acute falls in stroke volume and blood pressure in response to postural changes. After weight loss, although the baroreflexes become more sensitive, they reset and modulate heart rate and sympathetic nerve activity at lower MAP levels.[[3,21]] However, the absolute MAP at which syncope occurs remains the same (approximately 60mmHg), therefore the lower the MAP levels at which the baroreflex curve operates, the more likely the patient is to develop syncope.[[22]] Other studies have used head-down bed rest (over three weeks) to lower blood volume and reported no changes in arterial baroreflex function despite clear demonstration of orthostatic intolerance.[[23]] We emphasise that in our study (and other weight loss studies) the weight change was greater and over a much longer time interval, therefore a major “left” shift of the baroreflex curves towards lower MAP levels is likely.[[3,21]] Re-setting is complicated and involves not only arterial but also cardiopulmonary baroreflexes which control renin, vasopressin and endothelin secretion.[[24,27]] Furthermore, cardiopulmonary baroreflexes also modulate sympathetic activity and augment arterial baroreflex function when central blood volume is decreased.[[28,29]] In view of these interactions and the nature of baroreflex responses, it is not surprising that we were unable to demonstrate a strong linear correlation between the recent duration of weight loss and syncope symptoms.
Limitations
In this study, the estimation of duration of syncope symptoms and weight loss depended on patient recall. Onset of syncope after weight loss may have biased how some patients remembered their symptoms. We think this was partly mitigated by sending the patients a written questionnaire and checking their reported weight data with the electronic record as described in the methods. We were unable to directly measure central blood volume or compare absolute stroke volume levels at baseline. Sample size and statistical power were limited by the numbers of controls and patients presenting with weight loss. Multiple comparisons between these groups may have increased the risk of a type I error. An ideal future study would prospectively measure weight loss, tilt responses, and symptoms before and after dietary intervention.
Conclusion
In the majority of patients presenting to our clinic with recurrent blackouts occurring in a standing or sitting position, the diagnosis is vasovagal syncope.[[15]] It is usually made by taking a careful history.[[10,12,14]] When the history is unclear, other less common causes can be excluded by the appropriate investigations, for example long-term cardiac monitoring for arrhythmia or tilt testing for postural hypotension.[[10,12]] If these results are normal, patients can be reassured that the diagnosis is still most likely to be VVS because it is so prevalent in all age groups. In some, the diagnosis is supported by a satisfactory response to treating predisposing factors e.g., anaemia, dehydration, prolonged bedrest, drugs, pregnancy, or fever; but in others there are no associated changes other than weight loss. The results of this study are consistent with that in a subset of patients with recent onset VVS, there may be an association with simultaneous moderate weight loss. This association is generally not recognised by patients and has not previously been reported. This may be because the temporal association between duration of weight loss and onset of syncope is not simple. We suspect that when weight stabilises at a lower level and the baroreflex mechanisms re-set, the time interval during which the patient remains symptomatic is variable. We plan a follow-up study to examine the length of this time interval and what baroreflex changes occur. In the meantime, we reassure our patients that the symptoms will improve (without any form of medication), and they are discouraged from putting the weight back on.
Summary
Abstract
Aim
In adults, the onset of vasovagal syncope is often unexplained. We wished to explore if moderate weight loss triggers the onset of vasovagal syncope (VVS).
Method
A retrospective case-control study comparing demographic characteristic, syncope symptoms, and tilt-table results of patients who had recently lost weight (n=57), with randomly selected weight-stable patients (n=73), and controls, patients without syncope (n=24).
Results
VVS was diagnosed in 480 out of 1,209 clinic patients of whom 57 (11.9%) reported moderate weight loss. The mean (SD) reported weight loss was 11.5 (7) kg over 18.7 (13) months. Age and gender did not differ between groups: in the weight loss, weight stable, and control groups the mean age was 44.8, 45.2, and 44 years respectively; and proportion female 60%, 64%, and 54%. Body weight, mass index and calculated blood volume at presentation were also similar in the different groups. Weight loss preceded or coincided the onset of syncope in 80% of patients; the length of time over which weight loss occurred was associated with the length of time of syncope symptoms, product moment correlation coefficient 0.45, p=0.001. Syncope in childhood and teenage years was less frequent in the weight loss group compared to the weight stable group: 37% vs 53%. After 10 minutes of head-up tilt, stroke volume was preserved in both syncope groups compared to controls; percentage of baseline mean (SD) in the weight loss, weight stable, and control groups: 71(18), 69(10), and 61 (11) respectively; despite lower blood pressure in the weight loss groups with mean (SD) 90 (14) mmHg, 93 (13) and 103 (14) respectively.
Conclusion
Some patients have onset of VVS within a few months of weight loss resulting in earlier presentation to clinic. The physiological mechanism for this is uncertain.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1) Billakanty SR, Kigman MD, Kanjwal YM et al. New onset orthostatic intolerance following bariatric surgery. Pacing Clin Electrophysiol 2008;31:884-888.
2) Ponnusamy V, Owens AP, Purkayastha S, et al. Orthostatic intolerance and autonomic dysfunction following bariatric surgery: a retrospective study and review of the literature. Autonom Neurosci 2016;198:1-7.
3) Grassi G, Seravalle G, Columbo M et al. Weight reduction, sympathetic nerve traffic and arterial baroreflex in obese normotensive humans.Circulation. 1998;97:2037-2042.
4) Lambert E, Esler MD, Schlaich MP et al. Obesity-Associated Organ Damage and Sympathetic Nervous Activity. Hypertension 2019;73:1150-1159.
5) Messerli FH, Christie B, DeCarvalho JG et al. Obesity and essential hypertension: hemodynamics, intravascular volume, sodium excretion and plasma renin activity. Arch Intern Med. 1981;141:81-85.
6) Reisin E, Frohlich ED, Messerli FH et al. Cardiovascular changes after weight reduction surgery. Ann Intern Med. 1983;98:315-319.
7) Stewart JM, McLeod KJ, Sanyal S et al. Relation of postural vasovagal syncope to splanchnic hypervolemia in adolescents. Circulation. 2004; 110:2575-2581.
8) van Lieshout JJ, Harms MP, Pott F et al. Stroke volume of the heart and thoracic fluid volume during head-up and head-down tilt in humans. Acta Anaesthesiol Scand. 2005;49:1287-1292.
9) Verheyden B, Liu J, van Dijk N et al.. Steep fall in cardiac output is the main determinant of hypotension in drug-free and nitroglycerin-induced orthostatic vasovagal syncope. Heart Rhythm. 2008;5:1695-1701.
10) Brignole M, Moya A, de Lange FJ et al. Guidelines for the diagnosis and management of vasovagal syncope. Eur Heart J 2018; 39:1883-1948.
11) Colman N, Nahm K, Ganzeboom KS et al. Epidemiology of reflex syncope. Clin Autonom Res 2004; 14 Suppl 1:9-17.
12) Shen WK, Sheldon RS. ACC/AHA/HRS guidelines for the evaluation and management of patients with syncope. J Am Coll Cardiol 2017;70:e41-e109.
13) van Dijk GG, Thijs RD, Benditt DG and Wouter Wieling. A guide to disorders causing transient loss of consciousness: focus on syncope. Nat Rev Neurol 2009;5:438-448.
14) Wieling W, Kaufmann H. What is the best method to diagnose vasovagal syncope? Clin Autonom Res 2021;3:335-337.
15) Al-Busaidi IS, Jardine DL. Different types of syncope presenting to clinic: do we miss cardiac syncope? Heart Lung Circ. 2019:S1443-9506(19)31454-4. doi: 10.1016/j.hlc.2019.09.008.
16) Moya A. Tilt testing and neurally-mediated syncope: too many protocols for one condition or specific protocols for different situations? Eur Heart J 2009;30:2174-2176.
17) Bogert LW, van Lieshout JJ. Non-invasive pulsatile arterial pressure and stroke volume changes from the human finger. Exp Physiol. 2005;90:437-446.
18) Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults. Surgery. 1962;51:224-232.
19) Funkhouser RK, Pritchard WH, Little AS. Change in relationship of blood volume to weight in congestive heart failure. Circulation 1957;16:548-557.
20) Alexander JK, Peterson KL. Cardiovascular effects of weight reduction. Circulation 1972;45:310-318.
21) Alvarez GE, Davy BM, Ballard TP et al. Weight loss increases cardiovagal baroreflex function in obese young and older men. Am J Physiol Endocrinol Metab. 2005;289:E665-E669.
22) Wieling W, Thijs RD, van Dijk N et al. Symptoms and signs of syncope: a review of the link between physiology and clinical clues. Brain 2009; 132: 2630-2642.
23) Kamiya A, Michikami D, Fu Q et al. Pathophysiology of orthostatic hypotension after bedrest: paradoxical sympathetic withdrawal. Am J Physiol Heart Circ Physiol 2003;285:H1158-H1167.
24) Grassi G, Giannattasio C, Cuspidi C et al. Cardiopulmonary receptor regulation of renin release. Am J Med. 1988;84 (Suppl 3A):97-104.
25) Hainsworth R. Cardiovascular control from cardiac and pulmonary vascular receptors. Exp Physiol 2014;99:312-319.
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Vasovagal syncope triggered by recent moderate weight loss?
We postulated that weight loss and decreased central blood volume may predispose some patients to posture-triggered vasovagal syncope. With 10kg of weight loss, total blood volume falls by about 500ml, representing 10% of circulating volume, and approximately half of this is central blood volume.
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