An association between low blood pressure and fatigue, in various forms, has been postulated for several decades but has remained unproven. In this issue of the journal, Lucas et al.  have demonstrated a prospective association between hypotension and unexplained chronic fatigue as an isolated symptom.
When discussing this topic, it is vital to be clear about which form of low blood pressure and which form of fatigue are being considered. First, it is clear that acute hypotension accompanying a catastrophic event such as myocardial infarction, severe trauma or septic shock, is a different entity from chronic hypotension. Fatigue is likely to be the least of the problems faced by a patient in one of these situations. Furthermore, the causes, associations and implications of ‘constitutional’ chronic hypotension (usually lifelong, present in both supine and standing positions in otherwise healthy people, often asymptomatic, and associated with longevity) are very different from those of orthostatic hypotension (usually acquired, often associated with supine hypertension, related to autonomic dysfunction and often secondary to disease states such as diabetes or extrapyramidal degenerative disorders which may reduce lifespan). Similarly, the implications of the presence of the isolated symptom, fatigue, or as operationalized by Lucas et al. , ‘easy fatiguability', differ markedly from those of a diagnosis of ‘chronic fatigue syndrome’ (CFS) based on standard diagnostic criteria.
Constitutional hypotension (usually defined as a systolic blood pressure of < 100 mmHg in females and < 110 mmHg in males) is regarded in some parts of the world (e.g. Germany and Austria) as a legitimate disorder associated with symptoms of dizziness, fatigue, palpitations, visual disturbances and headache. In these countries, it has been reported to be present in 17%  and 22%  of general practice samples, respectively, and is frequently treated with drugs such as fludrocortisone or sympathomimetics, which increase blood pressure. In other regions, such as the UK, North America and Australasia, people with chronically low blood pressure readings are generally regarded as belonging to the normal population, albeit at the extreme end of the distribution curve. Such individuals are assumed to autoregulate their cerebral perfusion around a low mean blood pressure and their ‘hypotension’ is therefore regarded as being unlikely to cause symptoms related to cerebral hypoperfusion. Standard medical textbooks in these regions do not include entries for the diagnosis or management of constitutional hypotension.
Over the past decade, it has become apparent that some individuals who do not have orthostatic hypotension nevertheless have abnormal cardiovascular responses to orthostasis associated with symptoms suggestive of cerebral hypoperfusion . Because of the non-specific nature of the symptoms and the lack of an objective change in blood pressure during orthostatic stress, many of these patients have been thought to have symptoms of psychosomatic origin. Young women, in particular, commonly report symptoms such as headache, dizziness, lightheadedness, visual disturbances, poor concentration, fatigue, palpitations, dyspnoea and tremulousness that are induced or exacerbated by the upright posture and relieved by lying down . Abnormal responses to head-up tilt, such as significant sinus tachycardia associated with symptomatic palpitations, lightheadedness and extreme fatigue, have been described in both adults  and adolescents  in the absence of objective orthostatic hypotension. This complex of symptoms and responses to tilt has been termed the ‘postural orthostatic tachycardia syndrome’ (POTS) or more generally ‘idiopathic orthostatic intolerance’ (OI).
OI has been claimed to be the commonest disorder of blood pressure regulation after primary hypertension . There is general agreement that most patients present at a relatively young age, and the female to male ratio is approximately 5 : 1 . The possible pathophysiology of this syndrome has been reviewed by Jacob and Biaggioni  and Grubb et al. . A variety of possible mechanisms has been proposed, including hypovolaemia, excessive venous pooling secondary to partial autonomic dysfunction, hypersensitivity of beta-adrenoceptors and abnormalities of central autonomic control, but none has been established as primary. It has been argued that, although OI does not lead to significant cardiovascular or neurological sequelae, it is associated with significant morbidity in the general community and should be regarded more seriously by practitioners .
The blood pressure–fatigue link has also been examined in relation to CFS. There is no known association between constitutional hypotension and chronic fatigue syndrome, but there has been considerable recent interest in the role of abnormal cardiovascular responses to orthostasis in the development of certain CFS symptoms. Interestingly, baseline blood pressure in the supine position is not consistently lower in CFS subjects compared to controls [9–11]. However, many patients with CFS report that symptoms such as headache, dizziness, fatigue, palpitations and tremulousness are exacerbated by the upright posture. A variety of abnormalities have been reported in CFS patients on head-up tilt testing  and prolonged standing . Symptomatic sinus tachycardia, qualitatively similar to that observed in POTS, is the commonest finding [10,13].
However, some tilt studies have shown no differences in cardiovascular responses to tilt in CFS patients compared to healthy controls [9,14], suggesting that neurally mediated hypotension is unlikely to play a major pathophysiological role in CFS. Furthermore, although open-label treatment with drugs designed to increase blood pressure, such as fludrocortisone or sympathomimetics, has appeared to be successful , double-blind trials have not been persuasive . The role of autonomically mediated abnormalities in orthostatic blood pressure control in CFS remains intriguing but uncertain, and is the subject of ongoing active investigation.
Given the high prevalence of symptomatic fatigue in Western communities, and the observation that some people with fatigue have constitutional hypotension by the European definition, there have been several attempts to determine whether or not constitutional hypotension is statistically associated with chronic fatigue.
Several large cross-sectional survey studies have suggested an association between low systolic blood pressure recordings and symptoms of tiredness or fatigue, particularly in women [16–19]. In this issue of the journal, Lucas et al.  provide the first report of a prospective association between low blood pressure measured in healthy young subjects and the development of the symptom of chronic fatigue over the next 5–10 years. Their study thus provides the additional information that, in some people, the presence of hypotension precedes the development of fatigue, adding another piece to the jigsaw puzzle of cause and effect.
The study by Lucas et al.  took advantage of a database established at Johns Hopkins Medical School in 1948 as part of the Johns Hopkins Precursors Study. The aim of the study was to identify characteristics in young adults (in this case medical students in the 1948–64 graduating classes, n = 1337) associated with later development of cardiovascular outcomes. Baseline characteristics were obtained by questionnaire and direct measurement, and included measurement of supine blood pressure (mean of approximately nine values obtained when subjects were students) and a question about ‘easy fatiguability'. The blood pressure was not measured during orthostatic stress, such as standing, and thus no information is provided about orthostatic intolerance or abnormal orthostatic responses. However, those individuals with systolic blood pressure recordings averaging under 100 mmHg (females) or under 110 mmHg (males) would meet the usual diagnostic criteria for constitutional hypotension as commonly defined in Germany.
The questionnaire that was completed at baseline and at 5- and 10-year follow-up was designed to elicit cardiovascular symptoms rather than chronic fatigue specifically, and the single item ‘easy fatiguability’ may not have been worded specifically enough to capture responses relating to an abnormal level of fatigue rather than the normal tiredness of a busy life. However, there is no reason to assume that this would lead to a false association of hypotension and positive responses to this question. The authors took care to exclude those subjects who already had fatigue at baseline, in addition to those with any other possible medical cause of fatigue, using a blinded review of medical records. Insufficient information was available to allow them to determine whether any of the subjects with fatigue at follow-up met the diagnostic criteria for CFS. A significant association between supine hypotension at baseline, and incident fatigue at either 5- or 10-year follow-up (or both) was demonstrated for women (odds ratio 7.2, 95% confidence interval 1.6–31.9) but not for men, in whom the development of fatigue was much less common (3.6 versus 15.9% for women). It is possible that a larger sample of men may provide the statistical power to demonstrate a similar, if smaller, association.
While Lucas et al.  acknowledge that their study was exploratory, it certainly supports the development of the hypothesis that constitutional hypotension is a risk factor for the later development of fatigue. This will need to be tested in a larger and more specific study, in which other factors such as body mass index, ethnic origin, physical training, orthostatic blood pressure and heart rate responses, and orthostatic symptoms, could also be explored.
The two extreme views in relation to constitutional hypotension are: (i) that it is a serious cause of significant morbidity in otherwise healthy young people and should be diagnosed and managed actively and (ii) that it does not exist as a pathophysiological entity, but rather is an artificial division of the normal blood pressure distribution curve, falsely having symptoms attributed to it that are actually psychosomatic in origin. In most of the Western world, the second view has prevailed with little challenge until the past decade or so, when several associations of low blood pressure and/or abnormalities of orthostatic blood pressure control with disorders including chronic fatigue syndrome and orthostatic intolerance have come to light.
Several cross-sectional studies have previously suggested an association between hypotension and coexisting fatigue. Now, Lucas et al.  have demonstrated for the first time that young women with supine hypotension have an elevated risk of developing fatigue over the next 5–10 years compared to their peers with higher supine blood pressure. Although the puzzling relationship between constitutional hypotension and ‘hypotensive symptoms', including fatigue, remains to be clarified, more clinicians may wish to consider the possibility that constitutional hypotension may indeed be a source of morbidity in young women complaining of fatigue.
1. Lucas KE, Rowe PC, Coresh J, Klag MJ, Meoni LA, Ford DE. A prospective association between hypotension and idiopathic chronic fatigue. J Hypertens
2. Donner-Banzhoff N, Kreienbrock L, Baum E. Hypotension – does it make sense in family practice? Fam Pract
3. Kunze M, Gredler B, Steinbach K. [Hypotension in Austria]. Wien Med Wochenschr
4. Jacob G, Biaggioni I. Idiopathic orthostatic intolerance and postural tachycardia syndromes. Am J Med Sci
5. Grubb BP, Kanjwal MY, Kosinski DJ. Review: the postural orthostatic tachycardia syndrome: current concepts in pathophysiology, diagnosis and management. J Intervent Cardiac Electrophysiol
6. Karas B, Grubb BP, Boehm, K, Kip K. The postural orthostatic tachycardia syndrome: a potentially treatable cause of chronic fatigue, exercise intolerance, and cognitive impairment in adolescents. Pacing Clin Electrophysiol
7. Robertson D. The epidemic of orthostatic tachycardia and orthostatic intolerance. Am J Med
Sci. 1999; 317
8. Owens PE, O'Brien ET. Hypotension: a forgotten illness? Blood Press Monit
9. LaManca JJ, Peckerman, A, Walker J, Kesil W, Cook S, Taylor A, Natelson BH. Cardiovascular response during head-up tilt in chronic fatigue syndrome. Clin Physiol
10. Stewart JM. Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Ped Res
11. Streeten DH, Thomas D, Bell DS. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci
12. Bou-Holaigah I, Rowe, PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA
13. Schondorf R, Benoit J, Wein T, Phaneuf D. Orthostatic intolerance in the chronic fatigue syndrome. J Auton Nerv Syst
14. Poole J, Herrell R, Ashton S, Goldberg J, Buchwald D. Results of isoproterenol tilt table testing in monozygotic twins discordant for chronic fatigue syndrome. Arch Intern Med
15. Rowe PC, Calkins H, DeBusk K, McKenzie R, Anand R, Sharma G, et al
. Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial. JAMA
16. Pemberton J. Does constitutional hypotension exist? BMJ
17. Wessely S, Nickson J, Cox B. Symptoms of low blood pressure: a population study. BMJ
18. Pilgrim J, Stansfield S, Marmot M. Low blood pressure, low mood? BMJ
19. Barrett-Connor E, Palinkas LA. Low blood pressure and depression in older men: a population based study. BMJ