Orthostatic hypotension (OH) is a relatively common heterogenous and multifactorial disorder, traditionally classified as neurogenic (less common but often more severe) or nonneurogenic (more common, with no direct signs of autonomic nervous system disease). The different clinical variants of orthostatic intolerance include initial, classical and delayed OH as well as postural tachycardia syndrome. Orthostatic instability may induce syncopal attacks either alone or in combination with other mechanisms, and is often dismissed as a precipitating factor. Moreover, prevalent OH is an independent risk factor for all-cause mortality and cardiovascular morbidity, and the majority of patients with OH are asymptomatic or have few nonspecific symptoms. Management of symptomatic orthostatic intolerance includes both nonpharmacological and pharmacological methods, but it is not always successful and may lead to complications. Future studies of OH should focus on mechanisms that lead to neurogenic and nonneurogenic OH, novel diagnostic methods and more effective therapeutic modalities.
Postural haemodynamic homeostasis in humans involves complex adaptive mechanisms controlled by the autonomic nervous system . On standing, as the gravitational challenge abruptly increases, cardiovascular reflexes are initiated to maintain stable blood pressure (BP) and perfusion in the upper body. Conversely, impairment of the compensatory response to orthostasis can lead to a temporary or sustained fall in BP, termed orthostatic hypotension (OH). If the cerebral circulation becomes critically compromised by OH, susceptible individuals may experience chronic fatigue, blurred vision, dizziness, pain in the neck and shoulders (‘coat hanger’ pain) and fainting [2-5]. Therefore, detection and management of OH is crucial to improve the quality of life of patients , prevent syncopal attacks and fall-related injuries  and to optimize treatment of concomitant diseases, such as hypertension and heart failure [8, 9]. Here, we present a historical review of OH, outline the aetiology and prevalence of the condition in the general population, discuss the involvement of orthostatic disorders in syncopal attacks and, finally, summarize how prevalent OH affects mortality and morbidity.
Historical review of OH
In 1925, two New York physicians, Bradbury and Eggleston, first described in three patients a newly discovered disorder termed postural hypotension . The main feature of this syndrome was an abrupt fall in BP on standing associated with an impaired chronotropic response, accompanied by a history of frequent syncope. Two years later, two Swedish clinicians, Bjure and Laurell, published an article on ‘arterial orthostatic anaemia’, reporting an acceleration of heart rhythm on standing with a reduction in systolic BP (SBP) and impaired physical capacity in young asthenic individuals . Indeed, Laubry and Doumer first used the term OH in 1932 (in French: l′hypotension orthostatique) to report their observations on orthostatic intolerance and comment upon the findings of Bradbury and Eggleston .
During the following decade, the term became commonly used for all forms of postural haemodynamic instability [13-16]. However, in the 1950s, Braunwald and Wagner suggested that pure autonomic failure (PAF; also known as Bradbury–Eggleston syndrome or idiopathic OH) was due to primary autonomic insufficiency , in contrast with other forms of orthostatic instability. Later, Shy and Drager described neurogenic OH associated with clear involvement of the central nervous system , whereas Hughes et al.  observed that neurogenic OH could exist both with and without nonautonomic neurological deficits; in the latter case, this is identical to PAF . At that time, studies of OH were in general based on short series of selected cases examined using different and nonstandardized protocols. In the 1980s, a more systematic approach towards OH emerged [21-25], focused mainly on neurogenic variants such as PAF, multiple system atrophy (MSA; also known as Shy–Drager Syndrome), or OH associated with Parkinson's disease. The advent of noninvasive continuous beat-to-beat BP measurement technology  increased the sensitivity and accuracy of orthostatic tests, making it possible to observe even minor and temporary postural BP variations.
Thus, in the 1990s, physiological studies provided more insight into the haemodynamics and variety of OH-related syndromes [1, 27-32], which resulted in a consensus being reached on the definitions of OH, PAF and MSA . OH was defined as a decrease in SBP of ≥20 mmHg or to below 90 mmHg and/or a decrease in diastolic BP (DBP) of ≥10 mmHg within 3 min of standing or the during head-up tilt test (HUTT). Establishment of consensus led to a new era in the exploration of OH as a number of epidemiological surveys, such as the Cardiovascular Health Study, the Honolulu Heart Program, the Oulu and the Atherosclerosis Risk in Community Studies [34-40] were conducted to assess the general prevalence and risks associated with OH. In parallel, further efforts were made to improve understanding of orthostatic disorders, to explore and categorize their aetiology, to develop new diagnostic and therapeutic methods, and to find a way in which the two main specialties involved in the care of patients with OH, cardiology and neurology, could work together [8, 41-47]. Consequently, orthostatic disorders were classified according to haemodynamic and temporal patterns into initial, classical and delayed forms [48-50]; the latter was often associated with reflex syncope (also termed dysautonomic syncope by some ). A particular form of orthostatic intolerance, categorized as postural tachycardia syndrome (PoTS) [30, 50], was probably identical to the ‘arterial orthostatic anaemia’ reported by Bjure and Laurell. Recently, both diagnostic criteria of OH and its aetiology have been reinvestigated [52-55] and a new consensus on orthostatic intolerance syndromes has been reached , with a decrease in SBP of ≥30 mmHg suggested to be a more appropriate diagnostic limit amongst hypertensive patients (i.e. those with supine SBP ≥160 mmHg). At the same time, an increasing number of epidemiological studies have confirmed the role of OH as a potent and independent risk factor not only for syncopal attacks but also for total mortality and various conditions, such as coronary disease, stroke and heart and renal failure [57-62].
Aetiology and prevalence of OH
On standing, a gravitational volume shift causes an instant redistribution of circulating blood by pooling of 500–1000 mL within the capacitance vessels situated below the diaphragm. As a result, the venous return to the right atrium and the thoracic blood and stroke volume are all reduced, and reflex chronotropic and vasoconstrictive responses mediated by increased sympathetic outflow and decreased vagal activity compensate to maintain arterial pressure in the upper body at the pre-orthostatic level respectively[1, 43]. If one continues to stand, transcapillary filtration in the subdiaphragmatic space additionally reduces the central blood volume by about 15% , whereas the cardiac output decreases by nearly 20% . In a healthy subject, however, mean arterial pressure is preserved, because of compensatory increases in vascular tone in splanchnic, musculocutaneous and renal areas . The rapid circulatory adjustments are governed by autonomic neural pathways, whereas circulatory changes that occur during the prolonged orthostatic challenge involve neurohumoral mechanisms, such as activation of the renin–angiotensin system . Failure of any these adaptive reflexes may result in a temporary or persistent fall in BP in the upright position, either in the early or late phase of the orthostatic challenge (Fig. 1).
Traditionally, the aetiology of OH has been classified as neurogenic or nonneurogenic [54, 55], with neurologists caring for patients with the former. Neurogenic OH is a key manifestation of chronic autonomic failure in primary neurodegenerative disorders such as Parkinson's disease, MSA and PAF, but can also be observed as a secondary autonomic insufficiency in conditions including polyneuropathy associated with diabetes, amyloidosis and renal failure, or in autoimmune diseases such as Sjögren′s disease [45, 47, 54, 55, 64-66]. Neurogenic cardiovascular hyporesponsivness underlying OH (i.e. primary or secondary autonomic failure) is relatively easy to detect with the Valsalva manoeuvre and noninvasive beat-to-beat BP measurement; a pathological response is highly suggestive of neurogenic OH [67, 68]. Further tests, such as measurement of supine/standing plasma catecholamine levels and cardiac sympathetic and brain neuroimaging, may then be required to confirm peripheral noradrenergic denervation or central neurodegenerative processes . These tests are usually performed in specialized centres.
Factors that may cause nonneurogenic OH are well known and include treatment with vasodilators, diuretics, tricyclic antidepressants or chemotherapeutic agents, absolute or relative reduction in circulating blood volume (e.g. bleeding or diarrhoea), venous pooling, inotropic and/or chronotropic cardiac failure and ageing [55, 69]. It is interesting that female gender, hypertension, low body mass index and smoking were also found to be predictive of OH in large prospective studies [52, 58], but the underlying mechanisms are not completely understood. In summary, OH has a clear neurogenic aetiology in only a minority of patients, and no definite cause can be identified in nearly 40% of patients with moderate-to-severe classical OH (i.e. idiopathic OH) . Moreover, the prevalence of the delayed form, usually not reported in large cohort studies, is significant with at least as many patients presenting with delayed OH as those presenting with the classical type .
Genetic predisposition towards OH has not been comprehensively explored. The results of small population-based studies have suggested that polymorphisms of the G-protein-related genes GNAS1 and GNB3, which influence cardiovascular tone and reactivity , Insulin Promoter Factor 1 (PDX1) on chromosome 13, which is implicated in beta-cell function , and the neural precursor cell expressed, developmentally down-regulated 4-like gene (NEDD4L) on chromosome 18, which is an essential regulator of sodium retention in the distal nephron , may be associated with altered postural SBP responses. Recently, in a large meta-analysis, we found evidence for association between OH- and BP-related single-nucleotide polymorphisms in the EBF1, CYP17A1, NPR3-C5orf23, NPPA/NPPB and ADM loci, but the overall association between BP variants and OH was generally weak and the direction of effect inconsistent with findings of resting BP measurement . It is likely that resting BP and orthostatic cardiovascular response share limited genetic elements.
The prevalence of OH in the general population increases with age and comorbidities such as neurodegenerative, cardiovascular, metabolic and renal disorders [47, 61]. Large prospective studies have shown a distinct pattern of age-related OH prevalence ranging from <5% below 50 years of age to about 20% above z70 years [34, 38]. Of note, nearly 90% of individuals who met the classical OH criteria (i.e. within 3 min of standing) at screening were asymptomatic. In the Malmö Preventive Project, the largest epidemiological study to date with available data on prevalence of OH in younger middle-aged subjects, +45/7 years, (~33 000 participants), a very similar pattern of age-dependent increase in OH prevalence was observed (Fig. 2) . Other well-known comorbidities that strongly influence OH occurrence are Parkinson's disease (~50% of patients) [75-77], hypertension (~15–30% of patients) [34, 52, 78], diabetes (~20–25% of patients) [34, 79] and advanced kidney failure (up to ~40% of patients) .
Orthostatic intolerance and syncopal attacks
In general, between 4% and 15% of all syncopal attacks depend on underlying orthostatic instability [81, 82] with an increasing role amongst elderly patients, in whom up to 30% of syncopal attacks can be attributed to OH [50, 83]. However, the presence of orthostatic intolerance in such patients is likely to be underestimated as in the past studies rarely reported a potential overlap between OH and other causes of syncope . Impaired orthostatic responses may lead to syncopal attacks directly by abrupt (initial OH) or progressive decreases in BP on standing (classical and delayed OH), or indirectly by triggering the vasovagal reflex through hypotension (classical and delayed OH) or sinus tachycardia (PoTS). The typical syndromes of orthostatic intolerance associated with syncope are presented in Table 1. Diagnosis of orthostatic syncope is usually based on a characteristic history of syncopal attacks (i.e. associated with postural change of body position, prolonged standing or other symptoms of orthostatic intolerance) and results of the HUTT, ideally with beat-to-beat BP measurement and performance of additional tests (e.g. active standing, Valsalva manoeuvre) if indicated. The HUTT was introduced as part of the diagnostic tools of syncope in the 1980s  and has become important for detecting different forms of orthostatic intolerance in symptomatic patients.
Table 1. Classification of orthostatic intolerance syndromesa
Type of orthostatic intolerance
Time from standing to symptoms/haemodynamic changes
Adapted from the current syncope guidelines of European Society of Cardiology (2009) ref . with modifications; baccording to ref. [52, 53, 56]; cauthors' own observation.
BP drop ≥40/20 mmHg
Transient mismatch between CO and SVR
Dizziness, fatigue, sensorial disturbances, syncope may occur
Young asthenic subjects; old age; drug induced (α-blockers); CSS
Classical OH (classical autonomic failure)
30 s–3 min
BP drop ≥20/10 mmHg or ≥30/15 mmHg in hypertensive patientsa
Impaired increase in SVR and HR (autonomic failure) or volume depletion
Dizziness, sensorial disturbances, syncope may occur
Old age, autonomic failure, drug induced (vasodilators and diuretics)
BP drop ≥20/10 mmHg or ≥30/15 mmHg in hypertensive patientsa
Progressive fall in venous return (progressive impairment of adaptive mechanisms)
Prolonged prodromal symptoms (dizziness, fatigue, nausea, hyperhidrosis, sensorial disturbances, muscle pain in the upper body), frequent syncope
Old age; autonomic failure, drug induced (vasodilators and diuretics), comorbidities (diabetes mellitus, kidney failure, hypertension, heart failure etc.)
HR increase ≥120/min or ≥30/min above supine level
Severe deconditioning, impaired venous return or excessive blood pooling, sympathomimetic hyperactivation
Palpitations, lightheadedness, dizziness, fatigue, syncope may occur
Young subjects, predominantly females, gastrointestinal or respiratory (asthma) disorders, overlap with autoimmune disease?a
In our laboratory, we usually start an examination with carotid sinus massage in patients >40 years and, even if the result is positive, we proceed with orthostatic challenge as up to 50% of patients with carotid sinus hypersensitivity also demonstrate OH and, consequently, a mixed aetiology of syncope is likely [84, 86]. During the passive phase of the HUTT, two main types of orthostatic BP fall can be expected with a similar rate of occurrence, classical and delayed (Figs 3 and 4). In some cases, hypotension triggers the vasovagal response leading to abrupt haemodynamic collapse and, especially in the elderly, retrograde amnesia; thus, the affected individual may deny a syncopal episode [87, 88]. The relatively high rate of combined delayed OH and subsequent hypotension-induced vasovagal syncope has been reflected in current syncope guidelines, which classify this combination as a specific category of syncopal attacks . PoTS is another form of orthostatic intolerance, which may occasionally present as syncope. Patients with PoTS, predominantly young women (15–40 years), usually report similar symptoms as those affected by OH; however, they are more likely to experience palpitations. The aetiology of PoTS is still poorly understood but the main characteristic is reflective tachycardia caused by increased sympathetic outflow in the absence of adequate vascular response to orthostasis . Hyperadrenergic activation and sinus tachycardia are the crucial triggers of vegetative symptoms followed by the classical vasovagal reflex (Fig. 5). Additional tests, such as the Valsalva manoeuvre, may be performed when the results of orthostatic tests are conclusive to confirm or exclude a neurogenic background of orthostatic impairment as this has implications for both prognosis and management of OH. Finally, the active standing test is recommended for all patients with a history of syncope suggestive of initial OH and other orthostatic disorders (Fig. 6). Although initial OH is only sometimes associated with complete syncope, probably due to short duration of hypotension (15–30 s) and patients' own coping skills, the educational and prophylactic value of the test in syncopal patients should not be underestimated . Figure 7 shows the crucial role of the expanded HUTT in the diagnostic work-up of patients with suspected orthostatic intolerance syndrome.
Management of symptomatic orthostatic intolerance includes both nonpharmacological and pharmacological methods. However, it is not always successful and may be complicated due to the limited efficacy of therapeutic agents and the presence of concomitant disorders, such as hypertension or diabetes. A detailed description of current treatment strategies is beyond the scope of this review (for excellent overviews see [2, 54, 64, 90-93]). A brief summary is presented in Table 2. Hypertensive individuals with increased risk of cardiovascular events constitute an important group of patients. As withdrawal of antihypertensive drugs may be hazardous in this setting, dosage modification, change of therapeutic agents and bedtime administration are amongst recommended options; however, discontinuation of treatment may be the only solution for severely symptomatic patients with traumatic falls in BP [94-98].
Table 2. Summary of therapeutic modalities in symptomatic orthostatic hypotension
This therapeutic modality is crucial and often underestimated but rarely sufficient alone in pronounced orthostatic intolerance. Patients and their families should understand the basics of orthostatic physiology and importance of nonpharmacological methods. Special educational meetings and demonstration of counter-manoeuvres with beat-to-beat monitoring of BP and heart rate are recommended to increase patients' compliance. Educational materials such as instruction films may be distributed amongst patients
Acceptance and understanding of orthostatic intolerance
Avoidance of immobilization, prolonged diurnal recumbency and physical deconditioning
Gradual rising from supine and sitting position, especially in the morning, after meals and defecation
Small and frequent instead of large meals
Avoidance of prolonged standing, high environmental temperature and humidity (≈volume depletion)
Physical counter-manoeuvres (leg crossing, muscle tensing, squatting etc.) during standing and prodromal symptoms
Head elevation 10–30 grades during sleep
Reduction of nocturia (volume depletion↓) and supine hypertension
Increased salt and fluid intake incl. water bolus if needed
Volume expansion. A daily dietary intake of up to 10 g of sodium per day or salt tablets (e.g. 1 g TID) and a fluid intake of at least 1.5 L per day is recommended. A careful dosage regimen in heart and kidney failure should be followed
Custom-fitted elastic stockings
Reduction of peripheral pooling in the lower limbs and splanchnic region. Especially recommended for elderly patients but discomfort may prevent from using them
Midodrine (2.5–10 mg BID/TID)
Direct α1-adrenoreceptor agonist. One of the few pharmacological agents positively tested in placebo-controlled studies but efficacy is often questioned
Droxidopa (100–300 mg TID)
Norepinephrine precursor. Drug is widely used off-label in severe OH. Results of placebo-controlled studies are not unequivocal
Pirydostigmine (30–60 mg BID/TID)
Acetylcholinesterase inhibitor. Generally recommended for neurogenic OH only. BP increases marginally. Efficacy questioned
Fludrocortisone (0.05–0–3 mg daily)
Mineralocorticoid. Volume expander. Increases sodium reabsorption and enhances sensitivity of α-adrenoreceptors. May worsen supine hypertension and hypokalemia
Ephedrine and pseudoephedrine (25/30–50/60 mg TID)
Direct and indirect α1-adrenoreceptor agonist. Efficacy controversial
Vasopressin analogue. Volume expander. Increases water reabsorption and reduces nocturia. Efficacy uncertain
Antihypertensive drugs to be avoided: nitrates, long-acting vasoselective calcium channel blockers, loop diuretics
↑Diurnal vasodilatation and volume depletion. May worsen symptoms of orthostatic intolerance
Withdrawal, dosage reduction, or bedtime administration of antihypertensive drugs (short-acting preferable)
Reversed BP dipping is common in OH. Assessment of 24-h BP profile can be recommended to tailor the antihypertensive therapy
Bisoprolol 2.5–5 mg QD/BID
Cardioselective beta-blocker recommended in PoTS
Ivabradine 2.5–7.5 mg BID
Selective inhibitor of the cardiac pacemaker If current. Reduces tachycardia. Recommended in PoTS
Pacemakers in cardioinhibitory reflex
The role of pacemakers in orthostatic syncope is limited. However, if syncope preceded by BP fall occurs in parallel to reflex pause/bradycardia, especially in elderly patients with other signs of rhythm/conduction disorders, pacemaker may be indicated
Morbidity and mortality related to OH
It has been reported that the total annual rate of OH-related hospitalizations in the USA is 36 per 100 000 adults, with the highest hospitalization rate of 233 per 100 000 amongst those aged 75 years or above . In the elderly, the presence of OH is associated with approximately a twofold increase in the incidence of a BP fall [100, 101]. According to population-based prospective epidemiological data, the prevalence of OH is associated with increased mortality [35, 36, 57, 58, 62, 102], cardiovascular disease events (myocardial infarction and stroke) [38, 39, 58, 60, 102-104], incident heart failure [105, 106], atrial fibrillation  and chronic kidney failure . At present, it remains unclear whether the relationship between OH in generally asymptomatic patients and future adverse events is causal. Autonomic cardiovascular instability expressed by OH may also be a marker of premature deterioration of autonomic control mechanisms or generally increased individual cardiovascular disease risk, which is a combination of susceptible genotype, environmental factors and an unfavourable lifestyle . However, in cross-sectional studies, OH has been associated with reverse dipping of nocturnal BP [109, 110], arterial stiffness , left ventricular hypertrophy [112, 113], peripheral arterial disease , altered heart rate variability , increased carotid intima-media thickness and plasma fibrinogen concentration ; all of these are implicated in cardiovascular disease mortality and morbidity.
Moreover, we previously reported a strong longitudinal relationship between prevalent OH and both injury-related deaths and neurological mortality . Injury-related deaths might be caused by a temporary impairment of cerebral circulation and loss of consciousness, whereas subclinical neurodegenerative processes may have already been present in patients with neurological mortality and the accompanying autonomic dysfunction may have been detected by the orthostatic challenge. Thus, a dual role of OH in prediction of adverse events, both as the causal factor and as an independent marker of underlying diseases is most likely. Table 3 provides a summary of the most common long-term consequences and medical complications related to pre-existing orthostatic impairment based on the currently available data.
Table 3. The most common long-term consequences and medical complications related to the pre-existing orthostatic impairment according to the currently available epidemiological data and observational studies. The references are reported in square brackets
Type of the unfavourable event
Orthostatic hypotension (OH) was defined by consensus statement from 1996  as a systolic blood pressure drop ≥20 mmHg and/or diastolic blood pressure drop ≥10 mmHg within 3 min of active standing; aaged ≥70 years; bmean age, 68 years; cnonsignificant.
Prevalence of OH in the studied populations: 5.0–30.0a%
0.43% of all hospitalizations in the US are related to OH 
Overall annual rate of OH-related hospitalizations is 36 per 100 000 persons Amongst those aged ≥75 years the annual rate is 233 per 100 000 persons
4–15% of syncopal attacks are OH-related in an age-dependent manner [81, 82]
Amongst those aged ≥70 years up to 30% of syncopal attacks can be related to OH 
OH is associated with approximately twofold increase of fall incidence in the elderly [100, 101]
Orthostatic hypotension is a relatively common heterogenous and multifactorial disorder, usually classified as neurogenic (less common but usually more severe form) or nonneurogenic (more common, with no direct signs of autonomic nervous system disease). Different clinical variants of orthostatic intolerance include initial, classical and delayed OH as well as PoTS. Orthostatic instability may induce syncopal attacks either alone or in combination with other mechanisms, and is often dismissed as a precipitating factor. Moreover, prevalent OH is an independent risk factor for all-cause mortality and cardiovascular morbidity, and the majority of patients with OH are asymptomatic or have few nonspecific symptoms. Management of symptomatic orthostatic intolerance includes both nonpharmacological and pharmacological methods with, in general, limited efficacy. Future studies of OH should focus on the mechanisms that cause neurogenic and nonneurogenic OH, novel diagnostic methods and more effective therapeutic modalities.