Orthostatic hypotension: From pathophysiology to clinical applications and therapeutic considerations

Abstract

Orthostatic hypotension (OH), that is blood pressure fall when standing from the supine to the erect position, is a common cardiovascular disorder, highly prevalent in elderly and frail individuals and in patients with multiple comorbidities. Orthostatic hypotension is considered a manifestation of dysfunction of the autonomic nervous system, caused or facilitated by several neurological or non‐neurological diseases and conditions, while its clinical significance is increasingly recognized as a cause of impairment of quality of life and potentially of worse outcomes. Indeed, OH has been extensively studied and numerous prospective cohort studies support its association with adverse events, including coronary artery disease, heart failure, stroke, cognitive dysfunction, and, most importantly, mortality rates. Specific pharmacological and non‐pharmacological interventions have been established for the treatment of OH. However, randomized data evaluating the impact of therapeutic interventions on morbidity and mortality outcomes are lacking. Thus, despite that OH seems to have important prognostic implications indicated by several reported associations with adverse events, it remains unclear whether OH treatment could improve prognosis. In the present review, we discuss the clinical applications associated with ΟΗ by outlining the current perspectives on ΟΗ definition, diagnosis, pathophysiology, prognostic role, and treatment.

1. INTRODUCTION

Orthostatic hypotension (OH) is a common cardiovascular (CV) disorder, whose clinical significance is increasingly recognized as a cause of impairment of quality of life and potentially of worse prognosis.1, 2 Orthostatic hypotension has been extensively studied and numerous associations with adverse events have been reported, therefore being an established marker of impaired prognosis.1 However, the exact nature of the prognostic role of OH remains unclear, as treatment options confer no definitive benefit in prognosis improvement.1, 2 In this review, we discuss the clinical applications associated with ΟΗ by outlining the current perspectives on ΟΗ definition, diagnosis, pathophysiology, prognostic role, and treatment.

2. DEFINITION

Orthostatic hypotension is defined as a sustained reduction of systolic blood pressure (SBP) of at least 20 mm Hg or of diastolic blood pressure (DBP) of at least 10 mm Hg within 3 minutes of standing or head‐up tilt to at least 60° on a tilt table.3, 4 Current European Society of Cardiology (ESC) syncope guidelines propose that SBP reduction of <20 mm Hg from the supine to the erect position, but with standing SBP values <90 mm Hg, should also be considered as OH.3 In hypertensive subjects, a cut‐off of 30 mm Hg fall in SBP may be more appropriate, since blood pressure (BP) fall after standing up largely depends on baseline BP.2, 5 This is the classical form of OH. If BP fall occurs following standing of more than 3 minutes, OH is characterized as delayed. The situation where a more pronounced BP reduction, that is at least 40 mm Hg in SBP or at least 20 mm Hg in DBP, is observed immediately after standing (within 15 seconds) is called initial OH; in this OH type, BP values are quickly restored (within <40 seconds).5 Orthostatic hypotension may be asymptomatic or symptomatic.4 Dizziness, lightheadedness, pain in the neck and shoulder, sweating, hearing and visual disturbances, weakness, and nausea are the most common symptoms, while, in more severe cases, OH may result in loss of consciousness due to excessive hypotension and cerebral hypoperfusion;5 actually, OH is considered a major cause of syncope.3 The presence of symptoms seems to depend mostly on absolute BP value in the erect position rather than on the magnitude of BP reduction.5 Supporting this notion, a study with 210 patients with Parkinson's disease reported that standing mean BP < 75 mm Hg predicted presence of OH symptoms with a sensitivity of 97% and a specificity of 98%. On the other hand, only 31% of patients with OH, defined as either SBP fall of at least 20 mm Hg or DBP fall of at least 10 mm Hg after standing, reported OH symptoms and these diagnostic criteria predicted presence of symptoms with a sensitivity of 92% and a specificity of 58%.6 Moreover, another study with 205 patients with exaggerated SBP reduction (>60 mm Hg) during head‐up tilt test suggested that 33% of patients were asymptomatic, whereas the magnitude of SBP decrease was similar in symptomatic and asymptomatic patients.7

3. PATHOPHYSIOLOGY

Normally, transition from supine to upright position is accompanied by redistribution of intravascular volume, with 300‐800 mL of blood pooling in lower extremities and splanchnic veins due to gravity. This causes a transient reduction in venous return, a decrease in stroke volume and cardiac output (up to 40%) and finally in BP levels.4, 8 As a consequence, activation of BP regulating reflexes that rise from baroreceptors located in the carotid sinus and the aortic arch results in stimulation of the sympathetic system and diminished activity of the parasympathetic system that increase heart rate, venous return, cardiac contractility, and vascular tone. Thus, BP levels are restored.1, 5 Increase in peripheral vascular resistance is the major contributor to BP restoration, while an increase in heart rate may act supplementary.1, 2 These compensatory responses stabilize BP within seconds and are generally capable to maintain BP within normal values in the short‐term.1, 8 In case of prolonged upright posture, additional mechanisms are activated, that is activation of the renin‐angiotensin‐aldosterone system (RAAS) and increased secretion of vasopressin.8

Orthostatic hypotension occurs in patients with inadequate autonomic nervous system (ANS) adjustment (Figure 1) and can be divided into three major categories: drug‐induced, related to depletion of (total or effective) intravascular volume and neurogenic3 (Figure 2), while in many patients, such as the elderly, multiple causes may coexist. Antihypertensive agents (all types), antidepressants, and antiparkinsonian drugs may cause OH due to impairment of autonomic response,4, 9 and hypovolemia may hinder compensatory response even in the presence of a structurally normal autonomic system.3, 4, 10 As for neurogenic OH, this condition is considered to be present in patients that satisfy the criteria for OH and also have impaired ANS function due to structural damage, resulting in failure to achieve adequate compensatory vasoconstriction and heart rate increase after standing, thus causing OH.3 Neurogenic OH is mainly attributed to diminished release of norepinephrine from sympathetic nerves and is generally characterized by lower heart rate increase when standing in the erect position (usually <10‐15 bpm) compared with patients with non‐neurogenic causes of OH (usually >15 bpm).3, 9 Depending on the specific cause, that is whether it is a degenerative neurological disease or a non‐neurological chronic disorder, neurogenic OH can be further divided into primary and secondary, respectively. In secondary neurogenic OH, diseases like diabetes, chronic kidney disease (possibly even in the absence of diabetes or other OH risk factors), autoimmune diseases, endocrine disturbances, increased alcohol intake, and paraneoplastic syndromes can cause OH due to impairment of autonomic nerves.1, 3, 10, 11 The main causes of all types of OH are shown in Figure 2.

Figure 1.

The pathophysiology of autonomic failure resulting in orthostatic hypotension. The afferent pathway transfers information from the baroreceptors to the central nervous system, and the efferent pathway regulates the compensatory responses of the cardiovascular system. From 2018 European Society of Cardiology syncope guidelines, after permission.5 ANS, autonomic nervous system

Figure 2.

Classification of the main causes of orthostatic hypotension. ACEI, angiotensin‐converting enzyme; ARB, angiotensin receptor bloacker; HIV, human immunodeficiency virus

Aging predisposes to OH and orthostatic BP fall in the elderly merits special consideration. Several physiological changes that may affect proper response to orthostasis can be triggered by aging. Elderly individuals present impaired sensitivity of alpha‐1 adrenergic receptors, attenuated heart rate response, reduced baroreflex sensitivity, and decline in ANS function in general.2, 12, 13, 14 The stiffer myocardium and the concomitant diastolic heart dysfunction of the elderly precipitate stroke volume reduction as a result of orthostasis‐induced diminished preload,2 while arterial stiffness may contribute to inadequate vasoconstrictive response.15 Dehydration also occurs frequently in older individuals due to impaired response to thirst and diminished ability of kidneys to maintain adequate intravascular volume in case of reduced fluid intake.2 These physiological alterations can result in reduced intravascular volume, reduced stroke volume, and blunted chronotropic and vasoconstrictive response after standing, thus promoting OH. In addition, elderly people have a higher prevalence of conditions that can cause OH, such as medication use and deconditioning, and diseases that are considered risk factors for OH.2 In light of the above, OH in the elderly may occur with or without ANS dysfunction and can be considered as the result of the combined effect of several mechanisms and factors, which may be related to all OH subtypes.

Furthermore, hypertension, regardless of treatment status, is closely linked to OH, since hypertensives as well often present ANS dysfunction, cardiac hypertrophy, and increased arterial stiffness, conditions that together or separately blunt the response of the cardiovascular system to orthostatism.16, 17 In addition, supine hypertension, defined as SBP > 140 mm Hg and/or DBP > 90 mm Hg in the supine position, is very common in patients with OH, especially neurogenic OH.2, 9, 18 Orthostatic hypotension is believed to occur more frequently in the morning after awakening and after large meals (postprandial OH). Volume depletion due to increased nocturnal diuresis induced by supine hypertension (pressor diuresis) is the proposed mechanism in the first case.4, 18 Augmented capacitance of splanchnic veins after large meals predisposing to venous pooling probably mediates postprandial OH.10 Moreover, insulin‐mediated vasodilation may also contribute to postprandial OH, since insulin has vasodilating properties and increased insulin levels after large meals could decrease peripheral resistance.19 Supporting this notion, acarbose has been found to attenuate OH along with reduction in glucose absorption and postprandial insulin secretion (and possibly secretion of other gut hormones with vasodilating actions).19

4. DIAGNOSIS

Diagnosis of OH is typically determined through consecutive BP measurements in supine and erect position, a testing known as “active standing.”3 Patient should be in supine position for at least 5 minutes.2, 9 After standing, multiple BP measurements within 3 minutes may be necessary to detect a BP fall that satisfies the criteria for OH. Heart rate should be assessed, since blunted chronotropic compensatory response (<10‐15 bpm) is supportive of autonomic impairment and may be a practical tool to identify neurogenic OH.3, 9 Toward this direction, a recent study found that a rate of heart rate increase to SBP reduction from supine to upright position of less than 0.49 bpm/mm Hg has been associated with a high accuracy (sensitivity 91.3% and specificity 88.4%) in discriminating neurogenic and non‐neurogenic OH, suggesting that this simple index may have a clinical value in the usual practice.20 In case that supine BP measurements are impractical or not feasible, sitting BP values can serve as an acceptable alternative, though with reduced sensitivity, as being preferable to no measurements at all.2, 9 Interestingly, Shaw et al21 recently reported, after measuring supine, sitting, and standing BP values in 831 individuals, that a sit‐to‐stand SBP fall of at least 15 mm Hg and a sit‐to‐stand DBP fall of at least 7 mm Hg had acceptable sensitivity and specificity for detecting OH, thus proposing these thresholds for OH diagnosis when sitting instead of supine BP measurements are implemented. Use of continuous beat‐to‐beat non‐invasive BP measurement provides a more integrated BP assessment and should be used when rapid BP fluctuations are expected, especially when initial OH is suspected but not detected with the conventional sphygmomanometer.3 To control for BP changes related to different levels of daily physical activity, home BP measurements may be required, while performing the test right after awakening or after meals increases the possibility to capture OH phenomena.2

When OH is suspected but not detected with “active standing,” ambulatory blood pressure monitoring (ABPM) for 24 hours (or more if necessary) can be used.3 This test is useful for diagnosing OH only if patient's posture during each BP measurement is recorded.2 In this case, assessment of fluctuations between supine and standing BP values could unmask previously undetected OH, especially in presence of relevant symptoms.9 Ambulatory blood pressure monitoring values may reflect more precisely the extent of BP fall in OH.22 Moreover, ABPM can provide valuable information about BP variability and dipping status, which are often impaired in patients with OH. It can also identify triggering situations or exclude the diagnosis if symptoms occur in the absence of BP fall.3 Alternatively, head‐up tilt testing can be helpful to diagnose OH. This test is mainly indicated in patients with a high probability of OH when previous tests are inconclusive, usually due to delayed onset of OH. Patient is tilted in 60°‐70° angle for 20‐45 minutes in order to detect BP fall, increase or decrease in heart rate, and reproduction of symptoms.5

More specialized tests can be performed for confirming (or establishing) the diagnosis of neurogenic OH. Excessive and sustained BP fall with delayed recovery and without BP “overshoot,” along with concomitant blunted or absent compensatory heart rate increase during Valsalva maneuver, indicates neurogenic OH.2 Assessment of heart variability during deep breathing, sudomotor function testing, and plasma fractionated catecholamine levels are other tests that could be useful.9

Once OH diagnosis has been established, basic laboratory tests should be performed in all patients with OH (either neurogenic or non‐neurogenic), including electrocardiogram, complete blood count, fasting glucose, electrolytes, renal function blood tests, and thyroid‐stimulating hormone. Levels of B12 should also be measured, as B12 deficiency can cause OH.2 Liver function blood tests and serum albumin can be useful, especially for patients with weight loss, constitutional symptoms, and increased burden of comorbidities. Moreover, serum and urine protein electrophoresis can be performed for detecting paraproteinemias, mostly indicated for patients with features of peripheral neuropathy.2 Further investigation for specific causes of ANS dysfunction may be necessary depending on the findings from medical history, physical examination, and basic laboratory tests. Paraneoplastic panel tests should be conducted in patients with neurogenic OH and clinical suspicion of autoimmune disease or paraneoplastic syndrome, especially in case of subacute onset of OH and concomitant other neurological or constitutional symptoms.2 For example, a high titer of ganglionic acetylcholine receptor antibody is suggestive of autoimmune autonomic ganglionopathy diagnosis, while this finding may also be observed in pure autonomic failure.2, 23 Lastly, in OH patients with clinical features that raise the possibility of more rare causes of OH, disease‐specific tests should be performed, for example lumbar puncture, electromyography, and nerve conduction studies for Guillain‐Barre syndrome or simultaneous plasma and urinary osmolality, water deprivation test, and plasma vasopressin levels for diabetes insipidus.24, 25

5. PROGNOSIS

A summary of the main studies dealing with OH and their findings is presented in Table S1. Orthostatic hypotension is a rather common situation, and its prevalence increases with age ranging from 5% to 30% in most studies or even higher in frail and/or institutionalized cohorts. A recent meta‐analysis reported that OH prevalence in individuals aged >60 years old was 22% in community‐dwelling participants and 24% in residents in long‐term care facilities. Several studies have demonstrated significant associations between OH and hypertension, aging, diabetes, and renal disease establishing these conditions as risk factors for OH development. Patients with Parkinson's disease also present frequently with OH. Other possible risk factors are specific medication use (mainly antihypertensive agents and antidepressants), polypharmacy in general, presence of multiple comorbidities, and impaired physical activity (Table S1).

Regarding the prognostic role of OH, numerous large prospective studies and meta‐analyses have demonstrated relationships between OH and adverse CV outcomes such as coronary artery disease, heart failure, atrial fibrillation, strokes, chronic kidney disease, and venous thromboembolism. Moreover, remarkable data, including recent meta‐analyses, have reported associations with non‐CV disorders like dementia, cognitive dysfunction, decline in physical functioning, falls, fractures, and late‐life depression. Most importantly, presence of OH at baseline examination was an independent predictor of all‐cause mortality, vascular death, and non‐CV mortality in large studies, while recent meta‐analyses confirmed the relationship between OH and increased all‐cause mortality and other adverse clinical outcomes (Table S1). The predictive role of OH seems enhanced in younger individuals, probably due to longer exposure to OH and to smaller burden of comorbidities in these populations, that could blunt the impact of OH.27, 28

Certain mechanisms have been proposed to explain the associations of OH with adverse outcomes. Orthostatic hypotension could cause frequent episodes of myocardial, brain, and renal ischemia due to hypoperfusion, which in the long‐term may result in irreversible damage.29 Moreover, OH promotes increased BP variability28 and may contribute to abnormal dipping status (non‐dipping or reverse dipping),30 which are considered risk factors for target organ damage and adverse CV outcomes.27, 30, 31 Prolonged and repetitive orthostatic stress could result in increased activity and upregulation of RAAS,1 which can cause vasoconstriction, induce a prothrombotic state, accelerate atherosclerosis, or impair heart and renal function.33 Similarly, OH has been linked with enhanced activity of endothelin and vasopressin that cause vasoconstriction and may promote atherothrombosis.1, 8 On the other hand, OH is associated with several conditions that are themselves established risk factors for impaired prognosis and, despite the adjustment performed in the statistical analysis in most OH studies, the possibility of residual confounding cannot be excluded.29 Furthermore, autonomic dysfunction, often present in OH, could result in chronically elevated sympathetic activity, which has been associated with increased morbidity and mortality.28, 34 Arterial stiffness is also related to OH and could mediate the association between OH and unfavorable outcomes.15, 31 Finally, OH may serve as a marker of frailty, deconditioning, and increased disease burden,2, 35, 36 which contribute to worse prognosis.37 In summary, OH seems to have important prognostic implications, since several associations with adverse events have been reported in large observational studies. However, in the absence of randomized data evaluating the impact of OH treatment on hard clinical outcomes, it is difficult to conclude whether OH represents a marker of severity of specific diseases or impaired overall health status, an intermediate variable that mediates the action of actual causes or a true risk factor that independently affects prognosis and could become a novel therapeutic target.1, 18

6. TREATMENT

Most of the studies that examined the effect of various OH treatments were small, non‐randomized and with short follow‐up, while their main outcomes were amelioration of symptoms and reduction of orthostatic BP fall. Thus, robust data about long‐term effects of OH treatment options are lacking and findings from OH treatment studies should be interpreted with caution. Since there is no evidence indicating that treatment of OH can improve prognosis, symptom‐relief treatment is pursued and no specific BP levels are targeted.2, 9 Orthostatic hypotension is generally reversible to the extent that causative factors can be withdrawn or substantially modified. Treatment interventions for OH can be divided into three categories: modification of patient's medication, non‐pharmacological measures, and pharmacological options (Figure 3). Review of patient's medication can identify potentially causative drugs, usually antihypertensive agents, antidepressants, and antiparkinsonian agents, which may be discontinued or have their dose lowered.2, 3, 9 Decisions about medication management should be individualized with respect to each patient's comorbidities, frailty, life expectancy, drug tolerance, potentiality to improve quality of life, and estimated risk from discontinuation of specific drugs. In case of OH due to antihypertensive drugs, antihypertensive therapy should generally not be withdrawn,2 given the established benefits of BP lowering treatment.38 Moreover, uncontrolled BP can aggravate OH due to increased pressor diuresis2 and poor BP control has been related to higher OH rates in hypertensive patients39, 40 and increased risk of falls in OH patients.41 Thus, every effort should be made to combine amelioration of OH symptoms and optimal BP control. Provided that close monitoring is feasible, administration of other non‐pharmacological interventions that attenuate OH, modification of the antihypertensive regimen, dose lowering, and acceptance of more flexible BP targets in frail patient can be effective2, 31 Although data from studies are not completely consistent, it is generally considered that angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers are less likely to cause OH compared with beta‐blockers, alpha‐blockers, and diuretics (please see Table S1 for more detailed presentation of relevant evidence) and should be preferred.3

Figure 3.

Treatment options for orthostatic hypotension. BP, blood pressure; OH, orthostatic hypotensin

Non‐pharmacological lifestyle modifications can produce a modest BP increase (10‐15 mm Hg), which in many cases is enough to result in substantial clinical improvement.3 Patients should be advised to avoid triggering conditions, such as rapid standing up, standing motionless, being in hot environments, and consuming large meals.2, 3, 9 Moreover, they should get used to recognizing prodromal symptoms in order to return to seated or supine position or perform isometric counter‐pressure maneuvers, which attenuate venous pooling.2, 3 Elastic stockings and abdominal binding can be useful, especially the latter, as they also decrease venous pooling.2, 42 Physical conditioning and avoidance of prolonged bedrest should be encouraged, while sleeping with the head of the bed tilted may be helpful, as it reduces nocturnal diuresis, which can cause blood volume depletion.3, 9 Furthermore, expansion of intravascular volume through increased water consumption (2 to 3 L daily) and/or salt intake (6‐10 g) can prevent OH.2, 3 Bolus water drinking in the acute phase should also be advised,3, 43, 44 as it has been reported to be the most effective non‐pharmacological intervention45; rapid consumption of 16 ounces (approximately 470 mL) of water without any additive drink can produce remarkable amelioration of orthostatic BP fall.2, 46 Recommendations about water and salt consumption should always take into account patient's cardiac and renal status and long‐term risk from increased salt intake should be weighed against the estimated benefit from improvement in OH symptoms.9

If lifestyle measures turn out to be insufficient, pharmacological treatment is administered3 in combination with them, as it can produce additive results.47 Midodrine is a short‐acting alpha‐agonist that causes vasoconstriction and has been found to increase standing BP and diminish OH symptoms in randomized controlled trials (RCTs).48, 49 A recent meta‐analysis confirmed its efficacy but indicated that it was associated with a 6‐fold increased risk of supine hypertension.50 Avoiding the supine posture for a few hours following each dose or, if the latter is difficult, lying down in a head‐up position, could be useful in preventing high supine BP values.9 Fludrocortisone expands intravascular volume through water and salt retention and can be effective in OH.3, 51, 52 However, it may cause fluid overload, supine hypertension, hypokalemia, and, in high doses, other corticosteroid‐like side effects.2 Despite their potential side effects, these two agents are considered the most appropriate drugs for OH treatment3 and they can also be used in combination.9 A head‐to‐head retrospective comparison between midodrine and fludrocortisone that used data from medical files reported a higher rate of hospitalizations with fludrocortisone, especially in patients with heart failure.53 Thus, midodrine may be preferred as initial monotherapy. Moreover, it has been suggested that fludrocortisone is best avoided in heart failure patients.1, 2 Regarding other drugs, pyridostigmine and atomoxetine can increase sympathetic activity and have shown some encouraging results in single‐dose studies.54, 55 Acarbose has been reported to ameliorate postprandial OH and may be considered in such cases.19, 56 Other agents that have been tested in specific conditions that coexist with OH are erythropoietin in anemia, desmopressin in nocturnal polyuria, and octreotide in postprandial OH, but evidence supportive of clinical benefit is weak.3 Recently, droxidopa, a prodrug that is converted to norepinephrine, has emerged as a promising therapy for OH with positive results in randomized trials,57, 58 while a post hoc analysis of one of them reported a 66% reduction in falls.59 However, a meta‐analysis suggested that beneficial effects of droxidopa decreased gradually over time and lost statistical significance after 8 weeks of treatment.60 While ESC guidelines suggest that further evidence is needed to confirm the efficacy of this pharmaceutic agent,3 American College of Cardiology/American Heart Association syncope guidelines recommend droxidopa for syncope due to neurogenic OH with a class IIa indication44; thus, it could be considered an alternative treatment option.

Lastly, an important issue that should be addressed is the management of patients with OH and concomitant supine hypertension. Supine hypertension is common in patients with neurogenic OH, and these individuals may experience severe BP fluctuations.18 Moreover, these two entities represent hemodynamic opposites and pharmaceutic agents that improve the one condition may exacerbate the other. Thus, close monitoring is required and management should take into account each patient's comorbidities, life expectancy, and overall health status. Patients should be advised to avoid the supine posture during daytime if possible and sleep (or repose) with the head of the bed elevated, whereas fludrocortisone should be avoided.9 In patients with severe supine hypertension (SBP > 180 mm Hg or DBP > 110 mm Hg), short‐acting antihypertensive drugs can be administered, such as captopril, losartan, clonidine, hydralazine, and nitroglycerin patch.9 These agents should be given only at bedtime, while diuretics and long‐acting antihypertensive drugs should be avoided. In patients with high supine BP values, but lower than the aforementioned threshold, estimated risk and benefits from each therapeutic intervention should be balanced and management should be individualized.9

7. CONCLUSIONS

In summary, OH is a frequent cardiovascular disorder with ANS dysfunction being in the center of its pathogenesis. Specific conditions have been identified as causes and risk factors, and numerous prospective studies support its association with impaired prognosis. Some therapeutic interventions for OH are considered valid and recommended by guidelines, but evidence about their efficacy is derived from studies with relatively small sample, short follow‐up, without having assessed the effect of treatment on hard clinical outcomes and, in their majority, non‐randomized. Thus, a causal relationship between OH and adverse events cannot yet be established and no firm conclusions about OH therapies can be drawn until more data are available. Long‐term, large RCTs evaluating the impact of OH treatment on hard clinical outcomes are desirable.

CONFLICT OF INTEREST

None.

AUTHOR CONTRIBUTIONS

Magkas Nikolaos wrote the largest part of the manuscript. Tsioufis Costas conceived of the presented idea, co‐wrote the manuscript, made corrections throughout manuscript writing and revision, and gave final approval to submit the manuscript. Thomopoulos Costas co‐wrote the manuscript and made corrections throughout manuscript writing and revision. Dilaveris Polychronis made corrections throughout manuscript writing and revision. Georgiopoulos Georgios searched for studies cited in the manuscript. Sanidas Elias searched for studies cited in the manuscript. Papademetriou Vasilios made corrections throughout manuscript writing and revision. Tousoulis Dimitrios gave final approval to submit the manuscript.

Supporting information

 

Magkas N, Tsioufis C, Thomopoulos C, et al. Orthostatic hypotension: From pathophysiology to clinical applications and therapeutic considerations. J Clin Hypertens. 2019;21:546–554. 10.1111/jch.13521