Orthostatic hypertension, which appears to be mediated through excess neurohumoral activation while standing, is a common blood pressure trait among patients with and without arterial hypertension. However, lack of consensus regarding the definition of orthostatic hypertension makes it difficult to assess the true prevalence of this condition. Orthostatic hypertension appears to predict the risk for progression to arterial hypertension in younger and risk of cardiovascular morbidity and mortality in older persons. Yet, the risk may differ between populations. Whether orthostatic hypertension indicates a generally increased risk of death, constitutes an intermediate variable in the causal pathway of cardiovascular risk factors, a simple measure of disease severity, or an independently acting mechanism is not known. Since both orthostatic hypotension and orthostatic hypertension herald increased risk of cardiovascular disease, it appears reasonable to screen the patients for abnormal orthostatic blood pressure responses using simple orthostatic testing. However, how presence of orthostatic hypertension may affect clinical management decisions such as the choice of antihypertensive drugs is currently difficult to ascertain. Clearly, this issue deserves more attention.
The term orthostatic hypertension, which is an increase in blood pressure with standing, began to appear in the medical literature as early as in the 1940 and 1950s, typically in relation to kidney diseases.1 Given the hemodynamic burden imposed on the cardiovascular system with standing, an increase in blood pressure is counterintuitive and often goes unrecognized. A uniform definition of orthostatic hypertension has never been established and reports on orthostatic hypertension in population-based and interventional studies have been sparse. The state-of-affairs may be explained by changing diagnostic criteria of arterial hypertension and lack of interest among scientists and clinicians. Symptomatically of this situation, hypertension experts have rarely focused on orthostatic hypertension, and the term has neither been included nor defined in the most recent hypertension guidelines.2,3 This review provides an overview of the limited evidence about orthostatic hypertension and provides an impetus for further studies.
Definition of Orthostatic Hypertension
Over the years, various definitions of orthostatic hypertension have been proposed. None is based on normative data or cardiovascular risk estimates. Some definitions used the absolute difference in both systolic and diastolic blood between supine or sitting and standing position as diagnostic criteria. Others defined orthostatic hypertension as conversion from normal blood pressure values in the supine to hypertensive blood pressure on standing. Obviously, the latter strongly depends on the concurrent definition of hypertension. Recently, an expert group suggested an absolute systolic blood pressure increase while standing by at least 20 mm Hg or above 140 mm Hg for normotensive subjects as 2 alternative criteria for orthostatic hypertension.4 Defining orthostatic hypertension by elevated diastolic blood pressure is less reliable as diastolic blood pressure usually increases by 5 to 10 mm Hg on standing due to peripheral vasoconstriction and reduction in cardiac stroke volume.5–7
Another important aspect of orthostatic hypertension, only occasionally discussed in the literature is that blood pressure can change over time. When and how long should standing blood pressure be elevated to confirm orthostatic hypertension? The table provides an overview on orthostatic hypertension definitions that have been applied over the years.
Table. Orthostatic Hypertension Definitions From the Past Medical Literature Authors, y Criteria of Orthostatic Hypertension (All Criteria Refer to BP Change With Standing) Remarks and Comments Streeten et al12 DBP supine <90 mm Hg and DBP standing >90 mm Hg This definition does not include orthostatic change in SBP. There is a risk of OHTN overestimation due to normal increase in DBP on standing. Vriz et al15 DBP increase ≥11 mm Hg (post hoc analysis) The study was performed on a younger population of stage I hypertensive patients. This criterion identified ≈10% of patients as having hyperreactive orthostatic response. The term orthostatic hypertension was not applied. Matsubayashi et al57
Kohara et al58
Kario et al17 SBP increase ≥20 mm Hg The authors do not report the rationale for this specific cutoff limit. Kohara et al58 refers to study by Nardo et al39 where orthostatic increase >20 mmHg in SBP observed in a large population-based study is described as large. Kario et al16 SBP increase ≥10 mm Hg The authors performed head up tilt testing instead of active standing test. The rationale for such a sensitive SBP change criterion was not provided. Alagiakrishnan et al60 SBP increase ≥10 mm Hg or DBP increase ≥10 mm Hg The study was performed on an elderly population (71–93 y). There is a risk of OHTN overestimation due to sensitive diagnostic criteria in relation to SBP and DBP change. The rationale for such sensitive criteria was not provided. Yoshinari et al43 SBP increase from <140 mm Hg to ≥140 mm Hg or DBP increase from <90 mm Hg to ≥90 mm Hg This definition was applied in a population of patients with diabetes mellitus. The authors refer to studies by Kario et al where different definitions were proposed. Thomas et al45 SBP increase ≥5 mm Hg There is a risk of OHTN overestimation due to a very sensitive diagnostic criterion in relation to SBP change. The rationale for such sensitive criterion was not provided. In a large population-based study by Nardo et al,39 this criterion would classify 30% of all participants as having orthostatic hypertension. Hoshide et al59 SBP increase ≥11.5 mm Hg (=the top decile) The study was performed on a population of older hypertensive patients. The orthostatic change in SBP was measured from sitting to standing position. This criterion is dependent on the investigated population. Townsend et al42 SBP increase ≥20 mm Hg or DBP increase ≥10 mm Hg The study was performed on a large population of hypertensive patients. The authors performed one standing measurement only (after 1 minute). There is a risk of OHTN overestimation due to normal increase in DBP on standing. Weiss et al52 Any increase in SBP or DBP The study was performed on older patients admitted to emergency department. The rationale for this approach to orthostatic hypertension definition was not provided. The authors identified 86% of all patients as having orthostatic hypertension. Kostis et al38 SBP increase ≥15 mm Hg The study was performed on a large population of hypertensive patients. The orthostatic change in SBP was measured from sitting to standing position. The rationale for this criterion was not provided. Finucane et al4 A sustained increase (>1 min) in SBP ≥20 mm Hg or above 140/90 mm Hg, if patient is normotensive supine A practical guide to active standing test with beat-to-beat BP monitoring. The absolute DBP criterion is not included due to normal increase in DBP on standing. This definition combines both absolute SBP increase and conversion from normal supine BP to hypertension on standing.
Pathophysiological Studies in Orthostatic Hypertension
Much like orthostatic hypotension, orthostatic hypertension signals an abnormality in cardiovascular autonomic control mechanisms. Considering the burden imposed on the cardiovascular system with standing, an increase in blood pressure is unexpected. With standing, ≈500 to 1000 mL blood is pooled in capacitance vessels below the diaphragm. Furthermore, within 15 to 20 minutes of standing, hydrostatic pressure forces 10% to 20% of the plasma volume from the intravascular compartment into the interstitial space. Therefore, blood pressure transiently decreases with standing even in healthy persons. Efferent cardiovascular autonomic adjustments through baroreflex-mechanisms with rapid withdrawal of cardiac parasympathetic activity and subsequent sympathetic activation are crucial in maintaining blood pressure with standing.8,9 However, other mechanisms such as vestibular input and central command also contribute. Parasympathetic withdrawal raises heart rate while sympathetic activation augments heart rate and cardiac contractility, vascular tone, and renin-angiotensin-system activity. Baroreflex-mediated vasopressin release, which has limited effects on blood pressure in healthy persons, may serve as backup when these mechanisms fail to maintain blood pressure.10,11
Mechanistic studies on hemodynamic and neurohumoral contributions to orthostatic hypertension are scarce and often conducted in small samples. In a highly selected cohort of patients with orthostatic hypertension, cardiac output determined by carbon dioxide rebreathing decreased more with standing compared with control persons.12 This finding may suggest that orthostatic hypertension is primarily driven by increased vascular resistance. Given the contribution of blood viscosity to vascular resistance, excess plasma shifts with standing could contribute to the response. A recent analysis among patients with orthostatic intolerance referred for tilt-table testing showed similar abnormalities in those with orthostatic hypertension using pulse contour analysis of finger blood pressure tracings.13 In very old institutionalized persons, heart rate increased ≈1.5 bpm more in the group with orthostatic hypertension compared with the group with orthostatic normotension, which hardly explains the difference in blood pressure.14 Pressure suit inflation, which decreases venous pooling while standing, attenuated orthostatic hypertension.12 The finding suggests that reduction in cardiac preload is the trigger setting off orthostatic hypertension. In some patients, orthostatic hypertension may be triggered by excess venous pooling.12
The mechanisms driving orthostatic hypertension may be affected by age with a cardiac reactive type in younger adults often accompanied by orthostatic tachycardia15 and a vascular stiffness type in older individuals.16
An orthostatic pressor response or orthostatic hypertension could conceivably ensue when neurohumoral adjustments to standing overshoot. Indeed, venous plasma norepinephrine concentrations were within the normal range in patients with orthostatic hypertension and increased excessively with standing.12,17 Yet, others did not observe elevated norepinephrine levels in mildly hypertensive patients with orthostatic hypertension compared with hypertensive controls in 24 hour-urine samples.15 In case reports, the exaggerated orthostatic blood pressure response is ameliorated by α-adrenoreceptor blockade, even though such treatment may not be well tolerated.18,19 The efficacy of α-adrenoreceptor blockade for decreasing excess orthostatic blood pressure responses was confirmed in a small intervention study.20 Increased norepinephrine availability and increased responsiveness to the released norepinephrine may contribute to the response. Indeed, a case report showed substantially increased pressor sensitivity to norepinephrine and angiotensin II in a patient with orthostatic hypertension.19 The latter could be mediated through vascular hypersensitivity, impaired baroreflex blood pressure buffering, or both mechanisms combined.21 Excess vasopressin release, which is also regulated through baroreflex mechanisms, has been observed in these patients.17 The observation that blood pressure remains elevated while standing suggests that central nervous system mechanisms reset baroreflex control to higher blood pressure levels in patients with orthostatic hypertension.
There seems to be large overlap between orthostatic hypertension and an extreme dipping pattern in ambulatory blood pressure recordings,16 suggesting that orthostatic hypertension may not be a transient phenomenon. In contrast, orthostatic hypotension is associated with nondipping or reverse-dipping patterns in ambulatory blood pressure recordings.22
While neurohumoral mechanisms appear to be crucial in mediating orthostatic hypertension, increased arterial stiffness and altered ventriculo-aortic coupling could promote the response. The technology testing these ideas in human beings is available.23
The early suggestion that aberrant renal arteries curving around and compressing renal veins could elicit orthostatic hypertension was based on anatomic findings only and is not supported by clinical or experimental evidence.24
Rare Conditions Associated With Orthostatic Hypertension Provide Mechanistic Insight
The literature suggests that orthostatic hypertension can be associated with various underlying conditions, which may provide insight regarding underlying mechanisms. Most conditions associated with orthostatic hypertension are associated with altered cardiovascular adrenergic control mechanisms. Compared with control persons, patients with the postural tachycardia syndrome, which is characterized by increased cardiac sympathetic activation, are more likely to exhibit a pressor response to standing.25 An increase in blood pressure with standing can occur in patients with familial norepinephrine transporter deficiency,26 suggesting that increased norepinephrine release and reduced norepinephrine clearance can, both, contribute to orthostatic hypertension.
Afferent baroreflex failure results from damage to arterial baroreceptors or baroreflex afferents.27,28 The condition is characterized by volatile blood pressure with severe sympathetically mediated blood pressure surges. The phenomenon is explained by lack of dampening baroreflex input to cardiovascular control centers in the brain stem. Some patients with afferent baroreflex failure feature orthostatic hypertension.29 However, patients with baroreflex failure may also experience orthostatic hypotension despite sympathetic activation possibly due to disorganized efferent sympathetic nerve traffic.30,31 Orthostatic hypertension has also been observed in patients with inherited hypertension and brachydactyly through mutation in the gene encoding phosphodiesterase 3A.32 In addition to changes in vascular structure and function,33 these patients exhibit profound abnormalities in baroreflex regulation.32,34 Orthostatic hypertension has also been described in patients with medullary vascular compression,35 which appears to predispose to sympathetic excitation.36 Overall, these observations further support that idea that excess adrenergic drive not sufficiently restrained by the baroreflex predisposes to orthostatic hypertension.
Prevalence of Orthostatic Hypertension
In the year 1922, an increase in diastolic blood pressure from below 90 mm Hg while supine to above 90 mm Hg in the upright posture was reported in 4.2% of 2000 apparently healthy aviators aged 18 to 42 years.37 The same study showed an average orthostatic increase in systolic blood pressure by 2.3 mm Hg with a maximal change of 40 mm Hg. In another pioneering publication in 1985, orthostatic hypertension was found in 181 out of 1800 middle-aged persons referred with arterial hypertension.12 Since then, the definition of orthostatic hypertension has been evolving. Unfortunately, the lack of a standardized unanimous accepted definition and the absence of specific guideline recommendations regarding diagnostic criteria obscure the true prevalence of orthostatic hypertension and render comparison between studies unreliable.
In studies defining orthostatic hypertension as a sustained increase in systolic blood pressure ≥20 mm Hg and/or diastolic blood pressure ≥10 mm Hg within 3 minutes of standing, the reported prevalence of orthostatic hypertension ranged between 5% and 30%, which is generally in line with the prevalence of orthostatic hypotension, an opposite and much better-studied condition. Furthermore, a broad and relatively symmetrical distribution of orthostatic blood pressure changes was consistently observed across population-based studies and randomized clinical trials, including the Systolic Hypertension in the Elderly Program,38 the Atherosclerosis Risk in Communities,39 the Malmö Diet and Cancer Study,40 the Action to Control Cardiovascular Risk in Diabetes Blood Pressure,41 and the Systolic Blood Pressure Intervention Trial.42
The proportion of individuals with orthostatic hypertension increases with advancing age, greater body mass index, and chronic cardiovascular conditions such as essential hypertension—particularly among extreme dippers with abnormal diurnal variation. Patients with diabetes mellitus showed a 5-fold higher orthostatic hypertension prevalence compared with a nondiabetic population.43
Orthostatic hypertension is associated with various other types of blood pressure variability that are associated with increased cardiovascular risk, including an exaggerated morning blood pressure surge, abnormal circadian blood pressure variability with extreme dipping during the night, daytime hypertension, increased daytime blood pressure variability, and exercise-induced hypertension.44
Association Between Orthostatic Hypertension and Cardiovascular Risk
Orthostatic hypertension may not be a benign condition, however, the implications of the diagnosis in terms of risk stratification and clinical management are far from being clear. Orthostatic hypertension may herald sustained arterial hypertension later in life. In the Coronary Artery Risk Development in Young Adults study, younger normotensive persons with an orthostatic pressor response exhibited increased incidence of arterial hypertension during the follow-up period.45 On the contrary, no such relationship was observed in older persons in the Normative Aging Study.46
Orthostatic hypertension could conceivably contribute to daytime blood pressure variability, which has been linked to hypertensive organ damage, cardiovascular morbidity, and mortality.47 In older Japanese patients with arterial hypertension confirmed by ambulatory blood pressure monitoring, those with an orthostatic pressor response were more likely to show silent cerebrovascular disease in brain magnetic resonance images.17 The association remained significant after adjusting for confounding variables including ambulatory blood pressure. The orthostatic hypertension group also showed electrocardiographic signs of left ventricular hypertrophy, increased blood pressure variability, and extreme blood pressure dipping during the night.17
In a large Chinese cross-sectional community-based study enrolling 4711 patients with hypertension and 826 normotensive individuals, orthostatic hypertension was associated with peripheral arterial disease and stroke in patients with hypertension. However, no significant association between orthostatic hypertension and coronary artery disease was reported, in contrast with orthostatic hypotension.48
In the middle-aged community-dwelling population of the Atherosclerosis Risk in Communities study, orthostatic hypertension was significantly associated with subclinical cardiovascular disease. Individuals with orthostatic hypertension were more likely to have higher levels of high-sensitivity cardiac troponin T and N-terminal pro b-type natriuretic peptide, carotid plaques, and lacunar strokes regardless of traditional cardiovascular risk factors.49,50
In the prospective Italian cohort of the Progetto Veneto Anziani study, enrolling 2786 community-dwelling elderly aged ≥65 years, orthostatic hypertension, defined as increase in mean orthostatic systolic blood pressure ≥20 mm Hg, was associated with increased all-cause (adjusted hazard ratio, 1.23 [95% CI, 1.02–1.39]) and cardiovascular mortality (adjusted hazard ratio, 1.41 [95% CI, 1.08–1.74]), compared with orthostatic normotension.51 Similarly, compared with normal orthostatic responses, orthostatic hypertension—defined by an systolic blood pressure increase >20 mm Hg at the first and third minute of standing - was associated with increased combined cardiovascular morbidity and mortality (adjusted hazard ratio, 1.51 [95% CI, 1.09–2.08]) at the 2-year follow-up of the Predictive Values of Blood Pressure and Arterial Stiffness in Institutionalized Very Aged Population study. The study enrolled 972 institutionalized persons aged 88±5 years across Italy and France, with an orthostatic hypertension prevalence of 28%.14
However, orthostatic hypertension may not always be associated with increased risk. In 474 patients with mean age of 81.5 years admitted to an acute geriatric department, orthostatic testing was conducted at the end of the hospital stay. The authors diagnosed orthostatic hypertension when upright systolic or diastolic blood pressure exceeded supine measurements. In the follow-up period, survival adjusted for multiple risk factors was better in those with orthostatic hypertension.52 However, it should be emphasized that the authors identified 86% of patients as having orthostatic hypertension.
Post hoc analysis of data from the Systolic Hypertension in the Elderly, a multicenter, randomized trial on the effect of chlorthalidone-based antihypertensive treatment among older individuals with isolated systolic hypertension, showed increased all-cause mortality in patients with orthostatic hypertension. Mortality was similarly increased in the active and in the placebo treated group.38 All-cause mortality was also increased in patients with orthostatic hypotension in this38 and in another blood pressure trial,41 which implies that disruption of orthostatic blood pressure control is deleterious, regardless of the directionality of changes.
Diagnosis and Detection
In the absence of consensus regarding its definition, there cannot be a generally recommended and validated approach for diagnosing orthostatic hypertension. In addition to detecting orthostatic hypotension, which has important clinical and prognostic implications, a simple clinical orthostatic test is a useful screening tool for orthostatic hypertension.44,53–55 Testing includes 5 minutes of rest in the supine position followed by blood pressure measurement for 3 minutes during active standing, using a brachial blood pressure cuff. Pulse rate should also be recorded. The test can be easily performed in the clinic as well as in the patient’s home. Unfortunately, determination of orthostatic vital signs while commonly touted is rarely conducted in real life. In selected cases, active standing can be combined with beat-to-beat blood pressure and heart rate recordings; however, the methodology is not widely available.4
Head-up tilt table testing might be considered in cases where active standing testing provided inconclusive results. Usually, patients are tilted with the head-up to 60° to 70° under continuous blood pressure monitoring during 20 minutes.55 A typical response of a patient with orthostatic hypertension during head-up tilt testing is displayed in the Figure. Clearly, head-up tilt testing cannot be considered a screening tool for clinical routine in the absence of another compelling indication but rather a confirmatory test applied in selected cases
Figure. Head-up tilt test with noninvasive measurements of continuous finger blood pressure (upper tracing) and heart rate (lower tracing) in a 76-year old woman with unexplained syncope and dizziness. At baseline blood pressure is stable below 140/90 mm Hg. After head-up tilt, blood pressure increases above 170/100 and remains at this level during the test. After return to the supine position, blood pressure normalizes within 2 minutes.
Whether or not repeat orthostatic testing is required to confirm the diagnosis of orthostatic hypertension is unknown. We suggest that a single measurement is probably not sufficient in defining any blood pressure trait including orthostatic hypertension.
Ambulatory blood pressure monitoring may be used in cases where repeated measurements are indicated to confirm orthostatic hypertension. Patients should record changes in posture such as getting out of bed in the morning.44 In any case, ambulatory blood pressure monitoring may have utility in gauging the overall blood pressure load when patients are up during the day and detect abnormalities in diurnal blood pressure patterns, such as extreme blood pressure dipping during the night.16
Implications for Clinical Management of Orthostatic Hypertension
At least in younger persons, an orthostatic increase in blood pressure with supine blood pressure readings in the normal range heralds overt arterial hypertension later in life.45 Closer follow-up with repeat blood pressure measurements may be prudent in this population to detect the progression to overt arterial hypertension.
Treatment decisions in routine hypertension management are primarily informed by office blood pressure measurements with patients resting in the seated position. Whether and how systematically raised upright blood pressure affects benefits and risks of antihypertensive treatment is unknown. Indeed, recommendations for antihypertensive treatment in patients with either arterial hypertension accompanied by orthostatic hypertension or isolated orthostatic hypertension with normal supine blood pressure are limited due to the absence of larger scale clinical trials in this population. More importantly, the current hypertension guidelines provide no guidance for detection and management of orthostatic hypertension.2,3 According to observational and interventional studies, cardiovascular morbidity and mortality are strongly and linearly related to elevated blood pressure levels and pharmacological blood pressure lowering confers significant cardiovascular protection regardless of the drug class used.56 Since orthostatic hypertension is relatively common in hypertensive populations, has not been excluded from blood pressure trials, and appears to be associated with increased cardiovascular risk, it is reasonable to conclude that blood pressure should be lowered in patients with and without orthostatic hypertension alike. Ambulatory blood pressure may be particularly useful in guiding treatment in the orthostatic hypertension group.
There is no evidence that patients with orthostatic hypertension benefit from a particular drug class in terms of cardiovascular risk protection. However, the choice of medications may be guided by physiological reasoning. In the absence of clinical trials data, most patients requiring antihypertensive therapy will likely be started on first-line antihypertensive medications as recommended in current hypertension guidelines.2,3 Because the trigger setting of neurohumoral activation with standing is reduction in cardiac preload,12 diuretics, which exacerbate central hypovolemia, may not be the best choice for antihypertensive medications. Whether first-line medications should be substituted by α-adrenoreceptor blockers, which appear to be particularly efficacious in lowering blood pressure in patients with orthostatic hypertension,20 or sympatholytic drugs is an individual clinical judgement call.
Unanswered Questions and Future Research Directions
We believe that the following research questions ought to be addressed to provide guidance for physicians caring for patients with orthostatic hypertension:
There should be a uniform definition of orthostatic hypertension preferably based on normative data and risk estimates.
Additional studies may provide insight in mechanisms mediating additional risk in patients with orthostatic hypertension and help refining the design of treatment trials.
Assessment of orthostatic hypertension in prospective epidemiological studies should be encouraged and future randomized trials in chronic cardiovascular disease should include prespecified analyses in this population to explore prevalence, incidence, and independent prognostic significance.
Further studies are required to asses impact of orthostatic hypertension on the response to antihypertensive medications.
Disclosures J. Jordan served as consultant for Theravance in the development of therapies for orthostatic hypotension. A. Fedorowski reports personal fees from Medtronic Inc and Biotronik outside the submitted work. V. Hamrefors reports educational congress grant from Boston Scientific Inc outside of the submitted work. The other authors report no conflicts.
Footnotes