Orthostatic hypertension: From pathophysiology to clinical applications and therapeutic considerations

Abstract

Orthostatic hypertension (OHT), that is, sustained increase in blood pressure after standing, is an increasingly recognized cardiovascular disorder having been examined in much fewer studies compared with orthostatic hypotension (OH). However, in both OHT and OH, dysfunction of the autonomous nervous system is considered to be the primary pathophysiological disturbance, while significant associations with essential hypertension have been observed. Although in many studies OHT has been related to subclinical or clinical target organ damage, there is also evidence denying such an association. Because OHT is defined variably across different studies, the comparison of relevant outcomes is at least problematic. Since evidence about OHT treatment is exclusively based on limited non‐randomized studies, no specific recommendations have been developed. Therefore, both the prognostic role and the clinical significance of OHT remain largely undefined. The aim of the present review is to summarize the available evidence regarding the definition, diagnosis, pathophysiology, prognostic role and treatment of OHT and highlight potential clinical implications of this underestimated condition.

1. INTRODUCTION

When moving from supine to standing position, the transient reduction in blood pressure (BP) is quickly restored because of autoregulatory mechanisms modulated by the autonomous nervous system (ANS).1 Orthostatic hypotension (OH), that is, sustained reduction of systolic blood pressure (SBP) of at least 20 mm Hg or diastolic blood pressure (DBP) of at least 10 mm Hg after standing, is a common and extensively studied situation.1 Orthostatic hypertension (OHT) represents the hemodynamic opposite of OH and, similar to OH, is also caused by ANS dysfunction, but is less studied, rarely assessed during physical examination and with no unanimous definition.1, 2 Interestingly, although OH is an underrecognized cardiovascular (CV) disorder, some studies have reported a higher OHT prevalence compared with OH. Since both pathophysiology and prognostic role of OHT remain largely unclear and given that randomized data are lacking, no specific recommendations about OHT management have been developed.2, 4

The aim of the present review is to summarize the evidence so far about definition, diagnosis, pathophysiology, prognostic role and treatment of OHT and highlight potential clinical implications of this underestimated condition.

2. METHODS

We performed a systematic review of the literature, searching for contemporary data on definition, diagnostic criteria, prevalence, pathophysiologic mechanisms, associations with clinical outcomes, and treatment implications of orthostatic hypertension. Medline and Cochrane Library were reviewed for eligible articles and abstracts from large cardiovascular conferences by implementing appropriate search terms, that is, “orthostatic hypertension,” “orthostatic blood pressure increase,” “orthostatic blood pressure rise,” “postural hypertension,” “postural blood pressure increase,” and “postural blood pressure rise,” until September 2018. Articles and abstracts were limited to those published in the English language or with an available abstract in English. The reference list of eligible articles was manually searched to identify other relevant reports. Animal studies and studies that enrolled only non‐adults (<18 years old) were excluded. The flow chart to identify eligible studies is presented in Figure 1.

Figure 1.

Flow chart

3. DEFINITION‐DIAGNOSIS

Since there is no “official” definition for OHT,2 the majority of investigators have proposed that OHT can be defined as an increase in SBP of at least 20 mm Hg after standing.4 However, in recent large studies and in accordance with OH definition, an orthostatic increase in DBP of at least 10 mm Hg was also included in the definition of OHT.5, 6, 7Some authors have defined OHT as any BP increase from <140/90 mm Hg in supine position to >140/90 mm Hg when standing8 and others as an increase only in DBP from <90 mm Hg in supine position to >90 mm Hg in erect position.9 Increasing changes of SBP of either 10 mm Hg or 5 mm Hg have been proposed to define OHT as well.10, 11 Orthostatic hypertension is usually asymptomatic,2 but symptoms may occur such as dizziness, lightheadedness, headache, palpitations, nausea, sweating, and rarely syncope.12

Testing for diagnosis of OHT is not different from OH, including “active standing” (either in the clinic or at patient's home), ambulatory blood pressure monitoring (ABPM), and tilt‐table test.2, 13, 14 In active standing, BP is measured with the patient in supine position for at least 5 minutes followed by consecutive BP measurements for 3 minutes. Performing the same test at patient's home may eliminate a possible “white coat” effect, which could result in a false OHT diagnosis when BP is measured in the clinic. On the other hand, home BP measurements may provide more chances to capture previously undetected OHT.2 Alternatively, ABPM can be used and may provide additional advantages including the assessment of short‐term BP variability.2, 13 In cases of remaining clinical suspicion, a tilt‐table test can be offered. Although there are several tilt‐testing protocols,13 passive tilting (ie, with no pharmacological provocation) is performed with the method recommended by current guidelines.2, 14 After being in the supine position for at least 5 minutes, patient is tilted with the head up in angle between 60° and 70° for at least 20 minutes and BP is assessed.2, 14 Kario proposed that OHT diagnosis should be considered definite when SBP increases by 20 mm Hg SBP during either clinic active standing or tilting test and probable when SBP increases by 10 mm Hg SBP along with the same procedures. By contrast, for home active standing a more conservative threshold of 10 mm Hg SBP increase may be considered for the definite diagnosis of OHT.2

4. PATHOPHYSIOLOGY

The pathophysiology of OHT is not completely understood, but OHT is considered a manifestation of ANS dysfunction as has been reported for OH and common mechanisms acting in opposite mode are involved in either disorder.3 The main operating mechanisms underlying OHT development are shown in Figure 2. Orthostasis sequentially causes venous pooling, decrease in venous return, decrease in stroke volume and cardiac output, conditions that are associated with transient BP reduction. In normal subjects, BP fall stimulates arterial baroreceptors with parallel activation and deactivation of sympathetic and parasympathetic drive, respectively. This compensatory autonomic response restores BP within seconds through vasoconstriction and increased heart rate.1, 2 In patients with OHT, a sympathetic over‐response is observed causing excessive vasoconstriction which raises BP above supine position BP levels,2 while a more pronounced increase in heart rate may also contribute to this phenomenon though in a lesser extent.15 Indeed, Lee et al recently confirmed that OHT patients had higher peripheral vascular resistance compared with patients with normal orthostatic BP response during tilting,12 while two additional studies reported that OHT patients had higher norepinephrine plasma levels in the upright posture compared with their non‐OHT counterparts.9, 16 Moreover, Vriz et al observed that OHT patients had higher resting cardiac output and heart rate, as well as higher urinary norepinephrine output compared with non‐OHT individuals, suggesting that OHT is characterized by increased baseline sympathetic activity, and the orthostasis‐induced cardiac output reduction may trigger sympathetic over‐response.17 ANS dysfunction is attributed to impaired arterial and cardiopulmonary baroreceptors’ sensitivity and/or baroreflex failure to adjust to “normal” BP values, while alpha‐adrenergic vascular hyperactivity is believed to be another important mechanism mediating the excessive vasoconstriction.2, 18 Activation of the renin‐angiotensin‐aldosterone system (RAAS) and increased vasopressin secretion may also be involved in the development of OHT.2, 16, 18 Furthermore, arterial stiffness and small artery remodeling could aggravate orthostatic sympathetic response and promote an exaggerated increase in vascular resistance.2, 19, 20 In addition, excessive venous pooling may contribute to the pathogenesis of OHT.9 The reason why common triggering factors and mechanisms may promote the development of OH in some patients and OHT in others still remains unclear.3

Figure 2.

Mechanisms proposed to underlie pathogenesis of orthostatic hypertension

Conditions enhancing activation of the sympathetic system and ANS degeneration, such as aging, essential hypertension, diabetes mellitus, and neurological disorders, may be considered as clinical promoters of OHT.2, 4 More specifically, essential hypertension may be bidirectionally linked to OHT. The observation that young subjects with orthostatic SBP increase ≥5 mm Hg were at increased risk for developing essential hypertension further extended to diabetic patients without hypertension support the concept that OHT may be a form of pre‐hypertension in non‐hypertensives.11, 21 Moreover, two other studies indicated that OHT was associated with masked hypertension.10, 22 Thus, it is undetermined whether OHT is a cause, a consequence, or a particular subtype of essential hypertension.

Another clinical entity that may coexist with OHT is postural tachycardia syndrome (POTS), defined as an increase of at least 30 beats/minute after standing in the absence of OH.23 A significant proportion of patients with POTS present high plasma norepinephrine levels in the upright position and an exaggerated sympathetic response to orthostatic stress, a situation classified as the hyperadrenergic type of POTS.23, 24 Different intensity of OHT may develop in this subtype of POTS patients. Thus, there is a clinical overlap between OHT and POTS, with increased sympathetic activity being at the pathophysiologic cross‐road linking these two types of orthostatic intolerance.23, 24 Structural and/or functional abnormalities of the renal vasculature may also be involved in OHT pathogenesis. Renal blood flow reduction due to renal artery disease can activate RAAS with increased renin secretion and elevated angiotensin levels, that in turn cause vasoconstriction, water and salt retention, and increased BP values (renovascular hypertension).25, 26 Orthostatic hypertension may develop in cases of reduced renal blood flow during standing. This particular condition has been observed in patients with nephroptosis, a clinical entity characterized by increased mobility of the kidneys and defined as significant descend of the kidney (by at least 5 cm or two vertebral bodies on intravenous urography) when standing.18, 27 Descend of the kidney can cause stretching and torsion of the renal artery, reduction of renal blood flow and, consequently, OHT.18, 27, 28 Lastly, other, relatively rare, OHT causes that should be suspected in cases of extreme orthostatic BP increase are pheochromocytoma, mast cell activation, and norepinephrine transporter deficiency.4

5. EPIDEMIOLOGY‐PROGNOSTIC ROLE

In general, OHT has been examined in much fewer studies compared with OH. The main findings from OHT studies are shown in Table S1. Unfortunately, lack of a worldwide accepted definition of OHT renders comparison between studies at least problematic. In studies that defined OHT as an increase in SBP ≥20 mm Hg, prevalence ranged from 1.1% in a study with relatively young participants to 28% in the very elderly institutionalized cohort of the Predictive Values of Blood Pressure and Arterial Stiffness in Institutionalized Very Aged Population (PARTAGE) Study. As expected, studies that also considered orthostatic DBP increase or used lower SBP increase thresholds have generally reported higher rates of OHT (Table S1). Notably, some studies that used the broader OHT definition demonstrated higher rates of OHT compared with OH.5, 6, 29 Among risk factors, age seems to be a major determinant of OHT. A higher prevalence of OHT in diabetics and frail subjects has also been reported, while other studies have suggested a link with both obesity and metabolic syndrome. Orthostatic hypertension has been associated in most studies with supine or sitting hypertension or higher BP values, at variance with other studies reporting a relationship between OHT and lower BP values (Table S1).

Limited data support association of OHT with clinical outcomes. Participants of the Atherosclerosis Risk in Communities (ARIC) Study with orthostatic SBP increase had an increased estimated 8‐year risk for coronary artery disease, while the follow‐up of the same study demonstrated a relationship between OHT and greater incidence of lacunar strokes. Kario et al indicated that hypertensives with OHT had higher incidence of silent cerebral infarcts and advanced deep white matter lesions compared with hypertensives without OHT, while Fan et al found that OHT was linked to a history of stroke. Furthermore, OHT was associated with cognitive decline, poor verbal fluency, leukoaraiosis, and impaired neurobehavioral function in population studies. Relationships between OHT and damage in other target organs, for example, left ventricular hypertrophy (assessed by electrocardiogram), increased levels of brain natriuretic peptide (BNP) or N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), proteinuria, peripheral artery disease, macular degeneration, increased arterial stiffness, and increased carotid intima‐media thickness have also been reported in cross‐sectional studies. On the other hand, Aries et al found that OHT in the acute phase of stroke was associated with more favorable neurological outcome and OHT subjects had lower rates of heart failure in the community‐dwelling cohort of the Progetto Veneto Anziani (Pro.VA) Study (Table S1). Regarding hard clinical outcomes in prospective studies, OHT was associated with increased CV and all‐cause mortality in the Pro.VA Study and with increased CV morbidity and mortality in the PARTAGE study. A relationship with increased CV and all‐cause mortality was also reported by Kostis et al, who assessed the vital status and cause of death of participants of the Systolic Hypertension in the Elderly Program, however, statistical significance was lost after adjustment for comorbidities. In addition, another population study reported that only systolic OHT at 3 minutes was a predictor of mortality, while a link between diastolic OHT and increased risk for myocardial infarction was observed in the Normative Aging Study. In contrast, Wijkman et al suggested that diastolic OHT was related to lower rates of CV events in a cohort of diabetics and Weiss et al found that OHT was associated with lower all‐cause mortality in a study that used a very flexible OHT definition (any SBP or DBP increase after standing) and enrolled frail individuals. Similarly, Hartog et al reported a possible association between OHT and lower all‐cause mortality in a study with nursing home residents (Table S1). Finally, the Malmö Preventive Project investigators demonstrated an inverse relationship between systolic BP increase after standing and incidence of heart failure, however, no separate analysis was performed for subjects with OHT, that is, for subjects with orthostatic systolic BP increased above a threshold of 10 or 20 mm Hg.30

It seems plausible that OHT may represent an independent risk factor for adverse outcomes, since increased BP in the erect position could cause target organ damage (TOD) similarly to essential hypertension,31 especially if it indeed represents a form of masked hypertension or pre‐hypertension.10, 11, 22 Another possible mechanism for OHT‐mediated adverse prognosis might be the increased BP variability.16, 32 Besides BP variations resulting from postural changes, OHT has been related to augmented morning BP surge33 and extreme dipping status16, 34; morning BP surge has been associated with adverse CV outcomes,33 while extreme dipping may predispose to strokes and silent cerebral infarcts.35 Moreover, it has been proposed that OHT is a component of the systemic hemodynamic atherothrombotic syndrome (SHATS). In this syndrome, traditional risk factors (diabetes, dyslipidemia, chronic kidney disease), hemodynamic disturbances (OHT and increased arterial stiffness, central pressure and BP variability) and neurohumoral mechanisms (activated sympathetic system and RAAS) create a vicious cycle favoring atherosclerosis and TOD.2 However, OHT could also be either an integrated marker of sympathetic overactivity, ANS dysregulation, and vascular dysfunction, indicating individuals at high risk for adverse events,2, 7, 36, 37 or a disorder with minor clinical significance in case of asymptomatic normotensive subjects.3 Unfortunately, most of OHT studies were cross‐sectional with inconsistent results, randomized data are lacking and evidence linking the severity of OHT (ie, magnitude of orthostatic BP increase, absolute levels of BP, and OHT duration) with the extent of TOD is scarce.38 Thus, based on the available evidence, it is difficult to suggest any causal or prognostic relationship between OHT and adverse outcomes.2, 16, 39

6. TREATMENT

There are no specific recommendations for OHT management and the paucity of robust evidence associating OHT with adverse outcomes limits any type of discussion on OHT treatment. Moreover, no randomized trials have assessed therapeutic interventions specifically for OHT and there is no direct evidence suggesting that treatment of OHT improves prognosis,2, 4 while only few therapeutic options have been tested in small series of OHT patients. Thus, management should be individualized, depending on symptoms and comorbidities.4 Taking into account that OHT has been linked to masked and future hypertension,10, 11, 21, 22 OHT patients should be closely monitored for prompt detection of essential hypertension, which should be treated according to relevant guidelines.31 Indirect evidence about a beneficial effect of OHT treatment with alpha‐blockers is coming from the Japan Morning Surge‐1 Study. This was a randomized trial that enrolled 611 hypertensives with morning SBP >135 mm Hg and demonstrated that 6‐month treatment with doxazosin given at bedtime and added on standard therapy significantly reduced the urinary albumin/creatinine ratio (UAR).40 Subsequently, study participants were divided into deciles of orthostatic BP change and patients in the top decile, corresponding to orthostatic SBP increase >7.8 mm Hg, were classified as OHT patients. In the OHT group, treatment with doxazosin reduced home orthostatic SBP increase compared with controls, while no effect was observed on sitting SBP. In the whole cohort, UAR reduction was independently associated with reduction in standing BP.41 Similarly, a study with 55 hypertensives (10 with OHT and 45 with no OHT/OH), reported that treatment with doxazosin administered at bedtime reduced standing BP without affecting sitting BP in OHT patients.16 These findings support that alpha‐adrenergic vascular overactivity could partly mediate an OHT response.2

Clonidine may also be useful4 due to its sympatholytic properties in severe symptomatic OHT, as shown in a small study with 11 patients with baroreflex failure42 and in a case report with severe OHT.43 In contrast, a pressor effect of beta‐blockers in standing position has been reported in a large observational study,44 however, it is debatable whether this can aggravate OHT.45 Moreover, an old study indicated that use of an inflated pressure suit may improve OHT through prevention of venous pooling.9 Avoiding sudden changes in posture may help as well.18 Thoracic sympathectomy eliminated OHT in a small series of five patients, but at the expense of developing OH after surgery.46 In OHT patients with nephroptosis, surgical correction with nephropexy has been reported to be curative, however, this procedure is not routinely used due to high rates of complications.18, 27 Finally, renal revascularization could be a therapeutic option in case of concomitant significant renal artery stenosis.25, 26, 28

7. FUTURE DIRECTIONS

A consensus for OHT definition would unequivocally facilitate further research. Based on pathophysiological considerations, the definition of OH, and the overall review of the literature, we propose that OHT can be defined as “a sustained SBP increase of at least 20 mm Hg or DBP increase of at least 10 mm Hg within 3 minutes of standing or during title‐table test to at least 60°.” Active standing (at office or home), tilt‐table test and ABPM are the main diagnostic tools to uncover and diagnose OHT.2, 13 Although we acknowledge that a lower diagnostic threshold may be more appropriate for BP values measured by home active standing2 or ABPM, we suggest a simple and uniform definition that resembles OH definition, which will facilitate assessment of this underrecognized entity in the everyday clinical practice. In order to detect possible overlap between OHT and essential hypertension, we suggest that all patients with OHT who have seated BP values within normal ranges, should be screened for masked essential hypertension with repeated office BP measurements, home BP measurements, and/or ABPM. Conversely, orthostatic BP change should be assessed in hypertensive patients for prompt detection of OHT.10, 22 Doxazosin may be considered as the first‐choice drug if standing BP values exceed 140/90 mm Hg,16, 41 provided that essential hypertension (increased sitting BP values) is absent or well‐controlled, while clonidine can also be used in severe OHT cases.4, 42

For the future clinical research, OHT assessment should be performed in all population studies, hypertension trials, and studies of cardiovascular interest that require several BP measurements, a strategy that will provide more prospective data about possible associations between OHT and clinical outcomes. Conduction of randomized OHT trials in both hypertensive and non‐hypertensive cohorts should be performed to elucidate whether OHT is a distinct entity or a subtype of essential hypertension and determine OHT prognostic role and therapeutic approach.

8. CONCLUSIONS

Orthostatic hypertension is an underappreciated, but frequent CV disorder. Although OHT is the hemodynamic opposite of OH, both conditions stem from similar pathophysiological pathways and may share common risk factors. Autonomous nervous system dysfunction is considered to play a crucial role in the pathogenesis of OHT, while a significant overlap with essential hypertension has been reported. Accumulating evidence indicates associations between OHT and TOD and/or adverse clinical outcomes, however, findings are not always consistent. Importantly, absence of a uniform OHT definition makes comparison of relevant studies difficult. Regarding OHT treatment, randomized data are completely lacking and evidence from non‐randomized studies is scarce. Thus, the clinical significance of OHT remains largely unknown. Large randomized trials are needed to provide more evidence of this underestimated condition.

CONFLICT OF INTEREST

None declared.

Supporting information

 

Magkas N, Tsioufis C, Thomopoulos C, et al. Orthostatic hypertension: From pathophysiology to clinical applications and therapeutic considerations. J Clin Hypertens. 2019;21:426–433. 10.1111/jch.13491