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Diagnostic and therapeutical management of supine hypertension in autonomic failure

a review of the literature

Vallelonga, Fabrizio; Maule, Simona

doi: 10.1097/HJH.0000000000002008
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Supine hypertension is defined as a blood pressure at least 140 mmHg systolic or at least 90 mmHg diastolic in the supine position; supine hypertension is present in over 50% of patients with autonomic failure and orthostatic hypotension, but it is often overlooked. It may be related to antihypotensive drugs, but its presence in untreated patients suggests a neurogenic origin. Supine hypertension is often asymptomatic although it is associated with multiple organ damage. There are no official guidelines on its treatment and long-term benefits have never been proved. The present review is focused on the management of supine hypertension, including nonpharmacological and pharmacological approach. All the tested drugs have been individually revised, focusing on their hypotensive effect and their ability to act on ancillary targets, such as morning orthostatic tolerance or sodium urine excretion. Moreover, the main pathogenic mechanisms and the correct approach to the diagnosis of supine hypertension have been resumed.

Autonomic Unit and Hypertension Unit, Department of Medical Sciences, University of Turin, Città della Salute e della Scienza Hospital, Turin, Italy

Correspondence to Fabrizio Vallelonga, Autonomic Unit and Hypertension Unit, Department of Medical Sciences, University of Turin, Via Genova 3, 10126 Torino, Italy. Tel: +39 011 633 6959; fax: +39 011 633 6931; e-mail: vallelonga.fabrizio@gmail.com

Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure; CCB, calcium-channel blocker; MSA, multiple system atrophy; PAF, pure autonomic failure

Received 29 July, 2018

Accepted 30 October, 2018

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INTRODUCTION

In autonomic failure, the regulation of circadian blood pressure (BP) and heart rate is altered. As a result, patients fluctuate between orthostatic hypotension and supine hypertension [1]; while the former entity is well known, the latter is often overlooked, perhaps due to the physicians’ typical practice of evaluating mainly seated BP values [2]. Supine hypertension has been defined as a SBP at least 150 mmHg or DBP at least 90 mmHg in clinostatic position [3], although a 140/90 mmHg cutoff point was suggested in a recent consensus [4]; it may occur in previously normotensive patients or may overlap with a preexisting essential arterial hypertension. Supine hypertension is present in over 50% of patients with pure autonomic failure (PAF) and multiple system atrophy (MSA) [5]. In Parkinson's disease with autonomic failure, supine hypertension is found in up to 50% of the patients [6], and an abnormal BP night-time dipping is reported in 40–93% [7]. Prevalence of supine hypertension is greater in women than men (63 and 52%, respectively), without any significant association with age [5]. Supine hypertension is strongly related to orthostatic hypotension, particularly in the context of primary autonomic neuropathies (PAF, Parkinson's disease, MSA) [8].

No established taxonomy for supine hypertension currently exists. Naschitz proposed a classification for ‘supine hypertensionorthostatic hypotension syndrome’ according to the clinical picture, pathophysiology, and hemodynamic patterns on head-up tilt; he underlined how the association between supine hypertension and orthostatic hypotension could be found even in diseases with normal autonomic function, such as effector organs failures (heart failure, venous insufficiency, capillary leak), baroreflex failure in essential hypertension, hypovolemia, and drug-induced alterations [9]. The prevalence of the ‘supine hypertensionorthostatic hypotension syndrome’ in essential hypertensive patients was estimated at between 5.5 and 26.5% [10–12]. The present review focuses on the management of supine hypertension in the context of primary autonomic failure; conditions other than this are not discussed.

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PATHOGENESIS OF SUPINE HYPERTENSION

The pathophysiology of supine hypertension in autonomic failure changes according to the underlying disease because the autonomic nervous system could be affected by peripheral and/or central degeneration. In peripheral forms, the neurodegenerative process affects the postganglionic noradrenergic fibers; whilst in central forms, the autonomic nuclei are involved. MSA is an example of central neurodegeneration; PAF is an example of peripheral neurodegeneration; in Parkinson's disease, neurodegeneration involves both the central and peripheral nervous systems. As a result, plasma norepinephrine levels are low in PAF [13] and Parkinson's disease with orthostatic hypotension [14], while they remain nearly normal in MSA [13]. With regard to this, some authors evaluated the action on autonomic nervous system of several agents: on one hand, the administration of trimetaphan (nicotinic acetylcholine receptors antagonist leading to a ganglionic blockade) significantly reduced BP in patients with MSA, while the effect was more variable in patients with PAF; on the other, the administration of yohimbine (alpha2-selective blocker with the effect of sympathetic stimulation) led to a greater increase in BP values in MSA than in PAF [15]. These results indicate a residual sympathetic tone (turned off by ganglionic blockade) in MSA that could contribute to supine hypertension; in fact, norepinephrine release in the supine position is similar in MSA patients and healthy individuals [16], whereas it is reduced in PAF patients [17]. A relative sparing of postganglionic neurons with normal norepinephrine release does not explain supine hypertension, however; an increased vasoconstrictive response to norepinephrine, justified partly by adrenoreceptor upregulation [18] and baroreflex dysfunction, is necessary. In response to the reduced sympathetic tone, adrenoreceptors upregulate and receptor sensitivity increases (adrenoreceptor hypersensitivity), as demonstrated by the paradoxical hypertensive response to clonidine shown by patients with severe autonomic failure: the effect on hypersensitive peripheral (postsynaptic) alpha2-receptors (vasoconstrictive response and BP rise) prevails over that on central (presynaptic) alpha2-receptors (reduction of sympathetic drive and BP) [19].

Baroreflex dysfunction is present in all forms of autonomic failure and also in other conditions [20]; both efferent and afferent arcs of the reflex are disrupted in MSA, whilst only efferent pathways are damaged in PAF [21]. Baroreflex dysfunction could lead to a high BP variability [8], and hypersensitivity to vasoactive agents [22,23].

Hemodynamic studies suggest that high systemic vascular resistance is a factor in supine hypertension [24]; a possible role of endogenous vasoconstrictive mediators (such as endothelin, vasopressin, and angiotensin) was hypothesized to explain those situations in which vascular resistance is increased despite an absent residual sympathetic tone, as in some patients with PAF.

In patients with autonomic failure, normal aldosterone levels and minimal plasma renin activity, with loss of renin-producing cells in autopsied kidneys, were found [25], together with higher concentrations of angiotensin II compared with normal individuals [26]. In Arnold's study, the absence of a captopril-induced BP reduction with a sustained hypotensive response to losartan suggested that renin-independent mechanisms could be involved in angiotensin II production in autonomic failure [26]. Furthermore, recent findings suggested a possible role of inappropriate mineralocorticoid receptor activation in promoting the increase in vascular resistance [27]. A reduction in nitric oxide production was also proposed, but not confirmed, as a pathogenic mechanism; on the other hand, an increased nitric oxide function/sensitivity was identified in autonomic failure, explaining the abnormal hypotensive effect of nitric-oxide-releasing drugs [28].

In patients with autonomic failure, BP is linearly correlated with changes in plasma volume because fluid homeostasis is impaired [29,30]; but intravascular volume, cardiac output, diuresis, and natriuresis were no different in patients with and without supine hypertension [24,31–33]. Finally, it is suggested that supine hypertension, despite being part of autonomic failure itself, could be favored by antihypotensive drugs used for treatment of concomitant orthostatic hypotension [34,35].

Possible pathogenic mechanisms are summarized in Fig. 1.

FIGURE 1

FIGURE 1

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DIAGNOSIS OF SUPINE HYPERTENSION: OFFICE BLOOD PRESSURE MEASUREMENT OR AMBULATORY BLOOD PRESSURE MONITORING?

The diagnosis of supine hypertension should be made with office BP measurements, preferably after maintaining the patient supine for at least 10 min [36]. The term supine hypertension should not be confused with nocturnal hypertension or reverse dipping pattern. Supine hypertension is defined as SBP at least 140 mmHg and/or DBP at least 90 mmHg in the supine position [4]. Nocturnal hypertension is defined as SBP at least 120 and/or DBP at least 70 during night-time. Reverse dipping is defined as a ratio between systolic night-time and daytime BP at least 1.0 [37]. Supine hypertension is diagnosed with office BP measurements, while the diagnosis of nocturnal hypertension and reverse dipping requires 24-h ambulatory BP monitoring (ABPM). Supine hypertension may occur in autonomic failure during both daytime and night-time; BP rise during the night leads to nocturnal hypertension and reverse dipping pattern. Although the three entities (supine hypertension, nocturnal hypertension, and reverse dipping pattern) often coexist in autonomic failure, some authors observed a normal dipping pattern in about one-third of patients with supine hypertension [33].

Nocturnal hypertension and reverse dipping may also be found in secondary hypertension, chronic kidney disease, sleep apnea syndrome, diabetic neuropathy, and malignant hypertension [38].

Recent data suggest a practical use of ABPM both for the diagnosis of autonomic neuropathy and for prognostic implication [39]. The presence of nocturnal hypertension and reverse dipping are suggestive of autonomic failure, especially when other abnormalities, such as orthostatic, postprandial, or exercise-induced hypotension, are present [7], although cardiovascular autonomic testing is needed to confirm the diagnosis of autonomic failure. As BP readings during a clinical visit are not reflective of those of daily life, other studies suggest considering ABPM in all patients with the ‘supine hypertensionorthostatic hypotension syndrome’ to conduct a proper personalized therapy [40,41].

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Consequences of supine hypertension

Supine hypertension, along with reverse dipping pattern, high BP variability, and orthostatic hypotension, are associated with cardiovascular damage in autonomic failure [1]; among target organ damage, left ventricular hypertrophy [42,43], renal function impairment [44], and cerebral white matter lesions [45] have been described.

In autonomic failure patients, an increased arterial stiffness, correlated to high BP variability, high night-time BP values, and reverse dipping pattern, was also described [46]. Mechanisms of increased vascular resistance have not been fully clarified; significantly, a role of old age and isolated systolic hypertension cannot be excluded in older patients with autonomic failure, namely PAF and Parkinson's disease.

Lastly, supine hypertension has a further consequence: an elevated BP during night-time causes pressure natriuresis and nocturia, resulting in volume depletion and worsening of diurnal orthostatic hypotension. This mechanism probably explains the correlation between severe supine hypertension and severe orthostatic hypotension [47] and the paradoxical worsening of orthostatic hypotension after the withholding of antihypertensive drugs [48].

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TREATMENT OF SUPINE HYPERTENSION

The essential premise for the correct management of cardiovascular autonomic failure is that the coexisting conditions of supine hypertension and orthostatic hypotension are antithetical from a hemodynamic point of view; consequently, any intervention on one of them interferes with the other [8,9]. No official guidelines regarding the treatment of supine hypertension are currently available, due to the absence of strong evidence in the literature. As a result, there are no ideal BP targets to pursue and there is no proof that treating supine hypertension improves long-term outcome, as it does in essential hypertension [2]. The current recommendations [3] are therefore based on expert opinion.

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Nonpharmacological treatment

Nonpharmacological measures may be helpful in the management of both supine hypertension and orthostatic hypotension, although they are often neglected. The following behavioral rules should reduce supine hypertension with minimal worsening, or even slight improvement, of orthostatic hypotension [49]:

  • Sleeping with the head of the bed raised by about 20 cm (30°); lying in a semirecumbent position reduces night-time pressure natriuresis and improves morning orthostatic tolerance [50]. Head-up tilt position has been used for treatment of orthostatic intolerance since the 1940s in patients with severe autonomic failure, postural orthostatic intolerance syndrome [51] and postural-related syncope [52]; a randomized controlled trial showed no clinical benefit on BP and symptoms in patients over 60 years old with orthostatic hypotension from all causes [53].
  • Having a small snack before going to sleep, to induce mild postprandial hypotension during recumbent position [54]. However, the effect produced is transient, brief, and variable.
  • Drinking preferably during the day, declining abundant water consumption in evening hours. Drinking water increases seated BP by 30–40 mmHg; this effect may last up to 60 min after water ingestion [55].
  • Minimizing the supine position during the day; the use of a reclining chair for afternoon naps is preferable, especially for patients who are wearing compression stockings, or abdominal binders, or taking antihypotensive drugs in the morning. In the supine position blood volume and, consequently, BP increase because of an enhanced venous pooling associated with baroreflex dysfunction [56].
  • Reducing salt intake if supine hypertension prevails over orthostatic hypotension (and vice versa in presence of severe orthostatic hypotension). Patients with autonomic failure are much more sensitive to restricted salt intake compared with normal individuals because of an impaired renal salt conservation, particularly during the night [29,57]. A low salt diet is an excellent measure against supine hypertension but can worsen orthostatic hypotension severely.
  • Avoiding pressor agents in the evening, including over-the-counter drugs such as nasal decongestants, cyclooxygenase inhibitors, or nonsteroidal anti-inflammatory drugs, which may provoke a severe hypertensive response in autonomic failure [58].
  • Midodrine is often employed in the treatment of orthostatic hypotension. It is a selective alpha-1 agonist and may cause or exacerbate supine hypertension [59]. As half-life of the active metabolite is about 3 h [60], excessive nocturnal BP rise could be avoided by administering the drug before 1700 h. Phenyl-propanolamine, a sympathomimetic agent used as decongestant and appetite suppressant, leads to a potent pressor response in autonomic failure [61]. Among nonsteroidal anti-inflammatory drugs, indomethacin was the most effective in raising BP in autonomic failure, while ibuprofen was not statistically different from placebo [58].
  • Education is the keystone to good management; as high BP values arouse more concern than orthostatic hypotension, patients should be advised and reassured that a simple change in position (such as sitting up) can reduce BP to normal ranges [36]. Furthermore, they should be informed that, in presence of supine hypertension and orthostatic hypotension [3], the timing and doses of antihypertensive medications may be different from the normal recommended guidelines.

These behavioral measures are unlikely to be sufficient in patients with moderate-to-severe supine hypertension; in such cases, pharmacological treatment is often needed.

Nonpharmacological measures and their effects are resumed in Table 1.

TABLE 1

TABLE 1

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Pharmacological treatment

General indications

Current recommendations [3] propose to treat patients with severe supine hypertension, defined as SBP more than 180 mmHg and/or DBP more than 110 mmHg in clinostatic position, with bedtime administration of short-action antihypertensive drugs. In moderate supine hypertension, defined as SBP of 160–180 mmHg and/or DBP of 90–110 mmHg, pharmacological treatment should be individualized, balancing the negative consequences of supine hypertension [1] with both short and long-term negative drug effects on orthostatic hypotension [63]. No pharmacological treatment is recommended for supine BP values less than 160/90 mmHg; this category should be strictly monitored and managed with nonpharmacological measures alone.

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Individualized indications

All cases require an individualized therapy. The most problematic are patients with moderate supine hypertension; in this category, therapeutical interventions could be carried out according to the characteristics of the underlying disease related to autonomic failure.

In patients with MSA, the treatment of supine hypertension becomes less relevant: their short life expectancy reduces the probability of developing long-term adverse effects. Patients with Parkinson's disease and PAF have a better prognosis: in Parkinson's disease, there are robust indications to prioritize the treatment of orthostatic hypotension over supine hypertension [49]; in PAF, the near normal life expectancy of patients may support the prevention of hypertensive complications [64].

In all cases, quality of life should be the central concern of any medical intervention.

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The ideal treatment

No antihypertensive drug has ever been approved for the treatment of supine hypertension in autonomic failure; therefore, the medications listed below have been studied in small clinical trials that evaluated short-term efficacy. All available trials tested the hypotensive effect of the drugs over one or several nights; long-term antihypertensive effect has never been described, except for a recent small case series [41].

The ideal antihypertensive drug for supine hypertension is not currently available: its effect needs to be long enough to reduce nocturnal BP but short enough to be exhausted before getting up; it should reduce nocturnal pressure diuresis and sodium excretion, with consequent improvement in orthostatic tolerance; it should prevent cardiovascular events in terms of target organ damage and mortality [36]. As a result, physicians not only have to choose on a case by case basis whether or not to treat a patient, but the type of vasoactive drug to be used must also be customized. Finally, it must be remembered that, whatever drug is chosen, BP response is difficult to predict in the presence of autonomic dysfunction [61].

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Angiotensin-converting-enzyme inhibitors: captopril

Captopril was the first drug tested in primary autonomic failure, 30 years ago [65]. In Kooner’ s study, 12 patients with autonomic failure were compared with 12 normal individuals; BP, norepinephrine plasma levels, and plasma renin activity were measured in the supine position, before and at 10-min intervals after captopril (50 mg) administration, for up to 2 h. Captopril reduced BP by about 15 mmHg in patients with autonomic failure only; levels of plasmatic norepinephrine and renin activity were unchanged. Therefore, the hypotensive response was assumed to be related to the action of captopril rather than that of renin activity (i.e. accumulation of bradykinin, increased synthesis of prostaglandins). The inclusion of patients with and without supine hypertension and the absence of a placebo arm limit the interpretation of this data. More recently [26], the hypotensive effect of captopril (50 mg) was tested against a placebo with a randomized, double-blind crossover study in seven patients with autonomic failure; drugs were administered at 2000 h and patients were instructed to stay supine until 0800 h; BP was measured twice in a row at 2-h intervals with an automated sphygmomanometer. Captopril decreased SBP by 11 mmHg, which was not statistically different from that induced by the placebo; moreover, nocturnal pressure natriuresis and morning orthostatic tolerance, evaluated as secondary outcomes, were not influenced.

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Angiotensin II receptor blockers: losartan

Losartan was the only angiotensin II receptor blocker used in supine hypertension, due to its short half-life. It was tested on 11 patients affected by primary autonomic failure [26] in a randomized, double-blind crossover study; overnight supine BP reduction was the primary outcome, and nocturnal pressure natriuresis and morning orthostatic tolerance were the secondary ones. Losartan (50 mg) significantly decreased SBP by 32 mmHg, 6 h after administration; furthermore, it reduced nocturnal urinary sodium excretion without an improvement in morning orthostatic tolerance. The reduction of nocturnal natriuresis in autonomic failure disagrees with drug's effect on essential hypertension: chronic assumption increases sodium and water excretion [66], while no effect is triggered after acute administration [67].

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Aldosterone receptor antagonists: eplerenone

Another randomized, double-blind crossover study tested the efficacy of eplerenone (50 mg) versus a placebo in BP reduction in 10 patients with primary autonomic failure [27]; medications were given at 2000 h; with BP measured every 2 h until 0800 h. Eplerenone significantly decreased SBP by 32 mmHg, 8 h after administration, without any effect on nocturnal volume loss and natriuresis. These findings suggest a BP-lowering response independent from the traditional genomic renal volume effect of mineralocorticoid receptors, and due, rather, to the interference on rapid nongenomic effect of aldosterone (such as vasoconstriction and sympathetic activation) [68], or on the vasoconstrictive effect of angiotensin II [69].

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Nitro-vasodilator drugs: nitroglycerin

Transdermal nitroglycerin is the most tested drug in supine hypertension related to primary autonomic failure. Over 20 years ago, its effect was evaluated in seven patients with autonomic failure, placing a modified-release patch from 2000 to 0600 h [5]; the patients were instructed to remain supine from 2000 to 0800 h while BP was measured manually every 60 min throughout the night. The initial dose was 0.025 mg/h, progressively increased on consecutive nights until a hypotensive response was noted (maximal dose 0.1 mg/h): nitroglycerin reduced SBP by 36 mmHg. A further 10 patients were tested against a placebo, focusing on the duration of the hypotensive effect: nitroglycerin significantly reduced BP from the fourth hour of application and the effect was sustained for the whole testing period (until 0800 h).

Nitroglycerin was also tested in a single blinded manner against nifedipine and a placebo in 13 patients with autonomic failure [70]: initial dose was 0.025 mg/h, progressively increased on subsequent nights to a maximum of 0.2 mg/h. Patches (nitroglycerin or placebo) were applied at 2000 h, and oral nifedipine was administered at the same time; subjects patients in a supine position until 0800 h but patches were removed at 0600 h; BP values, measured with an automated sphygmomanometer at 1 h intervals, and urine samples were collected during the night. Compared with the placebo, the maximal decrease in SBP induced by nitroglycerin was 36 mmHg, 4 h after patch placement; supine and orthostatic BP at 0800 h were similar in the two groups, as were urinary output and sodium excretion. The decrease in supine BP induced by nitroglycerin should concomitantly reduce natriuresis; as this was not observed in the study, the authors hypothesized the role of nitric oxide donors in the increase of sodium excretion, as described in animals [71], or the presence of other causes of nocturnal natriuresis, unrelated to BP.

Nitroglycerin effect on supine hypertension, morning orthostatic tolerance and pressure natriuresis were more recently evaluated against clonidine and placebo in an overnight medication trial on 23 patients affected by primary autonomic failure [72]: the testing period was from 2000 until 0800 h, with BP measurements every 2 h using an automated sphygmomanometer; a nitroglycerin patch (0.1 mg/h) was applied at 2000 h and removed at 0600 h. Nitroglycerin maximally reduced SBP by 20 mmHg, 8 h after patch placement; no effect on sodium excretion and morning orthostatic tolerance was observed.

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Other vasodilator drugs: hydralazine and minoxidil

Hydralazine and minoxidil were tested against a placebo [5], measuring BP in supine position from 30 min before to 2.5 h after drug administration. Hydralazine (50 mg), evaluated in seven patients, reduced SBP by 13 mmHg; minoxidil (2.5 mg), evaluated in five patients, reduced SBP by 22 mmHg.

Hydralazine, being a pure arteriolar vasodilator, should theoretically provoke less orthostatic hypotension; however, its hypotensive effect on supine BP is less relevant when compared with venous-dilating drugs [36]. Minoxidil is a piperidin-pyrimidin-derivative vasodilator that could produce sodium and volume retention in long-term use, reducing its hypotensive effect [36].

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Calcium-channel blockers: nifedipine

Calcium-channel blockers (CCBs) are not included in current recommendations [3]. Immediate-release nifedipine (30 mg) was tested in an overnight single blinded medication trial with nitroglycerin and a placebo [70]. Nifedipine showed an important hypotensive effect in autonomic failure, with a maximal decrease in SBP of 37 mmHg, 4 h after drug administration; the depressor effect was still present at 0800 h (−23 mmHg compared with the placebo) with worsening of morning orthostatic tolerance. Furthermore, nifedipine increased sodium excretion and urine volume, making sense of the sustained depressor effect (more than 12 h) despite the short half-life. Previous studies highlighted the interference of CCBs on sodium handling through a decrease in tubular reabsorption [73]. Under normal conditions, sodium loss with CCBs can be attenuated by a compensatory increase in proximal and distal sodium reabsorption [74]; but these mechanisms, dependent on sympathetic activation, are impaired in autonomic failure.

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Central alpha-2 agonists: clonidine

Clonidine was tested for the first time in 2006 on 23 patients (12 MSA and 11 PAF) in an overnight medication trial with transdermal nitroglycerin and a placebo [72]. Clonidine decreased SBP by 26 mmHg, 8 h after drug administration (2000 h). it significantly reduced urinary sodium excretion compared with the placebo, though with no improvement in morning orthostatic tolerance.

A prolonged hypotensive effect is assumed to be the main cause for the lack of improvement in morning orthostatic tolerance; the authors hypothesized a counteraction by yohimbine (alpha2-adrenoreceptor antagonist), but this thesis requires experimental validation.

The hypotensive effect of the drug on supine BP did not significantly differ between MSA and PAF, although the mechanism underlying the pharmacological action should be a reduction in residual sympathetic tone, more frequent in patients with central autonomic dysfunction. Ten patients (six MSA and four PAF) consented to the administration of a ganglionic-blocker to evaluate sympathetic activity, allowing the authors to demonstrate a significant association between clonidine hypotensive response and residual sympathetic tone.

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Beta-blockers: nebivolol and metoprolol

Nebivolol is a selective beta1-adrenoreceptor blocker with the capacity of inducing vasodilation via an increase in nitric oxide bioavailability; as patients with autonomic failure are very sensitive to the vasodilator properties of nitric oxide, nebivolol was tested in 20 patients with supine hypertension [75]. Patients were randomized to receive nebivolol 5 mg, metoprolol 50 mg, sildenafil 25 mg and a placebo on separate evenings in a double-blind, cross-over study. Metoprolol and sildenafil were, respectively, negative and positive controls to test the hypothesis that the nitric oxide-mediated vasodilatation, rather than the beta-blocking properties of nebivolol, reduced supine BP. Drugs were administered at 2000 h and BP was measured twice in a row every 2 h until 0800 h with an automated sphygmomanometer. Nebivolol maximally reduced SBP by 24 mmHg, 8 h after administration; whilst the maximum reduction induced by metoprolol (7 mmHg) was not significantly different compared with the placebo. No effect on urinary sodium excretion and morning orthostatic tolerance was detected for either treatment. Dividing patients into responders and nonresponders to sildenafil, the authors demonstrate that nebivolol decreased SBP in the first group (−44 mmHg) but was indifferent in the second one (+1 mmHg); thus confirming the role of nitric oxide in the BP-lowering effect of this beta-blocker.

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Phosphodiesterase inhibitors: sildenafil

Sildenafil, a phosphodiesterase type 5 inhibitor, is the only drug of its category tested in patients with supine hypertension related to autonomic failure [75]. Sildenafil induced a maximum decrease in SBP of 20 mmHg, 8 h after administration, with no effect on natriuresis or morning orthostatic tolerance.

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Combination therapy

Multiple drugs combination has never been evaluated in supine hypertension related to autonomic failure in any randomized clinical trials. Di Stefano recently described an improvement in night-time sisto-diastolic BP (of about 20 and 10 mmHg, respectively, at ABPM evaluation) after 4 months of antihypertensive therapy with losartan (25 mg) and barnidipine (10 mg), in a patient affected by Parkinson's disease [41]; this is the only example of combination therapy for supine hypertension in autonomic failure. By performing ABPM after 4 months of therapy, the authors suggested, for the first time, a potential long-term effect of short-acting antihypertensive drugs in patients with supine hypertension related to autonomic failure.

Tested drugs and current recommendations are summarized in Table 2.

TABLE 2

TABLE 2

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Antihypertensive drugs to avoid or minimize

If possible, it is important to avoid long-acting antihypertensive α-blockers and diuretics [3,49] because of their negative effect on orthostatic hypotension. The use of β-blockers could also be uncertain in autonomic failure because these drugs can reduce the already minimal chronotropic response to orthostatism, with consequent impairment to peripheral perfusion [49].

However, patients with autonomic failure could also be affected by concomitant cardiovascular comorbidities, particularly in secondary autonomic failure (i.e., related to diabetes mellitus) rather than primary forms, as described in this review. In the presence of heart failure or coronary artery disease, these ‘dangerous’ drugs could prove to be life-saving. In such instances, clinical experience must weigh the risks and benefits on a case-by-case basis.

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Choice and timing of antihypertensive therapy

The current evidence does not allow to define a specific drug as first choice. However, we suggest a flowchart based on clinical trials, pathophysiological mechanisms, and clinical experience (Fig. 2).

FIGURE 2

FIGURE 2

Losartan may be employed as first choice treatment for its beneficial actions on both BP and nocturnal natriuresis. In hypertensive patients, losartan reduces arterial stiffness [76], often present in autonomic failure.

Nitroglycerin and eplerenone may be employed as second choice treatment; their effect on BP has been demonstrated; however, both drugs do not reduce nocturnal natriuresis and may worsen orthostatic tolerance in the morning. Nitroglycerin is often administered via transdermal patches: it is recommended the removal of the patch at least half an hour before rising in the morning.

Clonidine reduces nocturnal natriuresis and can be employed as first or second choice in MSA patients only, to avoid the risk of paradoxical hypertensive effect in those patients without a residual sympathetic tone.

Finally, short-acting CCBs may be used as third choice. Nifedipine is the only drug studied in autonomic failure patients. It is effective on supine BP and improves arterial stiffness in nonautonomic failure patients [77], but worsens morning orthostatic tolerance. Other CCBs with a short duration are nicardipine and barnidipine (at the lowest dosages), but their efficacy has not been tested in autonomic failure patients.

All the suggested agents must be administered in the evening, between 1800 and 2200 h. ABPM may be helpful in the choice of drug timing, also allowing to consider personal habits of the patients.

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SUMMARY AND CONCLUSION

The treatment of supine hypertension in autonomic failure is still uncertain; the poor quality of the available trials did not lead to the approval of any drug among those tested. There are two main arguments in favor of antihypertensive therapy in supine hypertension: the evidence of multiple organ damage related to supine BP; and the evidence of nocturnal volume depletion, with consequent worsening of orthostatic hypotension, related to pressure natriuresis. At present, no medication has been shown to improve these features.

Treatment of supine hypertension in autonomic failure should be evaluated on a case-by-case basis, considering supine BP, orthostatic BP, and circadian rhythm at ABPM, but, above all, the quality of life and the prognosis of the underlying disease.

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Future perspectives

The treatment of supine hypertension in autonomic failure needs further studies:

  • To confirm short-term and long-term efficacy of antihypertensive drugs in larger populations of primary autonomic failure;
  • To validate the use of ABPM for drug timing;
  • To evaluate the outcome of treated patients in terms of target organ damage and mortality;
  • To evaluate the effect of these treatments on quality of life of such disabled patients.
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ACKNOWLEDGEMENTS

Conflicts of interest

The authors did not receive any funding or support and have no conflict of interest to declare.

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    Keywords:

    autonomic failure; autonomic neuropathy; orthostatic hypotension; supine hypertension

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